AU2020201638A1 - c-Met modulators and methods of use - Google Patents

Abstract

C:\Interwo n\NRPortbl\DCC\SXD\19945432_l.doc-4/03/2020 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

This application is a divisional application derived from Australian Patent Application No. 2017200555, which is a divisional of Australian Patent Application No. 2013204031, which is a divisional of Australian Patent Application No. 2010204461, which is a divisional of Australian Patent Application No. 2004275842, the entire contents of each of which, as originally fded, are incorporated herein by reference.

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 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.

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 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.

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 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. Furthermore, abnormal protein kinase activity has been related to a host of

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2020201638 05 Mar 2020 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. Receptortype 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 EGFR (HER1), HER2, HER3, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGFIR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-Kit and FLK-H. 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 fms-Iike tyrosine kinase-1 (flt-1). The PDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptortype 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, FesZFps, Fak, Jak, Ack, and LIMK. 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, Lek, BIk, Hck, Fgr, and Yrk. The 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,

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2020201638 05 Mar 2020 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® (imatinib 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. Drag Disc Technol 2001 6,1005-1024), is an attractive goal for development of small-molecule drugs. Antiangiogenic therapy represents a potentially important approach for the treatment of 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 slow 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

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2020201638 05 Mar 2020 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-Mct 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 are 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 Then 77, 151-181; Kiyokawa E, Takai S, Tanaka M et a] 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 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-Zuckerman 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

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2020201638 05 Mar 2020 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: 19791986; Lennartsson et al Oncogene 1999 18: 5546-5553 ; Timokhina et al EMBO J 1998 17;6250-6262; Chian et al Blood 2001 98(5)1365-1373; Blume-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 J 1991 10:647654). 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 are 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 (Hirota et al Science 1998 279:577-580; Singer et al J Clin Oncol 2002 203898-3905; Longley et al Proc Natl Aca Sci USA 1999: 1609-1614; Tian 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 cKit, 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 (NF1). 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 haploinsufficiency at NF1 partially rescues some of the phenotypes associated with mutations in the gene for c-Kit, indicating that these genes function along

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2020201638 05 Mar 2020 a common developmental pathway (Ingram, et al. J. Exp Med 2000 191:181-187). Also, cKit 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 for treating patients with NF-1.

[00201 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 Opin 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] Flt-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 2002 1: 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 quinazdine kinase inhibitors typically have fairly simple substitution about the quinoline or quinazoline fused ten-membered ring system, but recently more complex molecules are

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2020201638 05 Mar 2020 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 are an object of 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-Met, KDR, c-Kit, flt-3, and flt-4.

[0026] In another aspect, the invention provides methods of screening for modulators of cMet, 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 kits comprising one or more containers filled with one or more of the ingredients of pharmaceutical 7

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2020201638 05 Mar 2020 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] Tn 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 cMet, KDR, c-Kit, flt-3, and flt-4.

[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 THE INVENTION [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-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.

[0032] It is appreciated that in some cases the cells may not be in a hyper- or hypoproliferative and/or migratory state (abnormal state) and still require treatment. For example, during wound healing, the cells may be proliferating “normally”, but

S

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2020201638 05 Mar 2020 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, -NH₂, -NR³R⁴, and optionally substituted lower alkyl;

A¹ is selected from =N-, =C(H)-, and =C(CN)-;

Z is selected from -S(O)q.2-, -O-, and -NR⁵-;

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

wherein,

R² is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(O)0.₂R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl;

q is 0 to 4;

G is a group -B-L-T, wherein

B is selected from absent, -N(R¹³)-, -N(SO₂R¹³)-, -O-, -S(0)o-2-, and -C(=O)-;

L is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, -SO2N(R¹³>, -SO2-, -C(=O)N(R¹³)-, -N(R¹³)-, -C(=O)Ci.2alkylN(R¹³)-, -N(R^,3)C1_₂alkylC(=O)-, -C(=O)C₀₁alkylC(=O)N(R¹³)-, -C_o_₄alkylene-, -C(=O)C₀.ialkylC(=O)OR³-,

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-C(=NR¹⁴)CcMaIkylC(=O)-, -C(=O)-, -C(=O)C₀-ialkylC(=O)-, 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.4alkyl, -Co^alkylQ, -OCWlkylQ, -Co^alkylOQ, -N(R¹³)C0.₄alkylQ, -SOzCo^alkylQ, -C(=O)C(HalkylQ, -C₀.₄alkylN(R¹³)Q, and -C(=0)N(R^I3)Co-₄alkylQ, wherein each of the aforementioned C<Malkyl is optionally substituted;

J is selected from -S(0)o-2-, -O-, and -NR¹⁵-;

R³ is-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

R and R , 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, 0,8, and P;

A² and A³ are each independently selected from =N-, =C(R²)-;

R⁵ is -H or optionally substituted lower alkyl;

D is selected from -O-, -S (€))0 2-, and -NR¹³-;

R⁵⁰ is either R³, or according to formula FV;

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 -C(r5r⁷-, -O-, ~S(0)o.₂-, and -NR⁸-;

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2020201638 05 Mar 2020 each X² is independently an optionally substituted bridgehead methine or a bridgehead nitrogen;

each X³ is independently selected from -C(R⁶)R⁷-, -O-, -S(O )0-2-, 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 X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R or R ; 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 1-4;

n is 0-2, when n = 0, 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, -NR³R⁴, -S(O)0.2R⁴, -SO2NR³R⁴, -CO2R³, -C(O)NR³R⁴, -N(R³)SO2R⁴, -N(R³)C(O)R³, -NCO2R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, 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;

R^s is selected from -R³, Y, -SO2NR³R⁴, -CO2R⁴, -C(O)NR³R³, -SO2R⁴, and -C(O)R³;

R¹³ is selected from -H, -C(=O)R³, -C(=O)OR³, -C(=O)SR³, -SO₂R⁴, -C(=O)N(R³)R³, and optionally substituted lower alkyl,

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2020201638 05 Mar 2020 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 ary] 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, -NO₂, -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 -M’-M², wherein M¹ is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, -SO2N(R¹³)-, -SO2-, -C(=O)N(R¹³)-, -C(=O)C(=O)N(R¹³)-, -Co. 4alkylene-, -C(=O)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M² is selected from -H, -Co^alkyl, alkoxy, -C(=Q)Co-4aikylQ, -Co-aalkylQ, -OCo.4alkylQ-, -N(R^!3)C(MaIkylQ-, and -C(=O)N(R¹³)C(ualkylQ; 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, trihalomsthyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(O)q.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2> -OR³, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally 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 II, if Y is a Ci^ alkylene; Z is -NH- or -N(CH₃)-; R¹ is a Chalky! optionally substituted in the 2-position by -OH or a Ci4alkoxy 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, X or X, 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 -OC(O)CH₂-,

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-CH₂OC(O)-, -OC(O)CH₂CH_r, -CH₂OC(O)CH₂-, -CH₂CH₂OC(O)-, -OC(O)CH₂NH-_f -OC(O)CH₂N(C_I._i(alkyl)-_J and -OC(O)CH₂O-; or

2) either a piperazine or a 4-(Ci-4alkyl)-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-(Ci4alkyI)-piperazine, cannot be one of -CH₂OC(O)CH₂-, -CH₂CH₂OC(O)-, and either of the two aforementioned bridges optionally substituted by one or two Ci.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 the 4-position of said piperazine, cannot be one of -C(O)OCH₂CH₂-, -CH₂OC(O)CH₂-, and either of the two aforementioned bridges optionally substituted by one or two C^alkyl 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-oxomorpholine, said 2-oxpmorpholine 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 -(CH₂)_g-_t -CH₂WCH₂-, -CH₂WCH₂CH₂-, and -CH₂CH₂WCH₂-, wherein W is -O-, -S(O)₀.₂-, -NH-, or -N(Ci4alkyl)- wherein g is 2, 3, or 4;

and with the proviso that when Z is-Ο-, Ar is according to formula Π, and the portion of G directly attached to Ar is selected from:

vYv	v! T !v	vVv
0		o
		ΟΙ

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then R⁵⁰ must be of formula IV;

and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(0)o-2- or O O

H ' \

-O-, then the portion of G directly attached to Ar cannot contain R⁷⁰ R⁷⁰ when R⁷⁰ is selected from -H, C^alkyl, and Ci^alkoxyl.

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

[0035] Tn another example, the compound is according to paragraph [0034], wherein G is selected from the following;

R13 r13 I I || 'Am Y14	R13 r13 I I / \0-3 1,° R14	f 'J'2 Γ Ψ . x Y o
r-W1-2 I J. 1 \°‘3 Y Y^Q O 0	____,)0-2 O	R«
7~{ 9O	R13 I P L Yv )o-2 tN	R13 X>YVYM W°
R13 R13 I I V A Vfo-4 O 0	R13 1 f Y4 n	R13 O 0
R13 I f \0“2 <γγ< O 0	r13 V || ' /0-3 O	0, P 0 AV. R13 ___—

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0 0 V 1 \V3 yfi N Q R13	V<2 ^ΎΧ o	Y-Y v >< R13 O
V Y r” 0	17 / \03 P Y R13 0	Yn Υγ%’3 0
r13 R1S s	R13 R13 I I 1 \0-3 Ηγ-γΗ. S 0	^Ν^,Ν^^,Ο S
Λύ s o	Y B’3 s	.FL -R V Y s
r13 I ( \l-2 , <0-3 /vMq 0	R13 1 / \0-4 ^NYQ 0	R’3 ,/ΎΎ0 V //\ \ /0-4 O O
R13 I ( rfo-3 -FL A. Ύ SH O	R13 (^Q I t P0-3 yfi >< oh 0	R13 N lY^R13 X Pt n II h 0
I I ,FL -IK „ x Y R O	q13 I , vO-2 >YV 'r,s O 0	rY o
c> P JY >Μ!εΥ γ N E R13	Q 0! / v>-“ V >Po <n	Ov P R13 V ( V'2 J, γΚΧ» A« I

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R13 I ! \0-2 r- 0 o	R13 R13 1 1 f 10-3	R13 ° N-OR3
R13 ° OR’	r13 R13 I ( \0-2 I	I, / -,0-2 _ V 'Yjf 'c^ikyi

wherein wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from -O-, -N(R¹³)-, -CH2-, and -S(0)o-2-; M is selected from -O-, -N(R¹³)-, -CH2-, and -C(=O)N(R¹⁰)-; 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, -NO2, -NH2, -OR³, -NR³R⁴, -S(0W<³, -SOsN^R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)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 heteroalicyclic, two of R²⁵ on a single carbon can be oxo.

[0036] In another example, the compound is according to paragraph [0035], wherein Ar is according to one of formula Ila, Hb, and Illa.

Ha nb Illa [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 -OHor-OCi^alkyl.

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2020201638 05 Mar 2020 [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:

R13 O O R13	r13 r13 I I / >0-3 GT	R13 R13 I I / N n TY q I 1Γ ^0-3 o o
R13 0	m0.4 r13 r'V'E	W0'2 R13 J J
R13 I , >0-4 -T	R13 o o	R13 r13 1 t \0-l 1, VW'· o o
/>0-2 R13 Xe (R%-4	R13 iVf	o n^3 OR3

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, trihalomethyl, oxo, -CN, -NO2, -NHz, -OR³, -NR³R⁴, -S(O)0.₂R³, -SO2NR³R³, -COsR³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)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 sevenmembered alicyclic or heteroalicyclic.

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

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2020201638 05 Mar 2020 [0043] In another example, the compound is according to paragraph [0042], wherein Ar is according to formula Ha, and G is selected from·

0 w 0	0 I fo-2
(Ηθν 9 Ml λ Λ aJ v II N [^ 0 f/Q-2	(r60)(M o / n -μ 0 Λ? (R<4 1 Z0-2	H II .N. ^R3 V ][ n O R13

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above, and 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(0)o_2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)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 sevenmembered alicyclic or heteroalicyclic.

[0044] In another example, the compound is according to paragraph [0042], wherein Ar is according to formula lib, and G is selected from:

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A A 1 A wherein Q, R , R , E, and R 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 R²⁵ is selected from halogen, trihalomethyl, oxo, -CN, -NCb, -NHj, -OR³, -NR³R⁴, -S(0)o_2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)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 sevenmembered alicyclic or heteroalicyclic.

[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 heteroalicylic or a Ci^alkyl-heteroalicylic.

[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 [2.2.1], [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].

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2020201638 05 Mar 2020 [0052] In 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(O)NR³R³, -SO₂R³, and -C(O)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 -O-, -S(0)o.₂-, -NR⁸-, -CR^R⁷-, and absent; and e is 0 or 1.

[0055] In another example, the compound is according to paragraph [0054], wherein Y is -CH₂-.

[0056] In another example, the compound is according to paragraph [0055], wherein U¹ is -NR⁸-, wherein R⁸ is selected from -H, optionally substituted lower alkyl, -CO2R³, -C(O)NR³R³, -SO2R³, and-C(O)R³.

[0057] In another example, the compound is according to paragraph [0055], wherein U¹ is -O-.

[0058] In another example, the 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 -CH₂CH₂-, -CH₂-, and absent. ¹ [0060] In another example, the compound is according to paragraph [0059], wherein said saturated bridged ring system is of formula VI,

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VI wherein R⁹, R¹⁰, and Rⁿ are each independently selected from -H, and -OR¹²; or

R⁹ is selected from -H, and -OR¹², and R^w and R¹¹, when taken together, are either an optionally substituted alkylidene or an oxo;

R¹² is selected from -H, -C(O)R³, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, 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 R ’s, when taken together, form 1) a corresponding spirocyclic ketal when said two R^l2’s stem from R¹⁰ and R¹¹, or 2) a corresponding cyclic ketal when said two R^,2’s stem from R⁹ and one of R¹⁰ and R¹¹.

[0061] In another example, the compound is according to paragraph [0060], wherein one of R¹⁰ and R¹* is -OR¹², wherein R¹² is selected from -H, -C(O)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 -CH2- 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.

^r8—

VII [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.

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2020201638 05 Mar 2020 [0067] hi another example, the compound is according to paragraph [0053], wherein said saturated bridged ring system is of formula VUI.

VIII [0068] hi 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

wherein U² is selected from -O-, -S(0)o.₃-, -NR⁸-, -CR⁶R⁷-, and absent.

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

[0072] In another example, the compound is according to paragraph [0071], wherein U² is either -CR⁶R⁷- or absent.

[0073] In another example, the compound is according to paragraph [0072], wherein U² is either -CH2- or absent.

[0074] In another example, the compound is according to paragraph [0073], wherein Y is -CH₂-.

[0075] In another example, the compound is according to paragraph [0053], wherein said saturated bridged ring system is according to formula X.

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X [0076] In another example, the compound is according to paragraph [0075], wherein R⁸ is methyl or ethyl.

2020201638 05 Mar 2020 [0077] In another example, the 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]pyrrol5-ylmethyI]oxy} quinazolin-4yl)oxy]phenyl }amino)carbono thioyl]-2-phenylacetamide
2	N-{[(3-fIuoro-4-{[7({[(3aR,6aS)-2methylocfahydrocyclopenta[c] pyrrol-5-yl]methyl }oxy)-6(methyloxy)quinazolin-4yl]oxy} phenyl)amino]carbono thioyl }-2-phenylacetamide	XVXo.i' . H-P-H 0N V Η H !
3	N-{[(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3fluorophenyl)(methyl)amino]c arbonothioyl}-2phenylacetamide	1 H
4	l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3fluorophenyl)imidazolidin-2one	E /°-C>=r^VNH
5	l-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy]-3-fluorophenyl)-3(phenylmethyl)imidazolidin2-one	—O ' Λ o N-y

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Table 1

Entry	Name	Structure
6	l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -3-fluorophenyl)-3- (phenylacetyl)imidazolidin-2- one	F —0 z _J ° X)
7	ethyl [(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3ftuorophenyl)amino] (oxo)acet ate	R Ο, O _O p—4 NH o—x o-<^ \
8	N-{[(4-{[6,7bis(methyloxy)quinazolin-4yl]amino}-3fluorophenyl)amino]carbonot hioyl }-2-phenylacetamide	F Η H
9	N’-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-3 -fluorophenyl)-Nmethyl-N-(2phenylethyl)sulfamide	xo x Yi F ΊΥ XXV·
10	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-3(phenylmethyl)-1,2,4oxadiazol-5-amine	I r-O WyS Y °
11	l-(4-{[6,7bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one	N—·*

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Table 1

Entry	Name	Structure
12	N-(4-{[6,7- bis(methyloxy)quiiiolin-4- yl]oxy} -3-fluorophenyl)-N'(phenylmethyDethanedi amide	F\ °\ /° —ο 2=\ 0—4 U-NH HN—\ Uj O N—
13	N-(4-{[6,7- bis(methyloxy)quinolm-4- yl]oxy} -3’fluorophenyl)-4phenyl-1,3-thiazol-2-amlne	u uxta
14	N-(4-{[6,7- bis(methyloxy)quinoIin-4yl]oxy)-3-fluorophenyl)-N'(2-phenylethyI)ethanediamide	’x O k 70 —0 )=\ O-< J— NH HN-^, o J U UU %
15	N-(4-{[6,7- bis(methyloxy)quinoIin-4yl]oxy} -3-fluorophenyl)-lphenylmethanesulfonamide	F\ 0./-O —o / \ 0Ά /~nh °
16	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-2phenylethanesulfonamide	F —o >=v p-4 Unh o
17 —	4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluoro-N(phenylmethyl)benzenesulfon amide	F. —O θ )=\ 0-4^-^-nh Uu

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Table 1

Entry	Name	Structure
18	4-((6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluoro-N-methyl-N(phenylmethyl)benzenesulfon amide	F\ /^\ —o W\ 2 λΆ # °—4 p—s-n f o-4 /=4 ' b x /MT) N—
19	4-{[6,7- bis(methyloxy)quinolin-4yl] oxy} -3-fluoro-N-(2phenylethyl)benzenesulfonam ide	E >=\ O—G />—S-NH '° Th
20	4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluoro-N-methyl-N(2phenylethyl)benzenesulfonam ide	“°x o-< >=( '—( o x \_/
21	4-((6,7- bis(methyloxy)quinolin-4- yl] oxy }-3-fluoro-N-(3phenylpropyl)benzenesulfona mide	F _o V, O >=\ O-4 /V-S-NH A / \ / /7 1* \ / 0 A N—J
22	1-(4-((6,7- bis(methyloxy)quino]in-4- yl]oxy}-3- fluoropheny!)pyrrolidin-2-one
23	4-((6,7- bis(methyloxy)quinolin-4yl] oxy (phenyl (phenylmethyl)ca±amate	o z( y —o NH p -4 p- o

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Table 1

Entry	Name	Structure
24	4-([6,7- bis(methyloxy)quitiolin-4yl]oxy}phenyl (2phenylethyl)carbamate	Ο
25	4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy } -3-fluoro-N-methyl-N(3phenylpropyl)benzenesulfona mide	-°x >=V
26	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-N'phenylethanedi amide	-o °M° 0-^. λ-ΝΗ HN—C
27	N-{[(3-fluoro-4-{[7-{[(2methyloctahydrocyciopenta[c] pyrrol-5-yl)methyl]oxy )-6(methyloxy)quinolin-4yljoxy} phenyl)amino]carbono thioyl} -2-phenylacetamide	xo lil I AjO N 1
28	N-[(Z)-[(4-{ [6,7bis(methyloxy)quinolin-4~ yl]oxy}-3fluorophenyl)amino](imino)m ethy]]-2-phenylacetamlde	xo Vi i v -Co --k. W 0 ii
29	4-{[6,7- bis(methyloxy)quiiiolin-4yljoxy} -3-fiuoro-N-[2(phenyloxy)ethyl]benzenesulf onamide	F\ —0 o >== o-4 λ-S-NH / \ / % If 0 \ /°A 0 a d

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Table 1

Entry	Name	Structure
30	N,N-(4-{[6,7- bis(methy!oxy)quniolin-4yl]oxy} -3-fluorophenyl)-bis(3-phenylpropane-l sulfonamide)	_o V MI )=\ 0—4 /— N '— /°A_M ^o^~\ m —V // 0 / \ /
31	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-3phenylpropatie-1 -sulfonamide	MI ο.ζ-Τ'θ —o >=\ \=\ O—d NH 0 O—4 >=/ z
32	N2-[(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3fluorophenyl)sulfonyl]-Nlphenylglycinamide	F. )=\ 9 /=\ p“A # S-NH P ' # HN—e y N_y \=/
33	N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy)pyridin-3-yl)-2phenylacetamide	ο “j u il H
34	N-{[(6-{[6,7- bis(mcthyloxy)quinolin-4yl]oxy}pyridin-3yl)amino]carbonothioyl} -2phenylacetamide	I 1 n τη YA f 9 fY Η H
35	6-{[6,7- bis(methyloxy>quinolin-4yl]oxy}-l,3-benzothiazol-2amine	.S-s^· NHa —O^ z=Z Y )=\ pA z MMI N-27

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Table 1

Entry	Name	Structure 1
36	6-{[6,7- bis(methyloxy)quino!in-4yl]oxy}-5-fluoro-l,3benzothiazoI-2-aniine	zS^NH2
37	N-(6-{[6,7bis(methyIoxy)quinolin-4yl]oxy} -5-fluoro-l ,3benzothiazol-2-yl)-2phenylacetamide	—o /=< l[ T )=\ 0-4 )=( T j / λ F
3§	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N’(2-mo.rpholin-4ylethyljethanediamide	/==\ P”4 )-HN-x I-- p—4 )=/ fo-N O z / —z
39	benzyl- {[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylcarbamoyl]-methyl} carbamic acid tert-butyl ester	F SyxVxo
40	Nl-(4-{[6,7- bis(methy!oxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2(phenylmethyl)glycinamide	H
41	N2-acetyJ-Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }-3-fhioTophenyl)-N2(phenylmethyl)glycinamide	H

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Table 1

Entry	Name	Structure
42	N-(6-{[6,7bis(methyloxy)quinolin-4yljoxy} -1,3-benzothiazol-2yl)-2-phenylacetamide	—Q /=< If J 0—4 O-Λ )=( ^—7
43	benzyl-{ [6-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-3ylcarbamoyl]-methyl} carbamic acid tert-butyl ester	Wauco H
44	Nl-(6-{[6,7- bis(methyIoxy)quinolm-4yl]oxy} pyridin-3-yl)-N2(phenylmethyl)glycinamide	vWo H
45	N2-acetyl-Nl-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy }pyridin-3-yl)-N2(phenylmethyl)glycinamide	xo Wnxcc H
46	N-(6-{[6,7bis(methyIoxy)quinolin-4yljoxy} pyridin-3-yl)-3phenylpropanamide	O / —ο γ—7 . 0—^7 V-nh 0—4 )=( N—J
47	N-(6-j[6,7- bis(methyloxy)quinolin-4yl]oxy }pyridin-3-yl)-4phenylbutanamide	xo o T7 9 if^i iq H

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Table I

Entry	Name	- Structure
48	Nl-(6-{[6,7- bis(methyloxy)quinolin-4- yljpxy }pyridin-3-yl)-N2methyl-N2(phenylmethyl)glycmamide	“Ί TT u 1 [fA H
49	N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy} -3-fluorophenyl)“N'{2-[4(methyloxy)phenyl]ethyl }etha nediamide	-V / Ν-ζ J \
50	Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyI)-N2methyI-N2(phenylmethyl)glycinamide	xo WA ο o ii] Ϊ1 ? 1 ΓΊ J ------
51	4-[(2-amino-l ,3-benzothiazol- 6-yl)oxy]-6,7-bis(methyloxy)l-(2-oxo-2phenylethyl)quinolinium	^S^NH2 —q /=/ ff \ )=^/0¼.
52	N-{[(4-{[6,7- bis(methyloxy)quinolin-4yljamino }phenyl)amino]carbo nothioyl }-2-phenylacetamide	XX 1 Λ JO
53	N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-l,3benzothiazol-2-yl)-3phetiylpropanamide

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Entry	Name	- - - ..... Structure
54	N-{[(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin-3yl)amino]carbonothioyl} -2phenylacetamide	< A. ifi Π ® θ ίι
55	N-(4-{[6,7bis(mcthyloxy)quinolin-4yljoxy} -3-flnorophenyl)-N'(2,3-dihydro- ΙΗ-inden-1yl)ethanediamide	Fv /? fl u? )==\ 0—< Λ— NH HN—< J /0^-0 N_y
56	N-(4-{[6,7bis(methyloxy)quinoIin-4yljoxy} -3 -fluorophenyl )-N(2,3-dihydro-lH-inden-2yl)ethanedi amide	F. 0 O —O 7—{ /·><''% / \ 70¾ NH HNA I J
57	N-(4-{[6,7- bis(methyioxy)quinoIin-4yl]oxy} -3-fluorophenyl)-N'(1,2,3,4-tetrahydronaphthalenl-yl)ethanediaxnide	—0 %=\ 0-Ά #“NH HN_~( )
58	N'-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-3 -fluorophenyl)-N(2-phenylethyI)-N(phenylmethyl)sulfaniide	F )=\ z°“O“N-0 /°~vH o*s; MJ
59	Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2(trifluoroacetyl)glycinamide	0 -V >V°^F V=\ p—< λ-NH r F N-27 .

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Entry	Name	Structure
60	N-{ [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylcafbanioylj-methyl} benzamide	0 F. Ο HN—Y —o >—/ y^ >=\ 0—4 /—MH 7
61	N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy) pyridin-3-yI)-N'-(4- fluorophenyl)propanediamide	o νΧίΑΛΧΧ Η H
62	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-3-fluorophenyi)-N’[(2S)-1,2,3,4tetrahydronaphthaIen-2yljethanediamide	\ °\ /° / C r~ \=\ o—^ /—NH HN‘< /0^P
63	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N'[2-(4methylphenyl)ethyl]ethanedia mide	fl ο, P —0 \=\ p—NH ΗΝ—ξ X X—/ N—9
64	N-(4-{[6,7- bis(methy!oxy)quinoIin-4- yl]oxy} -3 -fluorophenyl)-N’(2phenylpropyl)ethanediamide	f, q o —o y=\ y-y y=x 0—4 /—NH HN~^
65	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-N'[2-(4chlorophenyl)ethyl]ethanedia mide	fl P —o M y=\ 0—4 y~NH HN^ z— o—y=q '—q yci

33'

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Table 1

Entry	Name	Structure
66	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyI)-N N’bis(phenylmethyl)sulfamide
67	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-N,N’bis(2-phenylethyl)sulfamide	F. —O /—7 0_>=V/0-<7-> Z ° «Η
68	ethyl [(6-((6,7- bis(methyloxy)quinolin-4yl]oxy} -5-chloropyridin-3yl)amino](oxo)acetate	Cl O 0 —o y~\ NH ο—ξ
69	N-(6-{[6,7bis(methyloxy)quinolm-4yl]oxy} -5-chlorop vridin-3yl)-N’-(2phenylethyljethanedi amide	Cl ___ \=x O—f y-NH ff—& /’-v^
70	N-(6-{[6,7bis(methyloxy)quinolm-4yljoxy) -5-chloropyridin-3yl)-N'-(4fluorophenyl)propanediamide	A°A ϊ t rrF
71	N-(4-{[6,7- bis(methyloxy)quinolin-4- yljoxy} -3-fluorophenyl)-N'(1,2,3,4-tetrahy dronaphthalen2-yl)ethanedi amide

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Entry	Name	Structure
72	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyI)-N’[2-( 1 -methylpyrrolidm-2yl)ethyl]ethanediamide	E O 0 >=\ O“4 NH HN-x hrc /0”m5
73	N-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy} -3-fluorophenyI)-N'[2(phenyloxy)ethyl]ethaiiediaini de	-V XW )=\ °~4 # NH HN—\
74	N-(4-{[6,7bis(methyloxy)quinolin-4yI]oxy}-3-fluorophenyl)-bT[2-hydroxy-l(phehylmethyl)ethyljurea	xo ϊ XT Xa a jZO
75	l-(4-{[6,7- bis(methyloxy)quinolin-4- yljoxy} -3-fluorophenyl)-3[(4-methylphenyl)sulfonyl]-4(phenylmethyl)imidazolidin2-one	O' w N o /^=\ T“N 1 rCyr X
76	N'-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy[-3-fluorophenyl)-Nmethyl-N-(2phenylethyl)ethanediamide	H 0 0 —o )== )=\ 0—k A-NH hl— 0-4 )=( ( zOa M2
77	N-(4-{[6,7- bis(methyloxy)quiiiolin-4yl]oxy [-3-fluorophenyl)-N'{[3(trifluoromethy])phenyl]meth yl [ethanediamide	F. 0. O —o )=\ 0—4 A-NH HN—Λ 0—4 )=( >=\ z mT) Cj N fAC~/ A

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Entry	Name	Structure
78	N-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy} -3-fluorophenyl)-N’{2-[3(trifluoromethyl)phenyl]ethyl } ethanediamide	FX Q P -°v 70-¾ /~NH ΗΝ~Λ r'\
79	N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -5-chloropyri din-3- yl)-3-oxo-4phenylbutanamide	0 X 1Γ7 Ύ[1 ? 9 (D nA nJVUUA
80	N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -5-chloropyridin-3yI)-2-[3(trifluoromethyl)phenyl]aceta mi de	xo x°y5l ci H f F
81	6-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-5-fluoro-N-[2(phenyloxy)ethyl]-l ,3benzothiazol-2-amine	-V 0_Xl\O
82	6-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -5-fluoro-N-(2piperidin-l-ylethyl)-l ,3benzothiazol-2-amine	-0 /=(τ ΐ ] \=x o—4 y-N aa 7 F
83	6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -5-fIuoro-N-methyI-N(2-phenylethyI)-1,3benzothiazol-2-amine	......

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Entry	Name	Structure
84	6-((6,7- bis(methyloxy)quino!in-4- yl]oxy} -5 -fluoro-N-(2pyrrolidin- 1-ylethyl)-1,3benzothiazol-2-amine	_o /=( Y G /0Yj>
85	6-((6,7- bis(methyloxy)quinoIm-4yl]oxy}-5-fluoro-N-{ [3(trifluoromethyl)phenyl]meth yl) -13-benzothiazol-2-amine	GjOv '°Q5
86	6-((6,7bis(methyloxy)quinolin-4yljoxy} -5-fluoro-N-{ 2-(3(trifluoromethyl)phenyl]ethyl ) -1,3-benzothiazoI-2-amine
87	N-(6-([6,7bis(methyloxy)quinolin-4yl] oxy} -5-chloropyridin-3yl)-N’-[3(trifluoromethyl)phenyljpropa nedi amide	Ci
88	N-(6-{[6,7- bis(methyloxy)quinolm-4yl]oxy}-5-fluoro~l,3benzothiazol-2-yl)-2-[3(trifluoromethyl)phenyl]aceta mide	F_|_F F
89	Nl-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy }-3-fluorophenyl)-N2{[3(trifluoromethyl)phenyl]meth yl}glycinamide

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Entry	Name	Structure
90	Nl-(4-{[6,7- bis(methy!oxy)quinolin-4- yl]oxy} -3-fluorophenyl).-N2- (2-phenylethyl)glycinamide	Fv 0, HN— -ο X» X=\ P-4 /—NH /O M?
91	Nl-(4-{[6,7bis(methyloxy)quinolin-4yljoxy} -3-fluorophenyI)-N2{2-[3(trifluoromethyl)phenyl]ethyl Iglycinamide	-o A / \ /° A # NH F
92	benzyl-{ [5-chloro-6-(6,7dimethoxy-quinolin-4-yloxy)pyridin-3-ylcarbamoyl]methyl} -carbamic acid tertbutyl ester	W0..rxo
93	Nl-(6-{[6,7bis(methyloxy)quinolinAyljoxy} -5-chloropyridin-3yl)-N2(phenylmethyl)glycinamide	Cl 1
94	bis(methyIoxy)quinolin-4yl]oxy }-5-fluoro-l ,3 benzothiazol-2-yl)-2-[3,5bis(trifluoromethyl)phenyl] ac etamide	F--F F
95	N-(6-{[6,7bis(methyloxy)quinolin-4yl] oxy} -5-fluoro-1,3 benzothiazol-2-yl)-2-[2chIoro-5(trifluoromethyl)phenyl]aceta raids	Sx-'^X^O A V·

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Entry	Name	Structure
96	N-(3-fluoro-4-[(6- (methyloxy)-7-{ [(1methyIpiperidin-4yl)methyl]oxy}quinolin-4~ yl)oxy]phenyl }-N'-(2phenylethyl)ethanediamide	H Q O -ο V. M Y=\ O—4 5— NH HN—\ O—k > b θ
97	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-3-fluorophenyl)-N'(1,2,3,4tetrahydroisoquinolin-lylmethyl)ethanediamide
98	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy J -3 -fluorophenyl)-N'[(2-methyl-l, 2,3,4tetrahydroisoquinolin-1yl)methyl]ethanediamide	κ 0 O —o )=\ y—( >=\ 0—< /-NH HN-^ /0 bp -tP
99	Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy ] -3-fluorophenyl)-N2methyl-N2-{[3(trifluoromethyl)phenyl]meth yllglycinamide	o 1 liq π ? 1 |Tl f H
100	Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2methyl-N2-{2-[3(trifluoromethyl)phenyl]ethyl }glycinamide	-V /=\ NH F
101	Nl-(4-{[6,7bis(methyloxy)quinolin^lyl] oxy} -3-fIuorophenyl)-N2methyl-N2-(2phenylethyl)glycinamide	-V. X'v )=\ 0—/-NH

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Entry	Name	Structure
102	l<4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fhiorophenyl)-4(phenylmethyl)imidazolidin2-one	H Y _/ 0
103	N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy }pyridazin-3-yI)-N'-(4' fluorophenyl)propanedi amide
104	N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-5-chloropyridin-3yl)-N'-(2chloiOphenyl)propanedi amide	Τι r ii ° 0 li ί YJ UaaAP
105	N-(6-{[6,7bis(methyloxy)quinolm-4yl]oxy]-5-chloropyridin-3yl)-N'-(3chlorophenyljpropanediamide	o f JU U^aanjCXc, Η H
106	Nl-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin-3yI)-N2-methyI-N2(phenylmethyl)glycinamide	°yS o ? «Ί Y|l π 1 ίίΥ
107	N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin-3yl)-N’-(4chlorophenyl)propanediamide	^°yS ? °yS g j? jTYcl

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Entry	Name	Structure
108	(2E)-N-(4-{[6,7- bis(methyloxy)quiiiolin-4yl]oxy}phenyl)-2[(methyloxy)imiiio]propanaini de	0—k Λ—NH N-q 0-4 >=( \ ' X) N—J
109	(2E)-N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }phenyl)-2[(ethyloxy)imino]propaiiamid e	< \ /° \> ^~NH N“O^__
110	(2E)-N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}pheiiyl)-2{[(phenylmethyl)oxy]imino}p ropanamide	~q /=\ Z=\ /° N~°\ ff~\ /
111	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-l' (phenylmethyl)prolinaniide	xo H [__/
112	l-(4-{[6,7- bis(methyloxy)quinolm-4yl]oxy}phenyl)-3-[(4methy]phenyl)sulfonyl]-4“ (phenylmethyl)imidazolidin2-one	0 ~O nv-n ,o
113	l-(4-{[6,7bis(methyloxy)qumolin-4yl]oxy)phenyl>4(phenylmethyl)imidazolidin2-one	.-TOTO 7 °

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Entry	Name	Structure
114	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-4(phenylmethyI)-4,5-dihydro1,3-oxazol-2-ajnine	xo /=- N H
115	6,7-bis(methyloxy)“4-({4-[4(phenylmethyl)piperazin-lyflphenyl} oxylquinoline	—0 /-\ /~^ o-f ¥-n n-7 N—v
116	l-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-4(phenylmethyl)piperazin-2one	— Q /V-/ v=\ o—4
117	Nl-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} plienyl)-N2(phenylmethyl)alaninamide	-V _/=\_0^ \=\ 0—4 A— NH HN—s. /°“CH H
118	Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N2-methyl- N2- (phenylmethyl)alaninamide	-°v_ _/=V°^ 0—4 /— NH N— b
119	Nl-(4-{[6,7- bis(methy!oxy)quinolin-4yl] oxy} phenyl)-N2(phenylmethyl)kucinamide	0 /—( —o z=\ 7—( 0—4 NH HN—Λ z°-vH H —V // \ //

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Entry	Name	Structure
120	Nl-(4-{[6,7- bis(methyloxy)quinolin-4“ yl]oxy}phenyl)-N2-methylN2(phenylmethyl)leucinamide	0 / —o /=x 7—( ' / \ 0“A NH zN~\
121	Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} phen yl)-N2(phenylmethyl)valinamide	— o
122	4-(6,7-dimethoxy-quinolin-4ylamino)-N-(3-phenylpropyl)-benzamide	xo li ] H 1 Ύ 1 1 H ί 1 O
123	4-benzyI-l-[4-(6,7dimethoxy-quinolin-4-yloxy)phenyl] -tetrah ydro-pyrunidin- 2-one	xo NH Γ| η
124	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'phenethyl-oxalamide	6°vXXyo H H

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Entry	Name	Structure
125	2-(Benzyl-methyl-amino)-N- [4-(6,7-dimethoxy-quinolin-4yloxy)-phenyI]-3-methylbutyramide (note: Alphabetic order of prefixes ignored while selecting parent chain)	ΤΚχ X) Η 1
126	N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-phenyl]-2phenoxyimino-propionamide	xo O' XI,
127	2-Benzyloxyimino-N-[4-(6,7dimethaxy-quinolin-4-yloxy)phenyl]-2-phenyl-acetamide	xo ΑθΆ ? n N τι
128	4-[4-(4-BenzyI-piperidin-1- yl)-phenoxy]-6,7-dimethoxy- quinoline	x° ' nA V 1 \ u
129 .	N-[4-(6,7-Dhnethoxyquinolin-4-yloxy)-3-fluorophenyl]-N'-(2-isopropyl1,2,3,4-tetrahydroisoquinolin-l-ylmethyl)oxalamide	xo Μ Ϊ M v qA

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Entry	Name	Structure
130	N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-N'-(2-ethyl-1,2,3,4tetr ahy dro-isoquinolin-1 yimethyl)-oxalamide	X p o T1 RPr X—z^__
131	4-(4-( 3-Chloro-5-[2-(4fluoro-phenylcarbamoyl)acetylaminoJ-pyridin-2yloxy} -6-methoxy-qumolin-7yloxymethyl)-piperidine-1carboxylic acid tert-butyl ester	xo U 1M °0JX, Ϊ h J Φ F
132	N-{5-Chloro-6-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxyl-pyridin-3yl} -N'-(4-fluoro-phenyl)malonamide	vo Γι'|ΐΥ,οΎϊ^Ίι 0 0 G J IP H HI Φ F
133	N-{ 5-Chloro-6-[6-methoxy-7(1 -methyl-piperidin-4yImethoxy)-quinolin-4yloxy]-pyridin-3-yl}-N'-(4fluoro-pheny])-malonamide	6%Λιι i H i Φ F

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Entry	Name	Structure
134	N- { 4-(7-(3-Diethylaminopropoxy)-6-methoxyquinolin-4-yloxy]-3-fiuorophenyl }-N*-phenethyIoxal amide	T 1 T Til fl N.> c?
135	N- {3-Fluoro-4-[6-methoxy-7- (3-morpholin-4-yl-propoxy)quinolin-4-yloxy]-phenyl }-N'phenethyl-oxalamide	Ύ .Ck /-V CXXoY 0 i 0) YI 9
136	N- {3-Fluoro-4-[6-methoxy-7(3-piperidin-l -yl-propoxy)quinoiin-4-yloxy]-phenyl} -N1phenethyl-oxalamide	Οόγγ o I Y| Yl} 9 0^ Y
137	N-{4-[7-(2-DiethyIaminoethoxy)-6-methoxy-quinolin4-yloxy]-3-fluoro-phenyl} -Nphenethyl-oxalamide	xo I ( Y i T < μ αχο H J Qi

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Entry	Name	Structure
138	N-{3-Huoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-N’-methyl-N'phenethyl-oxalamide	' Cf1
139	N- { 3-Fluoro-4-[6-methoxy-7(2-methyl-octahydrocyclopenta[c]pyrrol-5yhnethoxy)-qumolin-4yloxy]-phenyl l-N’-phenethyloxalamide	γΎτ i Q lij °vSl £ h-H-h ‘AX/’ H MN. 1 Γι
140	N-{ 3-Fluoro-4-[6-methoxy-7- (2-methyI-octahydrocyclopenta[c]pyrrol-5ylmethoxy)-quinazolin-4yloxyj-phenyl} -N'-phenethyloxalamide
141	2-(3,4-Dihydro-lHisoquinolin-2-yl)-N- {3-fluoro4-[6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl )-2oxo-acetamide	y m xxjy 1 H 1

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Entry	Name	Structure
142	N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -2oxo-2-(3-phenyl-pyrrolidin-l yl)-acetamide	Ά cAA° A A H H Ao
143	N- {3-FJuoro-4-[6-methc>xy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -2oxo-2-(2-phenyI-morpholin-4yl)-acetamide	A fl nj ? k J A A A -o Η H J, ° ¢0
144	N-(2-Dimethylamino-2phenyl-ethyl)-N'-{3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-qirinolin-4yloxy]-phenyl }-oxalamide	XvOsA o 0 M XlNv H H J ϊ [Q
145	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N(2-oxo-2-phenyl-ethyl)oxalamide	Acj, Η H J,

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Table 1

Entry	Name	Structure
146	N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)pyridin-3-yl] -2,2-difluoro-N'(4-fluoro-phenyl)-malonamide	zo. L JL ΎΎ # f i Up pl o
147	N-Benzyl-N’- {3-fluoro-4- [6methoxy-7-(1-methylpiperidm-4-yImethoxy)~ quinolin-4-yloxy]-phenyl} oxal amide	aXua o I Η 1
148	N- {3-Fluoro-4-[6-methoxy-7(piped din-4- ylmethoxy)qumolin-4-yloxy] -phenyl} -N’[2-(2-fluoro-phenyl)-ethy]]oxalamide	XO /WA 0 i]i iiY Ύ|| ? H H P 1 U1
149	N-[2-(3-Chloro-phenyl>ethyl]-N’-{ 3-fluoro-4-[6methoxy-7-(piped din-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	y ojiNjCi.o Cl

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Entry	Name	Structure
150	N-{ 3-Huoro4-[6-methoxy-7 (piped din-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'[2-(2-methoxy-phenyI)-ethyl]oxalamide	XtiX-A - (I YY ο ? H H hL η 0
151	N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} -N'(2-pyridin-3-yl-ethyl)oxalamide	H H ΗΝΓ UN
152	N-BenzyI-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyi }-oxaI amide	xo A A. V A Μ-Αγ0 H H ηΛ
153	N- [2-(2,5-Dimethoxyphenyl)-ethyl]-N'-{3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	H H A >> *0

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Entry	Name	Structure
154	N- {3-Fluoro-4-[6-methoxy-7 - (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(2-trifluOTomethyl-phenyl)ethyl]-oxalamide	A Η H ' F -
155	N-[2-(2-Ethoxy-phenyl)- ethyl]-N’-{3-fhioro-4-[6- methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxalamide	A Aui o u m u-v , H Hi HTL J θ |Q
156	N-[2-(2,4-Dimethyl-phenyl)ethyl]-N'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl} -oxalamide	xp 1 1
157	N-{3-Fluoro-4-[6-methoxy-7(piperi din-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N(1S -phenyl-2-p-tolyl-ethyl)oxalamide	όί/ά.νη H H hJ. JU

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Table 1

Entry	Name	Structure
158	N- [2-(4-Ch!oro-phenyl)ethylJ-N'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl j -oxalamide	Ά> Ay a i. H H hA
159	N- {3-Fluoro-4-[6“inethoxy-7(1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamic acid	t H Jh
160	N-{3-FluoiO-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phcnyl }-N’[2-(3-fluoro-phenyl)-ethyl]oxalamide	'-o 6A Ar H H
161	N-[2-(2-Chloro-phenyl)ethyl]-N- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxa!amide	0 0°AAv A

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Entry	Name	Structure
162	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N'[2-(3-methoxy-phenyl)-ethyl]oxalamide	6All. Μ Μ AA H H Ά i
163	N-(l,2-Diphenyl-ethyl)-N'-{ 3fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl}oxalamide	'Ο y iu Ji A° iQ
164	N-[2-(2,4-Dichloro-phenyl)ethyl] -Ν'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	xo 0¾ ύ,ν HN> Cl
165	N-[2-(3,4-Dimethoxyphenyl)-ethyl] -Ν'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl [-oxalamide	όΆν V nJ M-JAo H H A i 1 ^^0

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Entry	Name	Structure
166	N-[2-(4-Ethyl-phenyl)-ethyl]N’-{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	Ψ Ν·> 0ΑνΛ^ο
167	N-[2-(4-Ethoxy-phenyl)ethyl]-N'- {3-fluoro-4-[6methoxy-7-(pipeiidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide	xo όΥά,Α· H H J
168	N-[2-(4-Ethoxy-3-methoxyphenyl)-ethyl]-N’-{ 3-fluoro-4[6-methoxy-7-(piperidin-4yImethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	Φ M A γ > h H hL Ί i

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Entry	Name	Structure
169	N- {3-Fluoro-4-[6-methoxy-7 (piped din-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N'[2-(4-phenoxy-phenyl)-ethyl]oxalamide	F U X-Xj'yO H H Jh CMJ
170	N-[2-(3-Ethoxy-4-methoxyphenyl)-ethyl]-N’- {3-fluoro-4[6-methoxy-7-(piperidm-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	xo Mil H H >
171	N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N1(2-pyridin-2-yl-ethyl)oxalamide	xo Aux „ Q U U. v H H J Dn. U
172	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-pheny]} -ΝΓ(2-pyridin-4-yl-ethyl)oxalamide	v αανα^ H H hA

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Entry	Name	Structure
173	N- {3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'[2-(4-fluoro-phenyl)-ethyl]oxalamide	- Q H H HN
174	N-[2-(2-Bromo-phenyl)ethyl] -Ν' - {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	XO /w H H hI r 3r
175	N-[2-(2-Chloro-6-fluorophenyl)-ethyl]-N’- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	xo A WA - O rj Ό,ν > Cl JU'
176	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N*(2/?-phenyl-propyl)-oxal amide	aUijl

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Entry	Name	Structure
177	N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-N'indan- 1-yl-oxalamide	xo X· ,-U o ο Xx A v
178	N- {3-FIuoro-4-[6-methoxy-7- (l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxypphenyl} -N'-isobutyloxalamide	6¾¼ v 1 H >
179	N- {3-Huoro-4-[6-methoxy~7- (l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl) -N*-(3-methyIbutyl)-oxalamide	xo O U 'LljV 1 H
180	N- {3-Fluoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmcthoxy)-quinoIin-4yloxy]-phenyl }-N'-(2R' phenyl-propyl)-oxalamide	xo 6° v °A ι. ι H ΗΝ^Ί2

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Entry	Name	Structure
181	N-{3-FluoiO-4-[6-methoxy-7(1 -methyl -piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-N'-(2-phenylpropyl)-oxalamide	όΥύί! | Η I
182	N-{ 3-Fluoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinolln-4yloxyj-phertyl} -N*-indan-2-yloxal amide	Aya r' N N 1 JvH
183	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(llf-phenyl-ethyl)-oxalamide	xo ψ m +YN-y° γ, H H hLJU
184	N-i3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl |-N'(lS-phenyl-ethyl)-oxalaniide	A'vX F Γ ϊ Ί 1 Γ 1 Η ίΓ Il °

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Entry	Name	Structure
185	1 N-[2-(3-Bromo-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4yImethoxy)-quinolin-4yloxyj-phenyl} -oxalanu.de	f°Ti ί
186	N-[2-(2,6-DichIoro-phenyl)ethyl]-N’-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl [-oxalamide	TWO H Λ Cl C
187	N-[2-(2,4-Dichloro-phenyI)ethyl]-N’-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl }-oxalamide	xo κ H c, r X
188	N-(2-Benzo[l,3]dioxoi-5-ylethyl)-N - { 3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl [-oxalamide	xo H H ,NH 0^^ .

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Entry	Name	Structure
189	N-[2-(3-Bromo-4-niethoxyphenyI)-ethyI]-N'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yl oxy]-phenyl }-oxalamide	H H Λ
190	N-[2-(3,5-Dimetlioxyphenyl)-ethyl] -N1- {3-fluoro-4~ [6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide	mW. . 0 Ju H H Λ /0
191	N- [3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinoli n-4-yloxy] -phenyl} -N(2-o-tolyl-ethyl)-oxalamide	H Ok

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Entry	Name	Structure
192	N-{3-Ruoro-4-[6-methoxy-7“ (piperidin-4-ylmethoxy)~ quinolin-4-yloxy]-pheny] }-N'(2-m-tolyl-ethyl)-oxalamide	όθΊΧ°A N N H H
193	N-[2-(3-Ethoxy-phenyl)ethyl]-N'~ {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxaIamide	xo 0 Χάί ψ Μ ΝΑΝχ° Η Xi
194	N-[2-(3 ADiHiethyl-phenyl)ethylJ-N'- (3-fhioro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl }-oxalamide	χο Χτάο Μ Η Η .ΝΗ
195	N- [2-(2,5-Dimethyl-phenyl)ethyl]-N’- {3-fluoro-4-[6methoxy-7-(piperidin-4yhnethoxy)-quinolin-4yloxy]-phenyl]-oxalamide	όΛχ χΧχΗ

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Entry	Name	Structure
196	N-[2-(3-Chloro-4-propoxy- phenyl)-ethyl]-N'- {3-fluoro-4- [6-methoxy-7-(piperidin-4yhnethoxy)-quinolin-4yloxy]-phenyl }-oxalamide	xo ό H H NH x I J
197	N-[2-(4-Butoxy-3-chlorophenyl)-ethyl]-N - {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quino!in-4yloxy]-phenyl }-oxalamide	H H Ih Clx_X5x J Yj /x^^xo'^^
198	N-[2-(4~tert-Butyl-phenyl)ethyl]-N!-{ 3-fluoro-4-[6methoxy-7 -(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl} -oxal amide	H H Jh aC*

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Entry	Name	Structure
199	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylniethoxy)quinolin-4-yloxy]-phenyl }-N'- [2-(4-sulfamoyl-phenyl)“ ethyl]-oxalamide	xo Ck Px Xk H H JiH O o
200	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -N'[2-(4-hydroxy-3-inetlioxyphenyl)-ethyl]-oxalamide	xo φpyp, °XX
201	N- { 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl) -N'[2-(3-hydroxy-4-methoxyphenyl)-ethyl]-oxalamide	xo ίΑ'ΦγρΑ θ H H L

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Entry	Name	Structure
202	N-(2,4-Dichioro-benzyI)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	xo F M . Tj VS j? H H Jh Cl
203	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(4-fluoro-2-trifluoromethyIbenzyl)-oxalamide	ό°^οΑΝΑο H H Jh FJ f F aQ1 F
204	N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(l-p-tolyl-ethyl)-oxalamide	r°vS f fj iij °YjL I H ' NH Φ

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Entry	Name	Structure
205	N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} -N‘(3-fluofo-4-trifluoromethylbenzyl)-oxal amide	Ό 0 M v cf3
206	N-(3-Chloro-4-fluoro-benzyl)- N'- {3-fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide	k H .Ah F
207	N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-yhnethoxy)quinolin-4-yloxy]-phenyl} -N'[1 -(3-methoxy-phenyl)-ethyl] oxalamide	JL H tJn JO

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Entry	Name |	Structure
208	N- {3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(1 -naphthalen-2-yl-ethyI)oxalantide	iW
209	N-(4-Chloro-3trifluoromethyl-benzyl)-N’{3-fluoro-4-[6-methoxy-7(piperidm-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide	Υύ ju n n r H H NH FgC'O Cl
210	N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(l-p-tolyl-ethyl)-oxalamide	V Y V NH

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Entry	Name	Structure
211	N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4~yloxy]-phenyl }-N'(6-trifluoromethyl-pyridin-3ylmethyl)-oxalamide	fj «j? V nJ H H Ah cf3
212	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl)-N'(2-methyl-benzyl)-oxalamide	Αλ B kt
213	N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl }-N'(3-methyl-benzyl)-oxal amide	y nJ* j0

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Entry	Name	Structure
214	N- {3-Fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy> quinolin-4-yloxy]-phenyl} -N'(4-fluoro-3-trifluoromethyIbenzyl)-oxal amide	Λ'1φγ°γ\ o ψ N J UjAyO H H Ah FsC'^Y F
215	N-(3,5-Dichloro-benzy])-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinoIin-4-yloxy]-phenyl} oxalamide	.NH
216	N- { 3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(lR,2,3,4-tetrahydronaphthalen- l-yl)-oxalamide
217	N- {3-Fluoro-4- [6-methoxy-7(piperi din-4-ylmethoxy)quinolin-4-yloxy]-phenyl}-N'(18,2,3,4-tetrahydronaphthalen-l-yl)-oxalaniide	όΑ’ύ JL

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Entry	Name	Structure
218	N-Cyclopentyl-N1- {3-fluoro4-[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl} -oxalamide	‘'Ο 6¾ Αχ
219	N-[l-(4-Bromo-phenyl)ethyl] -Ν'- {3-fluoro-4-[6methoxy-7 -(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl} -oxalamide	X r Br
220	N-(2-Fluoro-benzyl)-N'- {3fluaro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	^o Xx, VVOkA o V V UL-X H Ah F'T1
221	N-[2-(3,4-Dichloro-phenyl)ethyl]-N’- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl} -oxalamide	Ό 6°ΖνΑχ H H Ih

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Entry	Name	Structure
222	N-(4-Huoro-benzyl)-N,-{ 3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	O o V V v F
223	N-(2,3-Difluoro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylniethoxy)quinolin-4-yloxy]-phenyl} oxalamide	Ay a a
224	N- {3-HuoiO-4-[6~m.ethoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(2-phenoxy-ethyl)-oxalamide	A o’-
225	N-(2,2-Diphenyl-ethyl)-N'-{3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide

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Entry	Name	Structure
226	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-N'[2-(4-methoxy*phenyl)-ethyl]oxal amide	nA <ΑνΑ^ο H H NH
227	N- {3 -Fluoro-4-[6-methoxy -7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'~ (2-phenyl-propyI)-oxalami de	qAaw
228	N- [2-(4-Bromo-pheny])ethyl]-N’-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxaiamide	□AA r $ Η 1 H H NH
229	N- {4-[7-(l-Ethyl-piperidin-4ylmethoxy)-6-methoxyquinolin-4-yloxy] -3 -fluoro phenyl} -2-oxo-2-(2-phenylmorpholin-4-yl)-acetamide	0 u Av A3

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Entry	Name	Structure
230	N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-pheny] }-N'(3-fIuoro-5 -trifluoromethylbenzyO-oxalamide	A A FgC'^^F
231	N-(3,5-Difluoro-benz.yl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4~ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	v nJ AA H H J1H
232	N-(2-Chlon>5trifluoromethyl-benzyl)-N’{ 3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyI} oxalamide	Ο Υύ Ω n Nr H H Ah AMI'01 Xj F3Cx^X
233	N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-N,-(2-dimethyIamino2-phenyl-ethyl)-oxalamide	F HI T τι Τι] ί nJ AA H NH [Air LJ 1

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Entry	I Name |	Structure
234	N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yk>xy]-phenyl }-N'(4-methoxy-benzyl)oxalamide	“O N r H
235	N- {3-Fhioro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N’(4-trifluoromethyl-benzyl)oxalamide	(Eb,. Μ Η I M NH Φ cf3
236	N- {3-Fluoro-4- [6-methoxy-7(piperidm-4-ylmethoxy)quinolin-4-yloxy]-phenyl ] -N1(3-methoxy-benzyl)oxalamide	^O H P NH

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Entry	Name	Structure
237	N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(3-trifluoromethyl-benzyl)oxalamide	''O γ°υ5 ί Q WA, N hl H H .NH
238	N- { 3-Fluoro-4- [6-methoxy-7 - (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -Ν'(3-trifluoromethoxy-benzyl)oxalamide	''O Λ LVA o Ov xj? o H H Ih
239	N-{ 3-Fluoro-4-[6-methoxy-7(piped din-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(2-methoxy-benzy])oxalamide	6°¾° A z H H .NiH
240	N- {3-Huoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(2-trifluoromethyl-benzyl)oxal amide	fbfS 1 v + Av f3c^L

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Entry	Name	Structure
241	N-(3-Chloro-benzyl)-N'-{ 3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	Ό n r Η H NH ώ C|
242	N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylniethoxy)quinolin-4-yloxy]-pheny] }-N'(2-trifluoromethoxy-benzyl)oxalamide	Ό r°YS i [Ί iiYovS j? F C'°vA T 0
243	i N-(2-Chloro-benzyl)-N'-{ 3fluOTO-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yIoxy]-phenyl} oxalamide	H H .NH “Ό

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Entry	Name	Structure
244	N- {3 -Fluoro-4- [6-methoxy-7 - (piperidin-4-ylniethoxy)quinolin-4-yloxy] -phenyl }-N’(4-trifluoromethoxy-benzyl)oxalamide	o h h i f3c
245	N- {3-Fluoro-4-[6-methoxy-7 (1 -methyl -piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-N'-(4methoxy-benzyl)-oxalamide	''Ο 0WA < n Hi
246	N- {3-Fluoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinoIin-4yloxyj-phenyl} -N'-(4trifluoromethyl-benzyl)oxalamide	Am V KT 1 H NH Φ cf3

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Entry	Name	Structure
247	N-(4-[7-(Azetidin-3yImethoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl }-N'-phenethyloxalamide	•Ό n <ANAy° c?
248	N- {3-Fluoro-4- [6-methoxy-7 (1 -methyl-azetidin-3ylmethoxy)-quinoiin-4yloxy]-phenyl) -N'-phenethyloxalamide	-0 y nY Ay
.249	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-bT(2-hydroxy-2-phenyl-ethyI)oxalamide	jl H R Sh ι^γ^ΟΗ U
250	N-[5-ChIoro-6-(6,7- dimethoxy-qumolm-4-yloxy)pyridin-3-yl]-N’-(2,4-difluorophenyl)-malonamide	I ''θ'Ίίι Cl ηνΎ F 1

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Entry	Name	Structure
251	N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)pyridin“3-yl]-N'-(4-fluorophenyl)-N,-methylmalonamide	Cl o Η 1 —N'X) F
252	N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(IR-phenyl-propyl)oxalamide	•Ο 9 vU/
253	N- {3-Huoro-4-[6-msthoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(IR-phenyl-propyl)oxalamide	H H Jh 0

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Entry	Name	Structure
254	N-(3,4-Difluoro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	H H Jh F
255	N-(2,6-Difluoro-benzyl)-N’{3-fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl }oxalamide	oXo H H Λ
256	N- {3-Fluoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-N'-[2-(4fluoro-phenyl)-ethyl]oxalamide	XXdr kJ * H ΝΉ jjj
257	N- {3-Fluoro-4-[6-methoxy-7(1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl }-N'-phenyloxalamide	^o XJyJji 1 N N 1 A/® U

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Entry	Name	~· ' Structure
258	N- {3-Fluoio-4-[6-methoxy-7- (piperidin-4~ylmethoxy)~ quinolin-4-yloxy]-pheny] }-N'(3-fluoro-phenyl)-oxalamide	0 cAkir F
259	N-(4-Chloro-3-fluorophenyl)-N'-{ 3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl }-oxal amide	^o F
260	N-(3,4-Dimethoxy-phenyl)N1- {3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyi }oxal amide	Η H J, ,
261	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N(3-methyl-butyl)-oxalamide	x A γ= 'Y'^H

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Table 1

Entry	Name	Structure
262	N-(3,3-Dimethyl-butyl)-N’{ 3-fIuoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolln-4-yloxy]-phenyI }oxalamide	Y r n nt H H NH 1
263	N-{ 5-Chloro-6-[6-methoxy-7(3-piperidin- 1-yl-propoxy)quinolin-4-yloxy]-pyridin-3yl }-N'-(4-fluoro-pheny])malonamide	ι 2 HN^O Φ F
264	N-{ 5-Chloro-6-[6-methoxy-7- (3-morpholin-4-yl-propoxy)quinolin-4-yloxy] -pyridin-3yl} -N'-(4-fluoro-phenyl)malnnamide	ο Γ°Ύ^ 9' Wv°yS j HN^O Φ F

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Entry	Name	Structure
265	N-[5-Chloro-6-[7-(3diethylamino-propoxy)-6methoxy-quinolin-4-yloxy]pyridin-3-yl} -N'-(4-fluomphenyl)-malonamide	Ό o i ΪΎ r 1 ft r'T Tx HN< 0 Φ F
266	N-(4-Chloro-bcnzyl)-N,-{ 3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	N N Η Η 1 Cl
267	N-(3,5-Dimethoxy-benzyl)- N'- {3-fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide	i.i Ln H H NH

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Table 1

Entry	Name	Structure
268	N-(4-ButyI-benzyl)-N'- {3fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolrn-4-yloxy]-phenyl} oxalamide	A Ok · y a.j uk-A h H O
269	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N'(2-p-tolyI-ethyl)-oxalamide	0 λΑ-ά y μ ukJUo H H L
270	N-(3,5-Bis-trifluoromethyl- benzyl)-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quino]in-4yloxy]-phenyl}-oxalamide	0°Ay°a a. H H NH f3A^cf3 i

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Table 1

Entry	Name	Structure
271	N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'pyrazin-2-ylmethyl-oxalami de	.ex ./L Γ HI F ij “J°01 2 H H NH u
272	N- {3-Fluoro-4-[6-methoxy-7 - (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N1pyridin-2-ylmethyl-oxalamide	'-o N NT H H NH 6
273	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinazolin-4-yloxy]-phenyl} N'-phenethyl-oxalamide	XCksA „ Y VyV H H NH 1
274	N- {3-Fluoro-4-[6-methoxy-7(1 -methyl-piperidin-4ylmethoxy)-quinazolm-4yloxy]-phenyl} -N'-phenethyloxalamide	Yy 1 h Ah σ

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Table 1

Entry	Name	Structure
1 275	N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- qui nolin-4-yloxy]-phenyl} -Ν'(2-fluoro-3-trifluorometiiylbenzyl)-oxalamide	X Ax JL AA AAx° fi fir H H NH kA's.
276	N-[2-(2-Bromo-6-methoxyphenyl) -ethyl] -Ν’- {3 -fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide	AX r H H Jh Br C Q
277	N-[2-(3,4-Dimethoxyphenyl)-ethyl]-N'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-N-methyloxalamide	Apv Χ'νχΑ
278	N-[2-(5-Bromo-2-methoxyphenyl)-ethyl]-N'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinoIin-4yloxy]-phenyl [-oxalamide	X 6°α°Αλο H NH 8|'χ,γί?ί>χΑ XXq/

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Table 1

Entry	Name	Structure
279	N- {3-Huoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxyI-phenyl} -N'(2-fluoro-5-trifluoromethylbenzyl)-oxalamide
280	N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[l-(4-fluoro-phenyl)-ethyl]oxalandde	H ” NH F
281	N-(lS-Benzyl-2-oxo-2pyrr01idin-l-yl-ethyl)-N'- {3fluoro-4-[6-methoxy-7(piperidm-4-ylmethoxy)quinolin-4-yloxy]-phenyI }oxalamide	Aa. HN,, JL _
282	N- {3-Fluoro-4-[6-methoxy-7(octahydrocyclopenta[c]pyrrol-5ylmethoxy)-quinazolin-4yloxy]-phenyl} -N'-phenethyloxalamide	At H-4—f-H N^N H <

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Table 1

Entry	Name	Structure
283	N-[2-(4-Amino-phenyl)ethyl]-N’-{ 3-fluoro-4-[6methoxy-7-(piperidin-4y!methoxy)-quinolin-4yloxy] -phenyl J -oxalamide	Ό V -N kA V H H NH H2N'^!^
284	2-(4-Benzyl-piperidin-1 -yl)N- {3-fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolirt-4-yloxy]-plienyl }-2oxo-acetamide	A WA. - ¢1
285	N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-phenyl]-N'(4-fluoro-phenyl)-malonaniide	--0 HN^O Φ F

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Table 1

Entry	Name	Structure
286	N-[5-Chloro-6-(6,7dimethoxy-qumolin-4-yloxy)pyridm-3-yl]-N'-(3-fluorophenyl)-malonamide	Ό ηΐ η Cl Y|i u N q H X A
287	N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-N'-phenyl- i malonamide	0 °yS ci XX^o^X fl] χΊι ? N η H X
288	N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-N'-(4-fluorophenyl)-2,2-dimethylmalonamide	Ό ιίχΓ ’ll ? / hL A A A/ N Η 1 ηνΆο Φ F
289	N-EthyI-N’-{3-fluoro-4-[6- methoxy-7-(piperidm-4ylmethoxy)-quinolin-4yloxy]-phenyl [-oxalamide	φΑά V «Α H H -NH

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Table 1

Entry	Name	Structure
290	N- {3-FIuoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-N'isopropyl-oxaJ amide	MUI 0 V Lk-v Η Η 1
291	N-Butyl-N'- {3-fluoro-446methoxy-7-(piperidin-4ylmethoxy)-qumoIin-4yloxy]-phenyl }~oxalamide
292	N- {3-FIuoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(2-methoxy-ethyl)-oxalamide	XVUA . 0 v \ A A
293	N-Cyclopropylmethyl-N’- {3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} oxalamide	to r h H Jh Δ
294	N-{3-FIuoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxyJ-phenyl }-N'(2-morpholin-4-yl-ethyl)oxalamide	4¾ Av

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Table 1

Entry	Name	Structure
295	N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-2oxo-2-pyrroHdin- 1-ylacetamide	'Ο 6¾ AA” 0
296	N-Ethyl-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-N-methyloxalamide	Ά AA v

[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

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and, C is selected from:

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E1 E1 A Y F Q o o (R2)q	Rs 1 1-2 0-3 (R2)q
R5 1 / X0 2 1 < jA'AT'^0 λ (R2)q	q(R2) θ AV V Aa AA-s i5
q(R2) O ArV_ ΛΑ L II / 7 ^4)-2^0-3 V R°	q<R Αά A2 jA3 l5 J
R5 r35 1 t \°'2 1 fY 0 0	R5 I , .0-2 , .Q-3 XrYA λ (R2)q

wherein R² is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR³, -NR³R³, -S(O)0.₂R³, -SOsNR^³, -CO2R³, -C(O)NR³R³, -N(R³)SO3R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted lower alkyl;

q is 0 to 2;

each R³ is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;

two R³, together with the nitrogen to which they are attached, form a four- to sevenmembered 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, -SO2NR⁵R^s, -CO₂R⁵, -C(O)NR³R⁵, ^C(O)R⁵, and optionally substituted lower alkyl;

each R³⁵ is independently selected from -H, -C(=O)R³, -C(=O)OR³, -C(>O)SR³, -SO₂R³, -C(=O)N(R³)R³, and optionally substituted lower alkyl;

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2020201638 05 Mar 2020 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 aryl fused thereto, said aryl optionally substituted with an additional one to four of R⁶⁰;

A¹ is selected from =N-, =C(H)~, and =C(CN)-;

A³ is either =N- or =C(H)-;

R⁵ is -H or optionally substituted lower alkyl;

R⁸ is selected from R³, -SO2NR³R³, -CO2R³, -0(Ο)ΝΚ^³, -SO₂R³, and -C(0)R³;

R⁹, R¹⁰, and R¹¹ 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(O)R³, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, 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 R¹²’s, when taken together, form 1) a corresponding spirocyclic ketal when said two Rⁿ’s stem from R¹⁰ and Rⁿ, or 2) a corresponding cyclic ketal when said two R¹²’s stem from R⁹ and one of R¹⁰ and R^{l l};

E¹ is selected from -O-, -CH2-, -N(R⁵)-, and -S(O)0.₂-;

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, -NO2, -NH2, -OR³, -NR³R³, -S(O)0.₃R³, -SO2NR³R³, -CO2R³, -C(O)NR³R^j, -N(R³)SO₂R³, -N(R³)C(O)R³, -N(R³)C02R³, -C(0)R³, and optionally substituted lower alkyl;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NHj, -OR³, -NR³R³, -S(0)o-2R\ -SOiNRV, -CO₂R³, -C(O)NR³R³, -N(R³)SOaR³, -N(R³)C(O)R³,

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-N(R³)CO2R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl;

two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;

each methylene in any of the above formulae is independently optionally substituted with R²⁵;

each R²⁵ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)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 sevenmembered alicyclic or heteroalicyclic, two of R²⁵ on a single carbon can be oxo;

with the proviso that when B is selected from:

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'a , then A must be one of:

			,R3	R8— N
			'1-4			ί ^0-2		ΓΤ1.4
									0-2(
cU	,NS				xz	Αγ		R9
			^1-4				'1-4		/\^0?
									R10 R11
						O			O
R8—n'			>—M°‘2	R8 N'		ΊΜ'	XR8	O'	/yvNz	R8
							r* 1-4			Ά-4
					NR8		ζ-2

and with the proviso that when C contains 'q , and B is selected from:

			?{0)o-2
?—0-χΧ 1		ϊ	Vm
R3-0'XM		R3_0-^\
	οζ		S{0)q-2
r3-°^x I		Rz°xZ	Ύ^α1
?—O'^U		UqX'

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2020201638 05 Mar 2020 then the portion of C directly attached to

cannot contain

, when R⁷⁰ is selected from -H, Ci^alkyl, and Cj.₄alkoxyl.

[0079] In another example the compound is according to paragraph [0078], wherein Q is selected from phenyl, napthy], 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyi, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, 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, -NO2, -NH2, -OR³, -NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted lower alkyl, [0080] In another example the compound is according to paragraph [0079], wherein B is either of the following:

wherein A¹ is either =N- or =C(H)-.

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

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2020201638 05 Mar 2020 [0082] In another example the compound is according to paragraph [0081], wherein C is selected from:

H . .0-2 Lj I l Y<r2°>« X R2	R? 9 99j9sYi V b R5
χτνγΧΧ X R2	Η H ,.0-2 χΧΤΎΥΧ>' R2
h i /9 7 irso)o-3	θ
rrrr<9 r2	.xf t R2
XX	wX' R2
(Λ-4 χ/γγΑ R2	a0 2 jQr YX (X R2
H A χχΝτχχ) V R2 (R6°)o-4	f \ E jyYr:9’“ V R2

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A 0 0 V R2	M0’2 Ij \ T II 0 IR60!^ AV OO \n /0-4 X R2
Αλ AxjP 0 0 AA X r2 ir^	|^-Τ-(Η60)θ4 AVN a—A N id il ΙΓ JL AAA 0 0 (R 5o-4 X R2
r2 or	AAq*·' V R2 °R

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, -CM, -NO2, -OR³, -NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl [0084] In another example the compound is according to paragraph [0083], wherein R² is halogen.

[0085] In 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 kinase activity according to Formula XI,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,

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2020201638 05 Mar 2020 each R¹ is independently selected from halogen, -OR³, -NO₂, -NH₂, -NR³R⁴, -D-R⁵⁰ and optionally substituted Ci^alkyl;

R⁷⁰ is selected from -H, halogen, -OR³, -S(O)q.2R³, -NO2j -NH₂, -NR³R⁴, and optionally substituted Cj^alkyl;

Q is selected from =N-, =C(H)-, and =C(CN)-;

Z is selected from -S(0)o.₂-, -O-, and -NR⁵-;

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

G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R² is independently selected from halogen, trihalomcthyl, -CN, -NO2, -ΝΗ2> -OR³, -NR³R⁴, -S(0)o-2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted Ci.6alkyl;

each R³ is independently -H or R⁴;

each R⁴ is independently selected from optionally substituted Cj-salkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Chalky]; or

R and R , 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 Cj^alkyl;

each D is independently selected from -O-, -S(O)q.₂-, and -NR⁵-;

each R⁵⁰ is independently either R³, or according to formula XII;

x^a

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,

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2020201638 05 Mar 2020 each X¹ is independently selected from -C(R⁶)R⁷-, -O-, -S(O)q.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-, -O-, -S(O)q.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 X“ when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R or R ; 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 equals zero, then there is a single bond between the two bridgehead X ’s;

R⁶ and R⁷ are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NOi, -OR³, -NR³R⁴, -S(0)o.2R⁴, -SOiNR^⁴, -CO2R³, -C(O)NR³R⁴, -NCR^OiR⁴, -N(R³)C(O)R³, -NCO₂R³, -C(O)R³, optionally substituted Chalky!, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Cj-ealkyl, and a bond to either Y or D; or

R^s 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, -SO₂NR³R⁴, -CO2R⁴, -C(O)NR³R³, -SO2R⁴, and -C(O)R³; and

100

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2020201638 05 Mar 2020 each R³⁰ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR⁰, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted Chalky!.

[0087] In one example, the compound is according 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 -O- and at least one other R¹ is -OR³.

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

XHIaorXnib:

wherein Q¹ is either =N- or =C(H)-.

[0091] In another example, the compound is according to paragraph [0090], wherein R⁵⁰ is selected from Ci-calkyl optionally substituted with at least one of optionally substituted amino, optionally substituted Chalky! 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 R^3a is Ci^alkyl.

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

[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

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2020201638 05 Mar 2020 [00951 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, Ci^ alkyl and perfluoro Ci-g alkyl.

[0097] In another example, the compound is according to paragraph [0096], wherein

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, -NO2, -NH2, -OR³, -NR³R⁴, -S(O)0.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Cj^alkyl, optionally substituted aryl, optionally substituted aryl Ci-galkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Chalky!;

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 J or fused to J;

E is selected from -O-, -N(R⁵)-, -CH₂-, and -S(0)o-₂-;

each R⁶⁰ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(O)q.3R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Chalky!, optionally substituted aryl, optionally substituted heteroaryl Chalky!, and optionally substituted aryl Ci^alkyl;

102

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R²⁵ is selected from halogen, trihalomethyl, oxo, -CN, -NOs, -NH2, -OR³, -NR³R⁴, -S(0)o.₂R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted aryl, optionally substituted aryl Chalky!, heteroaryl C_b6alkyl, and optionally substituted Chalky!; 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;

R^3bis 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 XlVb [0099] hi another example, the compound is according to paragraph [0098], wherein R³⁰ is Ct-galkyl optionally substituted with a group selected from optionally substituted amino, an optionally substituted alkylamino, optionally substituted dialkylamino, and optionally substituted heteroalicylic.

[0100] In another example, the compound is according to paragraph [0099], wherein the heteroalicyclic 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-morpholine, pyrrolidine, and azepine.

[0101] In another example, the compound is according to paragraph [0099], wherein R⁵⁰ is according to formula XII.

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2020201638 05 Mar 2020 [0102] In another example, the 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], [3.2.0], [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 -CH2CH2CH2CH2-, -CH2CH2CH2-, -CHiCHz-, -CH2-, and absent.

[0104] Tn another example, the 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].

[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.

[0106] 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, -CO2R³, -C(O)NR³R³, -SO₂R³, and -C(O)R³.

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

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

[0108] In another example, the compound is according to paragraph [0107], wherein Y is -CH2-.

[0109] Tn another example, the compound is according to paragraph [0108], wherein U¹ is -NR⁸-, wherein R⁸ is selected from -H, optionally substituted lower alkyl, -COaR³, -C(O)NR³R³, -SO2R³, and -C(O)R³.

[0110] In another example, the compound is according to paragraph [0108], wherein U¹ is

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2020201638 05 Mar 2020 [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-, -CH2-, and absent.

[0113] In another example, the compound is according to paragraph [0112], wherein said saturated bridged ring system is of formula XVI,

R’

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 R¹¹, when taken together, are either an optionally substituted alkylidene or an oxo;

R¹² is selected from -H, -C(O)R³, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkyiaryl, 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 R¹¹, or 2) a corresponding cyclic ketal when said two R¹²’s stem from R⁹ and one of R¹⁰ and R¹¹.

[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(O)R³, and optionally substituted lower alkyl; and R⁹ and the other of R¹⁰ and R¹¹ are both -H.

[0115] In another example, the compound is according to paragraph [0114], wherein Y is either -CHi- 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.

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xvn [0118] In another example, the compound is according to paragraph [0117], wherein Y is either -CHs- or absent.

[0119] In another example, the compound is according to paragraph [0118], wherein R 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.

R⁸—N

XVJII [0122] In another example, the compound is according to paragraph [0121], wherein Y is -CH₂-.

[0123] In another example, the compound is according to paragraph [0122], wherein R is methyl or ethyl.

[0124] In 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 -O-, -S(O )0.2-> -NR⁸-, -CR⁶R⁷-, and absent.

[0125] In another example, the compound is according to paragraph [0124], wherein R³ of formula XIX is selected from -H and optionally substituted alkyl.

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2020201638 05 Mar 2020 [0126] In another example, the compound is according to paragraph [0125], wherein U² is either -CR^fiR⁷- or absent.

[0127] In another example, the compound is according to paragraph [0126], wherein U² is either -CH₂- 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.

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 R² is selected from Ci.g alkyl, perfluoro Ci_e 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, -NO2, -NH2, -OR³, -NRV⁴, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, 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 XlVb.

[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 XlVaorXIVb.

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2020201638 05 Mar 2020 [0135] In another example, the compound is according to paragraph [0134], wherein R² is selected from Ci-e alkyl, perfluoro Ci-6 alkyl, and halogen.

A [0136] In another example, the compound is according to paragraph [0135], wherein R is selected from perfluoro Ci_3 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)quinolm-4yI]oxy}-5-chIoropyridin3-yl)-N'-(4fluorophenyl)cyclopropan e-1,1 -die arboxamide	χ/ΛΥ,
2	N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-chloropyridin- 3-yI)-N’-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide	:XX CAP F >XQ
3	N-(6-{[6,7bis(methyloxy)quinolm-4yl]oxy]-5-chloropyridin3-yl)-N’(phenyhnethyl)cyclopropa ne-1,1 -dicarboxamide	“ύύΆ!ί
4	N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-chloropyridin3-yl)-N’phenylcyclopropane-1,1dicarboxamide

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Entry	Name	Structure
5	N-[3-fluoro-4-({ 6- (methyloxy)-7-[(3morpholin-4yIpropyl)oxy]quinolin-4yl} oxy)phenyl] -N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	Λ = XrWO.,
6	N-[3-fIuoro-4-({6- (methyloxy)-7-[(3piperidin-lylpropyl)oxy]quino!in-4yl} oxy)phenyl]-N’“(4~ fluorophenyl)cyclopropan e-1,1 “dicarboxamide	o Xr!Aur
7	N-[3-fluoro-4-({6- (methyloxy)-7-[(3piperidin-1ylpropyl)oxy]qumolin-4yl }oxy)phenyI]-N'-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide	ΎτΆτ1
8	N-(6-[[6,7- bis(methyIoxy)quinolin-4- yl]oxy }-5-chloropyndin- 3-yl)-N'-(2- phenylethyl)cyclopropane -1,1-dicarboxamide	Λυό
9	N-(6-{[6,7- bis(methyloxy)quinoliii-4yl]oxy}-2-methylpyridin3-yl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	aW
10	N-{4- [(7-chloroquinolin4“yl)oxy]-3fluorophenyl }-N'-(4fluorophenyl)cyc!opropan e-1,1-dicarboxamide	/V o o

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Table 2

Entry	Name	Structure
11	N- {4-[(7-chloroquinolin4-yl)oxy]phenyl} -Ν'-(4fluorophenyljcyclopropan e-1,1 -dicarboxamide	rr’ErV
12	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N’-(4fhiorophenyl)cyclopropan e-1,1-dicarboxamide	AAA,
13	N-(4-{[6,7bis(methyloxy)quinazolin -4-yl]oxy }phenyl)-N'-(4fluoropheny])cyclopropan e-1,1-dicarboxamide	/AY ο o AArr Ό F Άό
14	N-(4-{[6,7bis(methyloxy)quinazolin -4-yl]oxy}-3fluorophenyl)-N'-(4~ fluorophenyl)cyclopropan e-1,1-dicarboxamide	XrAA,
15	N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl }oxy)phenyl]-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	0 A
16	N- {5-chIoro-6-[(6- (methyloxy)-7-{[(lmethylpiperidin-4yl)methyl]oxy} quinolin4-yl)oxy]pyridin-3-yl }Ν·-(4fluorophenyljcyclopropan e-1,1-dicarboxamide	XrXr’O.,

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Table 2

Entry	Name	Structure
17	N-[5-chloro-6-({6(methyloxy)-7[(piperidin-4ylmethyl)oxy]quinolm-4yl }oxy)pyridin-3-yl]-N’(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	XrWiX
18	N-[5-chloro-6-({6(methyloxy)-?[(phenylmethyl)oxy]quino lin-4-yl }oxy)pyridin-3yll-NXq. fluorophenyl)cyclopropan e-1,1 ~dicarboxamide	χτΆ'-α,
19	N-(4-{[7-{[2(diethylammo)ethyl]oxy} 6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)- N’-(4fluoTophenyl)cyclopropan e-1,1 -dicarboxamide
20	N-(4-{[7-{[2(diethylamino)ethyl]oxy}“ 6-(methyloxy)quinolin-4yl]oxy}-3-fluoropheny])N’-(4fluorophenyl)cyclobutane -1,1 -di carboxamide	0XJii ulf
21	N- {3-fluoro-4-[(6- (methyIoxy)-7-{[(lmethylpiperidin-4yl)methyl]oxy}quinazo]in -4-yl)oxy]phenyI}-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	XrW.
22	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -2-methylphenyI)- N'-(4- fluorophenyljcyclopropan e-1,1 -dicarboxamide

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Table 2

Entry	Name	Structure
23	N-(4-fluorophenyl)-N'-[2methyl-6-({6(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl}oxy)pyridin-3yl]cyclopropane-l ,1dicarboxamide
24	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy)-3-fluoropheny!)N‘-(4fluoropheny!)cyclopropan e-1,1-dicarboxamide	Wa,
25	N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-chloro-2methylpyridin-3-yl)-N'(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	Uu
26	N-[3-fluoro-4-({7- (methyloxy)-6-[(3morphoIin-4ylpropyl)oxy]quinazolin4-yl }oxy)phenyl]-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	o XtWo,
27	N-(4-{[6,7bis(methyIoxy)quino]in-4yl]oxy}-3,5difluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	JU
28	N-(4-{[6,7bis(methyloxy)quinolin-4ylloxy )-2,5difluorophenyl )-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	Uf0 0 LA

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Table!

Entry	Name	Structure
29	N-[3-fluoro-4-({7- (methyloxy)-6-[(3morpholin-4yIpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	o-Aa 0 0
30	N-{3-fluoro-4-[(6(methyloxy)-7-(2-methyl octahydrocyclopenta[c]pynol-5ylmethoxy)qumazolin-4yl)oxy]phenyl} -N’-(4fluorophenyljcyclopropan e-1,1-dicarboxamide	XrWn.,
31	N-{3-fluoro-4-[(7- (methyloxy)-6- ([(1 methylpiperidin-4yl)methyl] oxy [quinazolin -4-yl)oxy]phenyl }-N'-(4fluorophenyljcyclopropan e-1,1-dicarboxamide	. XrVm,
32	N-[5-fluoro-2-methyl-4- ({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyljcyclopropan e-1,1 -dicarboxamide	0 o xoVo
33	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy [-2,3,5trifluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	'nWn o F F
34	N-(4-W- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-2methylphenyl)-N’-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	XiWiX Xi j .

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Table 2

Entry	Name	Structure
35	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -2-chloro-5methylphenyl)-N'-(4~ fluorophenyl)cyclopropan e-1,1 -dicarboxamide	χύΤα, >3^00
36	N-(3-fluoro-4-{[6hydroxy-7(methyloxy)quinoIin-4yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide
37	N-(4-fluorophenyl)-N'-[2methyl-4-({6(methyloxy)-7-[(3morpholin-4ylpropyI)oxy]quinolin-4yl} oxy)phenyl]cyclopropa ne-1,1-dicarboxatnide	0 o XjXVo,
38	N-[3-fluoro-4-({ 6- (methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quinolin-4yl}oxy)phenyl]-N’-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	aS Ογι O H 0==( NH F

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Table!

Entry	Name	Structure
39	N-{3-fluoro-4-[(6- (methyloxy)-7- {[3-(4methylpiperazin-1 yl)propyl]oxy} quinolin-4yl)oxy]phenyl }-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	o . /—A \^/'N J I i H (/A s. il fX Ar0
40	N-{3-fluoro-4-[(6(methyloxy)-7-{ [(1methylpiperidin-4yl)methyl]oxy}quinolin4-yl)oxy]phenyl} -N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	NH ΓΊ f I i T
41	N-(4-fluorophenyl)-N’-[4({6-(niethyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]cyclopropa ne-1,1-dicarboxamide	ρ-ΆΧ V Λνη λ X οΊ ό Xu Γ ιΓ
42	N-(4-{[7-{[3(diethylamino)propyl]oxy } -6-(methyloxy )quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyc!opropan e-1,1-dicarboxamide	νχ-ΝΗ . cXnh \ Λ ΑΓ f Ύχτ Γ Γ

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Table 2

Entry	Name	Structure
43	N-(4-{[6,7bi s(methyloxy)quinolin-4yl]oxy}-2-cliloro-5fluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide
44	N-(4-{ [,6,7bis(methyloxy>-2(methylthio)quinolin-4yl]oxy} -3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	Y 1 γΛ ΐ ΓΪ Μ /? θ Λτ°ΥΎ Η X Ν η-' Η
45	N-(4-fluorophenyl)-N'-(4{[2-methyl-6,7- bis(methyloxy)quinazolin -4yl]oxy }phenyl)cyclopropa ne-1,1-dicarboxamide	f ι F. ZV° /A η I I Μ j 2 fY υύ Ν -^Α Ν^Ν
46	N-(4-{[2-amino-6,7bis(methyloxy)qinnolin-4yl]oxy} -3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	)=*\ f [ί Μγ? ΑΥυ ν-Α Λ, Η Λ 9 τ 4-4 Η ΝΗ2
47	N-(3-fluoro-4-{ [2- (methylaniino)-6,7bis(methyloxy)quinolin-4yl]oxy }phenyl)-N’-(4fluorophenyl)cyclopropan e-l,l-dicarboxamide	Α ι V\ f rr° M f ° AvSr n-\ U As. J ks,N H Λ ίί τ 4-4 H χΝΗ

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Table 2

Entry	Name	Structure
48	(lS,2R)-N-[3-fluoro-4({6-(methyloxy)-7-[(3morpholin-4ylpropyI)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide	X F H
49	(lR,2R)-N-[3-fluoro-4({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1di carboxamide	γο X a T Ί o W ΗΊ rX 0 HNv
50	N-(4-{[6-{[3(diethylamino)propyl]oxy } -7-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	HN c ) i /° F \ /=( P N HN—4 X~O /=< / Jho
51	N-(4-{[6-{[2(diethylamino)ethyl]oxy} 7-(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-l,l-dicarboxamide	HN OF J-/=4 Q hn-£J^o /=< (h x

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Table 2

Entry	Name	Structure
52	1,1-dimethylethyl 4-(3{[4-[(2-fluoro-4-{[(l{[(4fluorophenyl)amino]carbo nyl}cyclopropyl)carbonyl jamino }phenyl)oxy]-6(methyloxy)quinolin-7yl]oxy} propyl )piperazine1-carboxylate	(X n λ ft f] )¥ 1 T ' Q HN N F
53	(lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl] -N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	Tk J C/ Ύπ °Y^ °HN\ H
54	(lR,2R)-N-(4-{[7-{[2(diethylamino)ethyl]oxy )6-(methyloxy)quinazohn4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	°yS o Ύί °ΎΑ jTA N^N fAAnJU-O H A...
55	N-(4-{[7-{[3(diethylamino)propyl]oxy )-6(methyloxy)quinazolin-4yl]oxy }-3-fluorophenyl)N'-(4~ fluorophenyl)cyclopropan e-l,l-dicarboxamide	P F\ F iT^ Oji Λνγ Za h

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Table 2

Entry	Name	Structure
56	N-(4-{ [7-{ [3-(4acetylpiperazin-1 yl)propyI]oxy}-6(methyloxy)quinolin-4yl]oxy]-3-fluorophenyl)N’-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide	y f. A -o F flT M / e HyVy H
57	1,1-dimethylethyl 4-(3{[4-[(2-fluoro-4{[((lR,2R)-l-{[(4fluorophenyl)amino]carbo nyI}-2methylcyclopropyl)carbon yljamino }phenyl)oxy] -6(methyloxy)quinolin-7yl]oxy} propyl)piperazine1-carboxylate	Ajr 0 v ii j f Ul ΗΝγΟ H f - o
58	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} phenyl)-N1-(4fluoropheny])-l(phenylmethyl)azetidine3,3-dicarboxatnide	F Φ O^NH M /=\ p- {(|_Ι HN—< A-0 /=< A tA °' O N

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Table 2

Entry	Name	Structure
59	N-(4-{[6,7- bis(methyloxy)quiiioIin-4- yl]oxy }phenyl)-N'-(4fluorophenyl)azetidine3,3-dicarboxamide	F Φ °5A v- HN—' HN—< Λ-O /=(
60	(lR,2S)-N-{3-fluoro-4[(6-(methyloxy)-7-{ [3-(4methylpiperazm-1yl)propyl]oxy}quinolin-4yl)oxy Jpheny 1} -Ν’- (4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A v A 0 ΎΎ°ΥΊ οηγ( ΝχΙ Jk JL Ao H
61	(lR,2R)-N-(3-fluoro-4[(6-(methyloxy)-7-{ [3-(4methylpiperazin-lyl)propyl]oxy }quwiolin-4yl)oxy]phenyl }-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A θ-Α Γ\ ΤΧ ο A IlY °HNV NxA χΆ Jk JL Ao F N A Η /\
62	(lR,2R)-N-[3-fluoro-4- ({6-(methyioxy)-7-[(3piperazin-1ylpropyl)oxy]quinolin-4yl }oxy)phenyl] -N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A 1 ° z^/F °\xA. T 1 SrSx°Y?A oH,t r N /I

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Table 2

Entry	Name	Structure
63	N-(3-fluoro-4-{ [7-({ 3-[4(l-methylethyl)piperazinl-yl]propyl)oxy)-6(methy]oxy)quinolin-4yl]oxy}phenyl)-N'-(4fhiorophenyl)cyclopropan e-1,1 -dicarboxamide	A F Αα°Ί οΖϊ Γϊ Π 1
64	N-(4-{[7-{[3(diethyl amino)propyl]oxy }-6(methyloxy)quinazolin-4yl]oxy }-3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide	A 9 \ yr Ν r η Α η I I
65	(lR,2R)-N-(4-{[7-{[3(diethylamino)propyl]oxy } -6-(methyloxy)quinolin4-yI]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A °yS C/ «ΎΎιΐ Η i—'Ί,,,
66	(lR,2R)-N-(4-{[7-{[2(diethylamino)ethyl]oxy}6-(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)- N’-(4-fluorophenyl)-2methylcyclopropane-1,1dicarboxamidc	υ S a

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Table 2

Entry	Name	Structure
67	(lR,2S)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A 1 X° /F <LI θ Υγ ° A n J As- JL JL .Ao H
68	(lR,2S)-N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinolin-4yl]oxy) -3-fluorophenyl)- N'-(4-fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide	u S A) zF AA 11 o N-J AsJl Jk Η ZA,
69	N-(4-{[7-{[2- (diethyiamino)ethyl]oxy} 6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyclobutane -1, 1-dicarboxamide	F L-z-c· 0 \ / λ °-VNH X==/ Q—// \\_ Ύ h-ι F 0 1—
70	(lR,2S)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quinoIin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	pAlH X oAL AA 11 □ ΊιΥΆιΙ °HNv nA e AAA·^0 1 H ZX^

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Table 2

Entry	Name	Structure
71	(lR,2R,3S)-N-[3-fluoro- 4-({ 6-(methyloxy )-7-((3uaorpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyl)-2,3 dimethylcyclopropane1,1-dicarboxamide	P p 0 yay
72	(lR,2R,3S)-N-{3-fluoro4-[(6-(methyloxy)-7-{ [3(4-methylpiperazin-l yl)propyl]oxy}quinolin-4yl)oxy]phenyl} -N'-(4fluorophenyl)-23dimethylcyclopropaneIJ-dicarboxamide	X p Yap
73	(lR,2R,3S)-N-[3-fluoro- 4-( {6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl }oxy)phenyl]-N'-(4fluorophenyl)-2,3dimethylcyclopropanel,l-dicarboxamide	o WOp w
74 _	(lR,2R,3S)-N-{3-fluoro4-[(6-(methyloxy)-7- {[3(4-methylpiperazin-1 yl)propyl]oxy}quinazolin4-yl)oxy]phenyl) -N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1 -dicarboxamide	X 0-

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Table 2

Entry	Name	Structure
75	N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl }oxy)phenyl]-N’-(4fluorophenyl)cyclobutane -1,1-dicarboxanude	Ο i y /=/ 0—A—NH y --O )=7 y- F O L-J
76	(2R,3R)-N-[3-fluoro-4- ({6-(methyloxy)-7 [(3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyI]-N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide	λ 1 1 o >0 iiV0 ° HNv J JL X X /=ο
77	(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2,3dimethylcyclopropane- 1,1-dicafboxamide	C ΟχΑ. Il O zx li 1 T Π il H jA.,,,
78	N-(4-{[7-{[3- (diethylamino)propyl]oxy } -6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide	X° io 0 i ΙΎ°Ύ0Ι °Hu O F Η

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Table!

Entry	Name	Structure
79	N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yI} oxy )phenyl]-N'-(4fluorophenyl)-2?2dimethylcyclopropane1,1 -dicarboxamide	A
80	(IR,2R,3S)-N-(4-{[7-{[3(diethylamino)propyl]oxy j -6-(methyloxy)quinoiin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide	F Ί ΎΎ°~Π
81	N-(4-{[7-{[2(diethylamino)ethyl]oxy }6-(methyloxy)quinolin-4yl] oxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,2dimethylc yclopropane1,1-dicarboxamide	u A 0F
82	(lR,2R,3S)-N-(4-{[7-{[2(diethylamino)ethyl]oxy}6-(methyloxy)quinolin-4ylloxy}-3-fluorophenyl> N'-(4-fluorophenyl)-2,3dimethylcyclopropane- 1,1-dicarboxamide	u A xo / FxA
83	N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N’-(4fluorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide	Γ°υΑ O 1 I] °ΤΑ| ? An .n nA 0 Sr \

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Table 2

Entry	Name	Structure
84	N-(4-{[7-{[2- (diethylamino)ethyl]oxy}~ 6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide	γΑ P 'Ύ ΎΎΥΙ fHIY F Π Ya
85	N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6(methyloxy)quinazolin-4yI]oxy}-3-fluorophenyl)N'-(4-fluorophenyl)-2,2dimethylcyclopropane1,1-dicarboxainide	xcyl 0 r sHVn 1 η
86	N-(4-{[7-{[3- . (dieihylamino)propyl]oxy }-6- (methyloxy)quinazolin-4- yl]oxy} -3-fluorophenyl)N'-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide	\=/ 0—// mh -o A F 0	F	IH
87	N-{3-fluoro-4-[(6(methyloxy)-7-{[3-(4methylpiperazin-1yl)propyl]oxy} quinazolin4-yl)oxy]phenyl}-N'-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide	r— H < A < Ay 9 0_7 \_A O^NH O-# y-NH y AAp-b
88	N-[3-fluoro-4-({6- (methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quinazolin4-yl }oxy)phenyl] -N'-(4fluorophenyl)cyclobutane -1,1-dicarboxamide	^NH N-Y F 0Z	F	H

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Table 2

Entry	Name	Structure
89	(2R,3R)-N-[3-fluoro-4({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl Joxy)phenyH-N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1’dicarboxamide	A S A Ϊ1 o W Υί ΥΊ 0 A fAAn>A0
90	N-(4-{[7-{[3(diethylamino)propyl]oxy } -6-(methyloxy)quinolin4-yI]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide	( ν_λ, A3 __/ \ f/ )-=7 ο—V P— NH x o )—/ }/ F O	F	H
91	N-{3-fluoro-4-[(6- (methyloxy)-7-{ [3-(4methylpiperazin-1 yl)propyl]oxy }quinolin-4yl)oxy]phenyl} -N'-(4fluorophenyl)cyclobutane -1,1-dicarboxamide	ό )==7 O—€ V-NH x ο Y Ίγ~ F O	F J	H
92	(lR,2R)-N-(4-{[7-{[3(diethylamino)propyl]oxy )-6(methyloxy)quinazolin-4yl]oxy} -3-fluorophenyl)- N'-(4-fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	A /AF

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Table 2

Entry	Name	Structure
93	(lR,2R)-N-{3-fluoro-4[(6-(methyIoxy)-7-{ [3-(4methylpiperazin-1yl)propyl]oxy }quinazolin4-yl)oxy]phenyl} -N*-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	i Yr Yi ru
94	(2R,3R)-N-(4-{[7-{[2(diethylamino)ethyi]oxy} 6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2,3dimeihylcyclopropane1,1-dicarboxamide	xo F
95	(2R,3R)-N-(4-{[7-{[3(diethylaniino)prop y 1] oxy }-6(methyloxy)quinazoiin-4yl]oxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide	Y 0' (c Yuxk
96	(lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quinazolin4-yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	6°yS 0 k γνχ) pWJ N N ✓ N Y. Jk JL Υθ a
97	(2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy} 6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide

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Table 2

Entry	Name	Structure
98	N-(4-{[6,7bis(methyloxy)quinolin-4y IJoxy} phenyl)-N'- [(4fluorophenyl)methyl]cycl opropane-1,1dicarboxamide	F x Ϊ A M A'h'^
99	N-(4-{[6,7bis(methyIoxy)quinolin-4yljoxy} phenyl)-N'-(2morpholin-4ylethyl)cyclopropane-1,1dicarboxamide	Q> . A
100	N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy} phenyl)-N'-[2(piperidin-1ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide	kyra
101	N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} phenyl)-N'-[2(pyrrolidin-1ylmethyl)phenyl]cyclopro pane- 1,1-dicarboxamide	Χσ Ζδ η
102	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N’-[3(morpholiii-4ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide	/ — 0 /y.Xr

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Table 2

Entry	Name	Structure
103	N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy } phenyl j-N'-POnorpholin^ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide
104	N-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy }phenyl)-Nphenylcyclopropane-1,1di carboxamide
105	N-[3- (aminomethy l)pheny 1] -N(4-{[6,7bis(methyloxy)quinolm-4yljoxy }phenyl)cyclopropa ne-1,1-dicarboxamide	C-^NH2
106	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} phenyl)-N'-[3(piperidin-1ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide	V#
107	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[3(pyrrolidin-1ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide	ov γσΑ

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2020201638 05 Mar 2020 [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].

[0178] 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, flt-3, and flt-4.

[0181] Another aspect of the invention is the method according to paragraph [0125], 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, the 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

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PCT/US20M/031523 routes are desirable, particularly convergent syntheses. Thus, the present invention also comprises a process for preparing a compound of Formula XXI,

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

XXIII

P²-Z

XXIII

wherein, each R^l is independently selected from halogen, -OR³, -NO2, -NHz, -NR³R³, -D-R⁵⁰ and optionally substituted Ci-galkyl;

R⁷⁰ is selected from -H, halogen, -OR³, -S(0)o_zR³, -NOj, -NH2, -NR³R³, and optionally substituted Cpealkyl;

J is selected from =N-, =C(H)-, =C(halogen)-, and =C(CN)~;

Z is selected from -8(0)0-2-, -O-, and -NR³-;

each R³ is independently selected from -H, optionally substituted Ci-ealkyl, optionally substituted aryl, and optionally substituted aryl Ci_₆alkyl;

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

R² is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)COzR³, -C(O)R³, and optionally substituted Ci-ealkyl;

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;

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2020201638 05 Mar 2020 two R³, together with the nitrogen to which they are attached, form a four- to sevenmembered 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, -SO2NR⁵R⁵, -CO₂R⁵, -C(O)NR⁵R⁵, -C(O)R⁵, and optionally substituted- lower alkyl;

B is selected from absent, -N(R¹³)-, -NCSOiR¹³)-, -O-, -S(O)₀._r, and -C(=O)-;

L is selected from absent, -C(=S)N(R¹³)-, -C(-NR¹⁴)N(R¹³)-, -SO2N(R¹³)-, -SO2-, -C(=O)N(R¹³)-, -N(R¹³)-, -C(=O)Ci.2alkj'lN(R¹³)-, -N(R¹³)Cl.₂alkylC(=O)-,

-C(=O)C_MalkylC(=O)N(R¹³)-, -C(=O)-, -C0.4alkylene-, -C(=0)Co_ialkyIC(=0)OR³-, -C(=NR^w)Co-ialkylC(=0)-, -C(=O)C0.₁alkylC(=O)-, and an optionally substituted four- to six-membered heterocyclyl containing between one and three annular heteroatoms and comprising at least one nitrogen;

T is selected from -H, -R¹³, -Co^alkyl, -Co^alkylQ, -OCo^alkylQ, -Co^aikylOQ, -N(R¹³)C₀.₄aIkylQ, -SO₂C(MalkylQ, -C(=O^alkylQ, -C₀.₄alkylN(R¹³)Q, and -C(=O)N(R^I3)C(K4alkylQ, wherein each of the aforementioned Co^alkyl 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, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Ci.ealkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Chalky!;

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 -O-, -S(0)o.₂-, and -NR¹⁵-;

R⁵⁰ is either R³, or according to formula XXIV;

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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-, -O-, -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-, -O-, -S(0)o_₂-, and -NR⁸-;

Y is either:

an optionally substituted Cj.ealkylene linker, between D and either 1) any annular 2 2 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 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(O)q.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³X3(O)R³, -NCO2R³, -C(O)R³, optionally substituted Chalky!, optionally substituted aryl, optionally substituted aryl Ci-ealkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl a C^lkyl, and a bond to either Y or D; or

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R⁶ and R⁷, when taken together are oxo; or

R and R , 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, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -SO₂R³, and -C(O)R³;

R¹³ is selected from -H, -C(=O)R³, -C(=O)OR³, -C(=O)SR³, -SO₂R³, -C(=O)N(R³)R³, and optionally substituted Ci-galkyl;

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 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, -NO₂, -NH₂, -N(R³)R³, -CN, -OR³, optionally substituted Ci^alkyl, optionally substituted heteroalicyclyl Ci^alkyl, 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(=NR¹⁴)N(R¹³)-, -SO2N(R¹³)-, -SO2-, -C(=O)N(R¹³)-, -C(=O)C(=O)N(R¹³)-,

-Co^alkylene-, -C(=O)-, 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-galkyl, alkoxy, -C(=0)Co^alkylQ, -Co-^alkylQ, -OCo^alkylQ-, -N(R¹³)C0^alkylQ-, and -C(=O)N(R¹³)C0.₄alkylQ;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(O)0.2R³s -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Chalky], optionally substituted aryl, optionally substituted heteroaryl Chalky], and optionally substituted aryl Cj^alkyl;

two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;

P^! is a suitable leaving group; and

P² is selected from -H, a metal, and a group removed in-situ when combining ΧΧΠ and ΧΧΠΙ to make XXI.

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2020201638 05 Mar 2020 [0131] In one example, the process is according to paragraph [0130], wherein Ar is paraphenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene.

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

[0133] In another example, the process is according to paragraph [0132], wherein -B-L-T is selected from the following:

R13 R13 I I X- [f 'Am Ns <, R14	R13 R13 I I / \0-3 v'VVV	/ V-2 1 Ψ -hL .hL .Q z y 0
____/ y-2 ^TrQ 0 o	ri)0’2 0	R13 •AvA P TXu
R13	R13 ,/NV\ P L Ar )o-2 'N	R13 ΧγΥη° . Nx^v
p13 I I Y'vV L I /0-4 O 0	R13 I . .0-4 η	R13 0 o
R13 „ J, < \0-2 ΧγΎ O 0	R13 O^N Q Y Y-3 0	0, p 0 AV R13
c> P X jpt3 N Q R13	Y-y2 YyN< 0	YyV 0
0	(γγ: Yy%” 0	•Tn ^N, τ y -r« 0

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R13 R13 1 1' V γ H-4 s	r13 r13 1 1 , ,0-3 v-VX s o	r-r N ,N Q V γ s
1--------(]) 1 1 . ,0-3 ΛΫ*· S 0	r-J° /γ'-χ s	A .Nx ,N- x γ R” s
R13 0	R13 I f ,0-4 ΧγΥ 0	R'3 <[)£ .,χ-γ'Ύ 0 o
R13 irA0 I ' Γ'θ-3 ·/ Y^ SH O	R13 I i PtJ-3 .N- A A Y^ OH 0	R13 t A'0 I ' Po-3 pis Αχ II H 0
Γ 1 . ΑγΎ” 0	n13 1 ( \°-2 Yi o o	0
0, p M / J-3 Ak A XC N E R13	Q %Ao-4 O'8! Ά Αγ o Λ V O 0	Ov p R13 V ( ?’2 J. R13 0
R13	R13 r13 I I 1 ,0-3 vYX O 0	Rto N Ύιι Q 0 nAr3
r13 0 NAR3	R13 R13 1 I Ji A	g 13 1 f ,0-2 νΝγγ ''kw o o

wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from -0-, -N(R¹³)-, -CH2, and -S(0)o-2-; M is selected from -0-, -N(R¹³)-, -CH2-, and -C(=O)N(R¹³)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is

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2020201638 05 Mar 2020 independently optionally substituted with R²³; and R²³ is selected from halogen, trihalomethyl, -CN, -NO₂, -NH₂, -OR³, -NR³R³, -S(0)o_2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO₂R³, -N(R³)C(O)R³, -N(R³)CO₃R³, -C(O)R³, optionally substituted aryl, optionally substituted aryl Ci^alkyl, heteroaryl Cj-galkyl, and optionally substituted Ci^alkyl; two of R²³, together with the carbon or carbons to which they are attached, can combine to form an optionally substituted three- to seven-membered alicyclic or heteroalicyclic; two of R 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-R³⁰ and another of R¹ that is -OR^3a.

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

[0136] In another example, the process is according to paragraph [0135], wherein -O-R and -OR^3a are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula XXI.

[0137] In another example, the process is according to paragraph [0136], wherein -OR^3a is selected from -OH, -OSi(R³)(R³)R⁵, and optionally substituted -OCi-galkyl.

[0138] In another example, the process is according to paragraph [0137], wherein J is =Nor =C(H)-.

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

R13 0 I II f Λ3 O R13	R13 R13 1 1 t \0-3	R13 R13 Ύ YT YL ’ o o
R13 o	(R®°)0-4 uCl	M0'2 R13 ΛΑ J S <*°>M
Ri3 ! , i0-4	R13 o o	R13 R13 1 f t0'1 J,

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13 50 wherein Q, R , R , E, and R 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, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(OK2Rk -SO₂NR³R³, -CO₂R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted aryl, optionally substituted aryl C₁.₆alkyl, heteroaryl Ci^alkyl, and optionally substituted Chalky!; two of R²⁵, together with the carbon or carbons to which they are attached, can combine to form a three- to sevenmembered optionally substituted alicyclic 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,

XXV 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, -NO2, -NH2, -OR³, -NR³R³, -S(0)o_2R³, -SO^^³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally

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2020201638 05 Mar 2020 substituted Ci^alkyl; and R^3a and R^3b are each independently selected from -H and optionally substituted Ci-galkyl.

[0142] In another example, the process is according to paragraph [0141], wherein a compound of formula XXIIa is combined with a compound of formula XXIHa to make a compound of formula XXIa,

wherein -B-L-T, Z, J, R⁵⁰, and R² are as defined above; R⁷⁰ is selected from -Η, -NO2, -NH_2f and -NR’R³; provided when Z is -N(R⁵)- that R^s is selected from -H, Ci-salkyl, and aryl Ci-salkyl; 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 Ci_6 alkyl, perfluoro Cue alkyl, and halogen.

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2020201638 05 Mar 2020 [0149] In another example, the process is according to paragraph [0148], wherein XXIIa and XXIIIa are heated together, optionally with a base, optionally with microwave radiation, to form XXIa.

[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,N-dimethylarninopyridine, and a metal carbonate.

[0152] In another example, the process is according to paragraph [0151], wherein 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.

[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 XXIIa 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 200°C for between about one and ten hours to form la.

[0157] In another example, the 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.

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2020201638 05 Mar 2020 [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, the process is according to paragraph [0160], wherein said mixture is heated to reflux for between about four and six hours.

[0162] In another example, the process is according to paragraph [0155], wherein XXIIa is combined with XXHIa 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] Tn another example, the process is according to paragraph [0163], wherein the nonaromatic solvent is N,N-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°C 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] In another example, the process is according to paragraph [0167], wherein the aromatic solvent is 2,6-lutidine.

[0169] In 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 XXHIa is combined with more than one but less than two molar equivalents of XXIIa.

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2020201638 05 Mar 2020 [0173] In another example, the process is according to paragraph [0172], 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 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-Iutidine.

[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.

[0178] In another example, the process is according to any of paragraphs [0149] - [0177], wherein a compound of formula XXIIb is substituted for the compound of formula XXIIa, and either a compound of formula XXIIIb or a compound of formula XXIIIc is substituted for the compound of formula XXIIIa, in order to make a compound of formula XXIb or a compound of formula XXIc, respectively,

HO'

XXIIIb

XXIIb (R²)0-4 (^r2%-4

XXIIIc

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

[0179] Tn 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 in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in

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2020201638 05 Mar 2020 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, “a” means a triple bond. The symbol “λλλτ” 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.

Η Η H

[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, there 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 C-H bonds).

[0188] If a group “R” is depicted as “floating” on a ring system, as for example in the formula:

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2020201638 05 Mar 2020 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 “R” 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 -NH- 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 the 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. In the formula depicted above, when y is 2 for example, then 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.

101^01 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:

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where, in this example, “y” can be more 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 “R’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 form 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 include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, “Cg alkyl” may refer to an n-octyl, iso-octyl, cyclohexylethyl, 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, s-butyl, r-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 includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include cpropyl, c-butyl, c-pentyl, norbomyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. 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, sec-butyl, isobutyl, r-butyl, isobutenyl and but-2yne radicals; and for example, “propyl” or “C₃ alkyl” each include «-propyl, propenyl, and isopropyl.

[0193] “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, «-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

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2020201638 05 Mar 2020 (-CH₂CH₂-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)₂CH₂-), and cyclohexylpropylene (-CH2CH₂CH(C₆Hi3)).

[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 which itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthalene (TUPAC name) contains an n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.

[0197] “Alkoxy” or “alkoxy!” 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 -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy). One exemplary substituted alkoxy group is “polyalkoxy” or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -O(CH₂CH2O)_XCH3, 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

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2020201638 05 Mar 2020 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 more 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, z-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 acids and optical isomers thereof. Typical natural and commercially available a-amino acids 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 hydroxy proline. A “side chain of an α-amino acid” 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 -NH₂. “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, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example., diethylamino, methylsulfonylamino, fiiranyl-oxy-sulfonamino.

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

[0203] “Arylene” generically 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.

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2020201638 05 Mar 2020 (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 double 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, but 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 generically 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 same halogen; thus 4-chIoro-3-fluorophenyl is within the scope of dihaloaryl.

[0209] “Heteroarylene” generically refers to any heteroaryl that has at least two groups attached thereto. For a more specific example, “pyridylene” refers to a divalent pyridyl

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2020201638 05 Mar 2020 ring radical. A pyridylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.

[0210] “Heteroatom” 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 and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic 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. In a specific example, the group -S(O)₀.₂-, refers to -S(sulfide), -S(O)- (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 the invention having, for example, a pyridyl ring; the corresponding pyridyl-A-oxide is meant to be 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, purinyl, quinazolinyl, quinoxalinyl, qutnolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,

2-oxopyirolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

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2020201638 05 Mar 2020 [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 parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-l-yl) methyl, (morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-l-yI)-2-butenyl, and the like. Both the heterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion 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. “Heteroalicyclylalkyl” 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 Ci-galkyl” 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 sterically 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 “Ci.g 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-hexahydro-lH-indene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.”

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PCT/US20M/031523 [0217] “Spirocyclyl” or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring 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 carbocyclic or heteroalicyclic.

2020201638 05 Mar 2020 [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-hydroxyphenyl), optionally substituted arylalkyl (for example, 1-phenyl-ethyl), optionally substituted heterocyclylalkyl (for example, l-pyridin-3-yl-ethy]), optionally substituted heterocyclyl (for example, 5-chloro-pyridin-3-yl or l-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), carboalkoxy (that is, acyloxy or -OC(=O)R), carboxyalkyl (that is, esters or -CO2R), carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen, hydroxy, nitro, sulfanyl, sulfiny], sulfonyl, thiol, halogen, hydroxy, oxo, carbamyl, acylanuno, and sulfonanudo.

[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 bondforming 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

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2020201638 05 Mar 2020 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-(optionaIly substituted heterocyclyl).

[0221] “Sulfinyl” refers to the groups: -S(O)-H, -S(O>(optionaIly substituted alkyd), -S(0)-optionally substituted aryl), and -S(O)-(optional!y substituted heterocyclyl).

[0222] “Sulfonyl” refers to the groups: -S(O₂)-H, -S(0₂)-(optionalIy substituted alkyl), -S(O₂)-optionally substituted aryl), -S(O₂)-(optionally substituted heterocyclyl), -S(0₂)-(optionally substituted alkoxy), -S(0₂)-optionally substituted aryloxy), and -S(O₂)-(optionally substituted heterocyclyloxy).

[0223] “Yield” for each of the 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 this 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. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.

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2020201638 05 Mar 2020 [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, statically 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 (Rand 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, for example enzymatic oxidation or 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” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to

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2020201638 05 Mar 2020 both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.

[0232] “Kinase-dependent diseases or conditions refer to pathologic conditions that depend on the activity of one or more 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 conditions” 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 cel], undifferentiated large cell, adenocarcinoma),

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2020201638 05 Mar 2020 alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; 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, Karposi'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), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bong: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (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, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecologic al: 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, dysgenrunoma, 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, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,

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2020201638 05 Mar 2020 dermatofibroma, keloids, psoriasis; and Adrenal lands: neuroblastoma. Thus, the term “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 salts 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, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 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-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethyipiperidine, 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

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2020201638 05 Mar 2020 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. Higuchi 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 Pergamon 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 urisolvated 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

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2020201638 05 Mar 2020 been diagnosed as having it; (ii) inhibiting the disease-state, i.e,, arresting 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, drag 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, proteinligand 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 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

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2020201638 05 Mar 2020 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 the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted inodes 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 Tectally, 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 die 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

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2020201638 05 Mar 2020 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 monolaurate, 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 forms, the active compound is admixed with at least one inert customary excipient (or earner) such as sodium citrate or dicalcium phosphate or (a) fillers 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. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

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2020201638 05 Mar 2020 [0253] Solid dosage forms 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 form, if appropriate, with one or more of the above-mentioned excipients.

[0254] Liquid dosage forms for 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 like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3butyleneglycol, 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 nonirritating 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.

[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.

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2020201638 05 Mar 2020 [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 compound(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 salts, 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, flt-3, or flt-4, the protein is bound to a support, and a compound of the invention is added to the assay. Alternatively, the

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2020201638 05 Mar 2020 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 antidigoxin 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 ¹²³I, or with fluorophores. Alternatively, more than one component may be labeled with different labels; using ¹²⁵I 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 drag 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.

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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. Tn one example, exogenous agents further exclude antibodies to cMet, KDR, c-Kit, flt-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 biomolecules, 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. In 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

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2020201638 05 Mar 2020 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 are 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 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 firsk followed by the candidate agent. Displacement of the competitor is an indication the candidate agent is binding 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 value 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

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2020201638 05 Mar 2020 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 (although this may not be necessary), and alter its biological or biochemical activity as defined herein. The 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 terms have the indicated meanings throughout.

Abbreviation ____________ Meaning

Ac	acetyl
ATP	adenosine triphosphate
BNB	4-bromomethyI-3-nitrobenzoic acid
Boc	t-butyloxy carbonyl

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Abbreviation Meaning

br	broad
Bu	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
DIEA	N,N-diisopropylethyl amine
DMAP	4-N,N-dimethylarninopyridine
DMF	Ν,Ν-dimethylfonn amide
DMSO	dimethyl sulfoxide
DVB	1,4-di vinylbenzene
EEDQ	2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline
El	Electron Impact ionization
Et	ethyl
Fmoc	9-fluorenylmethoxycarbonyl
g	gram(s)
GC	gas chromatography
horhr	homfs)
HATH	0-(7-AzabenzotriazoH -yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate
HMDS	hexametliyldisiiazane
HOAc	acetic acid
HOBt	hydroxybenzotriazole
HPLC	high pressure liquid chromatography

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Abbreviation __________Meaning

L	liter(s)
M	molar or molarity
m	multiplet
Me	methyl
mesyl	methanesulfonyl
mg	milligram(s) __
MHz	megahertz (frequency)__
Min	minute(s)
mL	milliliter(s)
mM	millimolar
mmol	millimole(s)
mol	mole(s)__J
MS	mass spectra] analysis
ΜΓΒΕ	methyl t-butyl ether __
N	normal or normality
NBS	N-bromosuccinimide ____
NCS	N-chlorosuccinimide
nM	nanomolar _____
NMO	N-methylmorpholine oxide
NMR	nuclear magnetic resonance spectroscopy
PEG	polyethylene glycol ____
pEY	poly-glutamine, tyrosine
Ph	phenyl
PhOH	phenol
PfP	pentafluorophenol
PfPy	pentafluoropyridine
PPTS	Pyridinium p-toluenesulfonate
Py	pyridine
PyBroP	bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
q	quartet

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Abbreviation Meaning

RT	Room temperature
Sat’d	saturated
s	singlet
s-	secondary
t-	tertiary
t ortr	triplet
TBDMS	t-butyldimethylsilyl
TES	triethylsilane
TFA	trifluoroacetic acid
THF	tetrahydrofuran
TMOF	trimethyl orthoformate
TMS	trimethylsilyl
tosyl	p-toluenesulfonyl
Trt	triphenylmethyl
uL	microliterfs)
uM	Micromole(s) or micromolar

Synthesis of Compounds [0279] Schemes 1 and 2 depict general synthetic routes for compounds of the invention and are not intended to te limiting. More specifically, Scheme 1 depicts synthesis of 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 skilled in the art to make and use either quinazolines or quinolines of the invention.

Scheme 1 i

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[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 group, 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 regio- and chemoselective manner by methods well known in the art to give anthranilate derivative 3. Formation of quinazolin-4-one 4 is earned out by methods well known in the art, for example by heating 3 in formamide solution in the presence of ammonium formate or for example by heating directly with formamidine 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, c.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

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2020201638 05 Mar 2020 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.

[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 form 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,

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2020201638 05 Mar 2020 variations on any of the above steps are possible, and intermediates in these schemes, for example compounds 12,13, and 14 may also be compounds of the invention according to formula I. 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 R is typically but not necessarily a methyl radical and R¹ is typically but not necessarily one or more alkoxy or hydroxy groups. In 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 ΧΧΙΠ, convergent syntheses’ advantages over serial syntheses are realized more fully. Regioselective aromatic ring nitration, and reduction of the corresponding nitro 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-one 18 is carried out by methods well known in tire art. For example by heating 17 in formamide 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 J’ represents either carbon or nitrogen atom with

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2020201638 05 Mar 2020 the appropriate number of hydrogens to fill their respective normal valence bonding schemes; Γ is a precursor to J. Radicals J and R⁷⁰ are in accord with formula XXI. Introduction of 4-position functionality is carried out by methods known in the art. For example, 4-one 18 is converted to XXII, where “P¹” represents a suitable leaving group (in accord with formula XXI), e.g. chlorine (via dehydration/chlorination of 18 to give ΧΧΠ). In another example, a 4-hydroxy analog is converted to a sulfonyl ester, e.g. the trifluoromethane sulfonate.

Scheme 3

XXII

185] Scheme 4 shows a general route used to make compounds of formula XXIII. For example, aromatic compound 19, where “X” is a leaving group, such as fluorine and E 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 ^iUZT 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 XXI. 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 T’ (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 XXIII via conversion of T’ to T and introduction of P² (for example, when R is benzyl, removal of the benzyl after completion of-B-L-T).

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[0286] As discussed above, one aspect of the invention encompasses combination of XXII and ΧΧΙΠ 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.

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Quinoline and Quinazoline Syntheses Example 1

[0288] Synthesis of l-(4-Benzvloxy-5-methoxy-2-nitro-phenyl)-eth^Lone. 1-(4Benzyloxy-3-methoxy-phenyl)-ethanone (200 mmol, 51.3 g) dissolved in DCM (750ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 ml) 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. NaHCO3 (4 X 200 ml, or until neutral). The organic layer was dried over Na2SO4 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%). 1H NMR (CDCI3): 7.647 (1H, s), 7.446-7.333 (5H, m), 6.745 (1H, s), 5.210 (2H, s), 3.968 (3H, s), 2.487 (3H, s).

Δ [0291] Synthesis of l-(2-Amino-4-benzvloxv-5-methoxv-phenYl ketiianmie. A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31.g), l-(4-Benzyloxy-5methoxy-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

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Na2SO4, and concentrated to afford the product, 90%. 1H NMR (CDC13): 7.408-7.298 (5H, m), 7.130 (IH, s), 6.155 (2H, br), 6.104 (1H, s), 5.134 (2H, s), 3.834 (3H, s), 2.507 (3H, s). LC/MS (M+l = 272).

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Example 3 [0292] Synthesis of 7-Benzvloxv-6-methoxy-quinolin-4-ol. To a solution of l-(2-Amino4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was 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 be 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 IM HC1. The precipitate was filtered and washed with water, dried in vacuo to afford 22g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. IH NMR (CDC13): 10.7 (1H, br), 7.703 (IH, s), 7.493-7.461 (IH, t), 7.431-7.413 (2H, br d), 7.3727.333 (2H, t), 7.296-7.283 (IH, d), 6.839 (IH, s), 6.212-6.193 (IH, d), 5.212 (2H, s), 3.965 (3H,s). LC/MS (M+l =282).

Example 4 [0293] 7-Benzvloxv-4-(2-fluoro-4-nitro-phenoxv)-6-methoxv-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy-lHquinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150ml), DMF (150ml) and

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2020201638 05 Mar 2020 cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time l,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 acetate/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). ’H NMR ¢400 MHz, CDC1₃): 8.53 (d, 1H), 8.42 (dd, 1H), 8.16 (m, 1H), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H), 3.92 (s, 3H); MS (El) for C23H27EN2O5: 421 (MH*).

equipped with a magnetic stir bar was added 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6methoxy-quinoline ¢2.9 g, 6.9 mmol, l.Oeq) and 33% HBr in acetic acid (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-Fluoro-4nitro-phenoxy)-6“methoxy-quinolin-7-ol as a pale white solid (2.74 g, 97.5% yield). ^]H 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, 1H), 7.55 (s, 1H), 4.03 (s, 3H); MS (El) for C_wHhFN₂O₃: 421 (M+H*).

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2020201638 05 Mar 2020 [0295] 5-[4-(2-Huoro-4-nitro-phenoxy)-6-methoxv-quinolin-7-vloxvmethyfl-hexahvdrocvclopentarclpyrrole-2-carboxvlic acid benzyl ester. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quiiiolin-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 5methanesulfonyloxymethyl-hexahydro-cyclopenta[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 NaSO*. The solvent was removed to yield 5- [4-(2Fluoro-4-mtro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester as a cream solid (3.7 g, 94% yield).

NMR (400 MHz, CDClj): 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 (EQ for C₃₂H_3OFN₃O₇: 588 (M+H¹).

Example 7

[0296] 4-(2-Fluoro-4-nitro-phenoxv)-6-methoxv-7-(octahvdro-cvclopenta[c]pmQl=5ylmethoxvl-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]hexahydrocyclopenta-[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, l.Oeq), 33% HBr in acetic acid (5 ml) and acetic acid (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-Fluoro-4-nitro-phenoxy)-6-methoxy-7(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 'HNMR (400 MHz, CDC1₃): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d,

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1H), 5.3 (d, 2H>, 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H),

1.68 (m, 2H); MS (El) for C24H24FN3O5: 454 (M+HQ.

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Example 8

[0297] 4Y2-FIuoro-4-nitro-phenoxy)-6-methoxv-7-(2-methvl-octahydrocvclopentalclDviTol-5-ylmethoxv)-quinoline. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Huoro-4-nitro-phenoxy)-6-methoxy-7-(octahydrocydopenta[c]pyrroI-5-ylmethoxy)-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)₃BH 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 mi). Removal of the DCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-FIuoro-4-nitro-phenoxy)-6methoxy-7-(2-methy]-octahydrocyclopenta-[c]pyrrol-5-ylmethoxy)-quinoline (0.9 g, 50% yield). ). ^JH NMR (400 MHz, CDCI3): 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) for C₂₃H_2SFN₃O_S: 468 (M+H⁺).

Example 9

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2020201638 05 Mar 2020 [0298] 3-Fluoro-4-[6-methoxv-7-(2~methyl-octahvdro-cvclopentafclpyrrol-5-vlmethoxy)quinolin-4-yIoxvl-phenvlamine. To a par hydrogenation reaction vessel was added 4-(2fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[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 3fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin4-yloxy]-phenylamine as an off yellow solid (0.78 g, 99% yield), *H NMR ¢400 MHz, CDC1₃); S.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, 1H), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (El) for C₂₅H_2SFN₃O₃: 438 (Μ+1Γ).

Example 10

[0299] l-i3-Fluoro-4-[6-methoxv-7-(2-methv]-octahvdiO-cvclopenta[c1pvrrol-5vlmethoxv)-quinolin-4-vloxvl-phenyB-3-phenylacetvl-thiourea. To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-[6-methoxy-7-(2-methyloctahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine (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 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified with a biotage system using an eluent EtOAc and 4% TEA (2L) then EtOAc, 4% TEA, 1% MeOH (IL). The solvent was removed to give l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5ylmethoxy)-quinolin-4-yioxy]-phenyl}-3-phenylacetyI-thiourea ¢0.5 g, 50% yield).

NMR (400 MHz, DMSO): 8.48 (d, 1H), 7.92 (dd, 1H), 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, 2H), 4.02 (s, 3H), 3.81 (m, 3H),

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2.87 (d, 2H), 2.73 (m, 4H), 2.53 (m, 1H), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS (El) for C34H35FN4O4S: 615 (M+H*).

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Example 11

[0300] 6-(6,7-Dimethoxy-quinolin-4-vloxv)-5-fluoro-benzothiazol-2-vlamine. 4-(6,7dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (l.OOg, 3.18mmol) was dissolved in AcOH (8.0ml), to which 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 stirring. 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 stirring. 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 H₂O. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids were filtered, washed with H₂O, and dried under high vacuum to give 6-(6,7dimethoxy-quinolin-4-yIoxy)-5-fluoro-benzothiazol-2-ylamine (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 Calcd for [M+H]⁺ 372.1, found 372,2

Example 12

[0301] N-[6-(6.7-Diniethoxv-quinolin-4-vloxv)-5-fluoro-benzothiazol-2-vl1-2-phenylacetamide. 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95mg,

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0.25mmol), Et₂N (0.10ml, 0.72mmol), phenylacetyl chloride (0.044ml, 0.33mmol), and THF (1.0ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (0.044ml, 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:H₂O (1.0ml) and the resulting solids filtered, washed with 1:1 AcCN:H₂O and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-

2- yl]-2-phenyl-acetamide (72mgs, 59%). 'H-NMR (400MHz, DMSO): 12.80 (s, IH), 8.54 (d, IH), 8.18 (d, IH), 7.91 (d, IH), 7.60 (s, IH), 7.45 (s, IH), 7.34 (m, 4H), 7.28 (m, IH), 6.60 (d, IH), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+H]⁺

490.1, found 490.0.

[0302] 5-[4-(4-Amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl] hexahydro-cycIopenta[c]pyrrole-2-carboxylic acid benzyl ester. 4-Amino-2-fluoro-phenol (1.53g, 12.0mmol) 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)-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid 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 with sat’d NaHCOs (3x), H₂O (lx), sat’d NaCl (lx), dried (Na₂SO4), and concentrated in vacuo to give crude 5-[4-(4-amino-2-fluoro-phenoxy)-6methoxy-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. ’H-NMR (400MHz, DMSO): 8.50 (s, IH), 7.48 (s, IH), 7.34 (m, 5H), 7.28 (m, IH), 7.02 (t, IH), 6.48 (dd, IH), 6.40 (dd, IH), 5.40 (br 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, IH), 2.10 (m, 2H),

1.30 (m, 2H). LC/MS Calcd for [M+H]⁺ 559.2, found 559.4.

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Example 14

[0303] 5-14-[2-Fluoro-4-(3-phenylacetYl-thioureido)-phenoxy1-6-methoxv-quinazolin“7yloxYmethvll-hexahvdro-cvclopentarclpvirole-2-carboxylic acid benzyl ester. Phenylacetyl chloride (2.65ml, 20.0mmol) 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-ammo-2-fluorophenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2carboxylic acid benzyl ester (5.6g, lOmmol) 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 NaHCQj (3x), H₂O (lx), sat’d NaCl (lx), dried (Na₂SO₄), and concentrated in vacuo. The resulting oil was purified by flash chromatography (3:1 EtOAc:hexanes) to give 5-{4-[2-fluoro-4-(3-phenylacetyI-thioureido)-phenoxy]-6methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.61g, 49%) as a dark brown foam. *H-NMR (400MHz, DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, 1H), 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, 2H), 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, 2H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]⁺ 736.2, found 736.0.

Example 15

33% HBW AcOH

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2020201638 05 Mar 2020 [0304] 1- {3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)qumazoIin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea, dihydrobromide salt. 5-{4-[2Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid 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 Et₂O (1000ml) and the resulting solids filtered, washed with Et₂O, and dried under high vacuum to give the l-{3fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazoIin-4yloxy]-phenyl)-3-phenylacetyl'thiourea, dihydrobromide 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, 2H), 2.83 (m, 2H), 2.45 (m, 1H), 2.15 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]⁺ 602.2, found 602.1.

Example 16

Formaldehyde

Na(OAc)₃BH

[0305] l-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5ylmethoxy)-quinazolin-4-yloxy]-phenyl} -3-phenylacetyl-thiourea. 1- {3-Fluoro-4-[6methoxy-7-(octahydro-cycIopenta[c]pyrrol-5-ylmethoxy)-quinazoIin-4-y]oxy]-phenyl}-3phenylacetyhthiourea, dihydrobromide salt (3.4g, 4.5mmol) was dissolved in in a combination of AcCN (100ml), H₂O (30ml), and AcOH (2.45ml). Formaldehyde (37% in H₂O, 855ml, 10.5mmol) 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 NaHCOa and then concentrated in vacuo. The resulting aqueous mixture was extracted with CH₂C1₂ (3x). The combined extractions were washed with sat’d NaHCOa (lx), sat’d NaCl (lx), dried (Na₂SO4), and concentrated in vacuo. The

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2020201638 05 Mar 2020 resulting residue was purified by flash chromatography (100% EtOAc, followed by 4% Et₃N in EtOAc) to give the free base of l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydrocyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl]-3-phenylacetyl-thiourea (1.13g, 40%). The free base was converted to the HC1 salt by dissolving the free base in a mixture of 1:1 AcCN:H₂O containing 2-3 equivalents of 1 N HC1 and lyophilizing to give the HC1 salt of l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cycIopenta[c]pyrrol-5ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea as a white solid. ’HNMR (400MHz, 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, 5H), 2.35 (m, 1H), 2.15 (m, 2H), 1.45 (m, 2H). LC/MS Calcd for [M+H]⁺ 616.2, found 616.2. Alternatively, the free base was converted to the acetate salt by dissolving the free base in a mixture of MeOH and CH₂CI₂ to which was added 3 equivalents of acetic acid. The resulting mixture was concentrated in vacuo and the resulting residue lyophilized from 1:1 AcCN:H₂O to give the acetate salt of l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydrocyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea as a white solid. ^-NMR (400MHz, CDC1₃): 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+H]⁺ 616.2, found 616.2.

Example 17

[0306] (6,7-Dimethoxv-quinazolin-4-vI)-(2-fluoro-4-nitro-phenvl)-amine. A mixture of 4chIoro-6,7-dimethoxy-quinazoline (548mg, 2.4nunol), 2-fluoro-4-nitro-phenylamine (392mg, 2.5mmol), AcCN (10ml), and conc’d HC1 (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-dimethoxyquinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673mgs, 80%). ^-NMR (400MHz,

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DMSO): 12.18 (br 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), 4.02 (s, 3H). LC/MS Calcd for [M+H]⁺ 345.1, found

345.4.

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Example 18

[0307] N¹-(6,7-Dimethoxv-quinazolin-4-vl)-2-fluoro-benzene-l,4-diaimne. (6,7Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (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 Hz on a Parr hydrogenator at 40psi for 3hrs. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The resulting residue was triturated in EtOAcZEtaO. The resulting solids were filtered, washed with Et₂O, and dried under vacuum to give N¹ -(6,7dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-l,4-diamine (398mg, 65%) which was used in the next reaction without further purification. *H-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] 1-(4-(6,7-Dimethoxv-quinazolm-4-ylamino)-3-fluoro-iJhenyll-3-phenvlacetyIthiourea. Phenylacetyl chloride (0.18ml, 1.4mmol) and AgSCN (338mg, 2.0mmol) were

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2020201638 05 Mar 2020 combined in dry 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 N’-fbJ-Dimethoxyquinazolin-4-yl)-2-fluoro-benzene-l_!4-diamine (398mg, 1.3mmol) in 1:1:2 EtOH:toluene: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 the filtrate concentrated in vacuo to give l-[4-(6,7-dimethoxy-quinazolin-4-ylamino)-3fluoro-phenyl]-3-phenylacetyl-thiourea (105mg, 17%). ^lH-NMR (400MHz, DMSO):

12.53 (s, 1H), 11.86 (s, 1H), 11.44 (brs, 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). LCZMS Calcd for [M+H]*

492.1, found 492.4.

Example 20 [0309] 6.7-Dimethoxv-4-(5-nitro-Dyridin-2-yloxy)-quino]ine. To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-l.H-quino]in-4-one (1.8 g, 8.77 mmol, 1.0 eq.), anhydrous acetonitrile (90 niL) and CS2CO3 (3.13 g, 9.65 mmole, 1.1 eq.). The reaction mixture was stirred at room temperature for 5 minutes. Then, 2-C1-5nitropyridine (1.53 g, 9.65 mmol, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours. The 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 done on Biotage with solvent system EtOAc 100%. The collected pure fractions were concentrated and dried on high vacuum overnight to give 6,7-dimethoxy-4-(5-nitropyridin-2-yloxy)-quinoline as a yellow foam solid (0.902 g, 31.4% yield). NMR (400

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MHz, CDC13): 9.08 <d, 1H), 8.74 (d, 1H), 8.60 (dd, 1H), 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 C₁₆Hi₃N₃O₅: 328 (Μ+ΙΓ).

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[0310] 6-(6,7-Dimethoxy-2fluinolm-4_;ylQ.xv)-pvridin-3-vlamine· To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)quinoline (0.46 g, 1.41 mmol, 1.0 eq.), and THE (10 mL), MeOH (4 mL), DMF (2 mL), and TEA (2 mL). The 6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline 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 filled 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-ylaniine as a light brown solid (0.411 g, 98.1%). *H NMR (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 (El) for Ci₆H₁₅N₃O₃: 298 (M+HQ.

Example 22

[0311] 146-(6,7-Dimethoxy-quino]in-4-yloxy)-pvridin-3-yll-3-phenvlacetyI-thiourea. To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl

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2020201638 05 Mar 2020 isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 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 1-(6-(6,7-dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 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 (El) for C₂₅H₂₂N4O₄S: 475 (M+Hj.

Example 23

1. CICOCOOEt, Et₃N, CH₂Ci₂

2, phenethylamine, °C [0312] N-r4-(6,7-Dimethoxy<tuinoIin-4-vloxv)-3-fluoro-phenvll-N'-phenethvl-oxalamide. To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fIuoro-phenylamine (263 mg, 0.83 mmol) and Et₃N (0.223 ml, 1.67 mmol) in CH3CI2 (10 mL) was added dropwise a solution of ethyl oxalyl chloride in CH2CI2 (1 mL), The stirring was continued for 0.5 h at rt. The reaction mixture was then washed with aqueous saturated NaHCO₃ and dried over NaSOiRemoval of the solvent gave the crude 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-dimethoxy-quino!in-4-yloxy)-3fluoro-phenyl]-N’-phenethyl-oxalamide (310 mg, 76%). *H NMR (400 MHz, CDCI3) δ

9.35 (br s, 1 H), 8.70 (d, J = 6.3 Hz, 1 H), 7.83 (dd, J = 11.9, 2.5 Hz, 1 H), 7.60-7.54 (m, 2 H), 7.43 (s, 1 H), 7.38-7,32 (m, 3 H), 7.30-7.20 (m, 4 H), 6.41 (d, J= 5.3 Hz, 1 H), 4.07 (s, 3 H), 4.05 (s, 3 H), 3.67 (dt, J = 7.0,7.0 Hz, 2 H), 2.92 (t, J - 7.2 Hz, 2 H). LC-MS: 490 [M+H]⁺

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Example 24

[0313] N-{3-FluoiO-4-r6-methoxv-7-(l-methvl-piperidin-4-ylmethoxv)-quinolin-4vloxyl-phenyll-N-phenethyl-oxalamide, To a flask containing 7-benzyloxy-4-(2-fluoro-4nitro-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 rt; at this time, a large amount of precipitate formed. The crude product was filtered, washed with Et2O and dried in air, giving 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 92% yield).

[0314] To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMF (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4piperidinemethanol 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 (hexanes:EtOAc = 1:3). The resulting product, 4-[4-(2-fIuoro-4nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-l-carboxylic acid tertbutyl ester, was obtained as a solid (556 mg, 56%).

[0315] To a solution of 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7yloxymethyl]-piperidine-l -carboxylic acid tert-butyl ester (305 mg, 0,58 mmol) in CH2CI2 (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 NaHCO₃. 15% j 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-(lmethyl-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-4ylmethoxy)-quinoline (240 mg, 0.54 mmol) in EtOH (20 mL) was added 10% Pd/C (50

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2020201638 05 Mar 2020 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 3fluoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenylamine (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-ylmethoxy)quinolin-4-yloxy]-phenylamine (66 mg, 0.13 mmol) and Et₃N (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 CH₂C1₂ and washed with sat. aqueous NaHCO₃. After dried over MgSC>4 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[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl)-N¹-phenethyloxalamide (52 mg, 68% yield). ‘H NMR ¢400 MHz) δ 9.38 (br s, 1 H), 8.48 (d, J = 5.2 Hz, 1 H), 7.83 (dd, J = 11,7, 2.6 Hz, 1 H), 7.59 (t, J = 6.2 Hz, 1 H), 7.55 (s, 1H), 7.40-7.20 (8 H), 6.39 (d, J = 5.3 Hz, 1 H), 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-phenvlcarbamovl)-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-1,1-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-fluoroaniline (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

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2020201638 05 Mar 2020 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-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid as a white solid (23.71 g, 65.18%). ³H NMR ¢400 MHz, CDjOD): 7.57-7.53 (m, 2H), 7.05-7.00 (m, 2H) 1.46-1.43 (m, 2H), 1.401.37 (m, 2H).

Example 26

[0319] 1 -(4-Fluoro-phen ylcarbamoyll-cyclobutanecarboxylic acid. To a mixture of cyclobutane-1,1-dicarboxylic acid (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 stirring 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-fIuoroaniline (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-phenylcarbamoyI>

I cyclobutanecarboxylic acid as a light pink solid (5.75 g, 34.9%). ’H NMR (400 MHz, CDClj w/ldrop CD₃OD): 7.53-7.48 (m, 2H), 7.06-7.00 (m, 2H), 2.81-2.63 (m, 4H), 2.142.02 (m, 2H).

Example 27

HO

O O [0320] l-BenzylcmbamovLcvclopropanecarboxyliC—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-1,1-dicarboxylic acid (5.0 g, 38.4

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2020201638 05 Mar 2020 mmol, 1.0 eq.) in anhydrous THF (50 mL) under nitrogen was added drop wise triethylamine (3.89 g, 38.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0°C, followed by the addition of thionyl 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 benzylamine 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-Benzylcarbamoyl-cyclopropanecarboxylic acid as a white solid (4.39 g, 52.15%). *H NMR ¢400 MHz, CDC1₃): 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.32-7.26 (m, 3H), 1.82-1.70 (m, 4H).

Example 28 [0321] 1-Phenvlcarbamovl-cvcloDroDanecarboxvlic acid. 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, L0 eq.) with stirring for 30 minutes at 0°C, followed by the addition of thionyl chloride (4.84 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 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-phenylcarbamoylcyclopropanecarboxylic acid as a white solid (5.08 g, 60.8%). NMR (400 MHz, CDC1₃): 10.50 (br s, 1H), 7.56-7.54 (m, 2H), 7.35-7.31 (m, 2H), 7.15-7.10 (m, 1H), 1.941.91 (m, 2H), 1.82-1.79 (m, 2H).

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Example 29

(COCi)₂, DMF

[0322] 7-Benzvloxv-4-chloro-6-methoxv-ouinoline. Dry DMF (8.0ml, 103mmol) was dissolved in dry CHCI3 (40ml) and cooled in an ice bath. Oxalyl chloride (9.0ml, 105mmol) in CH₂C1₂ (10ml) was added dropwise with stilling at 0C. When the bubbling had ceased, this solution was added slowly to an ice-cold solution of 7-benzyloxy-6methoxy-3H-quinazolin-4-one (lO.Og, 35.4mmol) in dry CHC1₃ (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 CHCI3 extractions were washed with sat’d NaCl (lx), dried (Na^O^ and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 100%EtOAc) to give 7-benzyloxy-4chloro-6-methoxy-quinoline (5.1 Ig, 48%). LC/MS Calcd for [M+H|⁺ 301.1, found 301.1.

Example 30

[0323] Cvclopropane-l .1-dicarboxvlic acid [3-fluoro-4-(7-hvdroxy-6-methoxy-quinolin4-vloxv)-phenyl1-amide(4-fluoro-phenyl)-amide. To a solution of cyclopropane-1,1dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fhioro-phenyl] -amide (4-fluoro-phenyl)-amide (1.18g, 2.0 mmol) in EtOH (20 mL) was added 1,4cyclohexadiene (2.0 mL, 20 mmol) and 10% Pd/C (300 mg). The reaction mixture was then heated to reflux and the stilling was continued for 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).

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The EtOAc solution was washed with water, and dried over Na₂SO₄. 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.

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Example 31 [0324] N-(4-117-1 [S^fDiethylaminolethvlIoxY) -6-(methvlox v)qumolin-4-vi1oxv) -3fluorophenvl)-N^,-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide· To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)phenyl]-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 PPh₂ (141 mg, 0.54 mmol).

DIAD (109 mg, 0.54 mmol) was then added as a CH₂C1₂ (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 (MgSO4), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-([2-(diethylamino)ethyl]oxy}-6-(metliyloxy)quinolin4-yl] oxy} -3-fluorophenyI)-N'-(4-fluoro-phenyl)cyclopropane-l, 1 -dicarboxamide (74 mg, 34%) as a pale yellow solid. ^]H NMR (400 MHz, DMSO-c(_e) δ 10.40 (br s, 1 H), 10.02 (br s, 1 H), 8.47 (d, J = 5.2 Hz, 1 H), 7.91 (br d, J = 13.9 Hz, 1 H), 7.54-7.52 (m, 2 H), 7.55-

7.50 (m, 1 H), 7.52 (s, 1 H), 7.50-7.40 (m, 1 H), 7.41 (s, 1 H), 7.16 (br t, J - 8.7 Hz, 2 H), 6.41 (br d, J-4.7 Hz, 1 H), 4.18 (t, J- 6.0 Hz, 2 H), 3.94 (s, 3 H), 2.87 (br t, J = 6.3 Hz, 2 H), 2.59 (q, J = 7.1 Hz, 4 H), 1.47 (br s, 4 H), 1.00 (t, J = 7.0 Hz, 6 H).

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BnBr, K₂CO₃

[0325] l-(4-Benzvloxv-3-methoxvphenvl)ethanotie. A solution of 4-hydroxy-3methoxyacetophenone (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 the resultant solid was filtered. This material was washed with water and dried to give l-(4-benzyloxy-3methoxyphenyl)ethanone (61 g, 99 %).

[0326] l-(4-Benzvloxv-5-methoxv-2-nitrophenyl)ethanone. A stirred solution of 1-(4benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) in dichloromethane (750 mL) was cooled to 0 °C. Nitric acid (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 acid (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 Na₂SO4 and concentrated. The crude mixture was recrystallized from DMF to give l-(4-benzyIoxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 60 %). NMR (400 MHz, CDC1₃): δ 7.65 (s, LH), 7.45-7.33 (m, 5H), 6.74 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H).

[0327] l-fZ-Amino^-benzyloxv-S-methoxyphenvDethanone. A mixture of iron powder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol), l-(4-benzyloxy-5-methoxy-2nitrophenyl)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 ethy] acetate. The combined organic layers were washed with water and brine. The organic layer was

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2020201638 05 Mar 2020 dried over NaaSCXt and concentrated to afford l-(2-amino-4-benzyloxy-5methoxyphenyDethanone (29.3 g, 90 %). NMR (CDCh): δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.16 (br 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-Benzyloxv-6-methoxyquinolin-4-ol. Sodium ethoxide (74.8 g, 1.1 mol) was added to a solution of l-(2-amino-4-benzyIoxy-5-methoxyphenyl)ethanone (29.3 g, 108 mmol) in DME (700 mL) and stirred for 30 min. Ethyl formate (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 LC/MS). After the reaction was complete, the mixture was diluted with water (40 mL) and acidified to neutral pH with IM HC1. The solid was filtered, washed with water and dried to afford 7-benzyloxy-

6-methoxyquinolin-4-ol (22 g, 72%). NMR (400 MHz, CDCI3): δ 10.7 (br s, 1H), 7.70 (s, 1H), 7.49-7.46 (t, 1H), 7.43-7.41 (br 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).

[(1329] 7-Benzyloxv-4-chloro-6-methoxvquinoline. Phosphorus oxychloride (300 mL) was added to 7-benzyloxy-6-methoxyquinoIin-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-benzyIoxy-4-chloro-6-methoxyquinoline as a pale brown solid (40.2 g, 95%). *H NMR (400 MHz, de-DMSO): δ 8.61 (s, 1H), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H); ¹³C NMR (100 MHz, rfc-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; LC/MS (M+H = 300).

Example 33

OSOgCPg

Bn [0330] Trifluoromethanesulfonic acid 7-benzvloxv-6-methoxv-quinolin-4-vl ester To a dry 2L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g, 267 mmol) was added DCM (1 L), 4-dimethylaminopyridine (3.28 g, 26.8 mmol) and 2,6-lutidine (62 mL,

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534 mmol). The mixture was cooled to -20°C by controlled addition of dry ice to an acetone bath. Trifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added dropwise to the cooled solution with magnetic stirring over 25 minutes. After addition was complete, th© 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. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinoIin-4-yl ester as a light brown solid (92.2 g, 83.8%). NMR (400MHz, DMSO, dg): 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-dimethoxvquinolin-4-yl ester from 6.7Dimethoxv-quinolin-4-ol. To a dry IL 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. Trifluoromethanesulfonyl 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 (1 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 6, 7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). ^lH 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.

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Example 35

[0332] l-Benzvloxy-2-fluoro-4-nitrobenzene. A solution of 2-fluoro-4-nitrophenol (50,0 g, 318 mmol), benzyl bromide (42 mL, 350 mmol) and potassium carbonate (66,0 g, 478 mmol) in DMF (200 mL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured over ice and the resultant solid was filtered. This material was washed with water and dried to give l-benzyloxy-2-fluoro-4-nitrobenzene (75.0 g, 95 %).

NMR (400 MHz, 4-DMSO): 6 8.19-8.11 (m, 2H), 7.53-7.37 (m, 6H), 5.36 (s, 2H); ¹³C NMR (100 MHz, ^-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 (cm¹): 1499, 1346,1279, 1211,1142,1072, 986, 885, 812,789, 754, 742,700,648, 577.

[0333] 4-Benzyloxy-3-fluoroaniline. 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 %). M NMR (400 MHz, <4-DMSO): 6 7.43-7.26 (m, 5H), 6.90 (dd, 1H), 6.49 (dd, 1H), 6.34 (m, 1H), 4.99 (br s, 2H), 4.98 (s, 2H); ¹³C NMR (100 MHz, d₆-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] Ethyl r(4-benzvIoxv-3-fluoroDhenyl)aminol (oxo)acetate. Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of 4-benzyloxy-3-fluoroaniline (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 [(4201

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2020201638 05 Mar 2020 benzyloxy-3-fluorophenyl)amino](oxo)acetate (58.4 g, 100 %). NMR (400 MHz, d&DMSO): δ 10.87 (s, IH), 7.73 (d, IH), 7.69 (d, IH), 7.53 (d, IH), 7.46-7.40 (m, 4H), 5.17 (s, 2H), 4.31 (q, 2H), 1.31(1, 3H); IR (cm'¹): 1732, 1705, 1558, 1541, 1508, 1456, 1273, 1186,1167,1101, 999, 858, 741,694; LC/MS (M+H = 318).

[0335] AM4-Benzvloxv-3-flouroDhenvn-#’“(2-T)henylethvl)etbanediamide· Phenethylamine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3fluorophenyl)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 A-(4-benzyloxy-3-flourophenyl)-N^,-(2-phenylethyl)ethanediamide (100 g, 99 %). *H NMR (400 MHz, i^-DMSO): δ 10.72 (br s, IH), 9.05 (m, IH), 8.78 (m, IH), 7.77 (m, IH), 7.59 (m, IH), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm’ *): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H = 393).

[0336] N-(3-Fluaro-4-hvdroxvphenyD-?/^,-(2-phenvlethvl)ethanediamide. A mixture of N(4-benzyloxy-3-flourophenyl)-?/’-(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 A-(3-fluoro4liydroxyphenyl)-A^?’-(2-phenyIcthyl)ethanediamide as a slightly yellow solid (30.6 g, 99 %yield). *H NMR (400 MHz, ^-DMSO): 5 10.60 (s, IH), 9.02 (t, IH), 7.70 (d, IH), 7.47 (d, IH), 7.32-7.20 (m, 3H), 6.91 (t, IH), 3.43 (m, 2H), 2.81 (m, 2H); ¹³C NMR (100 MHz, dfi-DMSO): δ 160.5, 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

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2020201638 05 Mar 2020 [0337] l-Benzyloxv-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 for 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-nitrobenzene was 95g ¢83%). (Note: the product contains ca. 5% of 3,4-Bis-benzyloxynitrobenzene, which is carried into the next step without further purification.) NMR (400MHz, CDC1₃): δ 8.04 -8.00 (m, 2H), 7.43-7.37 (m, 5H), 7.08 (t, 1H), 5.26 (s, 2H).

[0338] 4-Benzvloxy-3-fluoro-nlienvlamine. A mixture of l-benzyloxy-2-fluoro-4-nitrobenzene (44g, 178 mmol), toluene ¢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-bcnzyloxy-3-fluoro-phenylamine as an oil (33.7 g, 87%). ^lH NMR (400MHz, CDC1₃): δ 7.41-7.29 (m, 5H), 6.79 (t, 1H), 6.45 (dd, 1H), 6.14 (dd, IH), 5.02 (s, 2H), 3.50 (s, 2H). LC/MS: (M+l) 218.

[0339] Cyclopropane-Ll-dicarboxvlic acid (4-benzvloxv-3-fluoro-phenyl)-amide. (4fluoro-phenvD-amide. To a stirred mixture of 4-benzyloxy-3-fluoro-phenylamine (155.3 mmol, 33.7 g), l-(4-fluoro-phenyIcarbamoyl)-cyclopropanecarboxylic acid (170.8 mmol,

38.13 g) and anhydrous dichloromethane (600 ml) was added EDCI (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. The precipitate was filtered and air dried to give the 1^st 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 2^nd crop of product. The combined yield of cyclopropane-1,1dicarboxylic acid (4-benzyloxy-3-fluoro-phenyl)-amide (4-fluoro-phenyl)-amide was 64.5

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2020201638 05 Mar 2020 g (98%). *H NMR (400MHz, CDC1₃): 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, 1H), 5.13 (s, 2H), 1.65 (s, 4H). LC/MS: ( M+l) 423.

[0340] Cyclopropane-Ll-dicarboxylic acid (3-fluoro-4-hydroxy-nhenyl)-amide (4-fluorophenvil-airtide. A mixture of cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-3~fluorophenyl)-amide (4-fluoro-phenyI)-amide (152.8 mmol, 64.5), ethanol (800 ml), cyclohexadiene (764 mmol, 71 ml), and 10% Pd/C (2 g) was refluxed for 2 hours. 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 I^s' crop of product. The filtrate was concentrated and stirred in DCM (150 ml) to give another precipitate, which was then filtered to give a 2^nd crop of product. The combined yield of cyclopropane-1,1dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyI)-amide was 43 g (85%) in 95% purity by HPLC (UV @ 254 nm). *H NMR (400MHz, DMSO-D6): δ 10.07 (br s, 1H), 9.92 (br s, 1H), 9.64 (br s, 1H), 7.64-7.60 (m, 2H), 7.55-7.51 (m, 1H), 7.17-7.12 (m, 3H), 6.89-6.84 (t, 1H), 1.43 (s,4H). LC/MS: (M+l) 333.

Example 37

,10% Pd/C

---------»

EtOH, reflux, 93% [0341] Cyclopropane-Ll-dicarboxylic acid (4-benzvloxy-phenyl)-amide—(4-fluoro-, phenvD-amide. To a 0 °C suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220 mmol) in CH₂C1₂ (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 2-4 h until the reaction was complete. CH₂C1₂ was removed under reduced pressure. H₂O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H₂O, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCO₃ solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night

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2020201638 05 Mar 2020 on a lyophilizer, affording cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)amide (4-fluoro-phenyl)-amide (75.8g, 95% yield) as an off-white solid.

[0342] Cvclopropane-U-dicarboxvlic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)amide. To a refluxing mixture of cyclopropane-l,l-dicarboxylic acid (4-benzyloxyphenyl)-amide (4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Pd/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 the reaction was complete. The mixture was cooled to it, filtered through celite, and wished with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHC1₃ (200 mL). The resulting suspension was stirred for 1.5 nun at rt. The solid was filtered, and dried in the air to give cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxyphenyl)-amide (34.4 g, 95%, yield).

Example 3S

EDCI, DMA, rt

88%

[0343] Alternate Synthesis of Cyclopropane-1,1-dicarboxvlic add (4-fluoro-phenyll: amide (4-hvdroxy-phenvl)-amide. To a solution of 4-ammophenol (2.93 g, 26.9 mmol) and l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (5.00 g, 22.4 mmol) in DMA (30 mL) was added EDCI ¢5.15 g, 26.9 mmol). The mixture was stirred vigorously until the reaction was complete (~ 3 h). With vigorous stirring, the reaction mixture was then poured into a flask containing sat. aqueous NaHCOs solution (200 mL). The stirring was continued for 1 h. The resulting suspension was then filtered. The solid was washed with water (50 mL), chloroform (50 mL) and dried under vacuum, affording l-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid (6.22g, 88% yield) as a powder (>95% purity by HPLC and NMR).

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Example 39

[0344] N- {4-[(7-Benzyloxy-6-methoxyquinolin-4-vDoxy] -3-fluorophenyl phenyleth vllethanediamide. A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (30 g, 100 mmol), AH3-fluoro-4-hydroxyphenyl)-N’-(2-phenylethyl)ethanediamide (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 N-{4-[(7-benzyloxy-6-niethoxyquinolin-4-yl)oxy]-3-fluoroplienyl}-A’(2-phenylethyl) ethanediamide (34 g, 61 %). ^NMR (400 MHz, dg-DMSO): δ 11.05 (s, 1H), 9.15 (s, 1H), 8.47 (d, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.56-6.36 (m, 13H), 6.46 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 3.47 (q, 2H), 2.86 (t, 2H); ¹³C NMR (100 MHz, DMSO): δ 160.5, 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; 1R (cm^-1): 1657,1510,1481,1433, 1416,1352,1310,1252,1215,1609,986, 891, 868, 850, 742,696; LC/MS (M+H = 566).

[0345] N-(3-Fluoro-4-r(7-hvdroxv-6-methoxyquinolin-4-yl)oxvlphenyl]-AU(2_z phenyleth vfiethanediamide. To a solution of 7V-{4-[(7-benzyloxy-6-methoxyquinolin-4206

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2020201638 05 Mar 2020 yl)oxy]-3-fluorophenyl}-N’-(2-phenylethyl)ethanediannde (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 Parr 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 N-{3-fiuoro-4-[(7hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N’-(2-phenylethyl)ethanediamide as an offwhite solid (25.6 g, 95 %). NMR (400 MHz, dg-DMSO): 5 11.06 (s, 1H), 10.25 (br 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); TR (cm-1): 1666, 1624,1585,1520,1481, 1427, 1377,1256,1211,1194,1022, 880, 850, 839, 802, 750,700; LC/MS (M+H = 476).

[0346] N-i3-Fluoro-4-H6-methoxv-7-(3-morphoHn-4-vlpropoxy)quinolin-L vlloxv)phenvl)-N^,-(2-phenvIethyl)ethanediamide. A solution of N-(3-fluoro-4-[(7hydroxy-6-methoxyquinolin-4-y 1) ox yjphenyl} -N ’ - (2-phenylethyl)ethanedi aim de (25.6 g, 54 mmol), N-(3-chloropropyl)morpholine 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 the 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 HC1 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 N-(3-fluoro-4-{[6-methoxy-7-(3-morphoIin-4ylpropoxy)quinolin-4-yl]oxy}phenyl)-N’-(2-phenylethyI)ethanediamide as a yellow solid (24 g, 74 %). NMR (400 MHz, CDC1₃): δ 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, 4H), 2.13 (m, 2H); ¹³C NMR (100 MHz, rfs-DMSO): δ 160.1, 160.0, 159.5, 155.2, 152.7, 152.6, 150.2, 149.5, 147.1,

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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 (cm¹): 1655, 1506, 1483, 1431, 1350, 1302,

1248,1221, 1176, 1119, 864, 843, 804,741, 700; LC/MS (M+H = 603).

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Example 42

[0347] Cvclopropane-Ll-dicarboxvlic acid r4-(7-benzvloxv-6-methoxy-guinqlin-4_z vloxv)-3-fluaro-phenvll-amide (4-fluoro-phenyD-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 trifluoromethanesulfonic acid 7-benzyloxy-6-methoxyquinolin-4-yl ester (1.87 g, 4.5 mmol) was added dry 2,6-lutidine (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 _r 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 1 N HC1. The crude product precipitated as the HC1 salt, which was filtered and washed with EtOAc and H₂O (88% purity by analytical HPLC). The HC1 salt was free-based with saturated aqueous NaHCO₃ solution. Further purification by column chromatography (hexans:EtOAc = 1:4) gave cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3fluoro-phenyl]-amide (4-fluoro-phenyl)-annde as an off-white solid (1.3 g, 48% yield. H NMR (400 MHz, DMSO, d₆): 10.41 (s, IH), 10.02 (s, IH), 8.48 (d, IH), 7.92 (dd, IH), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43 (d, IH), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for [M+H]* 596.2, found 596.3.

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Example 43

[0348] Cyclopropane-1,1-dicarboxylic acid r3-fluoro-4-(7-hydroxv-6-methoxv-quinolm4-yloxy)-phenyH-amide (4-fluoiO-plienyl)-amide. To a solution of the cyclopropane-l,ldicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-pheny[)-amide (22.4 g, 37.6 mmol) in EtOH (340 mL) was added 1,4cyclohexadiene (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: H2 gas is released from 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 MgSO₄ and concentrated m vacuo. Cyclopropane- 1,1-dicarboxylic acid [3^Lfluoro-4~(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluorophenyl)-amide was obtained as a yellow solid (17.3 g, 91.1% yield), which were carried on to the next reaction without further purification. ^!H NMR (400 MHz, DMSO, d6):

10.39 (s, 1H), 10.15 (s, 1H), 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, 1H), 7.14 (m, 2H), 6.33 (d, 1H), 3.95 (s, 3H), 1.47 (m, 4H). LC/MS Calcd for [Μ+ΗΓ 506.2, found 506.3. Anal. HPLC: 99.4% pure.

Example 44

[0349] A-r3-fluoro-4-({6-(methvloxv)-7-r(3-morpholin-4₌yIpropvl)oxylquinolin-4vl 1 oxvlphenvll -N-(4-fluorophenyI)c yclopropane-1.1-dicarboxamide, To a mechanically stirred slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide ¢16.6 g, 32.8 mmol) and

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2020201638 05 Mar 2020 potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4-(3chloropropyl)-morpholine 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% Li Cl (aq.) (3X) and brine (IX) followed by drying over MgSO4 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 NHj/MeOH (95.5.0.5), 3) DCM:MeOH:7N NH3/MeOH (95:5:0.5); 4) DCM:MeOH: 7N NH₃/MeOH (93:8:1)], affording N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4yl}oxy)phenyl]-N'-(4-fluorophenyI)cyclopropane-l,l-dicarboxamide 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] Cyclopropane-1,1 -dicarboxvlic acid [4-(7-benzyloxv-6-methoxv-quinazolin-4yloxv)-3-fluoro-phenvll-amide ('4-fluoro-phenvl)-amide: A mixture of 7-benzyloxy-4chloro-6-methoxy-quinazoline (5 g, 16.67 mmol), cyclopropane-1,1-dicarboxylic acid (3fluoro-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 crude was purified on silica get column eluting with 30% acetone in hexanes to yield cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6210

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76%). NMR (CDC1₃): 8.64 (1H, br. s), 8.55 (1H, s), 8.33 (1H, br. s), 7.74-7.71 (1H, dd), 7.54 (1H, s), 7.48-7.33 (8H, m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2H, s),

4.06 (3H, s), 1.77-1.74 (2H, m), 1.63-1.61 (2H, m).

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Example 46 [0351] Cyclopropane-l,l-dicarboxylic_____acid r3-fluoro-4-(7-hydroxy-6-methoxvquinazolin-4-vloxy)-phenvll-amide (4-fluoro-phenyl)-amide. To a mixture of cyclopropane-1,1 -dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3fluoro-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 acid [3-fluoro-4-(7-hydroxy-6-methoxyquinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (6.1 g, 95% yield). NMR (dmso-d6): 10.86 (1H, br. s), 10.34 (1H, br. s), 10.04 (1H, br, s), 8.46 (1H, s), 7.84-7.80 (1H, dd), 7.66-7.62 (2H, m), 7.55 (1H, s), 7.47-7.45 (1H, m), 7.41-7.37 (1H, m), 7.24 (1H, s), 7.18-7.13 (2H, t), 3.98 (3H, s), 1.46 (4H, s).

Example 47 [0352] N-r3-Huoro-4-({6-(methvloxv)-7-r(3-morpholin-4z.vlpropyl)oxvlguinazolin-4yl) oxv)phenvl1-N^,-i4-fluoiophenyl)cvclopropane-1,1 -dicafboxamide. To a mixture of

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2020201638 05 Mar 2020 cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3hydroxypropyl)morpholine (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). The mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the crude mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dichloromethane to give N-[3-fluoro-4-({6(methyloxy)-7-[(3-morpholin-4-yIpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N'-(4fluorophenyl)cyclopropane-l,l-dicarbox-amide (890 mg, 47% yield). 1HNMR (400MHz, DMSO-d6): d 10.36 (br 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), 3.99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]⁺ 634.2, found 634,3.

Example 48

[0353] N-(4-H6.7-bis(methyloxv)quinolin-4-vlloxy)phenyl)-N'-(4-fluorophenvl)cvclo>ane-1,1 -dicarboxamide. To a solution of cyclopropane-1,1-dicarboxylic acid (4fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6lutidine (50 mL) was added trifluoromethanesulfonic acid 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 on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 ml.), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAchexanes, affording N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)-N’-(4fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). ’H NMR (400 MHz, dgDMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H),

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7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS:

M+H= 502.

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Example 49

[0354] 4.7-Dichloroquinoline. Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinoline 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 NaHCOa (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79g, 88.5% yield).

Example 50

[0355] 4-Γ4-(2-ΡΙοογο-4-( [l-(4-fluoro-phenylcarbaniovl)-cvclopropanecarbonyll-amino)phenoxv)-6-methoxv-quinazolin-7-yloxvmethvfl-piperidine-l-carboxylic acid tert-butyl ester. Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4methanesulfonyloxymethyl-piperidine-l-carboxylic acid 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-methanesulfonyloxymethylpiperidine-1-carboxylic acid 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

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2020201638 05 Mar 2020 was allowed to cool to room temperature, then diluted with EtOAc and washed with H₂O (3x), sat’d NaCl (lx), dried (Na₂SO₄) 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-fluoro-4-{[l-<4-fluoro-phenylcarbamoyl)cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-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] Cvclopropane-Ll-dicarboxvlic acid {,3-fluoro-4_:f6-methoxy-7-(piperidin_4_ vlmethoxy)-quinaz;olin-4-vloxv1-phenyl Iramide (4-fluoro-phenvD-amide, TFA salt 4-[4(2-Huoro-4-{[l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6methoxy-quinazolin-7-yloxymethyl]-piperidine-l-carboxylic acid tert-butyl ester (273 mg, 0.39 mmol) was dissolved in CH₂C1₂ ¢8 ml) to which was added TFA (8 ml) and the mixture stirred at room temperature for Ihr. The reaction mixture was concentrated in vacuo and the resulting oil triturated with Et₂O. The resulting solids were filtered, washed with Et₂O and dried under high vacuum to give cyclopropane-1,1-dicarboxylic acid {3fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-amide (4fluoro-phenyl)-amide, TFA salt (222 mg, 80%). LC/MS Calcd for [M+H]⁺ 604.2, found

604.3.

Example 52

[0357] N-f3-Fluoro-4-i(6-(methvloxy)-7-{r(l-methvlpiperidin-4-yl)methYl]oxy}fluim azolin-4-vDoxvlphenvl I-N^,-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide.

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Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy]-phenyI) -amide (4-fluoro-phenyI)-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 CH₂C1₂ (3x). The combined CH₂C1₂ extractions were washed with sat’d NaCl (lx), dried (Na₂SOi) and concentrated in vacuo. The resulting residue was dissolved in a minimum of 1:1 dioxane:EtOAc to which was added 4M HC1 in dioxane (1-2 ml). The resulting solids were filtered, washed with EtOAc and dried under high vacuum to give N-{3-fluoro-4-[(6-(methyloxy)-7-{[(lmethylpiperidin-4-yl)methyl]oxy} quinazolin-4-yl)oxy] phenyl} -N’-(4fluorophenyi)cyclopropane-l,l-dicarboxamide, HCI salt ¢167 mg, 83%), 1HNMR (400MHz, DMSO-d₆): 6 1040 (s, 1H), 10.17 (br 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. In the context of this invention, these alkylating agents are used, for example, to alkylate the quinazoline or quinolines on the βατ 7-oxygens to make compounds of the invention. The invention is not limited to alkylation chemistry to append such bridged bicyclics, but father the aforementioned description is meant only to be illustrative of an aspect of the invention.

Example 53 [0359] l,4:3.6-dianhvdro-2-O-methvl-5-0>-(methylsulfonvl)-D-glucitQl: To a solution of l,4:3,6-dianhydro-2-O-methyl-D-glucitol (1.19g, 7.4 mmol) in dichloromethane was added pyridine (ImL, 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

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2020201638 05 Mar 2020 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 1,4:3,6-dianhydro-2-0-methyl-5-0(methylsulfonyl)-D-glucitol (1.67g, 94% yield) as a colorless oil. GC/MS calculated for

C₈Hi₄SO₆: 238 (M⁺).

Example 54 [036©] l,4:3.6-dianhvdro-5-O-fphenvlcarbonvl)-D-fructose .ethylene glycol acetal: A solution of l,4:3,6-dianhydro-5-f>-(phenylcarbonyl)-D-fructose (2.00g, 8.06 mmol), ethylene glycol (5.00g, 80.6 mmol), and p-toluenesulfonic acid (1.53g, 8.06 mmol) in benzene (lOOnaL) 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 l,4:3,6-dianhydro-5-(9-(phenylcarbonyl)-Dfructose ethylene glycol acetal as a colorless solid. 'H NMR (400 MHz; CDClj): 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-di gnhvdro-D-ftuctose ethylene glycol acetal: To a solution of 1,4:3,6dianhydro-5-0-(phenylcarbonyl)-D-fructose ethylene glycol acetal (1.44g, 4.93 mmol) in methanol (40mL) 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 IM HC1, followed by concentration and column chromatography on silica (1:2 hexane/ethyl acetate) provided 0.74g (80% yield) of l,4:3,6-dianhydro-D-fiructose ethylene glycol acetal as a colorless solid. NMR (400 MHz; CDCI3): 4.60 (t, 1H), 4.32 (m, 1H), 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-dianhydro-5-0-(methvlsulfonvl)-D-fructose ethylene glycol acetal: To a solution of l,4:3,6-dianhydro-D-fructose ethylene glycol acetal (0.74g, 3.93 mmol) and triethylamine (I.20g, 11.86 mmol) in dichloromethane (40mL) was added

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2020201638 05 Mar 2020 methanesulfonyl chloride (0.90g, 7.S8 mmol) at 0°C under nitrogen. The solution was warmed to room temperature and stirred for 13 h. Dichloromethane (50mL) was added, and the organic layer was washed with saturated aqueous sodium bicarbonate (30mL), water (30mL), and brine (30mL) then dried over anhydrous sodium sulfate. Filtration and concentration provided 1.02g (97%) of l,4:3,6-dianhydro-5-0-(methylsulfonyl)-Dfructose ethylene glycol acetal as a yellow oil. NMR (400 MHz; CDCI3): 5.08 (m, IH), 4.82 (t, IH), 4.13 (dd, IH), 4.04 (m, 4H), 3.93 (dd, IH), 3.87 (d, IH), 3.81 (d, IH),

3.13 (s, 3H).

Example 56 [0363] 1.4:3.6-dianhydro-2-deoxv-2-methvlidene-D-urrtbmo-hexitolL To a solution of l,4:3,6-dianhydro-2-deoxy-2-methylidene-5-(?-(phenylcarbonyl)-D-araZ>ino-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-methylidene-D-arabiHC*-hexitol as a colorless solid. H NMR (400 MHz; CDC1₃): 5.37 (m, IH), 5.20 (m, IH), 4.80 (m, IH), 4.54 (m, 2H), 4.43 (m, IH), 4.26 (m, IH), 3.95 (dd, IH), 3.54 (dd, IH), 2.70 (d, IH).

[0364] i.4:3.6-dianhvdro-2-deoxv-2-methvlidene-5-Q-(methylsul.fonyl)-D-arabmor hexitol: To a solution of l,4:3,6-dianhydro-2-deoxy-2-methylidene-D-«rabmo-hexitol (135mg, 0.95 mmol) and triethylamine (288mg, 2.85 mmol) in dichloromethane (lOmL) was added methanesulfonyl chloride (222mg, 1.94 mmol) at 0°C under nitrogen. The solution was wanned 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. Filtration and concentration provided 213mg (72%) of l,4:3,6-dianhydro-2-deoxy-2methylidene-5-O-(methylsulfonyl)-D-arobmo-hexitol as a yellow oil. *H NMR (400 MHz; CDCI3): 5.40 (m, IH), 5.23 (m, IH), 5.04 (m, IH), 4.85 (m, IH), 4.73 (t, IH), 4.58 (m, IH), 4.41 (m, IH), 4.08 (dd, IH), 3.86 (dd, IH), 3.14 (s, 3H).

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Example 57 [0365] L4:3,6-dianhvdro-2-deoxv-5-C*-(phenylcarbonvl)-L-amZ>nio-hex-l-enitol: To a mixture of l,4:3,6-dianhydro-5-i?-(phenylcarbonyl)-(P)-glycitol (4.32g, 17.3 mmol), triethylamine ¢4.91 mL, 35.3 mmol) and 4-dimethylaminopyridine (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 stirred 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 1,8diazabicyclo[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 the 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-l?-(phenylcarbonyl)-Lara/wio-hex-l-enitol, as a white solid, 3.10g, 77% yield. 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] Methyl 3,6-anhydro-5-O-(r)henvlcarbonvl)-B-L-glucofuranoside: To a solution of l,4:3,6-dianhydro-2-deoxy-5-0-(phenylcarbonyl)-L-arabino-hex-l-enito] (LOOg, 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-<9(phenylcarbonyl)-P-L-glucofuranoside as a white solid, L03g, 83% yield. *H NMR (400MHz; CDCI3): 8.11-8.08 (d, 2H), 7.61-7.56 (tr, 1H), 7.48-7.44 (m, 2H), 5.24-5.17

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2020201638 05 Mar 2020 (m, 2H), 4.96 (s, 1H), 4.57-4.56 (d, 1H), 4.27 (s, 1H), 4.22-4.18 (dd, 1H), 4.08-4.04 (dd, 1H) 3.36 (s, 3H).

[0367] Methyl 3.6-anhvdro-2-C>-methvl-5-O-fohenvlcarbonvl)-B-L-gIucofuranoside: A mixture of methyl 3_?6-anhydro-5-C>-(phenylcarbonyl)-p-L-glucofuranoside (1.03g, 3.7 mmol), silver (I) oxide (O.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 methyl 3,6-anhydro-2-0-methyl-5-0-(phenyIcaibonyl)-3-L-glucofuranoside as a colorless oil, 0.82g, 76% yield. 'H NMR (400MHz; CDCI3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4,08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).

[0368] Methyl 3,6-anhydro-2-0-methvl-a-D-idofuranoside: A solution of methyl 3,6anhydro-2-(?-methyl-5-0-(phenylcarbonyl)-p-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-G>-methyl-a-D-idofuranoside as a colorless oil, 420 mg, 85% yield. ^lH NMR (400MHz; CDCI3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, 1H), 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-2-0-methvl-5-0-(methvlsulfonvl)-B-L-gIucofuranoside: Methyl 3,6-anhydro-2-0-methyl-a-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-2-0-methyl-5-0-(methylsulfonyl)-PL-glucofuranoside as a colorless oil, 669mg, 95% yield, which was used without further purification.

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Example 59 [0370] 3.6-anhvdro-5-<?-(phenylcarbonvl)-g-L-glucofuranose: A mixture of osmium tetroxide (4% in water, 0.25 mL, 0.03 mmol) and N-methylmorpholine (505 mg, 4.3 mmol) in 3 mL of 50% acetone in water was warmed to 60°C. A solution of 1,4:3,6dianhydro-2-deoxy-5-6>-(phenylcarbonyl)-L-ara&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-5-6(phenylcarbonyl)-a-L-glucofuranose as a white solid, 1.5g, 65% yield. NMR (400MHz; DMSO-dg): 8.01-7.95, (m, 2H), 7.68-7.66 (m, 1H), 7.57-7.53 (m, 2H), 5.185.11 (m, 2H), 4.85-4.81 (m, 1H, m), 4.37-4.35 (m, 1H), 4.05-3.96 (m, 2H), 3.85-3.83 (m, 1H).

[0371] 3.6-anhvdro-2-0-methvl-5-0-(phenvlcarbonvl)-a-L-glucofuranoside: 3,6Anhydro-5-C?-(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 (O.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-anhydro-2-O-methyl-5-O-(phenyIcarbonyl)-a-Lglucofuranoside as a white solid, 270 mg, 42% yield. *H NMR (400MHz; CDCI3): 8.098.07 (m, 2H), 7.61-7.57 (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, 1H), 4.20-4.16 (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-5-0-(methvlsulfonvl)-a-L-glucofuranoside: A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(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

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2020201638 05 Mar 2020 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 (27gL, 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-gIucofuranoside as a colorless oil, 190 mg, 96% yield.

Example 60 [0373] 3,6-Anh vdro-1,2-0-( 1 -meth vlethvlidene)-5-O-(phenvlcarbonvD-a-L-glucofuranose: A mixture of 3,6-anhydro-5-O-(phenylcarbonyl)-a-L-glucofuranose (l.OOg),

2,2-dimethoxy propane (0.63 mL), p-toluenesulfonic acid (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-anhydro-l,2-O-(l-methylethylidene)-5-O~(phenylcaibonyl)-a-Lglucofuranose as colorless oil, 0.85g, 74% yield. ’H 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), 5.105.08 (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-L2-O-(l-methylethvlidene)-5-O-(methylsulfonvl)-a-L-glucofuranose: A solution of 3,6-anhydro-l,2-O-(l-methylethylidene)-5-O-(phenylcarbonyl)-aL-glucofuranose (850mg) and 50% sodium hydroxide (111 mg) in methanol (lOmL) 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 dichloromethane (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-(1methylethylidene)-5-O-(methylsulfonyl)-a-L-glucofuranose as a colorless oil, 485 mg, 90% yield, which was immediately employed in the next step.

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Example 61 [0375] (35.8aS)-3-(Chloromethvl)hexahvdro-lH'-pyiTolor2,l-cl[1.41oxazine: (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 for 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). (35,8a5)-3-(Chloromethyl)hexahydro-lH-pyaolo[2,l-c][l,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): *H NMR (400 MHz, CDC1₃): 4.06 (dd, 1H), 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 C₈H₁₄NOC1: 176 (MH*). (3R,8aS)-3-(Chloromethyl)hexahydro-lH-pyrrolo[2,l-c][l,4]oxazine (1.54 g, 8.77 mmol, 15% yield): *H NMR (400 MHz, CDCI3): 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 (ET) for C_gH₁₄NOCl: 176 (MH*).

[0376] Using the same or analogous synthetic techniques and/or substituting with alternative starting materials, the following were prepared:

I [0377] (3R.8aZ?)-3-(Chloromethvl)hexahydro-Wrpvrroloi2.1-cl[l,41oxazine: ‘H NMR ¢400 MHz, CDC1₃): 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 C₈H₁₄NOC1: 176 (MH*).

[0378] (35.8a/?)-3-(Chloromethvl)hexahvdro-lH-pvrrolo[2,l-c.][l,41oxazine: ’H NMR (400 MHz, CDC1₃): 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 CgHwNOCl: 176 (MH*).

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Example 62 [0379] (35,8a5)-Hexahydro-lH-pvnolo[2,l-cl[L41oxazin-3-vlmethvl acetate: (35,8aS)-3(Chloromethyl)hexahydro-H7-pyrrolo[2,l-c][l,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylformamide (25 mL) at 140°C for 20 h. The 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 (35,8a5)-hexahydro-lZf-pyrrolo[2,lc][l,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). *H NMR (400 MHz, CDC1₃): 4.14-4.02 (m, 3H), 3.81-3.72 (m, IH), 3.37-3.31 (m, IH), 3.09 (dt, IH), 3.00 (dd, IH), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, IH); MS (El) for C10H17NO3: 200 (MH*).

[0380] (35,8a5)-Hexahvdro-lZI-pvrrolo[2,l-c1[l,41oxaztn-3-vlmethanol: (35,8a5)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-dioxane (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 (35,8a5)hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-ylmethanol as a brown oil (1.93 g, >100% yield). NMR (400 MHz, CDCI3): 4.05 (dd, IH), 3.73-3.65 (m, 2H), 3.62-3.56 (in, IH), 3.39-3.34 (m, IH), 3.10 (dt, IH), 3.00-2.95 (m, IH), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m, IH); MS (El) for C₈Hi₅NO₂: 158 (MH*).

[0381] (35,8a5)-hexahvdro-l/f-pyrrolo[2,l-cl[L41oxazin-3-vlmethvl___methanesulfonate:

(3S,8a5)-Hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (2.4 mL, 17.3 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmed 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 with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (35,8aS)-hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3223

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Example 63 [0382] Octah vdro-2ff-quinolizin-3-ylmethanol: Ethyl octahydro-2H-quinolizine-3carboxylate (2.35 g, 11.1 mmol) was added dropwise to a stirred suspension of lithium aluminum hydride (1 M 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 octahydro-2/Lquinolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol, 88% yield). MS (El) for CioHfoNO: 170 (MH*).

[0383] Octahydro-2/7-quinolizm-3-ylmethyl methanesulfonate: Octahydro-277-quinolizin-

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 warmed 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 aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro2ff-quinolizin-3-ylmethyl methanesulfonate as an orange oil ¢796 mg, 3.22 mmol, 91% yield). MS (El) for CnH₂iNO₃S: 248 (MH*).

Example 64 [0384] (35,8aS)-3-(Hvdroxvmethyl)hexahvdropvrroIo[l,2-fllpyrazin-lf2H)-one: A solution of methyl l-[(25)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl)amino)propyl]-L· prolinate (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 (35,8a5)-3-(hydroxymethyl)hexahydropyrrolo[l,2-ii]pyrazin“l(2fr)-one as 224

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2020201638 05 Mar 2020 a colorless solid (1.50 g, 8.83 mmol, 85% yield). ‘H NMR (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, 1H), 2.76-2.70 (m, 1H), 2.66 (dd, 1H), 2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (El) forCgHi^Ch: 171 (MH*>

[0385] (35,83^3-(.(111,1^ pvirololl .2-alpyrazin-1 (2H)-one; To a solution of (35,8a5)-3-(hydroxymethyl) hexahydropyrrolo[l,2-a]pyrazin-l(2fi)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was wanned to room temperature and stirred for 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

I and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (35,8a5)-3-({[(l,l-dimethylethyl)(dimethyl)silyI]oxy}methyl) hexahydropyrro]o[l,2-«]pyrazin-l(2£D-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). *H NMR (400 MHz, CDC1₃): 6.09-5.90 (m, 1H), 3.86-3.76 (m, 1H), 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, IB), 2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (El) for CjJLigNsChSi: 285 (MH^{* 1}).

[0386] (35,8a5)-3-( H( 1.1-Dimethvlethvl)(dimeth vDsilylloxv }meth vl)-2-methylhexahydro pyrrolo [ 1,2-alpyrazin-l (2H)-one: (35,8a5)-3-( {[(1,1-Dimethylethyl)(dimethyl)silyl]oxy} methyl)hexahydropyrrolo[l,2-a]pyrazin-l(2H)-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 (35,8a5)-3-({[(l,l-dimethylethyl)(dimethyl)si]yI]oxy}methyl)-2methylhexahydropyrrolo[l,2-a]pyrazin-l(2il)-one as a yellow oil (1.552 g, 5.21 mmol) which, was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium

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2020201638 05 Mar 2020 fluoride (1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at room temperature. The mixture was concentrated, in vacuo and purified by column chromatography (10% methanol in dichloromethane) to afford (3S,8aS)-3(hydroxymethyl)-2-methylhexahydropyrrolo[l,2-<z]pyrazin-l(2H)-one as a yellow oil (496mg, 2.70mmol, 51% yield from (3S,8aS)-3-({ [(1,1dimethylethyl)(dimethyl)silyl]oxy) methyl)hexahydropyrrolo[l,2-a]pyrazin-l(2H)-one). *ΗΝΜΚ (400 MHz, CDCfi): 3.98-3.93 (m, 1H), 3.86 (dd, 1H), 3.61-3.55 (m, 1H), 3.293.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, 1H), 3.02 (s, 3H), 2.93 (dd, 1H), 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 (El) for C₉H_I6N₂O₂: 185 (MH*).

Example 65 [0387] L2-Dideoxy- l-[(2S)-2-(methoxvcarbonvl)-1 -pvrrolidinyll-2- ΓΓ (phenylmethox y) earbonyllaminol-D-gZvcero-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 moi). The solution was heated to 64 °C for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to afford 1,2dideoxy-1 -[(2S)-2-(methoxycarbony 1)-1 -pyrroli din yl]-2-[[(phenylmcthoxy)carbonyl] amino]-D-gIycero-hexitol (6.81 g, 100%) as a clear and colorless oil. MS (BI) for C₂₀H₃₁N₂O_g: 427 (MH*).

Example 66 [0388] Methyl l-[(2S)-3-hydroxy-2-(] [(nhenylmethyDoxvlcarbonvllaminoIpropyll-Lprolinate; 1,2-dideoxy-1 -[(2S>2-(methoxycarbonyl)-l -pyrrolidinyl]-2-[[(phenylmethoxy) carbonyl]amino]-D-gfycerohexitol (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 stirred 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 borohydride

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2020201638 05 Mar 2020 (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[(25)-3-hydroxy-2-({ [(phenylmethyi)oxy]carbonyl} amino)propyl]-L-prolinate (4.9 g, 92%) as a white solid. MS (El) for CnH^NzOst 337 (MH*).

[0389] Methyl l-l(25)-3-[(methylsulfonypoxvl -2-( 1 KphenylmethyDoxvIcarbonyl 1 amino) propyll-L-prolinate: Methyl l-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl} amino) propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed 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 dropwise 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 1-((23)-3[(methylsulfonyl)oxy]-2-(( [(phenylmethyl)oxy]carbonyl }amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oil. MS (El) for C18H27N2O7S: 415 (MH7).

Example 67 [0390] Ll-Dimethvlethvl (3aR,6a3)-5-(hvdroxvmethvl)hexahydrocyclopenta[c]pyrrole2(lH)-carboxvlate: Under a nitrogen atmosphere, borane tetrahydrofuran complex (IM 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 (3aR,6a5)-5methylidenehexahydrocyclopenta[c]pyrrole-2(lZO-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

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2020201638 05 Mar 2020 combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 2.04 (95%) of 1,1-dimethylethyl (3aR,6aS)-5(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(177)-carboxylate, which was used without purification. NMR (400 MHz, CDCI3): 8.50 (broad s, 1H), 3,66-3.46 (m, 3H), 3.20-3.00 (m, 2H), 2.70-2.59 (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-Dimethylethvl i3a7?.6aS)-5-H(methvlsulfonvl)oxv1methynhexahvdrocyclopenta [c]pvrrole-2( 1771-carboxvlate: Methanesulfonyl chloride (0.2mL, 2.48mmol), was added dropwise to a solution of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxymethyl)hexahydro cyclopenta[c] pyrrole-2(lH)-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 I 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), IM aqueous sodium hydroxide, brine, IM 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 (3aR,6aS)-5- {[(methylsulfonyl)oxy]methyl} hexahydrocyclo- penta[c]pyrro]e-2(177)-carboxylate was used without further purification. MS (El) for C14H25NO5S: 320 (MET), 264 (M-tBu).

Example 68 [0392] 1,1-Dimethvlethyl (3aR.6aS)-5-(hvdroxv)-hexahydrocvclopenta[c] pyrrole-2( 177)-.

carboxylate: Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1dimethylethyl (3a7?,6aS)-5-oxo-hexahydrocyclopenta[c] pynole-2(l/7)-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), IM aqueous hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1,1-dimethylethyl (3a7f,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrrole-2( 177)carboxylate (0.44g, 98%). *H NMR (400 MHz, dg-DMSO): 4.08 (m, 1H), 3.40 (m, 2H),

3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS (El) for C₁₂H₂iNO3: 228 (MH*).

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2020201638 05 Mar 2020 [0393] 1,1-Dimethvlethvl___________(3aR,6aS)-5-{ f fmethylsulfonyl)oxy] lhexah ydrocycloz penta[clDvrrole-2(lfi)-carboxylate: Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3a7?,6aS)-5-(hydroxy)hexahydrocyclopentafc] pyrrole-2(l/i)-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 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), brine, IM 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- {[(methylsulfonyl)oxy]} hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate was used without further purification. MS (BI) for C13H23NO5S: 306 (MH¹).

Example 69 [0394] 3-(Chloromethyl)hexahvdro-177- [ 1,41oxazino[3,4-c] [1,41oxazine: A solution of (37?)-moipholin-3-ylmethanol (4.21 g, 36.0 mmol) in 2-(chloromethyl)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)hexahydro177-[l,4]oxazino[3,4-c][l,4]oxazine 2.44g (35%) as two separated diastereomers. (37?,9a5)-3-(chloromethyl)hexahydro-177-(1,4]oxazino[3,4-c] [ 1,4]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) for C8H14NO2CI: 192 (MH¹). (3S,9a5)-3-(chloromethyl)hexahydro-17f- [l,4]oxazmo[3,4-c][l,4]oxazine: (1.55 g, 22% yield): *H NMR (400 MHz, CDCI3): 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, 1H); MS (El) for C₈Hi4NO₂Cl: 192 (MH¹).

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2020201638 05 Mar 2020 [0395] Hexahvdiro-l.H'-ri,4]oxazmor3,4-cl[l₁41oxazin-3-ylmethyl acetate: A suspension of (3R,9aS)-3-(chloromethyl)hexahydro-1/7-(1,4]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°C 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 (S1O2, 1:1 hexanerethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%) of hexahydro-lH- [l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate as a yellow oil. Distinct diastereomers as described above were converted in this step to give: (3R,9aS)-hexahydro-liL [l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate: *H NMR (400 MHz, CDCI3): 4.18 (dd, 1H), 4.00 (m, 1H), 3.80 (dd, 1H), 3.68 (dt, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, 1H), 2.64 (dd, 1H), 2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and (35,9aS)hexahydro-l/7-[l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate: ¹H 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] (3 R,9aS)-Hexahydro- 1Η-Γ1,4]oxazino[3,4-c] [ 1,41oxazin-3-ylmeth yl methanesulfonate: To a solution of (3R,9a5)-hexahydro-lH-[l,4]oxazino[3,4-c][l,4]oxazin-3ylmethyl 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 4.0M 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 for 30 minutes at room temperature. The mixture was then partitioned between dichloromethane and saturated aqueous sodium 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,9aS)-hexahydro-l£L[l,4]oxazino[3,4c][l,4]oxazin-3-ylmethyl methanesulfonate which was taken on to the following reaction without purification.

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Example 70 [0397] (8aJ?)-6-CCh]oromejhylltetrahvdro-lH-ri_;31thiazolor4.3-ciri,41oxazine: A solution of (4R)-l,3-thiazolidin-4-yImethanol (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 (8a2?)-6-(chloromethyl)tetrahydro-lH- [l,3]thiazolo[4,3-c][l,4]oxazine as a mixture of diastereomers which was directly taken on to the next step.

Example 71 [0398] 1,1 -Dimethylcthyl (3-endo)-3-{ 2-r(methvlsulfonvl)oxvlethyl) -8-azabic yclo[3.2.1] octane-8-carboxylate: To a solution of 1,1-dimethylethyl (3-endo)-3-(2-hydroxyethyl)-8azabicyclo[3.2.1]octane-8-carboxylate (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 Ih. 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 1,1dimethylethyl (3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl }-8-azabicyclo [3,2.1 ]octane-8carboxylate, which was carried forward for alkylation without purification.

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Example 72

[0399] N-[3-Fluoro-4-( {7-(methvlox v)-6- Γ (3-morpholin-4-ylnrop vDoxylquinazolin-4ylI ox v)phenvl1-N'-(4-fluorophen vDcyclopropane-1,1 -dicarboxamide. Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methox y-quinazolin-4yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (333mg, 0.66mmol), PS-PPh₃ resin, (loading = 2.33mmol/g, 797mg, 1.86mmol), 3-morpholin-4-yl-propan-l-ol (0.26mt, 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 HC1 extractions were washed with EtOAc (2x). The acidic aqueous phase was then basified with IN NaOH and extracted with EtOAc (3x). The combined EtOAc extractions were washed with H₂O (lx), sat’d NaCl (lx), dried (Na₂SO₄), and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25mM NHjOAc/acetonitrile) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-yloxy]-phenyl} -amide (4-fluoro-phenyl)-amide (42.6mg, 10%). 1HNMR (400MHz, DMSO-d6): d 10.37 (br 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). LCZMS 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- ί 3-fluoro-4- [(7-(methvloxy)-6- {[(1 -meth ylpiperidin-4-vllmethvlloxv} quinazolin-4-y])oxv]phenyl)-N'-(4-fluorophenyl)c.Yclopropane₌l,.17dicarboxamide: Ή NMR (400MHz, CDCI3): δ 9.67 (s, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 7.75 (d, 1H), 7.52 (s, 1H),

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7.46 (m, 2H), 7.31 (s, 1H), 7.20 (m, 2H), 7.06 (t, 2H), 4.04 (d, 2H), 4.03 (s, 3H), 2.98 (d,

2H), 2.34 (s, 3H), 2.12-2.1.95 (m, 5H), 1.76 (m, 2H), 1.64 (m, 2H), 1.57 (m, 2H).

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HO'

Example 73 h₂n_ [0402] Preparation_____of____1 -14-(6,7-dimethoxy-quinolin-4-vlox v)-phenvlcarbamovllcyclopropanecarboxylic 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 room temperature under a nitrogen atmosphere for 40 minutes before adding thionyl chloride (250 pL, 3.44 mmol). The reaction was monitored by LCMS 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-4yloxy)-phenylamine (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. HC1 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-yloxy)-phenylcarbamoyl]cyclopropanecarboxylic acid, was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. ‘H NMR (D₂O/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

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2020201638 05 Mar 2020 [0403] ^,N-(4-fr6,7-Bis(methyloxv)quinolin-4-vlloxv)phenyl)-N^,-r(4-fluorophenyl)methvll cyclopropane-Ll-dicarboxamide, To a solution of l-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenylcarbamoyl]-cyclopropanecarboxylic acid (74.3 mg, 0.182 mmol), 4-Fluoro 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 N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N'-[(4-fluorophenyl)methyl]cyclopropane-l, 1 dicarboxamide (33 mg, 35% yield, 98% pure) as a white solid. NMR (DMSO, d<$): 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 compounds were prepared, in a similar manner as above, from the coupling of 1 -[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropane carboxylic acid with a corresponding alkylamine or arylamine.

[0405] N-(4- [ [6.7-Bis(methyloxv)quinolin-4-ylloxv I phenvl)-N^,-[2-(piperidin-1 vlmethvl)phenvllcvclopropane-l,l-dicarboxamide. 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, 2H), 3.49 (m, 4H), 3.25 (t, 2H),

3.13 (br., 2H), 1.42 (d, 4H).

[0406] N44- [ [6,7-Bis(methvloxv)qumolin-4-vl]oxy [phen vD-N'-rZ-fpiperidin-1 vlmethyl)phenvl1cvclopropane-Ll-dicarboxamide. 1H NMR (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 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (s, 2H),

2.17 (br., 4H), 1.49 (m, 4H), 1.41 (m, 4H), L32 (br., 2H).

I [0407] ^,N-i4-{i^,6,7-BisCmethyIoxy)_quinolin-4-yl|oxy}phenvr)-N'-r2-(pvn-olidin-lvlmethyDphenvilcyclopropane-1, 1-di carboxamide, 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), 7.177.27 (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-([6,7-Bis(methYloxy)quinolin-4-yl1oxv[phenyl)-N'-[3-(morpholin-4ylmethvDphenyllcvclopropane-1,1 -dicarboxamide, 1H NMR (DMSO-d6): 10.12 (s, 1H),

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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, 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] 'N-(4- f [6,7-Bis(methyIoxv)quinolin-4-vlloxv 1 phenyp-N’- [2-(morpholin-4ylmethvBphenvllcvclopropane-Ll-dicarboxamide, 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 (s, 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, 4H).

[0410] ^,N-(4-(r6,7-Bis(methvloxv')quinolin-4-vlloxv)phenvl)-N^,-r3-(piperidin-lvlmethvDphenvlIcvclopropane-l, 1 -dicarboxamide. 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, 1H), 7.24 (m, 3H), 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), 1.39 (br., 2H).

[0411] 'N-(4-{[6,7-Bis(mcthvloxv)quinolin-4-vHoxvlphcnvl)-N'-[3-(pvrroIidin-lvlmethyl)phenyllcyclopropane-l.l-dicarboxannide· 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, 3H), 3.52 (s, 2H), 2.42 (br., 4H), 1.69 (br, 4H), 1.48 (s, 4H).

Example 75

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[0412] Synthesis of N-(4-fl6.7-bis(methvloxv)-2-(methvlthio)quinolin-4-vl1oxv )-3fluprophenvl)-N^,-(4-fluorophenvl)c vclopropane-1, 1-dicarboxamide

Commercially available 5-(bis-methylsulfanyl-methy]ene)-2,2-dimethyl-[l,3]dioxane-4,6-dione (3.5 g, mmol) and 3,4-dimethoxyoaniline ¢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-dimethoxyphenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[l,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M-Η)'.

[0413] A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2dimethyI-[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. The mixture was cooled to room temperature and heptane was added. 6,7-Dimethoxy-2-methylsnlfanyl-quinoIin-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-quinolin-4-ol (1.0 g, 4.0 mmol), 3,4difluoronitrobenzene (0.4S mL, 4.3 mmol), cesium carbonate (2.6 g, 8.0 mmol), andDMF (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% LiCl_(aq.), water, (IX) and brine (IX), followed by drying over Na₂SO4 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)⁺. 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-(6,7-dimethoxy-2-methylsulfany]-quinolin-4yloxy)-3-fluoro-phenylamine as an orange oil (220 mg, 73% yield). LCMS: m/z 361 (M+H)⁺.

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2020201638 05 Mar 2020 [0415] To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluorophenylamine (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% LiCI^.) (3X), water, (IX) and brine (IX), followed by drying over NajSCfl and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N’-(4fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. *H NMR (DMSO-zfc) § 10.34 (s, IH), 9.94 (s, IH), 7.83 (d, IH), 7.59 (m, 2H), 7.56 (m, IH),

7.40 (m, 2H), 7.23 (s, IH), 7.09 (t, 2H), 6.12 (s, IH), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).

NHjOH, HgCla

THF *

Example 76

Ph₂O

260 °C, 30min

CsaCOg, DMF

2. Ammonium formate,

Fe, Tol/HgO reflux

[0416] Synthesis______of N-(4- ((2-amino-6,7-bis(methyloxy)qumolin-4-ylloxy] -3fluorophenyD-N'-H-fluorophenyDcyclopropane-l, 1-dicarboxamide. A mixture of 5-((3,4dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[l,3]dioxane-4,6-dione (1.0 g, 2.8 mmol), 30% ammonium hydroxide (8.5 mL), HgCl₂ (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 Na₂SO4, Concentration in vacuo afforded 5-[amino(3,4-dimethoxy-phenylamino)-methylene]-2,2-diniethyl“[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)‘.

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2020201638 05 Mar 2020 [0417] A mixture of 5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dimethyl- [l,3]dioxane-4,6-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-quinolin-4-ol 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-(6,7dimethoxy-2-methylsulfanyl-quino]in-4-yloxy)-3-fluoro-phenylamine, and obtained as a white solid (4.0% yield). LCMS: m/z 330 (M+H)⁺.

[0419] N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy)-3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l,l-dicarboxamide was synthesized from 4-(4-amino-2-fluorophenoxy)-6,7-dimethoxy-quinolin-2-ylamine in a similar manner as N-(4-{[6,7bis(methy!oxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyI)-N'-(4fluorophenyl)cyclopropane-l,l-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (4.0% yield). ’H NMR (DMSO-ds) δ 10.34 (s, IH), 9.95 (s, IH), 7.82 (d, IH), 7.58 (m, 2H), 7.44 (d, IH), 7.33 (t, IH), 7.25 (s, IH), 7.09 (t, 2H), 7.07 (s, IH), 6.17 (br s, 2H), 5.66 (s, IH), 3.79 (s, 3H), 3.77 (s, 3H),

1.40 (d, 4H). LCMS: m/z 535 (M+H)⁺.

MeNH_a, HgCla

THF

Example 77

CS2CO₃, DMF

2. Ammonium formate, Fe, Tol/HaO reflux

[0420] Synthesis of 'N-(3-fluoro-4-[ r2-(methvlamino)-6,7-bis(inethvloxv)quinolin-4yl]oxv)phenvl)-N^,-(4-fluorophenvl)cvcIopropane-l,l-dicarboxamide. A mixture of 5238

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2020201638 05 Mar 2020 [(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[ 1,3] dioxane-4,6dione (0.50 g, 1.4 mmol), methylamine (2 M in THE, 0.75 mL.' 1.5 mmol), HgCl₂ (0.38 g, 1.4 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 Na₂SO4. Concentration in 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-phenylamino)-methylamino-methylene]-2,2dimethyl-[l,3]dioxane-4,6-dione (0.40 g, 2.8 mmol) and diphenylether (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-methylamino-quinolin-4-ol 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-phenox y)-6,7-dimethoxy-quinolin-2-yl] -methyl-amine was i synthesized from 6,7-dimethoxy-2-methylamino-quinolin-4-ol in a similar manner as 4-(4Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine, and isolated as a yellow oil (58% yield). LCMS: m/z 330 (M+H)⁺.

[0423] 'N-(3-fluoro-4-{ [2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy [phenyl)N'-(4-fluorophenyl)cyclopropane-l,1-dicarboxamide was synthesized from [4-(4-amino-2fhioro-phenoxy)-6,7-dimethoxy-quinoIin-2-yl]-methyl-amine in a similar manner as N-(4{[6,7-bis(methyIoxy)-2-(methylthio)quinolm-4-yl]oxy}-3-fluorophenyI)-N'-(4-fluorophenyl)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). NMR (DMSO<fc) δ 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). LCMS: m/z 535 (M+H)⁺.

Example 78

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2020201638 05 Mar 2020 [0424] ’N-(4- (Γ6-Ι r3-(diethvlamino)propvlloxv)-7-fmethvlQ.xv)quinolin-4-ylloxvl-3fluorophenvl)-N'-(4-fluorophen ylk yclopropane-1,1 -dicarboxamide. To a slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)pheny]]-amide (4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydiOxypropyldiethylamine (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). The 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 NaaSCL. Concentration of the organic fraction in vacuo afforded N-(4- {[6- {[3-(diethylamino)propyl]oxy} -7-(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxaniide 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)⁺. 'HNMR (DMSO-rfc) 8 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

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2020201638 05 Mar 2020 [0425] 'N-(4-fluorophenyl)-N^>-(4-[r2-methvl-6,7-bis(methyloxv)auinazolin-4ylloxylphenyl)cvclopropaii&-Ll-dicarboxamide. Commercially available 2-amino-4,5dimethoxy-benzoic acid 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-benzoic add methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).

[0426] To the crude 2-acetylamino-4,5-dimethoxy-benzoic acid 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 acidified with aq. HC1 and extracted three times with EtOAc. The combined organic extract was dired over Na₂SO4 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-quinazolin-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 NaHCO₃. and adjusted to basic with K₂CO₃. The mixture was cooled to 0°C with stirring. The resulting precipitate was filtered, giving 4-chloro-6,7-dimethoxy-2-methyl-quinazoline (0.094g), which was used without further purification.

[0428] A mixture of the chloro quinazoline (0.094g, 0.397 mmol) obtained above, 4nitrophenol (0.1 Ig, 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, Et₂O was added and the reaction stirred 30 min and the precipitate was filtered, affording 6,7dirnethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline (0.081g) as a very light yellow solid. LC/MS: m/z 342 (M+H).

[0429] A mixture of 6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline (0.08 Ig, 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-2241

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2020201638 05 Mar 2020 methyl-quinazolin-4-yIoxy)-phenylandne (0.924g) was obtained as a yellow solid, which was used in the next reaction without further purification. LC/MS: m/z 312 (M+H).

I [0430] To a mixture of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (O.lOOg, 0.321 mmol) and l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.056g, 0.386 mmol) in DMF 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 Na2SO4, and concentrated in vacuo. The crude product was purified on preparative HPLC to give 'N-(4-fluorophenyl)-N'-(4-{ [2-methyl-6,7-bis(methyloxy)quinazolin-4yl]oxy[phenyl)cyclopropane-l,l-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), 2.43 (s, 3H), 1.53 (s,4H).

Example 80

[0431] Preparation of I-(4-Huoro-ohenylcarbamovl)-2-methvl-cyclopropanecarboxvlic acid. 2-Methylcyclopropane-l,l-dicarboxylic acid methyl ester was prepared by following the literature procedure (Baldwin, J. E.; Adlington, R. M.; Rawlings, B. J. Tetrahedron Lett. 1985, 481.) The carboxylic acid (700 mg, 4.4 mmol) was dissolved in CH2CI2 (10 mL). To the resulting solution was added 4-fluoroaniline (590 mg, 5.3 mmol), HOBt (890 mg, 6.6 mmol) andEDCI (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 Na₂SO4, CH2CI2 was removed under reduced pressure. Further purification by column chromatography gave 635 mg (57%) of the desired amide.

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2020201638 05 Mar 2020 [0432] The methyl ester obtained above was then treated with ΠΟΗΉ2Ο (116 mg, 2.78 mmol, 1.1 eqiv.) in THF (2 mL) and H₂O (1 mL) for 3h at rt. THF was removed under reduced pressure. The aqueous solution was diluted with 20 mL of H₂O, washed with ether (10 mL), and acidified with 1 N HC1. The solid was filtered, dissolved in EtOAc, and dried over Na₂SO4. Removal of EtOAc gave the crude product of l-(4-fluorophenylcarbamoyl)-2-methyl-cyclopropane-cafboxylic acid, which was used in the next reaction. NMR (400 MHz, DMSO-de) δ 12.99 (br s, 1 H), 10.33 (br s, 1 H), 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, 1 H), 1.30 (dd, J - 7.8,4.3 Hz, 1 H), 1.19 (d, J = 6.3 Hz, 3 H).

Example 81

[0433] Synthesis of (lS,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl) oxy]quinolin-4-yl }oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane-l, 1dicarboxamide. To a solution of 4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluorophenylamine (150 mg, 0.38 mmol) in CH₂C1₂ (3 mL) was added DIEA (341 mg, 2.64 mmol), l-(4-fluoro-phenylcatbamoyl)-2-methyl-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

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2020201638 05 Mar 2020 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-chIoropropyl)morpholine hydrochloride (70 mg, 0.35 mmol) and K₂COj (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 Na₂SO4. Removal of EtOAc and purification by column chromatography (CH₂C1₂ : MeOH = 10:1) gave '(lS,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane-l,ldicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv. of 1 N HCl/ether. Filtration and lyophilization gave the HC1 salt of ’(lS,2R)-N-[3-fluoro-

4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinoIin-4-yl}oxy)phenyl]-N’-(4fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide: *H NMR (400 MHz, DMSO-de) δ 10.49 (br s, 1 H), 10.26 (br s, 1 Η), 10.15 (br s, 1 H), 8.74 (br s, 1 H), 7.95 (br d, J = 13.2 Hz, 1 H), 7.8-7.5 (m, 6 H), 7.16 (t, J = 8.9 Hz, 2 H), 6.82 (br s, 1 H), 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), 3.173.07 (m, 2 H), 2.40-2.30 (m, 2 H), 2.04-1.95 (m, 1 H), L45 (dd, J = 7.2,4.7 Hz, 1 H), 1.36 (dd, J = 8.5, 4.5 Hz, 1 H), 1.09 (d, J = 6.2 Hz, 3 H).

EDCI, HOBt ch₂ci₂

Example 82

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2020201638 05 Mar 2020 [0436] Synthesis of___(lR,2R)-N-r3_-fluoro-4-(|6-(methvloxv)-7-r(3-morpholinA

Ylpropyl')oxyl-quinolin-4-vnoxv)phenvl1-N'-(4-fluorophenvl')-2inetlivlcyclopropane-l.ldicarboxamide. To a solution of 4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluorophenylamine (322 mg, 0.82 mmol) and 2-Methyl-cyclopropane-1,1-dicarboxylic acid methyl ester (195 mg, 1.23 mmol) in CH2CI2 (4 mL) was added HOBt (61 mg, 0.32 mmol) and EDCI (211 mg, 1.64 mmol). The stirring was continued for 12 h at rt. The reaction mixture was then diluted with EtOAc 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 LiOH’EfeO (15 mg, 0.35 mmol) in THF (1 mL) and H₂O (1 mL) for 2 h. THF was removed. 10 mL of HiO was added to the mixture. The aqueous solution was washed with ether, and acidified with 1 N 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) were dissolved in DMF (2 mL). To this solution was added DIEA (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 7-hydroxyquinoIine (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 over Na₂SO4. Removal of EtOAc and purification by column chromatography (CH2CI2 : MeOH = 10:1) gave '(lR.2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl} oxy)phenyl]-N’-(4-fluorophenyl)-2-methylcyclopropane-l, 1 dicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv. of 1 N HCl/ether. Filtration and lyophilization gave the HC1 salt of '(lR,2R)-N-[3-fluoro4-({6-(methyloxy)-7-[(3-morpholin-4-ylpiopyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4245

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2020201638 05 Mar 2020 fluorophenyl)-2-methyIcyclopropane-1,1 -dicarboxamide: 'H NMR (400 MHz, DMSO-dfi) δ 10.65 (br s, 1 H), 10.54 (br s, 1 H), 9.74 (s, 1 H), 8.75 (br s, 1 H), 8.01 (br d, J = 12.9 Hz, 1 H), 7.80-7.50 (m, 6 H), 7.20-7.10 (m, 2 H), 6.84 (br s, 1 H), 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, 1 H), 1.40-1.30 (m, 2 H), 1.10 (d, J = 6.2 Hz, 3 H).

Example 83

NaOH, MeOH, H₂O

80°C, 5 h

[0441] Synthesis_____of_____’(2R,3R)-N- [S-fluonM-i {6-(methwlpxy)-7-f(3j:mQrphQlin-4vlpropvl)oxyl-quinolin-4-vl]oxv)phenyllJ)J7(4-fluorpphenvD₌2.3zdimethvlcyclopronaneLl-dicarboxamide, 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-1,1-dicarboxylic 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 H₂O. The aqueous solution was washed with 20 mL of

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2020201638 05 Mar 2020 ether, and acidified with 1 N 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 CH2CI2 (15 mL). HATU (2.11 g, 5.56 mmol) and DIEA (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 LiOH*H₂O (175 mg,

4.17 mmol) in THF (100 mL) -H₂O (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. H₂O (10 mL) was added to the reaction, and a precipitate formed. The solid was filtered, washed with aqueous sat. Na₂COa and ether. Further purification by column chromatography gave 596 mg (60%) of the desired product. Debenzylation was done by following the standard procedure.

[0444] To a solution of the 7-hydroxyquinoline (261 mg, 0.49 mmol) in DMF (5 mL) was added 4-(3-chloropropyl)morpholine 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 Na₂SO4. Removal of EtOAc and purification by column chromatography (CH₂C1₂ : MeOH = 10:1) gave 122 mg (37%) of '(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3morpholin-4-ylpropyl)oxy]quinolin-4-yl} oxy)phenyl] -N’-(4-fluorophenyl)-2,3-dimethylcyclopropane-l.l-dicarboxamide. ¹H NMR (400 MHz, CDC1₃) 5 8.44 (d, 1 = 5.1 EL·, 1 H), 8.11 (br s, 1 H), 7.77-7.70 (m, 2 H), 7.53 (s, 1 H), 7.50-7.44 (m, 2 H), 7.40 (s, 1 H), 7.227.16 (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), 2.182.10 (m, 2 H), 1.80-1.66 (m, 2 H), 1.30-1.24 (m, 6 H).

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[0445] Synthesis of 'N-(4-[ r6,7-bis(methyloxy)quinolin-4-vlloxv)phenyl)-N'-(4fluorophenyl)-1 -Cphenylmethy])azetidine-3,3-dicarboxamide. 1 -Benzyl-azetidine-3,3dicarboxylic 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 1-benzyl-azetidine-

3,3-dicarboxylic acid ( 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 'N-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyI)-l(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 12% yield) as a white solid. ’HNMR (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, 1H), 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(methyloxy)quinolin-4-yl]oxy }phenyl)-N'~(4-fluorophenyl) azetidine-3,3-dicarboxamide. To a solution of 'N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy} phenyl)-N'-(4-fluorophenyl)-1 -(phenylmethyl)azetidme-3,3-dicarboxamide (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: MeCNZH2O/NH40Ac), affording N-(4- {[6,7-bis(methyloxy)quinolin-4-yl] oxy }phenyl)-N'-(4-fluorophenyl)

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8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t,

2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS):

517.3 (M+H).

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Example 85 [0447] N-i3-fluoro-4-r(6-(metlivloxv)-7-(r(l-methvIpiperidin-4-vl)niethvlloxv)quinolin4-vDoxvl phenyl }-N’-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide. To a solution of cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl}-amide (4-fIuoro-phenyl)-amide, TFA salt (-500 mg, 0.71 mmol) in C1CH₂H₂C1 (8 mL) were added 30% formaldehyde (4 mL) and NaBH(OAc)₃ (752 mg, 3.55 mmol). The reaction mixture was stirred overnight. It was then quenched with aqueous sat. NaHCO₃, extracted with EtOAc. The organic phase was washed with brine and dried over Na₂SO₄. Drying salts were filtered, washed with EtOAc and the filtrate concentrated in vacuo to give 210mgs of crude product. The resulting residue was redissolved in EtOAc and any insoluble material filtered. To the filtrate was added 4M HCI in dioxane (200μ1) 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-fluoro-4-[(6-(methyloxy)-7-{[(l-methylpiperidin-4yl)methyl]oxy }quinolin-4-yl)oxy]phenyl} -N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, HCI salt (113 mg, -25% yield). *HNMR (400MHz, DMSO-d6): δ 10.51 (s, 1H),

10.30 (br. s, 1H), 10.04 (s, 1H), 8.80 (d, 1H), 7.99 (dd, 1H), 7.55 (m, 2H), 7.67-7.53 (m, 4H), 7.16 (t, 2H), 6.89 (d, 1H), 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). L49 (m, 4H). LC/MS Calcd for [_M+H]4· ₆₁₇ j, _{found 617} 4 _Anal np_LC (₈ gradient): 98% pure, 3.11 min.

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Example 86

[0448] (1 R,2R,3S)-N-(4-{ 17-{ [2-(diethylamino)ethvllox y) -6-(methvloxv)quinolin-4Xll2S.y}-3-fluprppheny])-N'-(^,4-fluoi‘gRlienYlk2_J3-dimethvlcyclopropane-l.ldicarboxamide. 2,3-Dimethyl-cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy6-methoxy-quinolin-4-yloxy)-pheny]]-amide (4-fluoro-phenyl)-amide (210 mg, 0.39mmol), DMA (2mls), (2-chloro-ethyl)-diethyI-amine, HC1 salt (73 mg, 0.42mmol) and K2CO3 (136 mg, 0.98mmol) were combined and heated at 80C overnight. The reaction mixture was then diluted with H₂O and sonicated. The resulting solids were filtered, washed with H₂O and dried under high vacuum. The 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)ethyI]oxy }-6-(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N^,-(4-fluorophenyl)-2,3-dimethylcyclopiOpane-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, 1H), 7.15 (t, 2H), 6.41 (d, 1H), 4.20 (m, 2H), 3.94 (s, 3H), 2.87 (m, 2H), 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 [M+H]⁺ 633.3, found 633.4. Anal. HPLC (25 min gradient): 96% pure, Ί 18.52 min.

Example 87

HCI

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2020201638 05 Mar 2020 [0449] N-(Y{ [7- {L2-(diethvlamino)ethvlloxy)-6-(niethvloxvkiuinazolin-4-vlloxv 1 -3fluorophenvl)-N^,-(4-fluorophenyl)-2,2-dimethvlcycIopropane-l,l-dicarboxaniide· 2,2Dimethyl-cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-niethoxyquinazo!in-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (203 mg, 0.38mmol), DMA (2mls), (2-chloro-ethyl)-diethyl-amine, HCI salt (73 mg, 0.42mmol) and K₂CO₃ (146 mg, 1.05mmol) were combined and heated at 80C overnight. The reaction mixture was then diluted with H₂O and extracted with CH₂C1₂ (3x). The combined CH₂C1₂ extractions were washed with sat’d NaHCO₃ (lx), sat’d NaCl (lx), dried (NaaSCU), 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 lyophilized to give 'N-(4-{[7-{[2-(diethylamino)ethyI]oxy}-6(methyloxy)quinazolin-4-yl]oxy}-3-flubrophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane-l,l-dicarboxamide (70 mg, 29% yield). ¹HNMR (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). LC/MS Calcd for [M+H]⁺ 634.3, found

634.4. Anal. HPLC (25 min gradient): 94% pure, 24.08 min.

NaOH

BogjO

Example 88

[0450] Synthesis of N-r3-(antinomethvl)phen yll -N'-(4-{ [6,7-bis(methyloxv)quijiplm-4vlloxvlphenyDcvclopropane-1, 1-dicaiboxamidc. (4-Nitro-benzyl)-carbamic acid tert-butyl ester. 4-Nitro-benzyIamine, HCI salt (5.19g, 27.5mmol) was dissolved in dioxane (lOOmls). NaOH (3.4g, 85.0mmol) in H₂O (20mls) was added, followed by Boc

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2020201638 05 Mar 2020 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 NaCl (lx), dried (Na₂SO₄), 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-benzyl)-carbamic acid tert-butyl ester (6.34g, 91% yield). LC/MS Calcd for [M+H]⁺ 253.1, found 197.0 (minus t-butyl).

[0451] (4-Amino-benzyl)-carbamic acid tert-butyl ester. (4-Nitro-benzyl)-carbamic acid tert-butyl ester (6.34g, 25.1 mmol), iron powder (6.5g, 116mmol), ammonium formate (13.0g, 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 (Na₂SO₄), and concentrated in vacuo to give (4-amino-benzyl)-carbainic acid tertbutyl ester (5.02g, 90% yield). LC/MS Calcd for [M+H]⁺ 223.1, found 167.1 (minus tbutyl).

[0452] [3-({l-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyl }-amino)-benzyl]-carbamic acid tert-butyl ester. l-[4-(6,7-Dimethoxy-quinolin4-yloxy)-phenyfcarbamoyl]-cycIopropanecarboxylic acid (254 mg, 0.62mmol), (4-aminobenzyl)-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 H₂O and the resulting solids are filtered, washed with H₂O, followed by sat’d NaHCOs, and dried under high vacuum to give crude [3-({ 1-(4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]cyclopropanecarbonyl}-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 [M+H]⁺ 613.3, found613.1.

[0453] N- [3-(Aminomethyl)phenyl]-N'-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl) cydopropane-Ll-dicarboxamide, TFA salt. [3-({ 1-(4-(6,7-Dimethoxy-quinolin-4yloxy)-phenylcarbamoyl]-cyclopropanecaibonyl}-amino)-benzyl]-carbamic acid tert-butyl ester (50 mg, 0.081mmol) was dissolved in 50% TFA in CH₂C1₂ (lOmls) and stirred at room temperature. After 2hrs, the reaction mixture was concentrated in vacuo and the resulting residue was triturated with Et₂O. The resulting solids were filtered, washed with Et₂O and dried under high vacuum to give 'N-[3-(aminomethyl)phenyl]-N’-(4-{[6,7252

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2020201638 05 Mar 2020 bis(methyloxy)quinolm-4-yl]oxy}phenyl)cyclopropane-l,l-dicarboxamide as the TFA salt (54 mg, 100%). ‘HNMR (400MHz, DMSO-d6): S 10.28 (s, 1H), 10.19 (s, 1H), 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, 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 [M+H]⁺ 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	’ll-NMR
1	N-[3-fluoro-4-( {6-(methyloxy)- 7-[(3-piperazin-1ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)cyclopropane-l, 1 dicarboxamide	1H NMR (DMSO-d6): 10.52 (s, 1H), 10.02 (s, 1H), 9.38 (br., 3H), 8.79 (d, 1H), 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, 2H), 4.04 (s, 3H), 3.17-3.50 (m, 9H), 2.27 (br., 2H), 1.79 (m, 1H), 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-ly Ppropyl] oxy} quinolin-4yl)oxy]phenyl)-N'-(4fluorophen yl)cyclopropane-1,1dicarboxamide	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, 3H), 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-{ [(1 -methylpiperidin-4yl)methyl]oxy} quinolin-4yl)oxy]phenyl ] -N'-(4fluorophenyl)cyclopropane-l,ldicarboxamide	1H NMR (400MHz, DMSO-d6): d 10.51 (s, 1H), 10.30 (br. s, 1H), 10.04 (s, 1H), 8.80 (d, 1H), 7.99 (dd, 1H), 7.55 (m, 2H), 7.67-7.53 (m, 4H), 7.16 (t, 2H), 6.89 (d, 1H), 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-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]cyclopropane1,1 -dicarboxamide	‘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, 3H), 7.10 (m, 2H), 6.7 (d, 1H), 4.5 (m, 2H), 4.3 (m, 2H), 4.01(s, 3H), 3.5 (br, 2H), 3.3 (m, 2H), 3.1 (m, 2H), 2.51 (m, 2H), 1.9 (m, 2H) 1.6 (m, 4H).
5	N-(4-{[7-{[3- (diethylamino)propyl]oxy} -6(methyloxy)quinolin-4-yl] oxy }3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-1,1dicarboxaiiiide	*H NMR (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), 3.21 (m, 7H), 2.29 (m, 2H), 1.46 (d, 4H), 1.15 (t, 6H).

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Entry	Name	1H-NMR
6	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -2-chloro-5fluorophenyl)-N'-(4fluorophenyljcyclopropane-l, 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(methylthio)quinolin-4-yl]oxy} 3-fluorophenyl)-N’-(4fluorophenyl)cyclopropane-l, 1 dicarboxamide	Ή NMR (DMSO-dff) d 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, 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)-N’-(4-{ [2methyl-6,7bis(methy]oxy)quinazolin-4yljoxy} phenyl )cyciopropane1,1-dicarboxamide	‘HNMR (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, ΪΗ), 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-amino-6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N'-(4“ fluoiOphenyl)cyclopropane-l ,1 dicarboxamide	1H NMR (DMSO-d6) d 10.34 (s, 1H), 9.95 (s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H), 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)-6,7bis(methyloxy)quinolin-4yl]oxy} phenyl )-N'-(4fluorophenyl)cyclopropane-l ,1 dicarboxamide	NMR (DMSO-ris) 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-morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl] -N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	‘H NMR (400 MHz, DMSO-dJ d 10.49 (br s, 1 H), 10.26 (br s, 1 H), 10.15 (br s, 1 H), 8.74 (br s, 1 H), 7.95 (br d, J = 13.2 Hz, 1 H), 7.87.5 (m, 6 H), 7.16 (t, J = 8.9 Hz, 2 H), 6.82 (br s, 1 H), 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), 2.402.30 (m, 2 H), 2.04-1.95 (m, 1 H), 1.45 (dd, J = 7.2, 4.7 Hz, 1 H), 1.36 (dd, J = 8.5,4.5 Hz, 1 H), 1.09 (d, J = 6.2 Hz, 3 H).

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Entry	Name	1H-NMR
12	(lR,2R)-N-[3-fIuoro-4-({ 6- (methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4yi} oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide	*H NMR (400 MHz, DMSO-d^) d 10.65 (br s, 1 H), 10.54 (br s, 1 H), 9.74 (s, 1 H), 8.75 (br s, 1 H), 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, I H), 4.34 (br t, J = 5 Hz, 2 H), 4.04 (s, 3 H), 4.053.95 (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, 1 H), 1.40-1.30 (m, 2 H), 1.10 (d, J = 6.2 Hz, 3 H).
13	N-(4-{[6-{[3(diethylamino)propyl] oxy} -7 (methyloxy )quinolin-4-yl ]oxy} 3 -fluorophenyl)-N’-(4fluorophenyl)cyclopropane-l, 1 dicarboxamide	T-INMR (DMSO-4,) d 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).
14	N-(4-{[6-{[2- (diethy]amino)ethyl]oxy} -7(methyloxy)quinolin-4-yl]oxy} 3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l,ldicarboxamide	’HNMR (DMSO-dtf) 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-[(2fluoro-4-{[(l-{[(4fluorophenyl)amino]carbonyl}c yclopropyl)carbonyl] amino jphe nyl)oxy]-6(methyloxy)quinolin-7yljoxy }propyl)piperazine-1 carboxylate	‘H 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), 2.622.59 (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-morpholin-4ylpropyl)oxy]quinazolin-4yl}oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	’HNMR (DMSO-dd) d 10.40 (s, 1H), 9.65 (s, 1H), 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), 2.40 (t, 2H), 2.36 (m, 4H), 1.90 (m, 3H), 1.30 (m, 2H), 1.02 (d, 3H).
17	(lR,2R)-N-(4-{[7-{[2(diethylamino)ethyl]oxy}-6(methyloxy)quinazolin-4yljoxy} -3-fluorophenyl)-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	Ή NMR (DMSO-di) d 10.49 (s, 1H), 9.73 (s, 1H), 8.52 (s, 1H), 7.85 (dd, 1H), 7.61 (m, 2H), 7.54 (s, 1H), 7.41 (m, 3H), 7.12 (t, 2H), 7.23 (t, 2H), 3.96 (s, 3H), 2.86 (t, 2H), 2.56 (q, 4H), 1.98 (m, 1H), 1.34 (m, 2H), 1.07 (d, 3H), 0.97 (t,6H).

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Entry	Name	^-NMR
18	N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6(methyloxy)quinazolin-4yl]oxy)-3-fluorophenyl)-N'-(4fluorophenyl)cyc]opropane-1,1dicarboxamide	1H NMR (DMSO-d6) 8.51 (s, 1H), 7.78-7.84 (m, 1H), 7.58-7.64 (m, 2H), 7.53 (s, 1H), 7.347.48 (m, 3H), 7.13 (t, 2H), 4.22 (t, 2H), 3.98 (s, 3H), 2.84 (t, 2H), 2.55 (q, 4H), 1.48 (s, 4H), 1.39 (t, 6H).
19	N-(4-{ [7-{ [3-(4-acetylpiperazm- l-yl)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy} 3-fIuorophenyl)-N'-(4fluorophenyl)cyclopropane-1,1dicarboxamide	NMR (400 MHz, CDCIg): 10.04 (s, 1H), 8.48-8.47 (d, 1H), 8.21 (s, 1H), 7.79-7.76 (d; 1H), 7.57 (s, 1H), 7.52-7.44 (m, 3H), 7.28-7.20 (m, 2H), 7.09-7.05 (t, 2H), 6.40-6.39 (d, 1H), 4.30-4.26 (t, 2H), 4.04 (s, 3H), 3.64-3.62 (t, 2H), 3.49-3.47 (t, 2H), 2.62-2.58 (t, 2H), 2.502.44 (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	1,1-dimethylethyl 4-(3-{ [4-((2fluoro-4-( [((lR,2R)-l-{ [(4fluorophenyl)amino]carbonyl }2methylcyclopropyl)carbonyl]am ino} phenyl)oxy]-6(methyloxy)quinolin-7yl]oxy }propyl)piperazine-1 carboxylate	Ή NMR (400 MHz, DMSO-^): 10.54 (s, 1H), 9.72 (s, 1H), 8.47-8.46 (d, 1H), 7.96-7.93 (dd, 1H), 7.63-7.61 (m, 2H), 7.52 (br s, 2H), 7.427.40 (d, 2H), 7.17-7.12 (t, 2H), 6.44-6.42 (d, 1H), 4.22-4.18 (t, 2H), 3.95 (s, 3H), 3.42-3.40 (m, 2H), 2.36-2.26 (m, 8H), 2.00-1.98 (m, 3H), 1.58-1.54 (m, 2H), 1.40 (s, 9H), 1.10-1.09 (d, 3H).
21	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-(4fluorophenyl)-l(phenylmethyl)azetidine-3,3dicarboxamide	1HNMR (DMSO-d6): 10.0 (s, 1H), 9.9 (s, 1H), 8.45 (d, 1H), 7.8 (d, 2H), 7.7 (m, 2H), 7.5 (s, 1H), 7.4 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.7 (s, 4H), 3.6 (s, 2H).
22	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }phenyl)-N'-(4fluorophenyl)azetidine-3,3dicarboxamide	1HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt).
23	(lR,2S)-N-{3-fluoro-4-[(6(methyloxy)-7 - {[3 -(4methylpiperazin-1 yl)propyl]oxy }quinolin-4yl)oxy]phenyl }-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	*H NMR (400 MHz, DMSO-rfff): 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, 2H), 2.402.24 (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).

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Entry	Name	‘ll-NMR
24	(lR,2R)-N-{ 3-fluoro-4-[(6(methyloxy)-7-{ [3-(4methylpiperazin-1 yl)propyl]oxy }quinolin-4yl)oxy]phenyl}-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	‘HNMR (400 MHz, DMSO-dg): 10.56 (s, 1H), 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, 2H), 7.44-7.39 (m, 2H), 7.18-7.12 (m, 2H), 6.446.42 (d, 1H), 4.20-4.17 (t, 2H), 3.95 (s, 3H), 3.42-3.30 (m, 3H), 2.46-2.44 (m, 2H), 2.33 (br s, 2H), 2,15 (s, 3H), 2.05-1.94 (m, 2H), 1.89 (s, 5H), 1.40-1-35 (m, 1H), 1.10-1.09 (m, 3H).
25	(lR,2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-piperazin-ly]propyl)oxy]quinolin-4yl)oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	*HNMR (400 MHz, DMSO-ds): 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), 7.447.40 (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 (br s, 3H), 2.041.95 (m, 3H), 1.40-1.35 (m, 2H), 1.11-1.09 (m, 5H).
26	N-(3-fluoro-4-{ [7-({3-[4-(lmethylethyl)piperazin-lyl]propyl}oxy)-6(methyloxy)quino]in-4yl]oxy [phenyl )-N'-(4fluorophenyl)cyclopropane-l, 1dicarboxamide	’H NMR (400 MHz, DMSO-de): 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), 6.426.41 (d, 1H), 4.20-4.17 (t, 2H), 3.95 (s, 3H), 2.70-2.68 (m, 1H), 2.62-2.55 (m, 2H), 2.462.33 (m, 8H), 1.99-1.94 (m, 2H), 1.47 (s, 4H), 1.00-0.95 (m, 6H).
27	N-(4-{[7-{[3(diethylamino)propyl]oxy} -6(methyloxy)quinazolin-4yl]oxy} -3 -fluorophenyl)-N’-(4fluorophenyl)cyclopropane-1,1dicarboxamide	’HNMR (DMSO-de)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 (m, 3H), 7.12 (t, 2H), 4.22 (t, 2H), 3.94 (s, 3H), 2.522.61 (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~ (methyloxy)quinolin-4-yl]oxy} 3-fluorophenyl)-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarbox amide	!HNMR (DMSO-de) 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, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.55 (m, 2H), 2.31 (m, 4H), 1.98 (m, 1H), 1.88 (m, 2H), 1.35 (m, 2H), 1.07 (d, 3H), 0.94 (t, 6H).
29	(lR,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy} -6(methyloxy)quinolin-4-yl] oxy} 3-fluorophenyl)-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	iHNMR (DMSO-ife) d 10.52 (s, 1H), 9.70 (s, 1H), 8.44 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 2H), 7.51 (m, 2H), 7.41 (m, 2H), 7.12 (t, 2H), 6.41 Cd, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.85 (t, 2H), 2.57 (q, 4H), 1.98 (m, 1H), 1.34 (m, 2H), 1.07 (d, 3H), 0.98 (t, 6H).

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Entry	Name	1H-NMR
30	(lR,2S)-N-(4-{[7-{[3(diethylamino)propyl]oxy}-6(methyloxy)quinolin-4-yl]oxy) - 3-fluorophenyl)-N'-(4fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide	'H NMR (DMSO-ri6) 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-fluorophenyl)-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	^NMR (DMSO-<fc) 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 (m, 2H), 7.14 (m, 2H), 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- (diethylamino)ethyl]oxy}-6(methyloxy)quinazolin-4yl]oxy }-3-fluorophenyl)-N'-(4fluorophenyl)cyclobutane-1,1dicarboxamide	]HNMR (CDC13) 8.57 (s, 1H), 8.12 (s, 1H), 7.73-7.81 (m, 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, 2H). 2.76 (q, 4H), 2.67 (q, 4H), 2.01-2.15 (m, 2H), 1.10 (t, 6H).
33	,(lR,2S)-N-[3-fluoro-4-({6(methyloxy)-7-[(3-piperazin-lylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide	NMR (400 MHz, DMSO^): 10.28 (s, 1H), 9.80 (s, 1H) 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), 6.446.41 (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, 4H), 1.43-1.35 (m, 2H), 1.09-1.08 (m, 3H).
34	(lr,2R,3S)-N-[3-fluoio-4-({ 6- (methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxamide	1H NMR (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), 2Hf7.4 ppm, m), 2H ¢7.13 ppm, t), 1H (6.4 ppm, d), 2H (4.2 ppm, t), 3H (3.94 ppm, 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, m), 6 H(1.28 ppm, d).
35	(lr,2R,3S)-N-{3-fluoro-4-[(6(methyloxy)-7-{ [3-(4methylpiperazin-1 yl)propyl]oxy} quinolin-4y])oxy]phenyl}-N’-(4fluorophenyl)-2,3dimethylcyclopropane-l, 1dicarboxamide	1H NMR (DMSO-d6): 1H (10.12 ppm, s), 1H (9.6 ppm, s), 1H (8.46 ppm, d), 1H (7.88 ppm, dd), 2H (7.69 ppm, m), 1H (7.58 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 (3.95 ppm, s), 10H (2.35 ppm, m), 3H (2.14 ppm, s), 2H (1.97 ppm, t), 2H (1.8 ppm, m), 6H (1.28 ppm, d).

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Entry	Name	1H-NMR
36	N- [3-fluoro-4-( {6-(methyloxy)- 7- [(3-morpholin-4ylpropyl)oxy]quinazoIin-4yl }oxy)phenyl]-N'-(4fluorophenyl)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, 2H), 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-morpholin-4ylpropyl)oxy]quinolin-4yl[oxy)phenyl] -1^-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxamide	’H NMR (400 MHz, CDClj) d 8.44 (d, J = 5.1 Hz, 1 H), 8.11 (br s, 1 H), 7.77-7.70 (m, 2 H), 7.53 (s, 1 H), 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), 1.30-1.24 (m, 6 H).
38	(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy} -6(methyloxy)quinolin-4-yl]oxy}3-fluorophenyl)-N'-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxamide	NMR (400 MHz, DMSO-de) d 10.34 (s, 1 H), 10.05 (s, I H), 8.46 (br s, 1 H), 7.93 (br d, J = 4.7 Hz, 1 H), 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, 1 H), 4.30-4.20 (m, 2 H), 3.95 (s, 3 H), 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)quinolm-4-yl]oxy} 3-fluorophenyl)-N'-(4fluorophenyl)-2,2dimethylcyclopropane-l, 1 dicarboxamide	1H NMR (400MHz, DMSO-d6): d 10.47 (s, 1H), 10.16 (s, 1H), 8.43 (d, 1H), 7.92 (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-morpholin-4ylpropyl)oxy]quinazolin-4yl} oxy)phenyl]-N'-(4fluorophenyl)-2,2dimethylcyclopropane-1,1dicarboxamide	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, 3H), 1.17 (s, 3H).
41	(lR,2R,3S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy} -6(methyloxy)quinolin-4-yl]oxy} 3-fluorophenyl)-N'-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxamide	1H NMR (400MHz, DMSO-d6): d 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, 1H), 7.15 (t, 2H), 6.41 (d, 1H), 4.20 (m, 2H), 3.94 (s, 3H), 2.87 (m, 2H), 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.

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Entry	Name	*H-NMR
42	N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6(methyloxy)quinazolin-4y]]oxy}-3-fluorophenyl)-N'-(4fluorophenyl)-2,2dimethylcyclopropane-l, 1 dicarboxamide	1HNMR (400MHz, DMSO): d 10.24 (s, IH), 10.00 (s, IH), 8.54 (s, IH), 7.84 (dd, IH), 7.66 (m, 2H), 7.56 (s, IH), 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).
43	N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6(methyloxy)quinazolin-4yI]oxy}-3-fluorophenyl)-N’-(4fluorophenyl)-2,2dimethylcyclopropane-1,1dicaiboxamide	1HNMR (400MHz, DMSO-d6): d 10.21 (s, IH), 9.97 (s, IH), 8.51 (s, IH), 7.82 (dd, IH), 7.64 (m, 2H), 7.54 (s, IH), 7.48 (m, IH), 7.41 (m, IH), 7.37 (s, IH), 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, 6H).
44	N-(4-{[7-{[3(diethylamino)propy]]oxy} -6(methyloxy)quinazolin-4yl]oxy}-3-fluorophenyl)-N’-(4fluorophenyl)cyclobutane-1,1dicarboxamide	IH NMR (CDC13): 8.57 (s, IH), 8.50 (s, IH), 8.11 (s, IH), 7.81 (dd, IH), 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-methylpiperazin-lyl)propyl]oxy }quinazolin-4yl)oxy]phenyl }-frT-(4fhiorophenyl)cyclobutane-1,1dicarboxamide	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-moipholin-4ylpropyl)oxy]quinazolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxamide	NMR (400 MHz, CDClj) d 8.59 (s, 1 H), 8.11 (br s, 1 H), 7.80-7.76 (m, 2 H), 7.53 (s, 1 H), 7.50-7.46 (m, 2 H), 7.34 (s, 1 H), 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), 1.28-1.20 (m, 6 H).
47	N-(4-{[7-{[3(diethylamino)propyl]oxy} -6(methyloxy)quinolin-4-yl]oxy}3-fluorophenyl)-N’-(4fluorophenyl)cyciobutane-l, 1dicarboxamide	‘H NMR (400 MHz, DMSO-*): 9.98 (s, IH), 9.72 (s, IH), 8.45-8.43 (d, IH), 7.97-7.94 (dd, IH), 7.73-7.69 (m, 2H), 7.65-7.52 (m, 3H), 7.44-7.39 (m, IH), 7.18-7.14 (m, 2H), 6.436.42 (d, IH), 4.20-4.19 (t, 2H), 3.95 (s, 3H), 2.70-2.66 (m, 6H), 2.45 (brs, 2H), 1.91-1.84 (m, 6H), 0.98 (br s, 6H).

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Entry	Name	*H-NMR
48	N- {3-fluoro-4-[(6-(methyloxy)Ί-{ [3-(4-methylpiperazin-lyl)propyl]oxy} quinolin-4yl)oxy]phenyl} -N'-(4fluorophenyl)cyclobutane-1,1dicarboxamide	]H NMR (400 MHz, DMSO-^): 9.99 (s, IH), 9.73 (s, IH), 8.45-8.43 (d, IH), 7.97-7.93 (dd, IH), 7.73-7.69 (m, 2H), 7.65-7.52 (m, 2H), 7.44-7.38 (m, 2H), 7.18-7.14 (m, 2H), 6.436.42 Cd, IH), 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- (diethylamino)ethyl]oxy} -6(methyloxy)quinazolin-4yl]oxy }-3-fluorophenyl)-N'-(4fluorophenyl)-2,3dimethylcyclopropane-1,1di carboxamide	’H NMR (400 MHz, CDClj) d 8.59 (br s, 1 H), 8.29 (br s, 1 H), 7.93 (s, 1 H), 7.77 (d, J = 10.8 Hz, 1 H), 7.53 (s, 1 H), 7.50-7.45 (m, 2 H), 7.32 (s, 1 H), 7.26-7.22 (m, 2 H), 7.05-6.99 (m, 2 H), 4.27 (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), 1.22 (br t, J = 5.3 Hz, 6 H), 1.09 (bit, J = 7.2 Hz, 6 H).
50	(2R,3R)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6(methyloxy)quinazo]in-4yl]oxy )-3-fluorophenyl)-N,-(4fluorophenyl)-2,3dimethylcyclopropane-1,1dicarboxaniide	!H NMR (400 MHz, CDCh) d 8.58 (s, 1 H), 8.40-8.36 (m, 1 H), 8.02-7.96 (m, 1 H), 7.807.75 (m, 1 H), 7.53 (s, 1 H), 7.52-7.50 (m, 2 H), 7.31 (s, 1 H), 7.28-7.20 (m, 2 H), 7.02 (t, J = 8.5 Hz, 2 H), 4.25 (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)quinolin-4-yl]oxy}3-fluorophenyl)-N'-(4fluorophenyI)-2,3dimethylcyclopropane-1,1dicarboxamide	*H NMR (400 MHz, CDC13) d 8.47 (d, J = 5.2 Hz, 1 H), 8.17 (br s, 1 H), 7.80-7.74 (m, 2 H), 7.55 (s, 1 H), 7.52-7.46 (m, 2 H), 7.42 (s, 1 H), 7.24-7.20 (m, 2 H), 7.05 (t, J = 8.6 Hz, 2 H), 6.38 (br d, J = 5.4 Hz, 1 H), 4.27 (t, J = 6.4 Hz, 2 H), 4.03 (s, 3 H), 3.04 (br t, J = 7.2 Hz, 2 H), 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 (br t, J = 7.2 Hz, 6H).
52	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[(4fluorophenyl)methyl]cyclopropa ne-1,1-dicarboxamide	1HNMR (DMSO-d6): 10.82 (s, IH), 8.80 (d, IH), 8.50 (t, IH), 7.83 (d, 2H), 7.74 (s, IH), 7.56 (s, IH), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, IH), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).
53	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} phenyl )-N'-(2morpholin-4ylethyl)cyclopropane-1,1dicarboxamide	1HNMR (DMSO-d6): 10.62 (s, IH), 8.79 (d, IH), 8.24 (t, IH), 7.83 (d, 2H), 7.72 (s, IH), 7.58 (s, IH), 7.37 (d, 2H), 6.76 (d, IH), 4.04 (s, 3H), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2H), 3.49 (m, 4H), 3.25 (t, 2H), 3.13 (br., 2H), 1.42 (d, 4H).

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Entry	Name	‘h-nmr
54	N-(4-([6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[2(piperi din-1 ylmethyl)phenyl]cyclopropane1, l-dicarboxamide	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 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (s, 2H), 2.17 (br., 4H), 1.49 (m, 4H), 1.41 (m, 4H), 1.32 (br., 2H).
55	N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy} phenyl )-N'-[2(pyrrolidin-1y]methyl)phenyl]cyclopropane1,1 -dicarboxamide	1HNMR (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), 7.17-7.27 (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).
56	N-(4-{[6,7- bis(methyIoxy)quinolin-4yl]oxy} phenyl)-N*-[3(morpholin-4ylmethyl)phenyl]cyclopropane1,1-dicarboxamide	1H NMR (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, 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).
57	N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[2(morpholin-4ylmethyl)phenyl]cyclopropane1 , l-dicarboxamide	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 (s, 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,4H).
58	N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-Nphenylcyclopropane-1,1dicarboxamide	1H NMR (DMSO-d6): 10.14 (s, 1H), 10.03 (s, 1H), 8.44 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 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-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)cyclopropane' 1,l-dicarboxamide	1H NMR (400MHz, DMSO-d6): d 10.28 (s, 1H), 10.19 (s, 1H), 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, 1H), 4.03 (s, 6H), 3.39 (m, 2H), 1.53 (m, 4H). Note: all peaks are very broad and unresolved.
60	N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy }phenyl)-N’-[3(piperidin-lylmethyl)phenyl]cyclopropane1,1 -dicarboxamide	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, 1H), 7.24 (m, 3H), 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), 1.39 (br., 2H).

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Entry	Name	XH-NMR
61	N-(4-{[6,7- bis(methyloxy)quinolin-4yI]oxy}phenyl)-N'-[3(pyrrolidin-lylmethyl)phenyl]cyclopropane1,1-dicarboxamide	IH NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, IH), 7.77 (d, 2H), 7.59 (s, IH), 7.53 (d, IH), 7.51 (s, IH), 7.39 (s, IH), 7.23 (m, 3H), 6.99 (d, IH), 6.43 (d, IH), 3.95 (s, 3H), 3.93 (s, 3H), 3.52 (s, 2H), 2.42 (br., 4H), 1.69 (br, 4H), 1.48 (s, 4H).

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 SM-1891) by incubation of 60ul/well of 20pg/ml MBP in Tris-buffered saline (TBS; 50mM Tris pH 8.0, 138mM NaCl, 2.7mM KC1) for 24 hours at 4° C. Plates were washed 3X with ΙΟΟμΙ TBS. Kinase reactions were carried out in a total volume of 34μ1 in kinase buffer (5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506), lOmM MgCl₂, 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, for example. A mixture of unlabeled ATP and γ³³P ATP was added to start the reaction (2xl0⁶ cpm of γ-³³Ρ ATP per well (3000Ci/mmole) and either 10μΜ or 30μΜ unlabeled ATP, typically. The reactions were carried out for 1 hour at room temperature with shaking. Plates were washed 7x with TBS, followed by the addition of 50gl/well scintillation fluid (Wallac). Plates 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 IC50 for inhibition and/or the inhibition constant, Ki. 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 ICjq’s 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 100 nM, and still further, for example, less than about 10 nM. The Ki for a compound may be

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2020201638 05 Mar 2020 determined from the IC50 based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity. 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:

z (E0+Z0 + Xrf)-7(£0+Z0 + KJ2-4£0Z0 2E0

where V is the observed rate, V^, is the rate of the free enzyme, Iq is the inhibitor concentration, Eo is the enzyme concentration, and Kj is the dissociation constant of the enzyme-inhibitor complex.

Kinase specificity assays:

[0457] Kinase activity and compound inhibition are investigated using one or more 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. Doseresponse 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 4- (Max - Min) / (1 + (X/IC₅₀)^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 the 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 close 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.

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Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, IpM ATP, IpM polyEY and lOnM c-Met (baculovirus expressed human c-Met kinase domain P948-S1343) in a 20uL assay buffer (20mM Tris-HCL pH7.5, 10mM MgCl₂, 0.02% Triton X-100, lOOmM DTT, 2mM MnCl₂). The mixture is incubated at ambient temperature for 2hours 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.

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 pM ATP, 1.6 pM poly-EY and 5 nM KDR (baculovirus expressed human KDR kinase domain D807-V1356) in a 20uL assay buffer (20mM TnsHCL pH7.5, lOmM MgCl₂, 0.01% Triton X-100, ImM DTT, 3mM MnCl₂). 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 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 ng/mT. 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 excitation 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.

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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(GIu, Tyr) and 1 nM Flt-4 (baculovirus expressed human Fit-4 kinase domain D725-R1298) were combined in a volume of 20 pL in a 384well 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 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.

flt-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 TrisHCL pH7.5, lOmM MgCfi, 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 assessed using AlphaScreen ™ (Perkin Elmer) technology, described above. Test compounds, ATP, biotinylated poly(Glu, Tyr) and cKit kinase 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/mT. AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM

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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 IC50 with the following key: A = IC50 less than 50 nM, 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 the quinazoline or quinoline, exemplary compounds of the invention exhibit selectivity for any of c-Met, KDR, c-Kit, fit-3, and flt-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, fms-like tyrosine kinase-4, representative of the FLK family of receptor tyrosine kinases; c-Kit, also called stem cell factor receptor or steel factor receptor; and flt-3, fms-like tyrosine kinase-3. Empty cells in the tables indicate lack of data only.

Table 4

Entry	Name	-4-J ώ	1	c-Kit	S3 c	§
1	N- [({3-fluoro-4-[(6-(methyloxy)-7 - {[(3aR,6aS)octahydrocyclopenta[c]pyrrol-5ylmethyl]oxy} quinazolin-4yl)oxy]phenyl} amino)carbonothioyl]-2phenylacetamide		A			A
2	N-{ [(3-fluoro-4-{ [7-( {[(3aR,6aS)-2methyloctahydrocyclopenta[c]pyrrol-5yl]methyl}oxy)-6-(mcthyloxy)quinazolin-4yl]oxy} phenyl)amino]carbonothioyl }-2phenylacetamide	A	A	A		A
3	N- {[(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)(methyl)amino]carbonothioyl}-2phenylacetamide	C
4	1 - (4- {[6,7-bis(methyloxy )quinolin-4-yl] oxy} -3 fluorophenyl)imidazoIidin-2-one	C		C	c
5	1-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy [-3- fluorophenyl)-3-(phenylmethyl)imidazolidin-2-one	C		B	c
6	l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fiuorophenyl)-3-(phenylacetyl)imidazolidin-2-one	B

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7	ethyl [(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)amino] (oxo)acetate	B	B	C		B
8	N- {[(4- {[6,7-bis(methyloxy)quinazolin-4-yl]amino} -3fluorophenyl)aimno]carbonothioyl} -2phenylacetamide	A	B	C		B
9	N'-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3- fluorophenyl)-N-methyl-N-(2-phenylethyl)sulfamide	C
10	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-3-(phenyhnethyl)-1,2,4-oxadiazol-5amine	C		B	c
11	1-(4-( [6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)piperidin-2-one	c		C	c
12	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-(phenylmethyl)ethanedi amide	B	B	B	c	B
13	N-(4-{[6,7-bis(methyIoxy)quinoIin-4-yl]oxy}-3- fluorophenyl)-4-phenyl-1,3-thiazol-2-amine	c		C	B
14	N-(4- {[6,7-bis(methyloxy)quinoIin-4-yl]oxy }-3- fluorophenyl)-N'-(2-phenylethyl)ethanediamide	A	A	A	c	A
15	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-!-phenylmethanesulfonamide	C		C	B
16	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-2-phenylethanesulfonamide	C		C	C i
17	4~{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fluoro-N(phenylmethyl)benzenesulfonamide	C		c	c
18	4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fluoro-Nmethyl-N-(phenylmethyl)benzenesulfonamide	C		c	c
19	4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy }-3-fluoro-N(2-phenylethyl)benzenesulfonamide	C		c	c
20	4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- methyl-N-(2-phenylethyl)benzenesulfonamide	C		c	c
21	4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- (3-phenylpropyl)benzenesulfonamide	C
22	l-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3- fluorophenyl)pyrrolidin-2-one	C		c	B
23	4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl (phenylmethyl)carbamate	C
24	4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy [phenyl (2phenylethyl)carbamate	c
25	4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3-fluoro-Nmethyl-N-(3-phenylpropyl)benzenesulfonamide	c
26	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N'-phenylethanediamide	B	D	c		C
27	4-{[6,7-bis(methyloxy)quinolin-4-y]]amino}-N-(3- phenylpropyl)benzamide	c

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28	N-{ [(3-fluoro-4-{ [7-( [(2methyIoctahydrocyclopenta[c]pyrrol-5yl)methyI]oxy}-6-(methyloxy)quinolin-4yl]oxy }phenyl)amino]carbonothioyl} -2phenylacetamide	A	A	A	A	A
29	N-[(Z>[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)annno] (iminojmethyl] -2phenylacetamide	C
30	4-{[6,7-bis(methyIoxy)quinolin-4-yl]oxy}-3-fluoro-N[2-(phenyloxy)ethyl]benzenesulfonamide	C
31	This type of multiplicative nomenclature is not supported in current version!	C
32	N-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3- fluorophenyl)-3-phenylpropane-l-sulfonamide	C
33	N~2~-[(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy }-3- fluorophenyl)sulfonyl]-N-phenylglycinamide	C
34	N-(6- {[6,7-bis(methyloxy)quino]in-4-yl]oxy}pyridin- 3-yl)-2-phenylacetamide	C
35	N-{ [(6- {[6,7-bis(methyloxy)quinolin-4yl]oxy}pyridin-3-yl)amino]carbonothioyl}-2phenylacetamide	A	C	D		C
36	6-{ [6,7-bis(methyloxy)quinolin-4-y]]oxy}-1,3- benzothiazol-2-amine	C		C	C
37	6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro- 1,3-benzothiazol-2-amine	C		C	c
38	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- fluoro-1,3-benzothiazol-2-yl)-2-phenylacetamide	B	C	D		B
39	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-(2-morpholin-4ylethyl)ethanedi amide	C		B	B
40	1,1-dimethylethyl {2-((4-( [6,7bis(methyloxy)quinolin-4-yl]oxy} -3fIuorophenyl)amino]-2oxoethyl} (phenylmethyl)carbamate	C
41	N-(4-{ [6,7-bis(methy!oxy)quinolin-4-yl]oxy} -3fluorophenyl)-N~2—(phenylmethyl)glycinamide	B
42	N-2—acetyl-N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-N~2~(phenylmethyliglycinamide	C
43	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-l,3benzothiazol-2-yl)-2-phenylacetamide	B
44	1,1-dimethylethyl (2-[(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)amino]2-oxoethyl} (phenylmethyl )carbamate	C
45	N-(6-([6,7-bis(methyloxy)quinolin-4-yI]oxy]pyridin- 3-yl)-N~2—(phenylmethyl)glycinamide	C

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46	N~2~-acetyl-N-(6-{[6,7-bis(methyloxy)qumolin-4yl]oxy} p yridin-3-yI)-N~2~(phenylmethyl)glycinamide	C
47	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oKy} pyridin- 3-yl)-3-phenylpropanamide	C
48	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} pyridin- 3-yl)-4-phenylbutanamide	c
49	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy [pyridin - 3-yl)-N~2~-methyl-N~2—(phenylmethyl)glycinamide	c
50	N-(4- {[6,7-bis(methyloxy)quinoIin-4-yl]oxy} -3fluorophenyl)-N'- {2-(4(methyloxy)phenyl]ethyl [ethanedi amide	c		C	C
51	N-(4-([6,7-bis(methyIoxy)quinolin-4-yI]oxy}-3fluorophenyl)-N~2~-methyl-N-2~(phenylmethyl)glycinamide	B	A	B	B	A
52	N-( [(4-( (6,7-bis(methyIoxy)qumolin-4yl]amino [phenyl )amino]carbonothioyl} -2phenylacetamide	A	B	B	C	A
53	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy [-5fluoro-l,3-benzothiazol-2-yl)-3-phenylpropanamide	C
54	N-{ [(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy [-5chloropyridin-3-yl)amino]carbonothioyl}-2phenylacetamide	A	B	C		B
55	N-(4-{[6,7-bis(methyloxy)qumolin-4-yl]oxy)-3fluorophenyl)-N'-(2,3-dihydro-lH-inden-lyl)ethanediamide	A	B	B		B
56	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N'-(2,3-dihydro-lH-inden-2yl)ethanediamide	C
57	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-( 1,2,3,4-tetrahydronaphthalen-l yl)ethanediamide	B	B	C		C
58	N'-(4- {[6,7-bis(methyloxy)qumolin-4-yl] oxy [-3fluorophenyl)-N-(2-phenylethyl)-N(phenylmethyl)sulfamide	1470 .06
59	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N~2~-(trifluoroacetyl)glycinamide	B	C	B		B
60	N-{ 2-((4- {[6,7-bis(methyk>xy)quinolin-4-yl]oxy} -3fluorophenyl)amino]-2-oxoethyl}benzamide	B	A	A	A	A
61	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy [pyridin- 3-yl)-N'-(4-fIuorophenyl)propanediamide	A	B	B		B
62	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3- fluOTOphenyl)-N,-[(2S)-l,2,3,4-tetrahydronaphthalen-2yl]ethanedi amide	C

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63	N-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-[2-(4methylphenyl)ethyl]ethanediamide	C		C	C
64	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N’-(2-phenylpropyl)ethanedi amide	B	A	B	B	B
65	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N'-[2-(4chlorophenyl)ethyl]ethanediamide	A	C	B	C	C
66	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N,N'-bis(phenylmethyl)sulfamide	C
67	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyI)-N,N'-bis(2-phenylethyl)sulfamide	C
68	ethyl [(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridin-3-yl)amino](oxo)acetate	C
69	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-N'-(2-phenyIethyl)ethanediainide	C
70	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5- chloropyridm-3-yl)-N'-(4fluorophenyl)propanediamide	A	B	B		c
’ 71	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N,-[(2R)-1,2,3,4-tetrahydronaphthalen2-yl]ethanediamide	B	D	B		c
72	N-(4-{[6,7-bis(methyloxy)quinolin-4-yI]oxy)-3fluorophenyl)-N'-[2-(l-methylpyrrolidin-2yl)ethyl]ethanedi amide	C		C	C
73	N-(4- {[6,7-bis(methyIoxy)quinolin-4-yI]oxy} -3- fluorophenyl)-N’-[2-(phenyloxy)ethyl]ethanediamide	B	B	B		c
74	N-(4- {[6,7-bis(rnethyloxy)qumolin-4-yl]oxy }-3fluorophenyl)-N'-[2-hydroxy-1 (phenylmethyl)ethyl]urea	B
75	l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-3-[(4-methylphenyl)sulfonyl]-4(phenylmethyl)imidazolidin-2-one	B	B'	B	B	B
76	N'-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3- fluorophenyl)-N-methyl-N-(2phenylethyl)ethanediamide	A	B	B	B	B
77	N-(4-{[6,7-bis(methyloxy)quino]in-4-yl]oxy}-3- fluorophenyl)-N'-{ [3(trifluoromethyl)phenyl]methyl} ethanediamide	B		B	B
78	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N'- {2- [3(trifluoromethyl)phenyl]ethyl} ethanediamide	C		A	B
79	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy }-5- chloropyridin-3-yl)-3-oxo-4-phcnylbutanamide	C

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80	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-2-[3(trifluoromethyl)phenyl] acetamide	C
81	6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N[2-(phenyloxy)ethyl]-l,3-benzothiazol-2-amine	B
82	6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N(2-piperidin-l -ylethyl)-! ,3-benzothiazol-2-amine	C
83	6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fliioro-N- methyl-N-(2-phenylethyl)-1,3-benzothiazoI-2-amine	C
84	6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- (2-pyrrolidin-l -ylethyl)-1,3-benzothiazol-2-amine	C
85	6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N{[3-(trifluoromethyl)phenyl]methyl} -1,3-benzothiazol2-amine	C
86	6-{[6,7-bis(methyloxy)quinolin-4-yI]oxy}-5-fluoro-N- {2-[3-(trifluoromethyl)phenyI]ethyl}-1,3-benzothiazol- 2-amine	C
87	N-(6-{ [6,7-bis(methyloxy)qiiinolin-4-ylJoxy} -5chloropyridin-3-yl)-N’-[3(trifluoromethyl)pheny]jpropanediamide	C
88	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5fluoro-1,3-benzothiazol-2-yl)-2-[3(trifluoromethyl)phenyljacetamide	C	A	B	B	B
89	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N~2— {[3(trifluoromethyl)phenyl]methyl}glycinamide	B	A	B	B	A
90	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N~2—(2-phenylethyl)glycinamide	B
91	N-(4-( [6,7-bis(methyloxy)quinolin-4-yI]oxy} -3fluorophenyl)-N~2~- {2-[3(trifluoromethyl)phenyl]ethyl} glycinamide	B	B	B	B	A
92	1,1-dimethylethyl {2-((6-([6,7- bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3- yl)amino]-2-oxoethyl}(phenylmethyl)carbamate	C
93	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- chloropyridin-3-yl)-N~2~-(phenylmethyl)glycinamide	C
94	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -5fluoro-1,3-benzothiazol-2-yl)-2- [3,5bis(tiifluoromethyl)phenyl]acetamide	C	B	B	D	C
95	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5fluoro-l,3-benzothiazol-2-yl)-2-[2-chloro-5(trifluoromethyl)phenyl]acetamide	A	A	B	B	B
96	N-{3-fluoro-4-[(6-(methyloxy)-7-{[(lmethylpiperidin-4-yl)methyl]oxy}quinolm-4yl)oxy]phenyl} -N’-(2-phenylethyl)ethanediamide	A	A	A	A	A

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97	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-(l,2,3,4-tetrahydroisoquinolin-lylmethyl)ethanediamide	C
98	N-(4-{ [6,7-bis(niethyloxy)quinolm-4-yl]oxy} -3fluorophenyl)-N'-[(2-methyl-1,2,3,4tetrahydroisoquinolin-l-yl)methyl]ethanediamide	B	B	B	A	B
99	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N~2—methyl-N-2— {[3(trifluoromethyl)phenyl]methyl} glycinamide	C
100	N-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N~2—methyl-N-2—{2-[3(trifluoromethyl)phenyl]ethyl}glycinarnide	C
101	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N~ 2—methyl-N~2~-(2phenylethyl)glycinamide	C
102	1 -(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-4-(phenylmethyl)imidazolidin-2-one	B	B	B	B	C
103	N-(6- {[6,7-bis(methyloxy)quinolin-4- yl]oxy)pyridazin-3-yI)-N'-(4fluorophenyl)propanediamide	A	C	B	A	c
104	N-(6-{[6,7-bis(methyloxy)qiiinolin-4-yl]oxy}-5chloropyridin-3-yl)-N'-(2chlorophenyl)propanedi amide	B
105	N-(6-([6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridin-3-yl)-N’-(3chlorophenyl)propanediamide	C
106	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridin-3-yl)-N~2—methyl-N-2— (phenylmethyl)glycinamide	C
107	N-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-N'-(4chlorophenyl)propanediamide	B
108	(2E)-N-(4- {[6,7-bis(methyloxy)quinolin-4- yl] oxy} phenyl)-2-[(methyloxy)immo]propan amide	B	B
109	(2E)-N-(4-{[6,7-bis(methyloxy)quinolin-4- yl]oxy} phenyl)-2-[(ethyloxy)imino]propanamide	B	A
110	(2E)-N-(4- {[6,7-bis(methyloxy)qumolin-4yl]oxy}phenyl)-2{[(phenylmethyl)oxy]imino)propanamide	B	B
111	N-(4-{ [6,7-bis(methyloxy)qumolin-4-yl]oxy Jphenyl)- 1 -(phenylmethyl)prolinamide	C	C
112	1-(4- {[6,7-bis(methyloxy)quinoliii-4-yl] oxy} phenyl )- 3-[(4-methylphenyl)sulfonyl]-4(phenylmethyl)imidazolidin-2-one	B	C	B	C	c
113	1-(4- {[6,7-bis(methyloxy)quinolm-4-yl]oxy Jphenyl)- 4-(phenylmethyl)imidazolidin-2-one	C	C

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114	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)- 4-(phenylmethyl)-4,5-dihydro-l,3-oxazol-2-amine	C	B
115	6,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin- 1 -yl]phenyl }oxy)quinoline	C	C
116	1-(4-( [6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- 4-(phenylmethyl)piperazin-2-one	c	C
117	N-(4- {[6,7-bis(methyloxy)qumolin-4-yl]oxy Jphenyl)- N~2~-(phenylmethyl)alaninamide	c	C
118	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N~2—methyl-N~2—(phenylmethyl)alaninamide	c	C
119	N-(4-{[6,7-bis(methyloxy)quinoIin-4-yl]oxy}phenyl)- N-2~-(phenylmethyl)leucinamide	c	C
120	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy)phenyl)- N~2~-methyl-N~2—(phenylmethyl)leucinamide	c	C
121	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N-2~-(phenylmethyl)valinamide	c	C
122	N-[5-chloro-6-( {6-(methyloxy)-4-[(piperidm-4ylmethyl)oxy]quinolin-7-yl}oxy)pyridin-3-yl]-N'-(4fluorophenyl)propanedi amide	c	C
123	1 -(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy [phenyl)- 4-(phenylmethyl)tetrahydropyrimidin-2( 1 H)-one	c	C
124	N-[3-fluoro-4-((6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolm-4-yl }oxy)phenyl] -N'-(2phenylethyl)ethanediamide	A	A	A	A	A
125	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridin-3-yl)-N'-(4-fluorophenyl)cyclopropane1,1-dicarboxamide	A	A	B	A	B
126	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridiii-3-yl)-N,-(4-fluorophenyl)cyclobutane1,1-dicarboxamide	c	C
127	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N~2—methyl-N~2~-(phenylmethyl)valinamide	c	c
128	(2E)-N-(4- {[6,7-bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2-[(phenyloxy)imino]propanamide	c	A
129	(2E)-N-(4- {[6,7-bis(methyloxy)quinolin-4yl]oxy}phenyl)-2-phenyl-2- {[(phenylmethyl )oxy]imino Jethanamide	B	C
130	6,7-bis(methyloxy)-4-({ 4- [4-(phenylmethyl)piperidin- l-yl]phenyl}oxy)quinoline	C	c
131	N-(4-{[6,7-bis(methyloxy)quinolm-4-yl]oxy}-3fluorophenyl>N'-{ [2-( 1-methylethyl)-1,2,3,4tetrahydroisoqiiinolin-l-yl]methyl}ethanedi amide	B	B
132	N-(4-{ [6,7-bis(meth yloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-[(2-ethyl-l ,2,3,4tetrahydroisoquinolin-l-yl)methyl]ethanediamide	B	C

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133	1,1-dimethylethyl 4-(( [4-{ [3-chloro-5-({ 3-((4fluorophenyl)amino]-3-oxopropanoyl} aminojpyridin2-yl]oxy}-6-(methyloxy)quinolin-7yl]oxy}methyl)piperidine-l-carboxylate	B	C
134	N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)pyridin-3-yl]-N’-(4fluorophenyl)propanediamide	A	B	B	A
135	N-{ 5-chloro-6-[(6-(methyloxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy]quinolin-4yI)oxy]pyridin-3-yl} -N'-(4fluorophenyl)propanedi amide	A	B	B	A
136	N-(4-{ [7-{ [3-(diethylamino)propyl]oxy }-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(2phenylethyl)ethanediamide	A	A	A	B	A
137	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(2phenylethyl)ethanediamide	A	A	A	B	A
138	N-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-piperidin-lylpropyl)oxy]quinoIin-4-yl} oxy)phenyl]-N'-(2phenylethyl)ethanediamide	A	A	A	A
139	N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(2phenylethyl)ethanediamide	A	A	A	A	A
140	N'-{3-fluoro-4-[(6-(methyloxy)-7-{[(lmethylpiperidin-4-yl)methyl]oxy]quinolin-4yl)oxy]phenyl }-N-methyl-N-(2- ' phenylethyl)ethanediamide	A	A			B
141	N-(3-fluoro-4-{ [7-( {[(3aR,5r,6aS)-2methyloctahydrocyclopenta[c]pyrrol-5yljmethyl} oxy)-6-(methyloxy)quinolin-4yl]oxy} phenyl)-N'-(2-phenylethyl)ethanediamide	A	A	A	A	A
142	N-(3-fluoro-4-{ [7-({ [(3aR,6aS)-2methyloctahydrocyclopenta[c]pyrrol-5yljmethyl) oxy)-6-(methyloxy)quinazolin-4yl]oxy} phenyl)-N1-(2-phenylethyl)ethanediamide	A	A	A	A	A
143	2-(3,4-dihydroisoquinolin-2(lH)-yl)-N-{3-fluoro-4[(6-(methyloxy)-7-{ [(l-methylpiperidin-4yl)methyl]oxy }quinolin-4-yl)oxy]phenyl} -2oxoacetamide	A	A
144	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidm-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-2-oxo-2-(3phenylpyrrolidin- l-yl)acetamide	A	A	A	A	A
145	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl]oxy)phenyl]-2-oxo-2-(2phenylmorpholin-4-yl)acetamide	A	B	B	B

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146	N-[2-(dimethylamino)-2-phenyIethyl]-N,-[3-fluoro-4- ({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quino!in-4-yl} oxy)phenyl]ethanediamide	A	A	B	A
147	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl[oxy)phenyl]-N'-(2-oxo-2phenylethyl)ethanediamide	A	B	B	B	B
148	N-(6- {[6,7-bis(methyloxy)qumolin-4-yl]oxy} -5chloropyridin-3-yl)-2,2-difluoro-N'-(4fluorophenyl)propanediamide	C	C
149	N- {3-fluoro-4-[(6-(methyloxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy[quinolin-4yl)oxy]phenyl} -N'-(phenylmethyl)ethanedi amide	A	A	A	B	A
150	N-[3-fluoro-4-({6-(methyIoxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-[2-(2fluorophenyl)ethyl]ethanedi amide	A	A	A	A	A
151	N-[2-(3-chlorophenyl)ethyl]-N'-[3-fluoro-4-({6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]qumolm-4yl} oxy)phenyl]ethanediamide	A	A	A	A	A
152	N-[3-fluoro-4-({6-(naethyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenylJ-N’-{ 2-[2(methyloxy)phenyl]ethyl [ethanedi amide	A	A	A	A	A
153	N-[3-fiuono-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-(2pjTidin-3-ylethyl)ethanedi amide	A	B	B	B
154	N-[3-fluoro-4-({6-(methyIoxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl} oxy)phenyl] -N'(phenylmethyl)ethanediamide	A	A	A	B	A
155	N- {2-[2,5-bis(methyloxy)phenyl]ethyl}-N'-[3-fluoro- 4-({6-(methyloxy)-7-[(piperidin-4ylmethyi)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A	A	A	A
156	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-{ 2-[2(trifluoromethyl)phenyl]cthyl [ethanedi amide	A	A	A	A	C
157	N- {2- [2-(ethyloxy)phenyl]ethyl} -N'-[3-fIuoro-4-( {6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl [oxy)phenyl]ethanediatnide	A	A	A	A	A
158	N-[2-(2,4-dimethylphenyl)ethyl] -Ν'- [3-fluoro-4-( {6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl [oxy)phenyl]ethanediamide	A	B	B	A	B
159	N-[3-fIuoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyI)oxy]quinolin-4-yl} oxy)phenyl]-N'-[(l S)-2- (4-methylphenyl)-l-phenylethyl]ethanediamide	B	C
160	N-[2-(4-chlorophenyl)ethyl]-N'-[3-fluoro-4-( {6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinoIin-4yl }oxy)phenyl]ethanediamide	A	A	A	A	B

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161	({3-fluoro-4-[(6-(methyloxy)-7- {[(1 -methylpiperidin4-yl)methyl]oxy}quinolin-4yl)oxy]phenyl }amino)(oxo)acetic acid	B	C
162	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N’-[2-(3fluorophenyl)ethyl]ethanedi amide	A	A			A
163	N-[2-(2-chlorophenyl)ethyl] -N'-[3-fluoro-4-({ 6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4- yl} oxy)phenyl]ethanediamide	A	A	A	B	A
164	N- [3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'- {2-[3(methyloxy)phenyl]ethyl}ethanedi amide	A	A	A	A	A
165	N-( l,2-diphenylethyl)-N'- [3-fluoro-4-( {6-(methyloxy)- 7-[(piperidm-4-ylmethyl)oxy]quinolin-4- yl }oxy)phenyl]ethanediamide	A	A	B	B	C
166	N- [2-(2,4-dichlorophenyl)ethyl] -Ν'- [3-fluoro-4-({ 6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	B	B	A	B
167	N- {2-[3,4-bis(methyloxy)phenyl]ethyl} -Ν’- [3-fluoro- 4-({6-(methyIoxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	B	B	B
168	N-[2-(4-ethylphenyl)ethyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	B	B	B	C
169	N-{ 2-[4-(ethyIoxy)phenyl]ethyl) -N'-[3-fluoro-4-( {6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	B	C	B	B
170	N-{ 2-[4-(ethyloxy)-3-(methyloxy)phenyl]ethyl }-N’-[3fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinoIin-4-yl}oxy)phenyl]ethanediamide	A	B	C	B
171	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- {2-[4(phcnyloxy)phenyl]ethyl}ethanedi amide	B	C	C	C
172	N-{ 2-[3-(ethyloxy)-4-(methyloxy)phenyl]ethyl} -N'-[3fluoro-4-({ 6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yI} oxy )phenyl]ethanedi amide	A	C	B	B
173	N-[3-fluoro-4-({ 6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yI}oxy)phenyI]-N'-(2pyridin-2-ylethyl)ethanediamide	A	A	A	B	B
174	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4y!methyl)oxy]quinolin-4-yl}oxy)phenyl]-N,-(2pyridin-4-ylethyl)ethanediamide	A	B	B	B	C
175	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl] -N’-[2-(4fluorophenyl)ethyl]ethanediamide	A	A	A	A	A

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176	N- [2-(2-bromophenyl)ethyl]-N'-[3-fluoro-4-({ 6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin^4yl }oxy)phenyl]ethanediamide	A	A	A	A	A
177	N-[2-(2-chloro-6-fluoropheny])ethyl]-N'-[3-fluoro-4({6-(methyloxy)-7-[(piperidm-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A	A	B	A
178	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperi din-4ylmethyl)oxy]qumolm-4~yl}oxy)phenyl]-N,-[(2R)-2phenylpropyl]ethanediamide	A	A	A	B	A
179	N-(2f3-dihydro-lH-inden-l-yl)-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyI)oxy]qumolin-4yl} oxy)phenyl]ethanediamide	A	A	A	A	A
180	N- {3-fluoro-4-[(6-(methyloxy)-7-{ [(1- methylpiperidin-4-yl)niethyl]oxy}quinolin-4yl)oxy]phenyl}-N’-(2-methylpropyl)ethanedi amide	A	B	B	B
181	N-{ 3-fluoro-4-[(6-(methyloxy>7-{ [(1methylpiperidin-4-yl)methyl]oxy}quinolin-4yl)oxy]phenyl}-N'-(3-methylbutyl)ethanediamide	A	B	B	B	B
182	N- {3-fluoro-4-[(6-(methyloxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy)quinolin-4yl)oxy]phenyl} -N'-[(2R)-2phenylpropyl]ethanediamide	A	A	A	A	A
183	N- {3-flnoro-4-[(6-(methyloxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy}quinolin-4yl)oxy]phenyl} -N’-(2-phenylpropyl)ethanediamide	A	A	A	A	A
184	N-(2,3-dihydro-lH-inden-2-yl)-N'-{3-fluoro-4-[(6- (methyloxy)-7-{[(l-methylpiperidin-4yl)methyl]oxy} quinolin-4yl)oxy] phenyl [ethanediamide	A	A	A	B	A
185	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4yImethyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-[(lR)-lphenylethyljethanediamide	A	B	B	B
186	N-[3-fluoro-4-( {6-(methyIoxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-[(lS)-lphenylethyllethanedi amide	A	B	A	B	C
187	N-[2-(3-bromophenyl)ethyl]-N’-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-y]methyl)oxy]quinoIin-4yl} oxy)phenyl]ethanedi amide	A	A	A	A	A
188	N-[2-(2,6-dichlorophenyl)ethyl]-N’-[3-fluoro-4-({6(methyloxy)-7-[(piperidm-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A	A	A	A
189	N-[2-(l,3-benzodioxol-5-yl)ethyl]-N'-[3-fluoro-4-((6- (methyloxy)-7-[(piperidin-4-ylmethyI)oxy]quinolin-4yl }oxy)phenyl]ethanediamide___________	A	A	B	A	B

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190	N- {5-chloro-6-[(6-(methyioxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy}quinolin4yl)oxy]pyridin-3-yl} -N'-(4-fluorophenyl)cyclopropane. 1,1-dicarboxamide	A	A	B	A	A
191	N-{2-[3-bromo-4-(methyloxy)phenyl]ethyl}-N'-[3fluoro-4-( {6-(methy loxy)-7 - [ (piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanedi amide	A	A	B	B	B
192	N- {2- [3,5-bis(methyloxy)phenyl]ethyl }-N’-[3-fluoro- 4-( {6-(methyloxy)-7- [(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanedi amide	A	A	A	B	B
193	N-[3-fluoro-4-({6-(methyIoxy)-7-[(pipericlin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-[2-(2methylphenyl)ethyl]ethanediamide	A	A	A	B	A
194	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-[2-(3methylphenyl)ethyl]ethanediamide	A	A	A	A	A
195	N-{ 2-[3-(ethyloxy)phenyl]ethyl} -N’-[3-fluoro-4-( {6- (methyloxy)-7-[(piperidm-4-ylmethyl)oxy]quinolm-4yl} oxy)phenyl] ethanediamide	A	A	B	B	B
196	N-[2-(3,4-dimethylphenyl)ethyl] -N'-[3-fluoro-4-( {6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	A	B	B	B
197	N-[2-(2,5-dimethylphenyl)ethyl]-N'- [3-fluoro-4-( {6- (methyloxy)-7-[(piperidin-4-ylmethyI)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A	A	A	A
198	N-{2-[3-chloro-4-(propyloxy)phenyl]ethyl}-N'-[3fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanedi amide	B	C
199	N- {2-[4-(butyloxy)-3-chlorophenyl]ethyl) -N'-[3- fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanedi amide	B	C
200	N- {2- [4-( 1,1-dimeth ylethyl)phenyl]ethyl} -Ν'- [3fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	B	c			I
201	N- {2-[4-(aminosulfonyl)phenyl]ethyl} -N'-[3-fluoro-4({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]qninolin-4-yl}oxy)phenyl]ethanedi amide	A	B	B	B	B
202	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ 2-[4hydroxy-3-(methyloxy)phenyl]ethyl} ethanedi amide	A	B	B	A	B
203	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl] -Ν'- {2-[3hydroxy-4-(methyloxy)phenyl]ethyl}ethanedi amide	A	B	B	B	B
204	N-[(2,4-dichIorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyI)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A	A	A	B

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205	N-[3-fluoro-4-( {6-(methyloxy)-7 - [(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- {[4fluoro-2- (trifluoromethyl)phenyl]methyl}ethanediamide	A	A	B	A	A
206	N-[3-fIuoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N’-[(lR)-1(4-methylphenyl)ethyl]ethanedi amide	A	B	B	δ	B
207	N-[3-fluoro-4-({ 6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- {[3fluoro-4- (trifluoromethyl)phenyl]methyl} ethanediamide	A	B	B	B	B
208	N-[(3-chloro-4-fluorophenyl)methyl]-N'-[3-fluoro-4({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yi[oxy)phenyl]ethanediamide	A	A	A	A	B
209	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N - {(1 S)-l [3-(methyloxy)phenyl]ethyl} ethanediamide	A	B	B	B	B
210	N-[3-fluoro-4-({6-(methyIoxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- [(1R)-1 naphthalen-2-ylethyl]ethanediamide	A	B	B	B
211	N-{ [4-chloro-3-(trifluoromethyl)phenyl]methyl [-N1[3-fluoro-4-( {6-(methyloxy)-7- [(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A	A	A	A
212	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- [(IS)-1 (4-methylphenyl)ethyl]ethanediamide	A	B	C	B
213	N- [3-fluoro-4-({ 6-(methyloxy)-7-[(piperidin-4ylmethyi)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [6(trifluoromethyl)pyridin-3-yl]methyl [ethanediamide	A	B	C	B	B
214	N-[3-fluoro-4-({6-(methyloxy)-7-[(pipeiidin-4yImethyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-[(2methylphenyi)methyl]ethanedi amide	A	A	A	A	B
215	N-[3-fluoro-4-( [ 6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl[oxy)phenyl]-N'-[(3methylphenyl)methyl]ethanedi amide	A	A	A	B	A
216	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [4fluoro-3- (trifluoromethyl)phenyljmethyl [ethanediamide	A	A	B	A	A
217	N-[(3,5-dichlorophenyI)methyl]-N'-[3-fluoro-4-( {6(methyloxy)-7“[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A	A	A	A
218	N-[3-fluoro-4-({ 6-(methyIoxy)-7 - [(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-[(lR)l,2,3,4-tetrahydronaphthalen-l-yl]ethanediamide	A	B	B	B	A

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219	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4yImethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'- [(1S)1,2,3,4-tetrahydronaphthalen-l-yl]ethanedi amide	A	A	A	A	A
220	N-cyclopentyl-N'-[3-fluoro-4-({6”(methyloxy)-7[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	B	B	B	B
221	N- [ 1 -(4-bromophenyI)ethyl]-N'-[3-fluoro-4-({ 6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	B	B	B	B
222	N- [3-fluoro-4-( {6-(methyloxy)-7- [(piperidin-4ylmethy])oxy]quinolin-4-yl} oxy)phenyl]-N'-[(2fluorophenyl)methyl]ethanediamide	A	A	B	B	A
223	N-[2-(3,4-dichlorophenyl)ethyl]-N'-[3-fIuoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinoIin-4yl} oxy)phenyl]ethanediamide	A	A	A	A
224	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-[(4fluorophenyi)methyl]ethanediamide	A	A	A	A	A
225	N-[(2,3-difluorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	A	B	B	A
226	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-[2' (phenyloxy )ethyl]ethanediamide	A	A	A	A	A
227	N-(2,2-diphenylethyl]-N'-[3-fluoiO-4-({6-(methyloxy)- 7-[(piperidin-4-yImethyl)oxy]quinolin-4- yl} oxy)phenyl]ethanediamide	A	B	B	A	B
228	N-[3-fluoro-4-( {6-(methyloxy)-7- [(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N’-{ 2-[4(methyloxy)phenyl]ethyl}ethanediamide	A	B	B	B	B
229	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl] -N'-(2pheny]propyl)ethanediamide	A	A	A	A	A
230	N-[2-(4-bromophenyI)ethyl]-N’-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanedi amide	A	A	B	B	B
231	N-(4-{ [7-{ [(l-ethylpiperidin-4-yl)methyl]oxy }-6(methyloxy)quinolin-4-yl]oxy)-3-fluorophenyl)-2-oxo2-(2-phenylmorpholin-4-yl)acetamide	A	B	B	B	B
232	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4y]methyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [3fluoro-5- (trifluoromethyl)phenyl]methyl}ethanediamide	A	A	B	A	B
233	N-[(3,5-difluorophenyl)methyl]-N’-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A	A	B	A

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234	N- {[2-chloro-5-(trifluoromethyl)phenyl]methyl} -bT[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinoIin-4-yl[oxy)phenyl]ethanediamide	A	A	B	A	B
235	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3fluorophenyl)-N'-[2-(dimethylamino)-2phenylethyl]ethanedi amide	B	B	B	A
236	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N’-{ [4(methyloxy)phenyl]methyl} ethanediamide	A	A	A	B	B
237	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [4(trifluoromethyl)phenyl]methyl} ethanediamide	A	B	B	B	A
238	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N’-{ [3(methyioxy)phenyl]methyl [ethanediamide	A	A	A	A	B
239	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [3- (trifluoromethyl)phenyl]methyl[ethanedianiide	A	A	A	A	B
240	N-[3-fluoro-4-((6-(methyloxy)-7-[(piperidin-4yImethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-({ 3[(trifluoromethyl)oxy]phenyl}methyl)ethanediamide	A	A	A	A	A
241	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yI }oxy)phenyl]-N'-{ [2(methyloxy)phenyl]methyl [ethanediamide	A	A	A	A	A
242	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N’-{ [2(trifluoromethyl)phenyl]methyl [ethanediamide	A	A	A	A	A
243	N-[(3-chlorophenyl)methyl]-N'-[3-fluoro-4-({6- (methyloxy)-7-[(piperidin-4-ylmethyl)oxy]qumolin-4yl [ oxy)phenyl]ethanediamide	A	A	A	B	B
244	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethy])oxy]quinolin-4-yl [ oxy)phenyl]-N'-( {2[(trifluoromethyl)oxy]phenyl[methyl)ethanedi amide	A	A	A	A	A
245	N-[(2-chlorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl [oxy)phenyl]ethanediamide	A	A	A	A	A
246	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-({ 4[(trifluoromethyl)oxy[phenyl}methyl)ethanediamide	A	B	B	B	B
247	N-{3-fluoro-4-[(6-(methyIoxy)-7-{[(lmethylpiperidin-4-yl)methyl]oxy}quinolin-4yl)oxy]phenyl [-Ν'- ([4(methyloxy)phenyl]methyl} ethanediamide	A	B	A	B
248	N- {3-fluoro-4-[(6-(methyloxy)-7-{ [(1methylpiperidin-4-yl)methyl]oxy[quinolin-4yl)oxy]phenyl }-N'- {[4(trifluoromethyl)phenyl]methyl} ethanediamide	A	B	B	B	B

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249	N-(4-{[7-[(azetidin-3-ylmethyl)oxy]-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(2phenylethyl)ethanedi amide	A	A
250	N-(3-fluoro-4- {[7- {[(1 -methylazetidin-3yl)methyl]oxy[-6-(methyloxy)quinolin-4yl]oxy [phenyl )-N,-(2-phenyIethyl)ethanediamide	A	A	A	A	A
251	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-(2hydroxy-2-phenyIethyl)ethanediamide	B	B	B	B
252	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}“5- chloropyridin-3-yI)-N'-(2,4difluorophenyl)propanediamide	A	C
253	N'-(6-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yI)-N-(4-fluorophenyl)-Nmethylpropanediamide	B	c
254	N-[3-fluoro-4-({6-(methyloxy>7-[(piperidin-4ylmethyl)oxy]qumolin-4-yl} oxy)phenyl]-N'-[( 1R)-1 phenylpropyljethanediamide	A	B	B	B	B
255	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-y]} oxy)phenyl]-N’- [(1S)-1 phenylpropyl]ethanediamide	A	B	C	B
256	N-[(3,4-difluorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	A	A	B	A
257	N-[(2,6-difluorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quiiiolin-4yl }oxy)phenyl]ethanediamide	A	A	A	B	A
258	N- {3-fluoro-4- [(6-(methyloxy)-7- {[(1methylpiperidin-4-yl)methyl]oxy}quino]in-4yl)oxy]phenyl }-N-[2-(4fluorophenyl)ethyl]ethanediamide	A	A	A	A	A
259	N-{3-fluoro-4-[(6-(methyloxy)-7-{[(lmethylpiperidin-4-yl)methyl]oxy}quinolin-4yl)oxy]phenyl}-N*-phenylethanediamide	A	B	C	C	B
260	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(3fluorophenyljethanediamide	A	C	B	C	C
261	N-(3-chloro-4-fluorophenyl)-N’-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-y]methyl)oxy]quinolin-4yl} oxy)phenyl]ethanediamide	A	c	C	B	B
262	N-[3,4-bis(methyloxy)phenyl]-N'-[3-fluoro-4-({6- (methyloxy)-7~[(piperidin-4-y]methyl)oxy]quinolin-4yl} oxy)phenyl]ethanediami de	A	c	C	B	B
263	N-[3-fluoro-4-({6-(methy]oxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N’-(3methylbutyl)ethanediamide	A	B	A	B	B

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264	N-(3,3-dimethyIbutyl)~N'-[3-fluoro-4-({6-(methyloxy)- 7-[(piperidin-4-ylmethyl)oxy]quinolin-4- yl }oxy)phenyl]ethanediamide	A	A	A	A	B
265	N-[5-chloro-6-({6-(methyloxy)-7-[(3-piperidin-lylpropyl)oxy]quinolin-4-yl} oxy)pyridin-3-yl]-N'-(4fluorophenyl)propanediamide	A	B	B	A	B
266	N- [5-chloro-6-( {6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl}oxy)pyridm-3-yl]-N'-(4fluorophenyl)propanediamide	A	B	B	A	B
267	N-(5-chloro-6-{ [7-{ [3-(diethy]amino)propyl]oxy}-6(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N,-(4fluorophenyl)propanediamide	A	B	B	A	B
268	N-[(4-chlorophenyl)methyl]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	A
269	N-{ [3,5-bis(methyloxy)phenyl]methyl} -N’-[3-fluoro-4({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A		A
270	N-[(4-butylphenyl)methyl]-N’-[3-fluoro-4-({6- (methyloxy)-7-[(piperidin-4-yhnetliyl)oxy]quinoIin-4yl }oxy)phenyl]ethanediamide	A	B	B	B	B
271	N-[3-fluoro-4-({6-(methyIoxy)-7-[(piperidin-4y!methyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-[2-(4methylphenyl)ethyl]ethanediamide	A	B	B	A	B
272	N-{ [3,5-bis(trifluoromethyl)phenyl]methyl }-N'-[3fluoro-4-( {6-(methyloxy)-7-[(piperidm-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A	C	B
273	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-(pyrazin- 2-ylmethyI)ethanediamide	B	C	C	B
274	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyljoxyJquinolin^-ylloxyjphenylJ-N'-ipyridin2-ylmethyl)ethanediamide	A	B	B	B	B
275	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(2phenylethyl)ethanediamide	A	A	A	A	A
276	N- {3-fluoro-4-[(6-(methyloxy)-7- {[< 1 methylpiperidin-4-yl)niethyl]oxy}quinazolin“4yl)oxy]phenyl} -N’-(2-phenylethyl)ethanedi amide	A	A	A	A	A
277	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [2fluoro-3- (trifluorome±yl)phenyl]methyl} ethanediamide	A	A	A	A	A
278	N-{ 2-[2-bromo-6-(methyloxy)phenyl]ethyl}-N '-[3fluoro-4-( {6-(methyloxy)-7-[(piperidin-4- ( ylmethyl)oxy]quinolin-4-yI} oxy)phenyl]ethanediamide	A	A	A	A	A

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279	N- { 2-[3,4-bis(methyloxy)phenyl]ethyl} -N'-[3-fluoro4-( {6-(methyIoxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-Nmethylethanedi amide	B	B	B	A	B
280	N- {2-[5-bromo-2-(methyloxy)phenyl]ethyl} -N'-[3fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]ethanediamide	A	A	A	A	A
281	N-[3-fluoro4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl }oxy)phenyl]-N'-{ [2fluoro-5- (trifluoromethyl)phenyl]methyl}ethanediamide	A	A	B	A	B
282	N-[5-chloro-6-((6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide	A	A	A	A	A
283	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl) oxy)phenyl]-N'-[ 1-(4fluorophenyl)ethyl]ethanediamide	A	A	B	A	B
284	. N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-[(lS)-2oxo-1 -(phenylmethyl)-2-pyrrolidin-1 ylethyl]ethanediamide	A	C	B	B	C
285	N- {3-fluoro-4-[(6-(methyloxy)-7- {[(3aR,6aS)octahydrocyclopenta[c]pyrrol-5ylmethyI]oxy}quinazolin-4-yl)oxy]phenyl}-N'-(2phenylethyl)ethanediamide	A	A	A	A	A
286	N-[2-(4-aminophenyl)ethyI]-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl} oxyjphenyljethanediamide	A	B	B	B	B
287	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinoIin-4-yI}oxy)phenyl]-2-oxo-2-[4(phenylmethyl)piperidin-l -yl] acetamide	A	A	B	A	B
288	N-(4-( [6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)- N’-(4-flnorophenyl)propanedi amide	A	A	A	A	A
289	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide	A	A	A	A	5.581
290	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-N'-(3fluorophenyOpropanedi amide	B	C
291	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5- chloropyridin-3-yl)-N’-phenylpropanediamide	A	C	B	A	C
292	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-N’-(4-fluorophenyl)-2,2dimethylpropanedi amide	B	B	B	A	B
293	N-ethyl-N'-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin- 4-ylmethyl)oxy]quinolin-4- yl }oxy)phenyl]ethanediamide___________	A	B	B	B	B

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294	N-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(lmethylethyl)ethanediamide	A	B	B	B	C
295	N-butyl-N'-[3-fluoro-4-( {6-(methyloxy)-7-[(piperidin4-ylmethyl)oxy]quinolin-4yl} oxy)phenyl]ethanedi amide	A	B	B	B	B
296	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-[2- (methyloxy)ethyllethanedi amide	B	B	B	B	C
297	N-(cycIopropylmethyl)-N'-[3-fluoro-4-({6(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4yl }oxy)phenyl]ethanediamide	A	B	B	B	B
298	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-N’-(2morpholin-4-ylethyl)ethanediamide	B	A	B	A	B
299	N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4-yl} oxy)phenyl]-2-oxo-2pyrrolidin-l-ylacetamide	A	B	B	B	B
300	N-ethyl-N'-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin- 4-ylmethyl)oxy]quinolin-4-yl} oxy)phenyI]-Nmethylethanediamide	A	B	C	B	B
301	N-(6- {[6,7-bis(methy]oxy)quinolin-4-yl]oxy} -5chloropyridin-3-yl)-N'-(phenylmethyl)cyclopropane1,1 -dicarboxamide	A	C	B	B	B
302	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -5chloropyridin-3-y])-N’-(2-phenylethyl)cyclopropane14-dicarboxamide	C	C
303	N- {4-[(7-chIoroquinolin-4-yl)oxy]-3-fluorophenyl} - N’-(4-fluorophenyI)cyclopropane-14-dicarboxamide	A	A	C	C	B
304	N-(4-{ [7- {[2<diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N’-(4fluorophenyl)cyclopropane-14-dicarboxamide	A	A	A	A	A
305	N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloropyridin-3-yl)-N’-phenylcyclopropane-14dicarboxamide	A	B	B	A
306	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy }-2- methyipyridin-3-yl)-N'-(4-fluorophenyl)cyclopropane- 14-dicarboxamide	A	B	B	C	B
307	N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy}-6(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4fluorophenyl)cyclobutane-1,1 -dicarboxamide	A	A	A	B	A
308	N-{4-[(7-chloiOquinolin-4-yl)oxy]phenyl}-N'-(4- fluorophenyl)cyclopropane-14-dicarboxamide	A	A	B	C	B
309	N- [5-chloro-6-({6-(methyloxy)-7[(phenylmethyl)oxy]quinolin-4-yl} oxy)pyridin-3-yI]N'-(4-fluorophenyl)cyclopropane-14-dicarboxaniide	A	C	C	B	C

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310	N-(4- {[6,7-bi s(methyloxy)quinazolin-4- yl]oxy }phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
311	N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1 dicarboxamide	A	A	B	A	A
312	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl }oxy)phenyl] -N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide	A	A	A	A	A
313	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-lylpropyl)oxy]quinolm-4-yl}oxy)phenyl]-N'-(4fluorophenyl)cyclopropane-l,l-dicarboxamide	A	A	A	A	A
314	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-lylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4fluorophenyl)cyclobutane-l, 1-dicarbox amide	A	A	A	B	A
315	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropy])oxy]quinazolin-4-yl}oxy)phenyl]-N’-(4fluorophenyl)cyclopiOpane-1,1 -dicarboxamide	A	A	A	A	A
316	N-{ 3-fluoro-4-[(6-(methyloxy)-7-{ [(1 methylpiperidin-4-yl)methyl]oxy}quinazolin-4yl)oxy]phenyl} -N'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
317	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -2inethylphenyl)-N'-(4-fluorophenyl)cyclopropane-l,ldicarboxamide	A	A	A	C	A
318	N-(4-fluorophenyl)-N'-[2-methyl-6-({6-(methyIoxy)-7[(3-morpholin-4-ylpropyl)oxy]quinolin-4yl }oxy)pyridin-3-yl]cyclopropane-l, 1 -dicarboxamide	A	A	B	B	B
319	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -3fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
320	N-(6- {[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5chloro-2-methylpyridin-3-yl)-N’-(4fluorophenyl)cyclopropane-l, 1-dicarboxamide	A	C	C	B	C
321	N-[3-fluoro-4-({7-(methyIoxy)-6-[(3-morpholin-4ylpropyI)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(4fluorophenyl)cyclopropane-1,1 -dicarboxamide	A	A	B	A	A
322	N-[3-fluoro-4-({7-(rnethyloxy)-6-[(3-morpholin-4ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4fluorophenyl)cyclopropane-1,1 -dicarboxamide	A	A	A	A	A
323	N-(4-{[6,7-bis(methyloxy)quinolm-4-yl]oxy}-3,5difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l,ldicarboxamide	A	A	B	A	A
324	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-l,ldicarboxamide	A	A	A	A	A

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325	N- {3-fluoro-4-[(7-(methyloxy)-6-{ [(1methylpiperidin-4-yl)methyl]oxy}quinazolin-4yl)oxy]phenyl} -N'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	B	A	A
326	N-[5-fluoro-2-methyl-4-([6-(methyioxy)-7-[(3morpholin-4-ylpropyl)oxy]quinolin-4-yl} oxy)phenyl]N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide	A	A	B	B	B
327	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} -2,3,5- trifluorophenyl)-N’-(4-fluorophenyl)cyclopropane-l,ldicarboxamide	A	A	B	B	B
328	N-(4-{[6,7-bis(mcthyloxy)quinolin-4-yl]oxy}-5fluoro-2-methylphenyl)-N‘-(4f[uorophenyl)cyclopropane-1,1-dicarboxamide	A	B	B	C	C
329	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl] oxy} -2chIoro-5-methylphenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide	A	B	B	c	B
330	N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4yljoxy }phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
331	N-(4-fluorophenyl)-N’- [2-methyl-4-({ 6-(methyloxy)-7[(3-morpholin-4-ylpropyl)oxy]quinoIin-4yl }oxy)phenyl]cyclopropane-l, 1-dicarboxamide	A	A	A	B	A
332	N-[3-fluoro-4-( {6-(methyloxy)-7-[(3-piperazin-1 ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4fluorophenyl)cyclopropane-1,1-dicarboxamide	A	A	A	A	A
333	N- {3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4methylpiperazin- l-yl)propyl]oxy }quino]in-4yl)oxy]phenyl }-N’-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
334	N- {3-fluoro-4-[(6-(methyloxy)-7- {[(1methylpiperidin-4-yl)methyl]oxy} quinolin -4yl)oxy]phenyl }-N,-(4-fluorophenyl)cyclopropane-1,1dicarboxamide	A	A	A	A	A
335	N-(4-fluorophenyl)-N'-[4-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]qumolin-4- yl}oxy)phenyl]cyclopropane-l,1-dicarboxamide	A	A	A	A	A
336	N-(4-{ [7-{ [3-(diethylamino)propyl]oxy }-6(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l, 1-dicarboxamide	A	A	A	A	A
337	N-(4- {[6,7-bis(methyloxy)quinoIin-4-yl]oxy} -2chloro-5-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l ,1 -dicarboxamide	A	B	B	C	C
338	N-(4- {[6,7-bis(methyloxy)-2-(methylthio)quinolin-4yl] oxy} -3-fluorophenyl)-N’-(4fluorophenyl)cyclopropane-1,1 -dicarboxamide	C	C

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339	N-(4-fluorophenyl)-N,-(4- {[2-methyl-6,7bis(methy!oxy)quinazolin-4yl]oxy} phenyl)cyclopropane-1,1-dicarboxamide	C	C
340	N-(4- {[2-amino-6,7-bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-1,1 -dicarboxamide	C	C
341	N-(3-fluoro-4-{ [2-(methylamino)-6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropane-l, 1 -dicarboxamide	c	C
342	(1 S,2R)-N-[3-fluoro-4-( {6-(methyloxy)-7-[(3morpholin-4-ylpropyI)oxy]quinolin-4-yl} oxy)phenyl]NL(4_fiuorophenyl)-2-methylcyclopropane-l,ldicarboxamide	A	A	B	A	A
343	(lR,2R)-N-[3-fluoro-4-( {6-(methyloxy)-7-[(3morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]N'-(4-fluorophenyl)-2-methylcyclopropane-l,ldicarboxamide	A	A	A	A	A
344	N-(4-{ [6-( [3-(diethylamino)propyl]oxy}-7(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l, 1-dicarboxamide	A	A		A
345	N-(4-{ [6-{ [2-(diethylamino)ethyl]oxy}-7- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-l,l-dicarboxaniide	A	A		A
346	1,1-dimethylethyl 4-(3-{ [4-[(2-fluoro-4-{ [(l-{ [(4fluorophenyl)amino]carbonyl} cyclopropyl)carbonyl] a mino}phenyl)oxy]-6-(methyloxy)quinolin-7yl]oxy} propyl)piper azine-1 -carboxylate	A	A		B
347	(lR,2R)-N-[3-fluoro-4-((6-(methyloxy)-7-[(3morpholin-4-ylpropyl)oxy]quinazolin-4yl)oxy)phenyl]-N'-(4-fluorophenyl)-2methylcyclopropane-1,1 -dicarboxamide	A	A
348	(lR,2R)-N-(4- {[7-{ [2-(diethylamino)ethyl]oxy )-6- (methyloxy)quinazoIm-4-yl]oxy}-3-fluorophenyl)-N'(4-fluorophenyl)-2-methylcyclopropane-1,1dicarboxamide	A	A		B
349	N-(4-{ [7-{[3-(diethylamino)propyl]oxy}-6(methyloxy)quinazolin-4-yl]oxy)-3-fluorophenyl)-N'(4-fluorophenyl)cyclopropane-l,l-dicarboxaniide	A	A		A
350	N-(4-{ [7- {[3-(4-acetylpiperazin-l -yl)propyl]oxy} -6(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide	A	A		A
351	1,1-dimethylethyl 4-(3-{ [4-[(2-fluoro-4-{ [((1R,2R)-1{[(4-fluorophenyl)amino]carbonyl}-2methylcyclopropyl)carbonyl]amino} phenyl)oxy]-6(methyloxy)quinolin-7-yl]oxy)propyl)piperazine-lcarboxylate	A	A		B

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352	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)N'-(4-fluorophenyl)-l-(phenylmethyl)azetidine-3,3dicarboxamide	A	C		C
353	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy }phenyl)- N’-(4-fluorophenyl)azetidme-3,3-dicarboxamide	B	C		C
354	(1R,2S)-N- {3-fluoro-4-[(6-(methyloxy)-7- {[3-(4methylpiperazin-l-yl)propyl]oxy}quinolin-4yl)oxy]pheny]}-N'-(4-fluorophenyl)-2methylcyclopropane-1,1 -dicarboxamide	A	A		A
355	(lR,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4methylpiperazin-l-yl)propyl]oxy}quinolin-4yl)oxy]phenyl} -N'-(4-fluorophenyl)-2methylcyclopropane-1,1-dicarboxamide	A	A		A
356	(lR,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3- piperazin-l-ylpropyl)oxy]quinolin-4-yl} oxy)phenyl]N’-(4-fluorophenyl)-2-methyicyclopropane-l, 1dicarboxamide	A	A		A
357	N-(3-fluoro-4-{ [7-({ 3-[4-(l-methylethyl)piperazin-lyl]propyl} oxy)-6-(methyloxy)quinolin-4yljoxy }phenyl)-N’-(4-fluorophenyl)cyclopropaiie-1,1dicarboxamide	A	A		A
358	N-(4-{ [7-{ [3-(diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N’(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide	A	A		A
359	(lR,2R)-N-(4-{ [7- {[3-(diethylamino)propyl]oxy} -6(methyloxy)quinolin-4-yl]oxy) -3-fIuorophenyl)-N’-(4fluorophenyl)-2-methylcyclopropane-l, 1 dicarboxamide	A	A		A
360	(lR,2R)-N-(4- {[7- {[2-(diethylamino)ethyl]oxy }-6(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(4fluorophenyl)-2-methylcyclopropane-l,ldicarboxamide	A	A		A
361	(lR,2S>N-(4-{ [7-{ [3-(diethylamino)propyl]oxy }-6- (methyloxy)quinolm-4-yl]oxy]-3-fluorophenyl)-N’-(4fluorophenyl)-2~methylcyclopropane-1,1dicarboxamide	A	A		A
362	(lR,2S)-N-(4- {[7-{ [2-(diethylamino)ethyl]oxy [-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(4fluor ophenyl)-2-methylcyclopropane-1,1dicarboxamide	A	A		A
363	N-(4-{ [7- {[2-(diethylarrdno)ethyl]oxy}-6(methyloxy)quinazolin-4-yl]oxy} -3-fluorophenyl)-N(4-fluorophenyl)cyclobutane-l, 1 -dicarboxamide	A	A
364	(lR,2S)-N-[3-fluoro-4.({6-(methyloxy)-7-[(3piperazin-l-ylpropyl)oxy]quinolm-4-yl}oxy)phenyl]- N'-(4-fluoropheny])-2-methylcyclopropane-1,1- dicarboxamide	A	A		A

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365	(lr,2R,3S)-N-[3-fluoro-4-( {6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]fT-(4-fluorophenyl)-2,3-dimethylcyclopropane-l,ldicarboxamide	A	B		B
366	(lr,2R3S)-N-{ 3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4methylpiperazin-1 -yl)propyl]oxy} quinolin-4yl)oxy]phenyl}-N'-(4-fluorophenyl)-2,3dimethylcyclopropane-l,l-dicarboxamide	A	B		B
367	(lr,2R,3S)-N-[3-fluoro-4-((6-(methyloxy)-7-[(3morpholin-4-ylpropyl)oxy]quinazolin-4yl} oxy)phenyl]-N'-(4-fluorophenyl)-2,3dimethylcyclopropane -1,1 -dicarboxamide	B	A		B
368	(lr,2R,3S)-N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4methyIpiperazin-l-yl)propyl]oxy]quinazolin-4yl)oxy]phenyl}-N’-(4-fluorophenyl)-2,3dimethylcyclopropane-1,1 -dicarboxamide	A	A		B
369	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(4fluorophenyl)cyclobutane-l, 1 -dicarboxamide	B	A		B
370	(2R,3R)-N-[3-fluoro-4-({ 6-(methyloxy)-7- [(3morpholin-4-ylpropyl)oxy]quinolin-4-yl} oxy)phenyl]N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-l,ldicarboxamide	A	A		B
371	(2R,3R)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy}-6- (methyloxy)quinolm-4-yl]oxy}-3-fluorophenyl)-N,-(4fluorophenyl)-2,3-dimethylcyclopropane-1,1dicarboxamide	A	A		B
372	N-(4-{ [7-{ [3-(diethylamino)propyl]oxy} -6- (methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N’-(4fluorophenyl)-2,2-dimethylcycIopropanc-l, 1 dicarboxamide	A	A		B
373	N-[3-fluoro-4-((6-(methyloxy)-7-[(3-morpholin-4ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N'-(4fluorophenyl)-2,2-dimethy]cyclopropane-l, 1dicarboxamide	A	A		C
374	(lr,2R,3S)-N-(4-{ [7-{ [3-(diethyiamino)propyl]oxy )-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-(4fluorophenyl)-2,3-dimethylcyclopropane-l,ldicarboxamide	A	B		B
375	N-(4-{ [7- {[2-(diethylamino)ethyl]oxy}-6- (metiiyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4fluorophenyl)-2,2-dimethylcyclopropane-1,1dicarboxamide	A	A		C
376	(lr,2R,3S)-N-(4-{ [7-( [2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N’-(4fluorophenyl)-2,3-dimcthylcyclopropane-1,1dicarboxamide	A	B		B

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377	N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4y!propyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-(4fluorophenyl)-2,2-dimethylcyclopropane-l,ldi carboxamide	A	A		B
378	N-(4-{ [7- { [2-(diethylamino)ethyl]oxy}-6(methyloxy)quinazolin-4-yl]oxy)-3-fluorophenyl)-N’(4-fluorophenyI)-2,2-dimethylcyclopropane-l, 1 dicarboxamide	A	B		C
379	N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- (methyloxy)quinazolm-4-yl]oxy}-3-fliiorophenyl)-N'(4-fluorophenyl)-2,2-dimethylcyclopropane-l,ldicarboxamide	A	A		C
380	N-(4- {[7- {[3-(diethylamino)propyl]oxy }-6(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N,(4-fluorophenyl)cyclobutane-l,l-dicaiboxamide	A	A		B
381	N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4methylpiperazin-l-yl)propyi]oxy}quinazolin-4yl)oxy]phenyl} -N'-(4-fluorophenyl)cyclobutane-1,1dicarboxamide	A	A		B
382	N-[3-fluoro-4-( {6-(methyloxy)-7-[(3-piperazin-1 ylpropyl)oxy]qumazolin-4-yl}oxy)phenyl]-N,-(4fluorophenyl)cyclobutane-1,1 -dicarboxamide	A	A		B
383	(2R,3R)-N-[3-fluoro-4-({6-(methy]oxy)-7-[(3morphoIin-4-yIpropyl)oxy]quinazolin-4~ yl}oxy)phenyl]-N'-(4-fluorophenyl)-2,3dimethy 1c ycloprop ane-1,1 -dicarboxamide	A	A		C
384	N-(4-{ [7-{[3-(diethylamino)propyl]oxy }-6(methyloxy)quinolin-4-yl]oxy}-3-fluoiOphenyl)-N'-(4fluorophenyl)cyclobutane-1,1 -dicarboxamide	A	A		C
385	N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4melhylpiperazin-l-yl)propyl]oxy}quinolin-4yl)oxy]phenyl} -N’-(4-fluorophenyl)cyclobutane-1,1dicarboxamide	A	A		C
386	(1 R,2R)-N-(4-{ [7- {[3-(dicthylamino)propyl]oxy} -6- (methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N'(4-fluorophenyl)-2-methylcyclopropane-l, 1 dicarboxamide	A	A		A
387	(1R,2R)-N- {3-fluoro-4-[(6-(methyloxy)-7- {[3-(4methylpiperazin-1 -yl)propyl]oxy }quinazolin-4yl)oxy]phenyl}-N'-(4-fluorophenyl)-2methylcyclopropane-1,1-dicarboxamide	A	A		A
388	(2R,3R)-N-(4-([7-{[2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinazoIin-4-yl]oxy}-3-fluorophenyl)-N’(4-fluorophenyl)-2,3-dimethylcyclopropane-l,ldicarboxamide	B	A		C

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389	(2R,3R)-N-(4- {[7- {[3-(diethylamino)propyl]oxy} -6(mβthyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N,(4-fluorophenyl)-2,3-dimethylcyclopropane-l, 1dicarboxamide	A	A		B
390	(lR,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3piperazin-l-ylpropyl)oxy]quinazolin-4yl}oxy)phenyl]-N'-(4-fluorophenyl)-2methylcyclopropane-1, l-dicarboxamide	A	A		A
391	(2R,3R)-N-(4-{ [7-( [2-(diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl] oxy} -3-fluorophenyl)-N'-(4fluorophenyl)-2,3-diinethylcyclopropane-1,1dicarboxamide	A	A		B
392	N-(4-([6,7-bis(methyloxy)quinolin~4-yl]oxy}phenyl)N’-[(4-fluorophenyl)methyl]cyclopropane-l, 1 dicarboxamide	B	B		A
393	N-(4- {[6,7-bis(methyIoxy)quinolin-4-yl]oxy}phenyl)N'-(2-morpholin-4-ylethyl)cyclopropane-1,1dicarboxamide	C	D		B
394	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy Jphenyl)- N,-[2-(piperidin-l-ylmettiyl)phenyl]cyclopropane-l,ldicarboxamide	B	D		B
395	N-(4- {[6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)- N'-[2-(pynolidin-1 -ylmethyl)phenyl]cyclopropane-1,1dicarboxamide	B	C		B
396	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy)phenyl)N’-[3-(morpholin-4-ylmethyl)phenyl]cyclopropane1,1-dicarboxamide	B	A		A
397	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)N'-[2-(morpholin-4-ylmethyl)phenyl]cyclopropane1, l-dicarboxamide	B	C		B
398	N-(4- {[6,7-bis(methyloxy)quinolin-4-yI]oxy Iphenyl)bT-phenylcyclopropane-l,l-dicarboxamide	A	A		A
399	N- [3-(aminomethyl)phenyl]-N'-(4- {[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)cyclopropane-l,l-dicarboxamide	B	A		B
400	N-(4-{ [6,7-bis(methyloxy)qumolm-4-yl]oxy Jphenyl)- N'-[3-(piperidin- l-ylmethyl)phenyl]cyclopropane-1,1dicarboxamide	B	A
401	N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N'-[3-(pyrrolidin-l-ylmethyl)phenyl]cyclopropane-l,ldicarboxamide	A	A

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2020201638 05 Mar 2020 [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 knowledge in 5 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 (168)

1 2

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 -OC(O)CH₂-, -CH₂OC(O>, -OC(O)CH₂CH₂-, -CH₂OC(O)CH₂-, -CH₂CH₂OC(O)-, -OC(O)CH₂NH-, -OC(O)CH₂N(CwalkyI)-, and -OC(O)CH₂O-; or

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1, 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, -NH₂, -NR³R⁴, and optionally substituted lower alkyl;

A¹ is selected from =N-, =C(H)-, and =C(CN)-;

Z is selected from -S(O)q.₂-, -O-, and -NR⁵-;

Ar is either a group of formula Π, or of formula ΠΙ,

wherein,

R² is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R , -S(O)0.₃R³, -SOsNR^³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl;

q is 0 to 4;

G is a group -B-L-T, wherein

B is selected from absent, -N(R¹³)-, -N(SO2R¹³)-, -O-, -S(0)o.2-> and -C(=O)-;

L is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, -SO^NiR¹³)-, -SO2-, -C(=O)N(R¹³)-, -N(R¹³)-, -C(=O)Ci.2alkylN(R'³)-, -N(R¹³)Ci_2alkylC(=O)-, -C(=0)Co-ialkylC(=0)N(R¹³)-, -C^alkylene-, -C(=O)C0-ialkylC(=O)OR³-, -C(=NR¹⁴)Co.ialkylC(=0)-, -C(=O)-, -C(=0)Co.]alkylC{=0)-, and an optionally substituted four to six-membered heterocyclyl containing

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T is selected from -H, -R¹³, -Chalky!, -Co.4alkylQ, -OCo.4alkylQ, -C0.4alkylOQ, -N(R¹³)C0.₄alkyIQ, -SO₂C₀^alkylQ, -C(=O)C₀.₄alkylQ_> -C₀.₄alkylN(R¹³)Q, and -C(=0)N(R^l3)Co.₄alkyIQ, wherein each of the aforementioned Cwalkyl is optionally substituted;

J is selected from -S(0)o-₂-, -O-, and -NR¹³-;

R³ is -H or R⁴;

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-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;

A³ and A³ are each independently selected from =N-, =C(R²)-;

R³ is -H or optionally substituted lower alkyl;

D is selected from -O-, -S(0)o-₂-, 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 -C(R⁶)R⁷-, -O-, -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-, -O-, -S(0)o_₂-, and -NR⁸-;

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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 -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 X ’s;

R⁶ and R⁷ are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR³, -NR³R⁴, -S(O)q.2R⁴, -SO2NR³R⁴, -CO2R³, -C(O)NR³R⁴, -N(R³)SO2R⁴, -N(R³)C(O)R³, -NCO₂R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, 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, -SO2NR³R⁴, -CO2R⁴, -CffW’R³, -SO₂R⁴, and -C(O)R³;

R¹³ is selected from -H, -C(=O)R³, -C(=O)OR³, -C(=O)SR³, -SO₂R⁴, -C(=O)N(R³)R³, and optionally substituted lower alkyl, 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

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2020201638 05 Mar 2020 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, -NO₂, -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 -M’-M², wherein M¹ is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, ' -SO2N(R¹³)-, -SO2-, -C(=O)N(R¹³)-, -C(=O)C(=O)N(R¹³)-, -Co. 4alkylene-, -C(=O)-, and an optionally substituted four to six-membered hetercyclyl annular containing between one and three heteratoms including at least one nitrogen; and M² is selected from -H, -Ce-salkyl, alkoxy, -C(=0)Co-4alkylQ, -Co^alkylQ, -OCo^alkylQ-, -N(R¹³)Co.4alkylQ-, and -C(=0)N(R^I3)Co^alkylQ; 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, -NH2, -OR³, -NR³R⁴, -S(O)0.2R³, -so2nr³r³, -CO2R³, -C(O)NR³R³, -N(R³)SO₂R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted lower alkyl;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R , -S(0)o.2R³, -SOiNR^³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally 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 II, if Y is a Ci-e alkylene; Z is -NH- or -N(CHj)-; R¹ is a C_b6alkyl optionally substituted in the 2-position by -OH or a C_{b 4}alkoxy 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:

2) either a piperazine or a 4-(C].₄alkyl)-piperazine, and any atom, X¹ or X², of either of said piperazine or said 4-(Ci-<alkyl)-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_4alkyl)-piperazine, cannot be one of -CH₂OC(O)CH₂-, -CH₂CH₂OC(0)-, and either of the two aforementioned bridges optionally substituted by one or two Ci.₂alkyl groups; or

3. The compound according to claim 2, wherein G is selected from the following.

R¹³ _R13 I I ^Y J Π₀_4 %14 R¹³ R¹³ I I, 1 \0-3 N_x R¹⁴ Μ’¹’^{2 x} T O r-Y)¹'² 1 7 \0-3 ^y Y r ^Q O 0 ____/^0-2 O R¹³ R¹³ yyW θ2 R¹³ Yx-N /° L Y^0-2 R¹³ γ-”γ^νγ^ΜΤ<₂ N^V R¹³ R^{13 1 1} Y^Nx _s ^zNM^Q x A '0-4 O O _r13 ¹ ! \°’⁴ V^N-'sTi'a Λ R¹³ .'Wo o o R¹³ I / 10-2 A/⁰ O 0 _R13 O^^N _WQ ^v || ' ω-3 0 0, p 0 AV. Rt3 o p V ω¹'³ R¹³ Ay¹’² Υγ^Ν< 0 0

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Y—r Υγ'Ν» 0 1-2 I Υ ⁽f^)±7 ^Q 0 (J⁰·³ “Υ-Ί /Y>’· o R¹³ R¹³ \ J Πο-4 s _R13 _R13 I I / >0-3 YY S 0 r-r ^x Y s rf AT S 0 , >0-3 i—(Q Η- ,Γ% ,, Y Y R s Α-Ί -TyT·» s 0 R^{13 1} / \⁰'⁴ ΑΛ 0 R¹³ _Y/^N-s-^NY^Q a Um o o R¹³ 1 ' Ρθ·3 γ Yf ^SH 0 R¹³ /Y³ 1 I MO-3 γ^Νγ^ oh o R¹³ (Y^Q I ¹ P0-3 _R13 Y Yr n k. || _H 0 1 1 Y Y R¹³ 0 R¹³ YyY%.3 O 0 ____L)⁰*² 0 O 0 %// / H Y AT γΤ N E R¹³ Q %^)θ-4 °^! _t >0-4 vY° 0 o R¹³ Λ/ / \i-2 I A< Yx / YY Q R13 r13 πγ^γΎ 0 o R¹³ R¹³ 1 1 / >0-3 tⁿyY° O 0 R¹³ I / >0-1 t \0-3 vW- °

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wherein wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from -0-, -N(R¹³)-, -CH2-, and -S(0)o.2-; M is selected from -0-, -N(R¹³)-, -CH2-, and -C(=O)N(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 R is selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)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 heteroalicyclic, two of R²⁵ on a single carbon can be oxo.

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 the 4-position of said piperazine, cannot be one of -C(O)OCH₂CH₂-, -CH₂OC(O)CH₂-, and either of the two aforementioned bridges optionally substituted by one or two Ci-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. The compound according to claim 3, wherein Ar is according to one of formula Ila, lib, and Illa.

Ila Hb Ilia

4) a 2-oxomorpholine, said 2-oxomorpholine 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 -CCH₂)g-, -CH₂WCH₂-, -CH₂WCH₂CH₂-, and -CH₂CH₂WCH₂-, wherein W is -O-, -S(0)o-₂-, -ΝΉ-, or-N(C₍.4alkyl)- wherein g is 2,3, or 4;

and with the proviso that when Z is-Ο-, Ar is according to formula II, and the portion of G directly attached to Ar is selected from:

0 AA 0 H 0 0 0 o Ax. 0* 0 O H

then R⁵⁰ must be of formula IV;

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2020201638 05 Mar 2020 and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(O)a-2- or

when R⁷⁰ is selected from -H, CYalkyl, and Ci^alkoxyl2. The compound according to claim 1, wherein In one example, the compound is according to paragraph [0033], wherein Z is either -O- or -NR -.

5. The compound according to claim 4, wherein D is -O- and R is -OR .

6. The compound according to claim 5, wherein -O-R⁵⁰ and R¹ are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to formula I.

7. The compound according to claim 6, wherein R¹ is -OH or -OCi-ealkyl.

8. The compound according to claim 7, wherein A¹ is =N- or =C(H)-.

9. The compound according to claim 8, wherein G is selected from:

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R¹³ O I 11 ! I⁰’³ \/ N Q O R¹³ R¹³ R¹³ I I / 10-3 R¹³ r13 ^V ΥΎ 0 0________ R¹³ O (R®)0-4 _r13 up'² r¹³ iiA Ari R¹³ I i Λ-4 -'''A 0 R¹³ 0 0 _R13 r13 R^{13 1} / \0-i .ii 1 YrY 0 0 (R⁶⁰)cm ¹%/γ_χ)0-2 r¹³ r ^{0 ,K}0_R3

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, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR , -NR^⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted aryl, optionally substituted arylalkyl, heteroaryl alkyl, and optionally substituted lower alkyl; two of R , together with the carbon or carbons to which they are attached, can combine to form a three- to sevenmembered alicyclic or heteroalicyclic.

10. The compound according to claim 9, wherein Q is selected from.

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.

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11. The compound according to claim 10, wherein Ar is according to formula Ila, and

G is selected from:

o O an H y (R®)o-4 ν^Νγγ/Ί ⁰ w2 H H C'» A-rh 0 JaA A)-2 Λ-4 θ rOji v^a-X0 ⁰ V ¹ '0-2 (R⁶°)0-4 θ V / λα ⁰ /A <R^M)m ' '0-2 o Af

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above, and 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, -NR³R⁺, -5(0)ο.^³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)COiR³, -C(O)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 sevenmembered alicyclic or heteroalicyclic.

12. The compound according to claim 10, wherein Ar is according to formula lib, and

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2020201638 05 Mar 2020 wherein Q, R²⁰, R¹³, E, and R^w 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 R²⁵ is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH₂, -OR , -NR³R⁴, -S(0)o-2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R^{21 * 23}, together with the carbon or carbons to which they are attached, can combine to form a three- to sevenmembered alicyclic or heteroalicyclic.

13. The compound according to claim 12, 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.

14. The compound according to claim 11 or claim 12, wherein R³⁰ is a heteroalicylic or a Ci^alkyl-heteroalicylic.

15. The compound according to claim 14, wherein at least one of R² is halogen.

16. The compound according to claim 14, wherein R⁵⁰ is according to formula IV.

17. The compound according to claim 16, 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 [2.2.1].

18. The compound according to claim 17, wherein Y is selected from -CH₂CH₂CH₂CH₂-, -CH₂CH₂CH₂-, -CH2CH2-, -CH₂-, and absent.

19. The compound according to claim 18, 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].

20. The compound according to claim 19, wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.

21. The compound according to claim 20, wherein said saturated bridged ring system contains -NR⁸-, wherein R® is selected from -H, optionally substituted lower alkyl,

-CO2R³, -C(O)NR³R³, -SOjR³, and -C(O)R³.

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22. The compound according to claim 20, wherein said saturated bridged ring system is of formula V,

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

23. The compound according to claim 22, wherein Y is -CH₂-.

24. The compound according to claim 23, wherein U¹ is -NR⁸-, wherein R is selected from -H, optionally substituted lower alkyl, -CO2R³, -C(O)NR³R³, -SO₂R , and -C(O)R .

25. The compound according to claim 23, wherein U¹ is -O-.

26. The compound according to claim 23, wherein U¹ is absent.

27. The compound according to claim 20, wherein Y is selected from -CH2CH2-, -CH2-, and absent.

28. The compound according to claim 27, wherein said saturated bridged ring system is of formula VI,

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 R¹¹, when taken together, are either an optionally substituted alkylidene or an oxo;

R¹² is selected from -H, -C(O)R³, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally

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or two R¹²’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.

29. The compound according to claim 28, wherein one of R¹⁰ and R is -OR , wherein R¹² is selected from -H, -C(O)R³, and optionally substituted lower alkyl; and R⁹ and the other of R¹⁰ and R¹¹ are both -H.

30. The compound according to claim 29, wherein Y is either -CHz- or absent.

31. The compound according to claim 30, wherein R⁹ is an alkyl group containing at least one fluorine substitution thereon.

32. The compound according to claim 21, wherein said saturated bridged ring system is of formula VII.

VII

33. The compound according to claim 32, wherein Y is either -CHj- or absent.

34. The compound according to claim 33, wherein R⁸ is methyl or ethyl.

35. The compound according to claim 21, wherein said saturated bridged ring system is of formula VIII.

36. The compound according to claim 35, wherein Y is -CH2-.

37. The compound according to claim 36, wherein R⁸ is methyl or ethyl.

VIII

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38. The compound according to claim 20, wherein said saturated bridged ring system is of formula IX

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R³

Ox N wherein U² is selected from -O-, -S(0)o.₂-, -NR⁸-, -CR^R⁷-, and absent.

39. The compound according to claim 38, wherein R³ of formula IX is selected from -H and optionally substituted alkyl.

40. The compound according to claim 39, wherein U² is either -CR^R⁷- or absent,

41. The compound according to claim 40, wherein U² is either -CH2- or absent,

42. The compound according to claim 41, wherein Y is -CH₂-.

43. The compound according to claim 21, wherein said saturated bridged ring system is according to formula X.

X

44.

The compound according to claim 43, wherein R⁸ is methyl or ethyl.

45.

The compound according to claim 1, selected from Table 1.

Table 1

Entry

Name

Structure

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Table 1

Entry Name Structure 1 N-[({3-fluoro-4-[(6(methyloxy)-7-{ [(3aR,6aS)octahydrocyclopenta[c]pyrrol5-ylmethyI]oxy} quinazolm-4yl)oxy]phenyl }amino)carbono thioyI]-2-phenylacetamide aS o i O NN Xjl a a jO 2 N-{ [(3-fluoro-4-{ [7(([(3aR,6aS>2methyloctah ydrocyclopentafc] pyrrol-5-yl]methyl} oxy )-6(methyloxy)quinazolin-4yl]oxy }phenyl)ami no]carbono thioyl} -2-phenylacetamide I ϊ Π N 3 N-{[(4-{[6,7- bis(methyloxy)quiiiolin-4yl]oxy}-3fluorophenyl)(methyl)amino]c arbonothioyl}-2phenylacetamide A SuXl I AO MI 4 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3fluorophenyl)inndazolidin-2one F. —o f \ / ^NMINH AQj I 5 l-(4-{[6,7bis(methyloxy)quinolm-4yl]oxy} -3-flnorophenyl)-3(phenylmethyljimidazolidin- 2-one ^F\ /MIAMI ^{z 0} 6 l-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }-3 -fluorophenyl)-3(phenylacetyl )imi dazolidin-2- one R —O )=\ _/—

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Table 1

Entry Name Structure 7 ethyl [(4-( [6,7- bis(methyloxy)quinolin-4yl]oxy}-3fluorophenyl)amino](oxo)acet ate E 0, ,0 -q )=. M )=\ 0-0 λ—NH o—\ N—⁷ 8 N-{[(4-{[6,7bis(methyloxy)quinazolin-4yl]amino}-3fluorophenyl)amino]carbonot hioyl }-2-phenylacetamide Ο Ά γ j. _w Η H 9 N'-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-tluorophenyl)-Nmethyl-N-(2phenylethyl)sulfamide °yS i u Χλμ 10 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-3(phenylmethyl)-l ,2,4oxadiazol-5-amine X ^Z°yS ^F r-ΖΛ Sj θύν?' H 11 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one xX/ 12 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N'(phenylmethyl)ethanediamide F. Ο O —Q X )=\ 0-4 λ—NH HN—\ /°AJH r\ _N_# \—f

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Table 1

Entry Name Structure 13 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -3-fluorophenyl)-4phenyl-1,3-thiazol-2-amine 0 ty °yS ry/Λ H 14 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N’(2-phenylethyI)ethanediamide F. Ο O —o \ ρ=ξ _z ^o~~\ /~^{NH HN}~\ 15 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -3-fluorophenyl)-1phenylmethanesulfonaimde ^F\ ^z 16 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-2phenylethanesulfonamide ^F\ )=\ /°O“^N^0 O-4 >==< > M? °'-x 17 4-1(6,7bis(methyloxy)quinolin-4yl] oxy} -3-fluoro-N(phenylmethyObenzenesulfon amide 18 4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluoro-N-methyl-N(phenylmethyl)benzenesulfon amide -ο )=\ 9 >=\ /°-V7 Λ O—4 >=< '—' o ' ^Z^O N— .

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Table 1

Entry Name Structure 19 4-{[6,7- bis(methyloxy)qumolin-4yl] oxy} -3-fluoro-N-(2phenylethyl)benzenesulfonani ide E P-4 >=< o —\ Λ? (Λ 20 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-3-fluoro-N-methyl-N(2phenylethyl)benzenesulfonam ide F. —o p /—v )=\ o-4 /)— s-n H ΡΆ /=\ o \ / / \ _n-J/ 21 4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluoro-N-(3pheriylpropyljbenzenesulfona mide F. —q )=\ O O—4 S-NH /°A_M ^s Y o 22 1-(4-((6,7- bis(methyloxy)quinolin-4- y]]oxy}-3- fluorophenyl)pyrrolidin-2-one ο-ΥγΥγ ^/ / ⁰ N— 23 4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} phenyl (phenylmethyl)carbamate v —0 /=\ /-NH o—4 /—o _N-^J 24 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (2- phenylethyl)carbamate ^xo μΥλυΟ H

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Table 1

Entry Name Structure 25 4-{[6,7- bis(methyloxy)quinolm-4- yl]oxy }-3-fluoro-N-methyl-N(3phenylpropyl)benzenesulfona mide ^F\ /—C ff —o )=\ 9 / 0—4 λ—S-N 26 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N'phenylethanediamide K o, p ”°\ \=\ O—4 /—NH HN--4 y ^/0”M^ 27 N-{[(3-fluoro-4-{[7-{[(2methyloctahydrocyclopenta[c] pyrrol-5-yl)methyl]oxy} -6(methyloxy)quinolin-4yl]oxy}phenyl)amino]carbono thioyl]-2-phenylacetamide 1 28 Ν-[(Ζ)-[(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3fluorophenyl)amino] (imino)m ethyl]-2-phenylacetamide ό YL o I _n Ij Xl T1 jO 29 4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluoro-N-[2(phetiyloxy)ethyl]benzenesulf onamide G 30 N,N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-bis(3-phenylpropane-lsulfonamide) O-A AA V-w ° / V/

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Table 1

Entry Name Structure 31 ' N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy) -3-fluorophenyl)-3phenylpropane-1-sulfonamide F )= 0-Π-ΝΗ ⁰ /Ο-γΜ N— 32 N2-[(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3fluorophenyl)sulfonyl]-Nl phenylglycinamide fi —q )=\ )=\ O—< S-NH O 0—)=( Ο ^λ \ J—Is / λ HN—7 33 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy}pyridin-3-yl)-2phenylacetamide ''O iiV Y|| ? i] ν^Λ_νΑχΑ> H 34 N-{[(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}pyridin-3yl)amino]carbonothioyl} -2phenylacetamide ^xo Υγ ΥΊ1 u u ΓΊ n^J Ν^Λ_ΝΑ_ΝΛχ>ν Η H 35 6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -1,3-benzothiazol-2amine Sx^-NH, —o /==< T /=\ pA # ^N /°<Q N—⁰ 36 6-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-5-fluoro-l ,3 benzothiazol-2-amine Sx/NH₂ —o /=< if )=\ o-( /=( ^z M. / ^F

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Table 1

Entry Name Structure 37 N-(6-{[6,7- bis(mcthyloxy)quinolin-4- yl]oxy }-5-fluoro-1,3benzothiazol-2-yl)-2phenylacetamide p'^! 38 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy)-3-fluorophenyl)-N’(2-morpholin-4ylethyl)ethanediamide -V AM )=\ NH HN-a /—\ 0—4 )=( '“Μ O _N y 39 benzyl- {[4-(6,7-dimethoxyquinolin-4-y!oxy)-3-fluorophcnylcarbamoyl]-methyl} carbamic acid tert-butyl ester ^x°yS V τ Wriuxo H 40 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2(phenylmethyl)glycinamide XT XX-M JU 41 N2-acetyl-Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2(phenylmethyl)glycinamide H 42 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy}-l ,3-benzothiazol-2yl)-2-phenylacetamide —o /=< T T \___k o__/ V-N Ό

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Entry Name Structure 43 benzyl- {[6-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-3ylcarbamoyl] -methyl} carbamic acid tert-butyl ester X x + k X ζθχ _n /X H 44 Nl-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}pyridin-3-yl)-N2(phenylmethyl)glycinamide X mX1_najJ0 H 45 N2-acetyl-N l-(6-{ [6,7bis(methyloxy)quinolin-4yljoxy} pyridin-3-yl)-N2(phenylmethyl)glycinamide X juXx_naXO H 46 N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy }pyridin-3-yl)-3phenylpropanamide o °)=\ O— ^N —v # 47 N-(6-{[6,7- bis(methy]oxy)quinolin-4yl]oxy} pyridin-3-yl)-4phenylbntanamide X v ΌςχχΟ H 48 Nl-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy )pyridin-3-yl)-N2methyl-N2(phenylmethyl)glycinamide X ^°Ί11 Sty°ΎΠι g i ip] H

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Entry Name Structure 49 N-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy} -3-fluorophenyl)-N'{2-Γ4(methyloxy)phenyl]ethyl} etha nediamide -v ₀_qp-v/^_nh 50 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy)-3-fluorophenyl)-N2methyl-N2(phenylmethyl)glycinamide XVA o ΥΎ ο ? i fη 51 4-[(2-amino-l ,3-benzothiazol- 6-yl)oxy]-6,7-bis(methyloxy)l-(2-oxo-2phenylethyl)quinolinium ,s^nh₂ —q /=( T o—^ 5=( _n+j7 1 / 0 52 N-{[(4-{[6,7- bis(methyloxy)quinolin-4yl]amino} phenyl)amino]carbo nothioyl} -2-phenylacetamide TXj^ _{q n} Mi 53 N-(6-{[6,7bis(methyloxy)quinolin-4yljoxy }-5-fluoro-l ,3benzothiazol-2-yl)-3phenylpropanamide ^w 54 N-{[(6-{[6,7- bis(m.ethyloxy)quinolin-4yl]oxy} -5-chloropyridin-3yl)amino]carbonothioyl} -2phenylacetarnide _{s 0} XX vX_na_naJQ Η H

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Entry Name Structure 55 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy)-3-fluorophenyl)-N'(2,3-dihydro- ΙΗ-inden-l yljethanediamide E /° —o 7—\ O—4 NH HIM—I o—4 )=4 IM—*⁷ 56 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy)-3-fluorophenyl)-N'(2,3 -dihydro-lH-inden-2yl)ethanedi amide E Ο, O —q )=, M /=\ °~A A^{nh hn—}\ JI J —/ 57 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N'(1,2,3,4-tetrahydronaphthalenl-yl)ethanediamide ^F\ °\ /° \ / —Ο /=\ / λ ΑΛ )=\ O—4 Λ—ΝΗ HN—( ) v // 58 N'-(4-{[6,7- bis(methyloxy)quinolm-4yl]oxy} -3 -fluorophenyl)-N(2-phenylethyl)-N(phenylmethyl)sulfamide E —O >\ _Z°A Z“^Nt\o / ZA /“\ e J—⁷ —(y 59 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl] oxy }-3-fluorophenyl)-N2(trifluoroacetyl)glycinamide 0 E 0» HNA p -°χ )=\ Λ )=\ O—4 d— NH F o-4 )=4 60 N-{ [4-(6,7-dimethoxyquinolin-4-yloxy)-3 -fluorophenylcarbamoyl] -methyl} benzamide p R 0 RNA /A 0—4 \sss/

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Entry Name Structure 61 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} pyridin-3-yl)-N’-(4fluorophenyl)propanediamide ΐί γ Y1 0 O rfV 62 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluoropheny])-N'[(25)-1,2,3,4tetrahydronaphthalen-2yl]ethanediamide R O 0 /=1 —o )==\ /-5 j—L )=\ 0—4 /—NH ΗΝ·< p— ^/O^Q 63 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N’[2-(4methylphenyl)ethyl]ethanedia mide ₀_>V/^oAy^nh 64 N-(4-([6,7- bis(methyloxy)quinoIin-4- yl]oxy }-3-fIuorophenyl)-N(2phenylpropyl)ethanediamide K o p —0 )=X, ΛΥ )=\ O—4 p— NH HN—\ 0-4 )=/ )— ⁷ M3 rC \ / 65 N-(4-{[6,7- bis(methyloxy)quinolin-4~ yl]oxy}-3-fluorophenyl)-N'[2-(4chlorophenyl)ethyl]ethanedia mide 66 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N,Nbis(phenylmethyl)sulfamide 'b

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Entry Name Structure 67 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-N,N'bis(2-phenylethyl)sulfamide F —0 ^f _)=\/⁰A/“ⁿv.c / / ° NH —---- 68 ethyl [(6- {[6,7- bis(methyloxy)quinolin-4yl]oxy} -5-chloropyridin-3yl)amino](oxo)acetate Cl 0 0 —ο Μ-λ \ )=\ ο—^o-\ o—{ >=<f N—^J 69 N-(6-{[6,7- bis(methyloxy)quinolin-4ylJoxy}-5-chloropyridin-3yl)-N’-(2phenylethyl)ethanedi amide Ci 0 p ο—TnH HN—\ Π—a KK ^N ff 70 N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin-3yl)-N'-(4fluorophenyljpropanediamide ^xo °rS ? θ θ ίΐ V AAaaJU Η Η 71 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }-3-fluorophenyl)-N'(1,2,3,4-tetrahydronaphthalen2-yl)ethanediamide F. 0 0 /=\ --0 )=\ 7—\ j—4 / /=\ °# ^{NH HN} \ / N^ 72 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-N'[2-(l-methylpyrrolidin-2yl)ethyl]ethanediamide F 0 0 -o )=\ M \ ⁷ M3 N—^J

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Entry Name Structure 73 N-(4~{[6,7- bis(methyloxy)quinolin-4- yljoxy }-3-fluorophenyl)-N'[2(phenyloxy)ethyl]ethanediami de /=\ /~^{NH HN}^\_ ^/0Ab b 74 N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy }-3-fluorophenyl)-N'[2-hydroxy-l(phenylmethyl)ethyl]urea Y°Ya-W 75 l-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-3[(4-methylphenyl)sulfonyI]-4(phenylmcthyl)imidazolidin2-one }=\ O—v y^- N 1 ^/_ν_ζ~Λ / Ί 76 N'-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-Nmethyl-N-(2~ phenylethyl)ethanediamide F 0 0 ”0 )=\ λ=\ O—4 NH N— 0—4 >=4 ( ^z mT) ml) 77 N-<4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -3-fluorophenyl)-lSr{[3(trifluoromethyl)phenyl]meth yljethanediamide fi P —o L=\ )=\ 0—4 HN=\ b ^N f^Af 78 N-(4-{[6,7- bis(methyloxy)quinolin-4yljoxy }-3-fluorophenyl)-N'{2-[3(trifluoromethyl)phenyl]ethyl lethanediamide f. o, a -q )= M ΛΛ °Ά J^{-NH HN—}\_/“A ^/0MJ Y/f V _F\

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Entry Name Structure 79 N-(6-{[6,7- bis(methyloxy)quinolin-4yljoxy} -5-chloropyridin-3yl)-3-oxo-4phenylbutanamide ^xo Til °T|| ? s Π H 80 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-chloropyridin-3yl)-2-[3(trifluoromethyl)phenyl]aceta mide ^xo IL d. CL Μ Π ? A F H F F 81 6-((6,7- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-N-[2(phenyloxy)ethyl]-l,3benzothiazol-2-amine -V Yvo /^0-¾ / C 2 f 82 6-((6,7- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-N-(2piperidin-l-ylethyl)-l,3benzothiazol-2-amine )=\ o-{ O /°AM r N— 83 6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-fluoLO-N-methyI-N(2-phenylethyl)-l ,3benzothiazol-2-amine —Q /=^ T T |l Y o—4 y* ^N Α /K n-⁷ 84 6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-N-(2pyrrolidin-l-ylethyl)-l,3benzothiazol-2-amine s IL xx x _₀ Ay O \_ ₀_Z Ln /“vJH / —\\ /) ^F

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Entry Name Structure 85 6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-fluoro-N-{ [3(trifluoromethyl)phenyl]meth yl}-l,3-benzothiazol-2-amine θ,λΧΧζ ;/<· ’ ' 86 6-{[6,7bis(methyloxy)quinolin-4yl]oxy }-5-fhioro-N-{ 2-[3(trifiuoromethyl)phenyl]ethyl } -1,3 -benzothiazol-2-amine /°X-O ^{f f}t^f N-⁹ 2 87 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy }-5-chloropyridin-3yl)-N'-[3(trifluoromethyl)phenyl]propa nediamide '“ο xr Ααλ,Α< 88 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy }-5-fluoro-l ,3benzothiazol-2-yl)-2- [3(trifluoromethyl)phenyl]aceta mide F-j-F F 89 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2{[3(trifluoromethyl)phenyl]meth yljglycinamide 90 _ Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}-3“fluorophenyl)-N2(2-phenylethyl)glycinamide F. 0, HN^ K v \=< 0-4 /— NH

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Entry Name Structure 91 Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyI)-N2{2-[3(trifluoromethyl)phenyl]ethyl }glycinamide -V vY^{NH F} 92 benzyl-{ [5-chloro-6-(6,7dimethoxy-quinolin-4-yIoxy)pyridin-3-ylcarbamoyi]methyl}-carbamic acid tertbutyl ester 93 Nl-(6-{[6,7bis(methyloxy)quinolm-4yljoxy }-5-chloropyridin-3yl)-N2(phenylmethy])glycinamide °Ύ ^α H 94 N-(6-{[6,7- bis(methyloxy)quinolin-4yljoxy }-5-fluoro-l ,3benzothiazol-2-yl)-2-[3,5bis(trifluoromethyl)phenyl]ac etamide —o | ^f\,f ⁷ / ^F γ M—⁷ F--F F 95 N-(6-{[6,7bis(methyloxy)quinolin-4yljoxy }-5-fluoro-1,3benzothiazol-2-yl)-2-[2chloro-5(tnfluoromethyl)phenyl]aceta mi de 96 N-{3-fluoro-4-[(6- (methyloxy)-7-{ [(1 methylpiperidin-4y])methyl]oxy}quinolin-4yl)oxy]phenyl} -N'-(2phenylethyl)ethanediamide F. O 0 —o )=\ 7—\ Y=\ o-Λ Jhnh hn—x PL d V-N \

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Entry Name Structure 97 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-N'(1,2,3,4tetrahydroisoquinolin-1 ylmethyl)ethanediamide F. °\ zP —o >=\ Ύλ Yx °Ύ #~^{nh hn}t 98 N-(4-{[6,7- bis(methyloxy)quinolm-4yl]oxy} -3-fluorophenyl)-N’[(2-meth yl-1,2,3,4tetrah ydroisoquinolin-1 yl)methyl]ethanediamide ^F\ °\ /° —q >=\ Ύχ °—4 γ-ΝΗ HN—y /=\ 1---Z 99 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)-N2methyl-N2-( [3(trifluoromethyl)phenyl]mcth yl}glycinamide °yS _o I ΥΎ Τη Ϊ i fi _F H 100 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)-N2methyl-N2-{2-[3(trifluoromethyl)phenyl]ethyl Jglycinamide 101 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)-N2methyl-N2-(2phenylethyl)glycin amide _F o —o >=\ 0—X λ-ΝΗ 102 1-(4-( [6,7- bis(methyloxy)quinolin-4- yl]oxy} -3-fluorophenyl)-4(phenylmethyl)imidazolidin2-one ^z { / ⁰ N-^J 103 N-(6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}pyridazin-3-yl)-N'-(4fluorophenyl)propanediamide

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Entry Name Structure 104 N<6-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin-3yl)-N'-(2chlorophenyl)propanediamide A Al ? nJ ΧΛ_ΝΑΛ_ΝΧΡ ^{H H} Ai 105 N-(6-{[6,7bis(methyloxy)quinoliiMyl]oxy}-5-chloropyridin-3yl)-N'-(3chlorophenyl)propanediamide A> ^Cl n J LI aa AA Η H 106 Nl-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy } -5-chloropyridin-3yl)-N2-methyl-N2(phenylmethyl)glycinamide A) ^χ0*Ίί^Ί ^Cl ii7°YS u ¹ ΓΊ H 107 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy} -5-chloropyridin-3yl)-N’-(4chlorophenyl)propanediamide A A ? τι ii ° ° ti Μ ΑΛΑΛΑ Η H IOS (2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2[(methyloxy)imino]propanami de °)_4 y=\ 0^-¾ ANH N-q oA )=( ^{x z} MA 109 (2E)-N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-2[(ethyloxy)imino]propanamid e -7 /-A X=\ O—4 A-NH n-o ο-Z A=z '—t — ^z ma N—y

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Entry Name Structure 110 (2E)-N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-2{[(phenylmethyl)oxy]immo}p ropanamide —ο /=\ Ο-Αλ—NH N-O^ N— 111 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-l(phenylmethyl)prolinamide A vV°ya o Y Y Y 1 π nJ WsAt ^H Az 112 l-(4-{[6,7bis(methyloxy)qumolin-4yl]oxy [phenyl )-3-((4methylphenyl)sulfonyl] -4(phenylmethyl)imidazolidin2-one —-O z=\ o—4 An I _n ⁰ 113 1-(4-((6,7bis(methyloxy)quino!m-4yl]oxy[phenyl)-4(phenylmethyl)imidazolidin2-one -0 /=\ O—/ \ ( V -7 y-NH N/ N-^ _______________ 114 N-(4-{[6,7bis(methyloxy)qumolin-4yl]oxy[phenyl)-4(phenylmethyl)-4,5-dihydrol,3-oxazol-2-amine KAAvA ΟΛ /A 115 6,7-bis(methyloxy)-4-({ 4-(4(phenylmethyl)piperazin-lyl]phenyl }oxy)qumoline 0-4 AZ ^{xz Z}^“Q N—7

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Entry Name Structure 116 l_(4-{[6,7bis(methyloxy)quinolin-4yl]oxy[phenyl)-4(phenylmethyl)piperazin-2one ^“*0 / \ / ^{N N}“^/ / ~y—4 4 c? ^/ 117 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy[phenyl)-N2(phenylmethyl)alaninamide -°v_ N—⁷ ' 118 Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy }phenyl)-N2-methyl- N2(phenylTnethyl)alaninamide X b 119 Nl-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy [phenyl )-N2(phenyhnethyl)leucinamide O /—( —q /=\ ^x )= 0-/ A— NH HN—\ o—< >=( '—⁷ )=\ ^f VX _N_y '—⁽ 120 Nl-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy[phenyl)-N2-methylN2(phenylmethyl)leucinamide o /—( —0 /=\ /—\ ^x o-4 A— NH N—\ /°xn _N_z \/ 121 Nl-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy[phenyl)-N2(phenylmethyl)valinamide o Y— —0 /=\ \ 0-4 λ—NH HN—X /°Λ_Μ ry w

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Entry Name Structure 122 4-(6,7-dimethoxy-quinolin-4ylamino)-N-(3-phenylpropy l)-benzami de _o.>L T 1 ^H NT O 123 4-benzyl-l-[4-(6,7- dimethoxy-quinolin-4-yloxy)phenyl]-tetrahydro-pyrimidin2-one ^xo z^CY J J Lil 124 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl [-N'phenethyl-oxalamide Ό όΜν 125 2-(Benzyl-methyl-amino)-N[4-(6,7-dimethoxy-quinolin -4yloxy)-phenyl]-3-methylbutyramide (note: Alphabetic order of prefixes ignored while selecting parent chain) Υ τΤτΊ ϊ Y N T ^H Y 126 N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-phenyl]-2phenoxyimino-propionamide _Xo./L ^u Yn

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Entry Name Structure 127 2-Benzyloxyimino-N-[4-(6,7dimethoxy-qumolin-4-yloxy)phenyl]-2-phenyl-acetamide ^xo Yujp O Hl 128 4- [4-(4-Benzy 1-piperidin-1 - yl)-phenoxy]-6,7-dimethoxyquinoline ^xo 129 N-[4-(6,7-Dimethoxyquinolin-4- yloxy )-3 -fluorophenyl]-N'-(2-isopropyl1,2,3,4-tetrahydroisoquinolin-l-ylmethyl)oxalamide \ p p_ 130 N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-3 -fluorophenyl]-N'-(2-ethyl-l ,2,3,4tetrahydro-isoquinolin-1 ylmethyl)-oxalamide Yd τΥύιι ϊ ^H hL 00

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Entry Name Structure 131 4-(4-{3-Chloro-5-[2-(4fluoro-phenylcarbamoyl)acetylamino] -pyridin-2yloxy} -6-methoxy-quinolin-7yloxymethyl)-piperidine-lcarboxylic acid tert-butyl ester x Λ A 0 V mLaa_nh Ϊ L/ h j* ° ⁰ P) F 132 N- {5-Chloro-6-[6-methoxy-7- (piperidin-4-yImethoxy)quinolin-4-yloxy]-pyridin-3yl }-N'-(4-fluoro-phenyl> malonamide φ) ΎΥ°ύΑ 9 j? H HI Φ F 133 N- {5-Chloro-6-[6-methoxy-7- (l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-pyridin-3-yI }-N'-(4fluoro-phenyl)-malonamide M u ^H F 134 N- {4- [7-(3-Diethylamino- propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-N’-phenethyloxalamide X -x Av

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Entry Name Structure 135 N-{ 3-Fluoro-4-[6-methoxy-7(3-morpholin-4-yl-propoxy> quinolin-4-yloxy]-phenyl }-N'phenethyl-oxal amide ’ ^xo NY 136 N- {3-Fluoro-4-[6-methoxy-7- (3-piperidin-l-yl-propoxy)quinolin-4-yloxy]-phenyl} -N'phenethyl-oxalamide A i bi Yi] ? _Λ U ^H hL Qr 137 N-{4-[7-(2-Diethylaminoethoxy)-6-methoxy-quinolin4-yloxy]-3-fluoro-phenyl} -N'phenethyl-oxalamide lMaI _o 138 N-{3-Fluoro-4-[6-methoxy-7- (l-methyl-piperidin-4ylmethoxy)-quinolm-4yloxyhphenyl} -N’-methyl-N'phenethyl-oxalamide Jy/i r. 1 H ¹

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Entry Name Structure 139 N-{ 3-Fluoro-4-[6-methoxy-7- (2-methyl-octahydrocyclopenta[c]pyrrol-5ylmethoxy)-quinolin-4yloxy]-phenyl }-N’-phenethyIoxalamide A </ ΎΎ ΥΊ 9 H-j· F-H £ 3 lj | 140 N-{ 3-Fluoro-4-[6-methoxy-7 (2-methyl-octahydrocyclopenta[c]pyrrol-5yImethoxy)-quinazolin-4yloxy]-phenyl }-N'-phenethyloxalamide A F f II 1 7 141 2-(3,4-Dihydro-lHisoquinolin-2-yl)-N-{3-fluoro4-[6-methoxy-7-(l -methylpiperidin-4-ylmethoxy)quinoIin-4-yloxy] -phenyl }-2oxo-acetamide ^X'C AW jl ^{1 H} A 142 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-2oxo-2-(3-phenyl-pyrrolidin-1 yl)-acetamide A 6% A v ^{H H} A

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Entry Name Structure 143 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-2oxo-2-(2-phenyl-morpholin-4yl)-acetairude /Am. . 144 N-(2-Dimethylamino-2- phenyl-ethyl)-N'-{ 3-fluoro-4[6-methoxy-7-(piperidin-4y!methoxy)-quinolin-4yloxy]-phenyl} -oxalamide ό Τ'°ίΑ.Lo ^{H H} HN. 145 N- {3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N¹(2-oxo-2-phenyl-ethyl)oxalamide όΑά,ν ^{H H} HhL ⁰nQ 146 N-[5-Chloro-6-(6,7dimethoxy-quinolin-4-yIoxy)pyridin-3-yl]-2,2-difluoro-N'(4-fluoro-phenyl)-malonamide ^xo °Y]i 9 j? H F Fl Φ F

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Entry Name Structure 147 N-Benzyl-N'-{ 3-flnoro-4-[6methoxy-7 -(1 -methylpiperidin-4-ylmethoxy)quinolin-4- yloxy] -phenyl} oxalamide ^xo λύΑλ „ Q u 1 Η I¹ 148 N- {3-Huoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl) -N'[2-(2-fluoro-phenyl)-ethyl]oxalamide ^xo 6° A A v ^{H H} HlL _c η r 149 N-[2-(3-Chloro-phenyl> ethyl]-N'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxalamide PAA· ^{H H} ΗΝ^Γ (Q Cl 150 N - {3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'[2-(2-methoxy-phenyl)-ethyl]oxalamide Γ°Ύ^1 ^F ό Μ ΧΑχθ

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Entry Name Structure 151 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} -N'(2-pyridin-3-yl-ethyl)oxalamide 6° Υή r ^{H H} HN. Y-n 152 N-Benzyl-N’- {3-fluoro-4-[6- methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide ^xo kJ <AXo ^{H H} hJ u 153 N-[2-(2,5-Dimethoxyphenyl)-ethyl]-N'- {3-fluoro-4[6-methoxy-7-(piperidin-4yImethoxy)-quinolin-4yloxy]-phenyl }-oxalamide ^xo >k k /k Γ ii Τι ίΓ Yn ⁰ k J ksjk Jk^-0 Η H ' ^ΗΝ\φ V 154 N- {3-Fluoro-4-[6-methoxy-7“ (piperidm-d-ylmethoxy)qumolin-4-yloxy]-phenyl}-N'[2-(2-trifluoromethyl-phenyl)ethyl]-oxalamide ^x° U XX UL Ko ii !_! 1 F ^{H H} HN. fYf Ό

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Entry Name Structure 155 N-[2-(2-Ethoxy-phenyl)ethylJ-N'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl [-oxalamide A'Jfo F XTXzV „ il iii Ύι] S Ψ J Α,Αο ^{H H} hn\ J 4? 156 N-[2-(2,4-Dimetbyl-phenyl)ethyl]-N'-{3-fIuoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide cVa k 157 N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(1S -phenyI-2-p-tolyl-ethyl)oxalamide V A V 158 N-[2-(4-Chloro-phenyl)ethyl]-N'-{3-iluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxal amide A V A ju ^{H H} UN JJ-CI

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Entry Name Structure 159 N-(3-Fluoro-4-[6-methoxy-7- (l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamic acid όΥάν 1 ^H OH 160 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(3-fIuoro-phenyl)-ethyl]oxalamide A ,α Λ M U AO ^{H H} HN-. 1TJ 161 N-[2-(2-Chloro-phenyl)ethyl]-N'-{3-fiuoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenylj-oxal amide A Q v U _v 162 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(3-methoxy-phenyl)-ethyl]oxalamide '‘Ο Q U ΙΧ_να^ο 13

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Entry Name Structure 163 N-(l ,2-Diphenyl-ethyl)-N'- {3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide k N N.M kk ^{H H} UM L 0 164 N-[2-(2,4-Dichloro-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl} -oxalamide cSYyYii V Η Η 1 ^HS Cl k. 165 N-[2-(3,4-Dimethoxyphenyl)-ethyl]-N’-{ 3-fluoro-4[6-methoxy-7-(piped din-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide ^xo TyA. r ^{H H} hI i i ? 166 N-[2-(4-Ethyl-phenyl)-ethyI]- N¹- {3-fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide XUvJ o Q M ULXo ^{H H} J

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Entry Name Structure 167 N-[2-(4-Ethoxy-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide Ή Yv 168 N-[2-(4-Ethoxy-3-methoxyphenyl)-ethyl]-N'-{3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide Ή JL ^{H H} hn\ 169 N- {3-FIuoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(4-phenoxy-phenyl)-ethyl]oxalamide όΥΆγ Cl Jlj

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Entry Name Structure 170 N-[2-(3-Ethoxy-4-methoxyphenyl)-ethyl] -N- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl [-oxalamide ^xo Η H 1 HN 171 N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(2-pyridin-2-yl-ethyl)oxal amide t b 172 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinoIin-4-yloxy]-phenyl}-N’(2-pyridin-4~yl-ethyl)oxalamide A A ^{H H} A 173 N- {3-Fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quino!in-4-yIoxy]-phenyl} -N'[2-(4-fluoro-phenyl)-ethyl]oxalamide ^xo 0 Xr Y-y

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Entry Name Structure 174 N-[2-(2-Bromo-phenyl)ethylj-N¹- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-plienyl f-oxalamide 6°¾⁰A r ^{H H} _R Y Br 175 N-[2-(2-Chloro-6-fluorophenyl)-ethyl]-N'-{ 3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide ^ηνί ^Cl 176 N-{3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -N'(2R-phenyl-propyI)-oxalarnide λ°Ύ°>λ o 0 M U_Nv ^{H H} hT Y 177 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N'indan-1 -y]-oxalami de ^xo Us, 6 v°Ag N N X Η H '

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Entry Name Structure 178 N- {3-Fluoro-4- [6-methoxy-7(1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -N'-isobutyloxal amide ^xo 0 M Ll.v 179 N-{ 3-Fluoro-4-[6-methoxy-7(1 -methyl-piperidin-4ylmethoxy)-qumolin-4yloxyj-phenyl} -N'-(3-methylbutyl)-oxal amide ^xo ί υά,ν ^{! H} 180 N- {3-Huoro-4-[6-methoxy-7(1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl} -N'-(2/?phenyl-propyl)-oxalamide ^xo 181 N- {3-Fluoro-4-[6-methoxy-7(1 -methyI-piperidin-4ylmethoxy)-quinolm-4yloxyj-phenyl} -N-(2-phenylpropyO-oxalamide γΥϋι ° ψ Μ ξΑ_ΝΑ^ο ^{1 H} ML |l

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Entry Name Structure 182 N- {3-Fluoro-4-[6-methoxy-7(1 -meth yl-piperi di n-4ylmethoxy)-quinolin-4yloxy]-phenyl} -N'-indan-2-yloxalamide 0¾¼ ryJ 183 N - {3-Fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(lR-phenyl-ethyl)-oxalamide Yy JL 184 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N(1 S-phenyl-ethyl)<ixalainide ο υ Α-χο 185 N-[2-(3-Bromo-phenyI)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamlde /Οχ XXVjl _o 0 XT XIL· ^{H H} Jh Brx^xJ

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Entry Name Structure 186 N-[2-(2,6-Dichloro-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl} -oxalamide Ψ A ^{H H} .HH Cl Y 187 N-[2-(2,4-Dichloro-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-oxal amide ^xo - _α y Cl·^⁵^ 188 N-(2-Benzo[l,3]dioxol-5-ylethyl)-N'- {3-fluoro-4- [6methoxy-7-(piperidin-4ylmethoxy)-qumolm-4yloxy]-phenyl} -oxalamide ^xo ό uAl ψ nY ΧΑ,,,Αγ ^{H H} Jh <XJ ' 189 N- [2-(3-Bromo-4-methoxyphenyl)-ethyl] -Ν'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-qumolin-4yloxy]-phenyl }-oxalamide ^xc Y A. r ^{H H} NH x. 1 J

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Entry Name Structure 190 N-[2-(3,5-Dimethoxyphenyl)-ethyl] -Ν'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide ο Λ° γγ° Y 2 ^{H H} Ν^ΓΗ 1ΓΎ 191 N- {3-Fluoro-4- [6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(2-o-tolyl-ethyl)-oxalamide ^xo ^{H H} Jh Ck 192 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-N'(2-m-tolyl-ethyl)-oxalamide ^xo 6 WA JC ψ Y 0Α_νΛ^ο

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Entry Name Structure 193 N-[2-(3-Ethoxy-phenyl)ethyl]-N'- {3-fIuoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-qui nolin-4yloxy]-phenyl [-oxalamide ^xo 194 N-[2-(3,4-Dimethyl-phenyl)ethyl]-N'-{ 3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxal amide ^xo y -X Ό- _N a^o Η H ¹ 195 N-[2-(2,5-Dimethyl-phenyl)ethyl]-N'-{ 3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxal amide X Λ X . C_NJ Μ υΧγο. Η Η 1 196 N-[2-(3-ChIoro-4-propoxyphenyl)-ethyl]-N'-{ 3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide X Xx - Cix^J

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Entry Name Structure 197 N-[2-(4-Butoxy-3-chlorophenyl)-ethyl]-N'-{ 3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide XULoA ₀ Q ΧΧΧΧχ ^{H H} Jh 198 1 N-[2-(4-tert-Butyl-phenyl)ethyl]-N’-(3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide ^xo U M kXXo 199 N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl}-N'[2-(4-sulfamoyl-phenyl)ethyl]-oxalamide ^xo Ata Μ Μ ΑΑ_νΑ^ο ^{H H} Jh h₂Nx„X^I o o

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Entry Name Structure 200 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(4-hydroxy-3-methoxyphenyl)-ethyl] -oxalamide ^xo ^{H H} Ah IJ 201 N-{ 3-Fluoro-4- [6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -N'[2-(3-hydroxy-4-methoxyphenyl)-ethyl J -oxalamide ^xo 6° v⁰ A z h b r ^{H H} NH HO-^xJ 202 N-(2,4-Dichloro-benzyl)-N'{3-fluoro-4- [6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide ^xo 6°¾° A a V ΑΑ_ΝΑγθ ^{H H} Ah Cl

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Entry Name Structure 203 N- {3-Fluoro-4- [6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N’(4-fluoro-2-trifluoromethylbenzyl)-oxalaxnide ^xo LA M ^{H H} Jh fJ f ^F u T F 204 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(1 -p-tolyl-ethyl)-oxalamide cj «Jr xi v ^H AJh V 205 N- {3-Fluoro-4- [6-methox y-7 - (piperidin-4-ylinethoxy)quinolin-4-yloxy] -phenyl }-N'(3-fluoro-4-trifluoromethylbenzyl)-oxalamide A v ^{H H} Jh cf₃

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Entry Name Structure 206 N-(3-Chloro-4-fluoro-benzy])“ N’-{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolm-4-yloxy]-phenyl }oxalamide ft cAy A To N N γ ^{H H} NH F 207 N- {3-Fluoro-4- [6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'[ l-(3-methoxy-phenyl)-ethyl]oxalamide όΥύ,ν 208 N- {3 -Fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} -N'(l-naphthalen-2-yl-ethyl)oxalamide 0

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Entry Name Structure 209 N-(4-Chloro-3trifluoromethyl-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yIoxy] -phenyl }oxalamide Ar ^H NH n CI 210 N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolm-4-yloxy] -phenyl }-N’(1 -p-tolyl-ethyl)-oxalamide a ? H ¹ h r ^H LA 211 N- {3 -Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N(6-ttifluoromethyl-pyridin-3ylmethyl)-oxal amide Ό u u kl_N v N NT ^{H H} ,NH V cf₃

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Entry Name Structure 212 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(2-methyl-benzyl)-oxalamide /ivA o 213 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl }-N'(3-methyl-benzyl)-oxal amide N N A 214 N- {3-Fluoro-4-[6-methoxy-7- (piperidm-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(4-fluoro-3-trifluoromethylbenzyl)-oxalamide 6¾¼ r L J -J kA V NH JO f₃c'^V F 215 N-(3,5-Dichloro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide /w, Q U tlXo ^{H H} NH Γ

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Entry Name Structure 216 N-{ 3-Huoro-4-[6-niethoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(lR,2,3,4-tetrahydronaphthalen-1 -yl)-oxalamide “Ο ψ Η Ύγ ^H 217 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(1S ,2,3,4-tetrahydronaphthalen-1 -yl)-oxalamide 0°Cy° A κ 218 N-Cyclopentyl-N'- {3-fluoro4-[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide 219 N-[ l-(4-Bromo-phenyl)ethyl]-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phcnyl} -oxalamide Ό ψ nA kAAo ^H !tJlH Br

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Entry Name Structure 220 N-(2-Fluoro-benzyl)-N'-{3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl) oxalamide V nA UAo ^H , NH Γ J 221 N-[2-(3,4-Dichloro-phenyl)ethyl]-N'-{3-fIuoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl} -oxalamide A 1J 222 N-(4-FJuoro-benzyl)-N'-{3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide 6A Ω F 223 N-(2,3-Difluoro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide o Aw, · U M VJy⁰ Η Η 1 NH

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Entry Name Structure 224 N- {3-Fluoro-4- [6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(2-phenoxy-ethyl)-oxalamide A. Μ Π κ ii i OU 225 N-(2,2-Diphenyl-ethyI)-N'- {3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-y loxy] -phenyl} oxalamide 226 N-{ 3-Fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'[2-(4-methoxy-phenyl)-ethyl]oxalamide Ό XYrVi · ^{H H} ^NH JL zr 227 N-{ 3-FIuoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(2-phenyl-propyl)-oxalamide Ό ^{H H} Sh

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Entry Name Structure 228 N-[2-(4-BiOmo-phenyl)ethyl]-hT- {3-fluoro-4- [6methoxy-7-(pipeiidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide V a v- v ^{H H} NH 229 N- {4-[7-( l-Ethyl-piperidin-4ylmethoxy)-6~methoxyquinolin-4-yloxy]-3-flaorophenyl}-2-oxo-2-(2-phenyImorpholin-4-yl)-acetamide N N ^k A Cj ⁰ 230 N- {3-Huoro-4-[6-methoxy-7(piperi din-4-ylmethoxy)quinolin-4-yloxy] -phenyl }-N(3-fluoro-5-trifluoromethylbenzyl)-oxalamlde A j °y5l a k J ^{9 H} Jh f₃c33_f 231 N-(3,5-Difluoro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide Cl JL oYAv ^{H H} Ih F

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Entry Name Structure 232 N-(2-Chloro-5trifluoromethyl-benzyO-N¹{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolm-4-yloxy]-phenyl }oxalamide to 0 u U-Xo Υγ·⁰¹ F,cM 233 N- [4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl] -N'-(2-dimethylamirio2-phenyI-ethyl)-oxal amide to ιιΥ Ύ|1 J ^H Jh Ct f 234 N-{ 3-Fluoro-4-[6-methoxy-7(pipcridin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(4-methoxy-benzyl)oxalamide to Υύ v M VA_NAp° /°

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Entry Name Structure 235 N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(4-trifluoromethyl-benzyl)oxalanu.de .NH Ο ' CFg 236 N-{3-Fluoro-4-[6-niethoxy-7(piperidin-4-ylmethoxy)quinoIin-4-yloxy]-phenyl} -N'(3-methoxy-benzyl)oxalamide ο Γ°Υ^Ί ^F Q υάΧο ^{H H} Ν^ΓΗ fl 237 N-{3-Fluoro-4-[6-methoxy-7(piperidi n-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(3-trifluoromethyI-benzyl)oxalamide X JL Μ Μ Μ/γΟ ^{H H} Ν^ΓΗ 238 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(3-trifluoromethoxy-benzyl)oxalamide ςΫΜγ ^{H H} .NH F₃Ck JCm ³

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Entry Name Structure 239 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl }-N’(2-methoxy-benzyl)oxalamide Ο Y ^N-> 240 N- {3-Fluoro-4- [6-methoxy-7 (piped dm-4-ylm.ethoxy)quinolin-4-yloxy]-phenyl} -Ν'(2-trifluoromethyl-benzyl)oxalamide xLa γ ^{H H} ,NH kJ 241 N-(3-Chloro-benzyl)-N'-{3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide o ^F 0YA„v ^π NH 242 N- {3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N'(2-trifluoromethoxy-benzyl)oxalamide Γ°Υ^ ^F φ γγ ^{H H} NH AY Lx f₃c

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Entry Name Structure 243 N-(2-Chloro-benzyl)-N'- {3fluoro-4-[6-methoxy-7(piperidin-4-yImethoxy)quinolin-4-yloxy]-phenyl} oxalamide H Yi ^M .NH 244 N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(4-trifluoromethoxy-benzyl)oxalamide N N ^{H H} L FgC^ 245 N- (3-Fluoro-4-[6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl }-N-(4methoxy-benzyl)-oxalamide Γ°ΊιΊ Ϊ 1 ^H NH V

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Entry Name Structure 246 N- {3 -Fluoro-4- [6-methoxy-7 (1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxyl-phenyl }-N'-(4trifluoromethyl-benzyl)oxal amide όΥάγ i · cf₃ 247 N-{4-[7-(Azetidin-3ylmethoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl} -N’-pheneth yloxalamide Υϋ ko N NY kA^O 248 N-{3-Fluoro-4-[6-methoxy-7(1 -methyl-azetidin-3ylmethoxy)-quinolin-4yloxy]-phenyl} -N’-phenethyloxalamide -Ο F N nY 9Χ_νΑ^.Ο 249 N- {3 -Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxyl-phenyI }-N’(2-hydroxy-2-phenyl-ethyl)oxalamide Y *=V ^M .NH YJr ^0H __y____1

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Entry Name Structure 250 N-[5-Chloro-6-(6,7dimethoxy-quinoIm-4-yloxy)pyridin-3-yl]-N’-(2,4-difluorophenyl)-malonaniide hi ^Ci N j Η 1 HN'NO F 251 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-N'-(4-fluorophenyl)-N'-methylmalonamide ^o ci Υγ^Ογ\ JL nY YA —nx> Φ F 252 N- {3-Hiioro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N’(IR-phenyl-propyl)oxalamide όΑά u

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Entry Name Structure 253 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quino!m-4-yloxy]-phenyl} -N’(lR-phenyl-propyl)oxaiamide Aw 254 N-(3,4-Difluoro-benzyl)-N'{3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl) oxalamide Xubi U V V. Xo ^{H H} ,NH F 255 N-(2,6-Difluoro-benzyl)-N'{3-fluoro-4- [6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl }oxalamide ΑΑά,ν Η Η 1 NH ^FxAz^F 256 N- {3-Fluoro-4-[6-methoxy-7 (1 -methyl-piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl }-N'- [2-(4fluoro-phenyl)-ethyl]oxalamide ..Ck /L 6 X s N N ir ι ^H

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Entry Name Structure 257 N- {3-FIuoro -4- [6-methoxy-7(l-methyl-piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl }-N'-phenyloxalamide —² /—\ \--/ o /A / /^Z=V° o A 258 N- {3-Fluoro-4-[6-methoxy-7- (piperidm-4-ylmethoxy)qumolin-4-yIoxy] -phenyl} -N'(3-fluoro-phenyl)-oxal amide Ό A F 259 N-(4-Chloro-3-fluorophenyl)-N’- {3-fluoro-4- [6methoxy-7 -(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide Ό ί η ϊ Λ °Tji i ^H Aj Cl'^y F 260 N-(3,4-Dimethoxy-phenyl)N*- {3-fluoro-4-[6-methoxy-7 (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }oxalamide Aav

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Entry Name Structure 261 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl} -N'(3-methyl-butyl)-oxalamide A 262 N-(3 ,3-Dimethyl-butyl)-N’- {3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide όΑ A y N ϋ f Η 263 d N-{ 5-Chloro-6-[6-methoxy-7(3-piperidin-l-yl-propoxy)quinolin-4-yloxy]-pyridin-3yl }-N'-(4-fluoro-phenyl)malonamide 1 Ij Os 1 I h 1 HN^O Φ F 264 N-{ 5-Chloro-6-[6-methoxy-7- (3-morphoIin-4-yl-propoxy)quinolin-4-yloxy]-pyridin-3yl} “N^L(4-fluoro-phenyl)malonamide a XT HN^O Φ p

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Entry Name Structure 265 N-{5-Chloro-6-[7-(3diethylamino-propoxy)-6methoxy-quinolin-4-yloxy]pyridin-3-yl} -N'-(4-fluorophenyl)-malonamide 0 A 1 CCV-Λ o Π HhVo F 266 N-(4-Chloro-benzyl)-N'-{3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)' quinolin-4-yloxy]-phenyl} oxalamide A A c^^NH Cl 267 N-(3,5-Dimethoxy-benzyl)N’- {3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl}oxal amide Ό Q W, v ^{H H} Th

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Entry Name Structure 268 N-(4-Butyl-benzyl)-N’-{ 3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} oxalamide A~X[-°yS 269 N-{ 3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy] -phenyl} -N'(2-p-tolyl-ethyl)-oxaIaniide 0°¾ r 270 j N-(3,5-Bis-trifluoromethylbenzyI)-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl}-oxalamide M UY ^{H H} Jh FgC^^CFg

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Entry Name Structure 271 N-{ 3-Huoro-4-[6-niethoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'pyrazin-2-ylmethyl-oxalamide Ό ^{H H} NH Ii ^N 272 N- {3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinoIin-4-yloxy]-phenyl} -N’pyridin-2-ylmethyl-oxalamide Y a f J nY ΧΑ_νΑ^Ο « ^H NH 6 273 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinazolin-4-yloxy]-phenyl} N’-pheiiethyl-oxalamide Ya . <7 N^N ΧΑ_ΝΧγΟ ^{H H} Ah QT 274 N-{3-Fluoro-4-[6-methoxy-7- (1 -methyl-piperidin-4ylmethoxy)-quinazolin-4yloxy]-phenyl} -N'-phenethyloxalamide 0 ό A Ax^y^{0 1} σ^H

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Entry Name Structure 275 N-{ 3-Huoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -Ν’(2-fluoro-3-trifluoromethylbenzyl)-oxalamide Aa _o ίΙ N] Til n N N Η Η 1 NH 276 N-[2-(2-Bromo-6-methoxyphenyl)-ethyl]-N’-{3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl [-oxalamide 0¼ A u ^{H H} A Br A 277 N-[2-(3,4-Dimethoxyphenyl)-ethyl]-N'- {3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxyj-phenyl} -N-methyloxalamide γ°υΗ ^e (I iiAaS ? B flj 278 N-[2-(5-Bromo-2-methoxyphenyl)-ethyl]-N'-{3-fluoro-4[6-methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide Ju 6jAr Η Η 1 . -NH XX

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Entry Name Structure 279 N-{ 3-FIuoro-4-[6-methoxy-7- (piperidin-4-yImethoxy)- quinoIin-4-yloxy]-phenyl} -N'(2-fluoro-5-trifluoromethylbenzyl)-oxalamide to a wa - 0 to O.„v YYcf₃ 280 N-{3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl }-N [1 -(4-fluoro-phenyl>ethyl]oxalamide ii — o O-Y 7=z / y=/ 281 N-(lS-Benzyl-2-oxo-2pyrrolidin- l-yl-ethyl)-N'- {3fluoro-4-[6-methoxy-7 (piped din-4-ylmethoxy)quinolin-4-yloxy]-plienyl} oxalamide PT o Cj 282 N- {3-Fluoro-4-[6-methoxy-7 (octahydrocyclopenta[c]pyrrol-5ylmethoxy)-quinazolin-4yloxy]-phenyl }-N’-phenethyloxalamide to 1 II Ί i O Vv°Yi ^{0 H}7r^{H N}^^N k 1 Hi -NH h r

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Entry Name Structure 283 N-[2-(4-Amino-phenyl)ethyl]-N'-{ 3-fluoro-4-[6methox y-7 -(piped din-4yImethoxy)-quinolin-4yloxy]-phenyl}-oxalamide A, ^H Λ 284 2-(4-Benzyl-piperidin-l-yl)- N- { 3-fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-y]oxy]-phenyl} -2oxo-acetamide 6°¾° A i, v >> x-v 285 N-[4-(6,7-Dimethoxyquinolin-4-yloxy)-phenyl] -N'(4-fluoro-phenyl)-malonamide Ό ΑΎ°ΥΊ| ° ηνΎ F

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Entry Name Structure 286 N-[5-Chloro-6-(6,7dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-N’-(3-fluorophenyD-malonamide X _o ϊ Λ i H 1 H[XO jO 287 N-[5-Chloro-6-(6,7dimethoxy-quinolin-4-yIoxy)pyridin-3-yl]-N'-phenylmalonamide x vX _Cl L A. a. A. V Ux ^H L hM° 288 N-[5-Chloro-6-(6,7dimethoxy-quinolin-4-yloxy)pyridin-3-yl]-N'(4-fluorophenyl)-2,2-dimethylmalonamide X ex JL Ύι T¹ 11 1 TX g , Φ F 289 N-Ethyl-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide όχΧ fi fir ^{H H} NH 1

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Entry Name Structure 290 N-{ 3-Fluoro-4~[6-methoxy-7- (plperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'isopropyl-oxalamide YWjl 291 N-Bntyl-N'-{3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy]-phenyl} -oxalamide ΥΥΰ u 292 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N'(2-methoxy-ethyl)-oxalamide 0 293 N-Cyclopropylmethyl-N'- {3fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxyJ-phenyl} oxalamide /0 kAA° ^{H H} NH Λ 294 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -N(2-morpholin-4-yl-ethyl)oxalamide O 6¾¼ jl ” yx JYnh

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Entry Name Structure 295 N-{ 3-Fluoro-4-[6-methoxy-7(piperidin-4-ylmethoxy)quinolin-4-yloxy]-phenyl} -2oxo-2-pyrrolidin- 1-ylacetamide A o JL ό WA Y tt trY 296 N-Ethyl-N'- {3-fluoro-4-[6methoxy-7-(piperidin-4ylmethoxy)-quinolin-4yloxy] -phenyl }-N-methyloxalamide A MAv N N Η Η 1 c

46. 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:

-R^{3 b}° νΥΧΥ·² R® N o l/i_4 Ά ^r®—( T > RtO \l1 R -Ύυ I I^0-2 R⁸—N k>—bJ 0 r! _λ 1 R^{e x}n'''Y'^/A'^x lA1-4

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___ Ϊ ,R⁸ ΓιΙ^^ν/ ‘ ' 1-4 (Ai R⁸ °Α'ί _Ra^z F4 R⁸ 0^00 N-FMIMIA- R«^Z Π , _R8 ' '1'4 n ^0-3 / ' '1-4 R^{8 1 4} R³ A. A R³ A 2-4 CCMI ' ^J1-4 ¢^5(0)0-2 _zN->MIA R^{s 14} _o=^-S<O)0.₂ rS^{Z m} GA MIl-4

B is selected from:

MIL R⁸ A /A o^x N S(0)o-2 ?—OMIMI I Aa¹ i--<Κζ I Ά^Α¹ %A_ai _R3-qA. r³-o'^' MIA A R³-O'^XJ a^a (J R® A N S(0)o.₂ r³-O^x R³-CMI R³-©^/ Aa¹ I —c> AA ?—<A MIA A ?—O'^ MIMI N

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rrV’Y^ xYv ο o ^X (R²)q ? 1-2 0-3 ^α2Ύ^νίΥ^{ε1 Q} χΥγ o (R²)q ¹ t A² Λ 1 o o (R²)q ,ΑΑΧΥ·· λ R⁵ q(R²) © Us, JL_e/ V ^o-a'Xj-a Y S -^(FY, _N ^1.2X3 I II —νΥΥο ,λΑ/ t I R^s R³⁵ I , .0-2 I xQⁿWⁿ'^r3! (R²)q R³ 1 , _x0-2 , .0-3 γγγγ (R%

wherein R² is selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR³, -NR’R³, -S(O)0.₂R³, -SO2NR³R³, -CO2R³, -0(0)^1¾³. -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted lower alkyl;

q is 0 to 2;

each R³ is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted hetero arylalkyl;

two R³, together with the nitrogen to which they are attached, form a four- to sevenmembered 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, -SO2NR⁵R³, -CO1R⁵, -C(O)NR⁵R⁵, -C(O)R⁵, and optionally substituted lower alkyl;

each R³⁵ is independently selected from -H, -C(=O)R³, -C(=O)OR³, -C(=O)SR³, -SO₂R³, -C(=O)N(R³)R³, and optionally substituted lower alkyl;

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2020201638 05 Mar 2020 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 aryl 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)-;

R³ is -H or optionally substituted lower alkyl;

R* is selected from R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -SO2R³, and -C(O)R³;

R⁹, R¹⁰, and R¹¹ are each independently selected from -H, and -OR¹²; or

R⁹ is selected from -H, and -OR¹², and R¹⁰ and R¹¹, when taken together, are either an optionally substituted alkylidene or an oxo; and

R¹² is selected from -H, -C(O)R³, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, 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 heteracyclylalkyl, and optionally substituted heterocyclyl;

or two R¹²’s, when taken together, form 1) a corresponding spirocyclic ketal when said two R^12,s stem from R¹⁰ and R¹¹, or 2) a corresponding cyclic ketal when said two R¹²’s stem from R⁹ and one of R¹⁹ and R¹';

E¹ is selected from -O-, -CH2-, -N(R³)-, and -S(0)o_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, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SOzNR’R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SOjNR’R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³,

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-N(R³)CO₂R³, -C(O)R³, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl;

two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;

each methylene in any of the above formulae is independently optionally substituted with R²⁵;

each R²⁵ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(O)0.₂R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)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 sevenmembeted alicyclic or heteroalicyclic, two of R²⁵ on a single carbon can be oxo;

with the proviso that when B is selected from:

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directly attached to , then A must be one of:

0 JL /R⁸ 001-4 ^rs CTAX R1 /X /X n γ O 071-4 0o_v4 COJ+ 0-2( A, ,Ο'-τΆ ^r9—\ X / V^o RlO \l1 « X>x. ί \θ-2 r—^N LA—K) o R1 _λ JL A Ν γ^Λ'Ν^/ 00*1-4 O I _,R⁸ U*^XxxJx>A 0^1-4 I''1-4 [ NR⁸}—A) L ! / ¹ '0-2

and with the proviso that when C contains , and B is selected from:

S(0)o-₂ ί— Ύ ?—Ox^- ΥΑ_Α ¹ _R3_o'^\ _Β3_₀Ά U'N^-^ S(0)o-2 R³-0x/ Π³-0χ^ I i ?— cr^· )—

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contain

, when R⁷⁰ is selected from -H, Ci^alkyl, and Ci^alkoxyl.

47. The compound according to claim 46, wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuran yl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidiny], triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidiny], isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindohnyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazoly]; each optionally substituted with between one and four of R²⁰; wherein each R²⁰ is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted lower alkyl.

48. The compound according to claim 47, wherein B is either of the following:

wherein A¹ is either =N- or =C(H)-.

49. The compound according to claim 48, wherein B is

50. The compound according to claim 49, wherein C is selected from:

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η^0-2 \0-2 H J, 1 iYVr Yj ^{0 0} A. _R2 / «0-4 h A A X r2 R² H , >0-3 if kJ 1 II II 1 (^r2%-3 A °

wherein R², R³, R⁵, R²⁰, R²⁵ and R⁶⁰ are as defined above.

51. The compound according to claim 50, R² is selected from halogen, trihalomethyl, -CN, -NO2, -OR³, -NR³R³, -CO₂R³, -C(O)NR³R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, and optionally substituted lower alkyl

52. The compound according to claim 51, wherein R² is halogen.

53. The compound according to claim 52, wherein R² is either fluorine or chlorine.

54. A compound for modulating kinase activity according to Formula XI,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, each R¹ is independently selected from halogen, -OR³, -NO₂, -NH₂, -NR³R⁴, -D-R⁵⁰ and optionally substituted Ci^alkyl;

R⁷⁰ is selected from -H, halogen, -OR³, -S(0)o_2R³, -NO2, -NH₂, -NR³R⁴, and optionally substituted Ci^alkyl;

Q is selected tom =N-, =C(H)-, and =C(CN)-;

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Z is selected from -S(0)o-2-, -0-, and -NR⁵-;

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

G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R² is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted Chalky!;

each R³ is independently -H or R⁴;

each R⁴ is independently selected from optionally substituted Ci^alkyl, optionally substituted aryl, optionally substituted aryl Chalky!, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Chalky!; 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 Cpgalkyl;

each D is independently selected from -O-, -S(O)q.₂-, and -NR⁵-;

each R³⁰ is independently either R³, or according to formula XII;

XII 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-, -O-, -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-, -O-, -S(0)o.₂-, and -NR⁸-;

Y is either:

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2020201638 05 Mar 2020 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 R*⁵ 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 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, -NO2, -OR³, -NR³R⁴, -S(0)o-2R⁴, -SO2NR³R⁴, -CO2R³, -C(O)NR³R⁴, -N(R³)SO2R⁴, -N(R³)C(O)R³, -NCO2R³, -C(O)R³, optionally substituted Ct.6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Chalky!, 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 spirocyclyi, said optionally substituted three- to seven-membered spirocyclyi optionally containing at least one additional annular heteroatom selected from N, O, S, and P;

R⁸ is selected from -R³, Y, -SO2NR³R⁴, -CO2R⁴, -C(O)NR³R³, -SO2R⁴, and -C(O)R³; and each R³⁰ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH₂, -OR³, -NR³R⁴, -S(O)0.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -NQTcOjR³, -C(O)R³, and optionally substituted Chalky!.

55. The compound according to claim 54, wherein Z is either -O- or -NR⁵-.

56. The compound according to claim 55, wherein at least one of R¹ is -D-R⁵⁰.

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57. The compound according to claim 56, wherein D is -O- and at least one other R¹ is -OR³.

58. The compound according to claim 57, of formula XHIa or XHIb:

XHIa

XIHb wherein Q¹ is either =N- or =C(H)-.

59. The compound according to claim 58, wherein R⁵⁰ is selected from Ci^alkyl optionally substituted with at least one of optionally substituted amino, optionally substituted Ci^alkyl amino, optionally substituted Ci^dialky] amino, optionally substituted heteroalicylic, and a group of formula ΧΠ.

60. The compound according to claim 59, wherein R^3a is Chalky!.

61. The compound according to claim 60, wherein Z is -O-.

62. The compound according to claim 61, wherein G is selected from cyclopropyl, aziradine, cyclobutyl, and azetidine, each optionally substituted with between zero and four of R³⁰.

63. The compound according to claim 62, wherein Q is either =N- or =C(H)-.

64. The compound according to claim 63, wherein R² is selected from -H, halogen, Cp 6 alkyl and perfluoro alkyl.

65. The compound according to claim 64, wherein -N(R^3b)R⁴ is selected from the following:

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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, -NO2, -NH2, -OR³, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted Cj^alkyl, optionally substituted aryl, optionally substituted aryl Ci-salkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci^alkyl;

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 J or fused to J;

E is selected from -O-, -N(R⁵)-, -CH₂-, and -S(0)o_₂-;

each R⁶⁰ is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted Chalky!, optionally substituted aryl, optionally substituted heteroaryl Chalky!, and optionally substituted aryl Ci^alkyl;

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)q.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, optionally substituted aryl, optionally substituted aryl C^alkyl, heteroaryl Chalky], and optionally substituted Chalky!; or

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R^3b is equivalent to R³ as defined above; and

R⁴ and R⁵ are as defined above.

66. The compound according to claim 65, of formula XlVa or XlVb:

67. The compound according to claim 66, wherein R⁵⁰ is C^alkyl optionally substituted with a group selected from optionally substituted amino, an optionally substituted alkylamino, optionally substituted dialkylamino, and optionally substituted heteroalicylic.

68. The compound according to claim 67, wherein the heteroalicyclic portion of said optionally substituted heteroalicyclic of Rⁱ⁰ is selected from the group consisting of piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, 2-oxo-morpholine, pyrrolidine, and azepine.

69. The compound according to claim 67, wherein R⁵⁰ is according to formula XII.

70. The compound according to claim 69, wherein the saturated bridged ring system according to formula XII 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 [2.2.1].

71. The compound according to claim 70, wherein Y is selected from -CH2CH2CH2CH2-, -CH₂CH₂CH₂-, -CH2CH2-, -CHr, and absent.

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72. The compound according to claim 71, 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].

73. The compound according to claim 72, wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.

74. The compound according to claim 73, wherein said saturated bridged ring system contains -NR⁸-, wherein R⁸ is selected from -H, optionally substituted Ci.$alkyl, -CO₂R³, -C(O)NR³R³, -SO2R³, and -C(O)R³.

75. The compound according to claim 73, wherein said saturated bridged ring system is of formula XV,

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

76. The compound according to claim 75, wherein Y is -CH₂-.

77. The compound according to claim 76, wherein U¹ is -NR⁸-, wherein R⁸ is selected from -H, optionally substituted lower alkyl, -CO2R³, -C(O)NR³R³, -SO2R³, and -C(O)R³.

78. The compound according to claim 76, wherein U¹ is -O-.

79. The compound according to claim 76, wherein U¹ is absent.

80. The compound according to claim 71, wherein Y is selected from -CH₂CH₂-, -CH₂-, and absent.

81. The compound according to claim 80, wherein said saturated bridged ring system is of formula XVI,

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R⁹ is selected from -H, and -OR¹², and R¹⁰ and R¹¹, when taken together, are either an optionally substituted alkylidene or an oxo;

R¹² is selected from -H, -C(O)R³, optionally substituted lower aikylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylidenehetefocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, 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 R^l2’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.

82. The compound according to claim 81, wherein one of R¹⁰ and Rⁿ is -OR¹², wherein R¹² is selected from -H, -C(O)R³, and optionally substituted lower alkyl; and R⁹ and the other of R¹⁰ and R¹¹ are both -H.

83. The compound according to claim 82, wherein Y is either -CH2- or absent.

84. The compound according to claim 81, wherein R⁹ is an alkyl group containing at least one fluorine substitution thereon.

85. The compound according to claim 74, wherein said saturated bridged ring system is of formula XVII.

XVII

86. The compound according to claim 85, wherein Y is either -CHj- or absent.

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87.

88.

The compound according to claim 86, wherein R⁸ is methyl or ethyl.

The compound according to claim 87, wherein at least one of R² is halogen.

* 89.

is of formula XVIII.

The compound according to claim 74, wherein said saturated bridged ring system

R⁸—N

XVIII

90. The compound according to claim 89, wherein Y is -CH2-.

91. The compound according to claim 90, wherein R⁸ is methyl or ethyl.

92. The compound according to claim 73, wherein said saturated bridged ring system is of formula XIX

XIX wherein U² is selected from -O-, -S(0)o-2-, -NR⁸-, -CR^R⁷-, and absent.

93. The compound according to claim 92, wherein R³ of formula XIX is selected from -H and optionally substituted alkyl.

94. The compound according to claim 93, wherein U² is either -CR⁶R⁷- or absent.

95. The compound according to claim 94, wherein U is either -CH₂- or absent.

96. The compound according to claim 95, wherein Y is -CH₂-.

97. The compound according to claim 74, wherein said saturated bridged ring system is according to formula XX.

?

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XX

98. The compound according to claim 97, wherein R⁸ is methyl or ethyl.

99. The compound according to any of claims 67 through 98, wherein R² is selected from Ci.6 alkyl, perfluoro Ci.6 alkyl, and halogen.

100. The compound according to claim 99, wherein R² is selected from perfluoro Ci_₃ alkyl and halogen.

101. The compound according to any of claims 67 through 98, wherein R²⁰ is selected from halogen, -CN, -NO2, -NH2, -OR³, -NR³R⁴, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-galkyl, 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 XFVa or XlVb.

102. The compound according to claim 101, wherein R²⁰ is selected from halogen, -NR³R⁴, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci. ealkyl, 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 XlVa or XlVb.

103. The compound according to claim 102, wherein R² is selected from Cm alkyl, perfluoro Cm alkyl, and halogen.

104. The compound according to claim 103, wherein R² is selected from perfluoro C1.3 alkyl and halogen.

105. The compound according to claim 54, selected from Table 2.

Table 2

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Entry Name Structure 1 N-(6-{[6,7- bis(methyloxy)qumolm-4yl]oxy}-5-chloropyridin3-yl)-N'-(4fluorophenyljcyclopropan e-1,1-dicarboxamide XtY/TX 2 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl] oxy }-5-chloropyridin3-yl)-N’-(4fluorophenyl)cyclobutane -1,1-dicarboxamide Cl N XJLn ‘ XjsIXa 3 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy}-5-chloropyridin3-yl)-N(phenylmethyl)cyclopropa ne-1,1-dicarboxamide .o A ° ° ό 4 N-(6-{[6,7bis(methyloxy)quinolin-4yl] oxy} -5-chloropyridin3-yl)-Nphenylcyciopropane-1,1dicarboxamide 5 N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide Αχό 6 N-[3-fluoro-4-({6- (methyloxy)-7-[(3piperidin-1ylpropyl)oxy]quinolin-4yl} oxy)phenyl] -N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide _n ΧτΊίΥο,

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Table!

Entry Name Structure 7 N-[3-fluoro-4-({ 6- (methyloxy)-7-[(3piperidin-1ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyl)cyclobutane -l,l-dicdrboxamide χτ π XX X γ or F ''‘hr 8 N-(6-{[6,7bis(methyloxy)quinolin-4yl]oxy} -5-ch!oropyridin- 3-yl>N^,-(2phenylethyl)cyclopropane -1,1-dicarboxamide MAM 9 N-(6-{[6,7bis(methyloxy)qumolin-4yl]oxy} -2-methylpyridin- 3-yl)-N'-(4fluorophenyl)cyclopropan e-1,1 -die arboxamide mam. 10 N- {4-[(7-chloroquinoIin- 4-yl)oxy]-3fluorophenyl }-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide m^sam, Xo 11 N-{4-[(7-chloroquinolin- 4-yl)oxy]phenyl}-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide mam. 12 N-(4-{[6,7- bis(methyloxy)quinolm-4yljoxy} phenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide mam.

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Table 2

Entry Name Structure 13 N-(4-{[6,7bis(methyloxy)quinazolin -4-yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide ο o O F cob 14 N-(4-{[6,7bis(methyloxy)quinazolin -4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide Ύύ 15 N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl}oxy)phenyl]-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide tYJCO 16 N-{5-chloro-6-[(6(methyloxy)-7-{ [(1methylpiperidin-4yl)methyl]oxy [quinolin4-yl)oxy]pyridin-3-yl} N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide XiLi^sQ._f 17 N-[5-chloro-6-({6(methyloxy)-7[(piperidin-4ylmethyl)oxy]quinolin-4yl }oxy)pyridin-3-yl]-N'(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide HN-X 18 N-[5-chloro-6-({6(methyloxy)-7[(phenylmethyl)oxy]quino lin-4-yl} oxy)pyridin-3yl]-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide

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Table 2

Entry Name Structure 19 N-(4-{[7-{[2(diethylamino)ethyl]oxy }6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,l-dicarboxamide XrWa_F 3^X0 20 N-(4-{[7-{[2(diethylamino)ethyl]oxy }6-(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)N'-(4fluorophenyl)cyclobutane -1, l-dicarboxamide 21 N-{3-fluoro-4-[(6- (methyloxy)-7-{ [(1methylpiperidin-4yl)methyl]oxy }quinazolin -4-yl)oxy]phenyl} -N’-(4fluorophenyl)cyclopropan e-1,l-dicarboxamide xrflro.. 22 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -2-methylphenyl)N'-(4fluorophenyl)cyclopropan e-1,l-dicarboxamide xxW-α. 23 N-(4-fluorophenyl)-N'-[2methyl-6-({6(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quiiiolin-4yl}oxy)pyridin-3yl]cyclopropane-l, 1 dicarboxamide 0 ,., 24 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)N’-(4fluorophenyl)cyclopropan e-1, l-dicarboxamide ΧτΎό., X11

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Table2

Entry Name Structure 25 N-(6-{[6,7- bis(methyloxy)quinolin-4yljoxy }-5-chloro-2methylpyri din-3-yl)-N'(4fluorophenyl)cyclopropan e-1,1-dicarboxamide XC.WO, 26 N-[3-fluoro-4-({7- (methyloxy)-6-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl]-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide H V7 Η /Ο ₀ΑΥ ο ο 27 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy )-3,5difluorophenyl)-N’-(4fluorophenyl)cyclopropan e-1,1 -dicarboxami de χτΜΜ, 28 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}-2,5difluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide 29 N-[3-fluoro-4-({7- (methyloxy)-6-[(3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyi)cyclopropan e-1,1-dicarboxamide χτίϊΌς 30 N-{3-fIuoro-4-[(6(methyloxy)-7-(2-methyl octahydrocyclopenta[c]pyirol-5ylmethoxy)quinazolin-4yl)oxy]phenyl}-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxami de XrWxx

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Table 2

Entry Name Structure 31 N-{ 3-fluoro-4-[(7(methyloxy)-6-{ [(1methylpiperidin-4yl)methyl]oxy}quinazolin -4-yl)oxy]phenyl} -N’-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide Υχό 32 N- [5-fluoro-2-methyl-4({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl] -N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide XxVVo., 33 N-(4-{[6,7- bis(methy!oxy)quinolin-4yl]oxy}-2,3,5trifluorophenyl)-N'-(4fluorophenyl)cyclopropan e-14-di carboxamide 0¼¼⁰ ° ^F 34 N-(4-{[6,7bis(methyloxy)quinolin-4yljoxy }-5-fluoro-2methylphenyl)-N’-(4fluorophenyl)cyclopropan e-14 -di carboxamide XiW, 35 N-(4-{[6,7- bis(methyIoxy)quinolin-4yl]oxy}-2-chloro-5methylphenyl)-N'-(4fluorophenyljcyclopropan e-14-dicarboxamide χύν-ο, 000 36 N-(3-fluoro-4-{[6hydroxy-7(methyloxy)quinolin-4yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropan e-14-dicarboxamide

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Table 2

Entry Name Structure 37 N-(4-fIuoroplienyl)-N^,-[2methyl-4-({6(methyloxy)-7-[(3morpholin-4ylpropy])oxy]quino]in-4yl }oxy)phenyl]cyclopropa ne-1,1-dicarboxamide _n AA, V /θγγΑ 38 N-[3-fluoro-4-( {6- (methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quino]in-4yl} oxy)phenyl]-N^r-(4fluorophenyl)cyclopropan e-1,1 -die arboxamide A /Ax Ay a^a_h NH 0 F 39 N-{ 3-fluoro-4-[(6(methyloxy)-7-{ [3-(4methylpiperazin-lyl)propyl]oxy} quinolin-4yl)oxy]phenyl}-N'-(4fluorophenyljcyclopropan e-l,l-dicarboxamide 0 κ -V A” Γ ¥ 40 N-{ 3-fluoro-4-[(6(methyloxy)-7-{ [(1methylpiperidin-4yl)methyl]oxy)quinolin4-yl)oxy]phenyl }-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide Λ ^ΗΝΆγ/ JPo ctah xb Ako Γ ¥

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Table 2

Entry Name Structure 41 N-(4-fluorophenyl)-N'-[4({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]cyclopropa ne-1,1 -dicarboxamide ^NH K οΆ_νη v x A 42 N-(4-{[7-{[3(diethylamino)propyl] oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide Ox Ο NH > ifS ? 1 ^F T ΠΓ 43 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} -2-chloro-5fluorophenyI)-N’-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide Q o AA_NAA_F An Za h 44 N-(4-{[6,7bis(methyloxy)-2(methylthio)quinolin-4yljoxy }-3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide A | Ά ^f A⁰ M /? ° Λύϊ nA A, A JI -N H J 45 N-(4-fluorophenyl)-N'-(4{[2-methyl-6,7bis(methyloxy)quinazolin yljoxy }pheny])cyclopropa ne-1,1-dicarboxamide f I Fv__ Jv*^{0 r}' A A γ

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Table 2

Entry Name Structure 46 N-(4-{ [2-amino-6,7bis(methyloxy)quinolin-4yl]oxy }-3-fluorophenyl)N-(4fluorophenyl)cyclopropan e-l,l-dicarboxamide O^X 1 R. A/ n-A A As. J* ^H Δ N i ⁿ nh₂ 47 N-(3-fluoro-4- {[2- (methylamino)-6,7bis(methyloxy)quinolin-4yl]oxy }phenyl)-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide _c Γ¹ >\ ^f A M ? At a MtA As J* H γ H Ah 48 (lS,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3morpholin-4ylpiOpyl)oxy]quinolin-4yl} oxy)phenyl] -N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide r^⁰ kA, o Ϊ 1 o tYAtAT, O HN 49 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3morpholm-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide AO A IX vy YA °^hu nJ ^h A

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Table 2

Entry Name Structure 50 N-(4-{[6-{[3- (diethylamino)propyl]oxy } -7-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyclopropan e-1,1 -dicarboxamide f / ^HMI° O F < J—/=/ p MI HN—\ Q /===/ / MIN 51 N-(4-{[6-{[2(diethylamino)ethyl]oxy }7-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)N'-(4fluorophenyljcyclopropan e-1,1 -dicarboxamide A MI <0 CMI ° MIN 52 1,1-dimethylethyl 4-(3{[4-[(2-fluoro-4-{[(l{[(4fluorophenyl)ainiiio]carbo nyl }cyclopropyl)carbonyl ]amino }phenyl)oxy]-6(methyloxy)qumolin-7yl]oxy }propyl)piperazine- 1-carboxylate ⁰ flF II 1 /\ Jk ΛΛ k_.N .N. MI ' u HN 7 (/ A F 53 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy )-7-((3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl]-N¹-(4fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide o Ί /^F II T T 1 11 Un H ZA„

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Table 2

Entry Name Structure 54 (lR,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy } 6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxaimde u Il O z. ^F Π A 55 N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6(methyloxy)quinazolin-4yl]oxy} -3-fluorophenyl)N'-(4fluorophenyljcyclopropan e-1,1 -dicarboxamide k -X-ο F Γ [Γ M 9 ΛίθΥιΤ ^S 4?^ ^N^^N 56 N-(4-{ [7-{ [3-(4acetylpiperazin-1yl)propyl]oxy}-6(methyloxy)quinolin-4yl]oxy}-3-fluorophenyl)N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide 1 cr^N'-J X \==\ f r T /? ⁰ rT Η X N toz- H 57 1,1-dimethylethyl 4-(3{[4-[(2-fluoro-4{[((lR,2R)-l-{[(4fluorophenyl)amino]carbo nyl}-2methylcyclopropyl)carbon yl]amino} phenyl)oxy]-6(methyloxy)quinolin-7yl]oxy}propyl)piperazine1-carboxylate jux J X Ψ Ό ^HNr°krv Ύ°

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Table 2

Entry Name Structure 58 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }phenyl)-N'-(4fluorophenyl)-l(phenylmethyl)azetidine3,3-dicarboxaniide p Φ CA.NH δ 59 _N_(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy }phenyl)-N'-(4fluorophenyl)azetidine3,3-dicarboxamide F Φ O^NH rH /=·\ /^0- HN-I HN-ti h-0 v— m 60 (lR,2S)-N-{3-fluoro-4[(6-(methyloxy)-7 - {[3-(4methylpiperazin-1 yl)propyl]oxy }quinolin-4yl)oxy]phenyl} -N'-(4fluorophenyI)-2methylcyclopropane-1,1 dicarboxamide |^X^'N^X’ ^ς1 A °yS \ / ύύ°ΥΊ rC F N Η ZY, 61 (lR,2R)-N-(3-fluoro-4[(6-(methyloxy)-7- {[3-(4methylpiperazin-1 yl)propyl]oxy}qumolin-4yl)oxy]phenyl} -N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide ΊιΥθνΥι °^hn\ Μ XI a>°

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Table 2

Entry Name Structure 62 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quino!in-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide νΆ A 11 o ' \V^C'A^:\ o ^hn Ύ T T o 1 A 63 N-(3-fluoro-4-{[7-({3-[4(l-methylethyl)piperazin1 -y l]pr°py 1} oxy)-6(methyloxy)quinolin-4yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide _o r ? Υ°Υύ \ θΆΑ AA Azⁿ >\/···' Q 64 N-(4-{[7-{[3(diethylamino)propyl]oxy }-6(methyloxy)quinazolin-4yl]oxy }-3-fluorophenyl)N’-(4fluorophenyl)cyclopropan e-1,1-dicarboxamide A. V oY JL A J* N<.^N -N- 65 (lR,2R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide Λ S ^x° /~/^F Yj XI1 >0 Η

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Table 2

Entry Name Structure 66 (lR,2R)-N-(4-{[7-{[2(diethylamino)ethyljoxy }6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)- bT-(4-fluorophenyl)-2methylcyclopropane-1,1 dicarboxamide Ψ A^X 67 (lR,2S)-N-(4-{[7-{[3(diethylamino)propyl]oxy } -6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2methylcyciopropane-1,1dicarboxamide I 1 o Y⁷ H 68 (lR,2S)-N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)- N'-(4-fluorophenyl)-2methylcyclopropane-1,1dicarboxamide u Ί z-_/^F 11 ο Y² ύυυί AJk £ >0 H 69 N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinazolin4-yl]oxy}-3fhiorophenyl)-N’-(4fluorophenyl)cyclobutane -1,1-dicarboxamide F

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Table 2

Entry Name Structure 70 (lR,2S)-N-[3-fluoro-4- ({6-(methyIoxy)-7- [(3piperazin-1ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2methylcyclopropane-1 ,1dicarboxamide I^NH \ 7 ΥΎθΤ'Ίι ?^HC 71 (lR,2R,3S)-N-[3-fluoro- 4-( {6-(methyloxy )-7-((3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N’-(4fluorophenyl)-2,3dimethylcyclopropane1,1 -dicarboxamide γ ^XO ^F 72 (lR,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{ [3(4-methylpiperazin-1yl)propyl]oxy }quinolin-4yl)oxy]phenyl }-N’-(4fluorophenyl)-2₁3dimethylcyclopropanel_fl-dicarboxamide 1 ^XO z^F v MX 73 (lR,2R,3S)-N-[3-fluoro- 4-({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl}oxy)phenyl]-N’-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide XI 0’

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Table 2

Entry Name Structure 74 (lR,2R,3S)-N-{3-fluoro4-[(6-(methyloxy)-7- {[3(4-methylpiperazin-lyl)propyl]oxy Jquinazolin4-yl) oxy ] phenyl} -N'-(4fluorophenyl)-2,3dimethylcyclopropane1 ₍1-dicarboxamide 3 A W^{F η} Λ- 75 N-[3-fluoix>-4-({6- (methyloxy)-7- [(3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl]-N'-(4fluorophenyl)cyclobutane -1,1 -dicarboxamide Ο χ ° \ / Κ CX.NH )=⁷ ο—ν Υνη Τ -ο )=⁷ Σ~ F Ο — 76 (2R,3R)-N-[3-fluoro-4({6-(methyloxy )-7-((3morpholin-4ylpropyl)oxy]quinolin-4yl} oxy)phenyl]-N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxainide [''Τ A I ⁰ ζ—/ °ύΑ ο nA fAAhA^⁰ 77 (2R,3R)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2,3dimethylcyclopropane- 1,1 -dicarboxamide ΑΑ 11 _ο ζ. ιίπ °^Htl

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Table 2

Entry Name Structure 78 N-(4-{[7-{[3(diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fIuorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide X Π 79 N-[3-fluoro-4-({6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl]-N’-(4fluorophenyl)-2,2dimethylcyclopropane- 1,1 -dicarboxamide cvX X N N zHx A./, 0 y ^f b ιγ 80 (lR,2R,3S)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6-(methyloxy)quinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide X 81 N-(4-{[7-{[2- (diethylaminojethyl ]oxy }6-(methyloxy)quinolin-4yljoxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide GJ 82 (lR,2R,3S)-N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinolin-4yl]oxy} -3-fluorophenyl)N¹-(4-fluorophenyl)-2,3dimethylcycloprop ane1,1-dicarboxamide y Αχ F ΥγθΧκ _o n J JUG

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Entry Name I Structure 83 N-[3-fluoro-4-( {6- (methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinolin-4yl }oxy)phenyl]-N'-(4fluorophenyl)-2,2dimethylcyclopropane1,1-dicarboxamide \θ ^F /sA Ci n NX \ 84 N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2,2dimethylcyclopropane1,1-dicarboxamide C rS 85 N-(4-{[7-{[3(diethylamiflo)propyl]oxy }-6(methyloxy)quinazolin-4yl]oxy} -3-fluorophenyl)N'-(4-fiuorophenyl)-2,2dimethylcyclopropane1,1 -dicarboxamide ^XO /^F 'OxJx ΑΆ ) LAyO Q N / I'L/f'l AsA JL j³¹© 86 N-(4-{[7-{[3(diethylamino)propyl]oxy )-6(methyloxy)quinazoliii-4yl]oxy }-3-fluorophenyl)N'-(4fluorophenyl)cyclobutane -1,1-dicarboxamide V· F O F H 87 N-{3-fluoro-4-[(6(methyk>xy)-7-{ [3-(4methylpiperazin-1 yl)propyl] oxy Jquinazolin4-yl)oxy]phenyl} -N'-(4fluorophenyljcyclobutane -1,1-dicarboxamide /— i/ F O F b IH

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Table 2

Entry

Name

N-[3-fluoro-4-( {6(methyloxy )-7-[(3piperazin-lylpropyl)oxy]quinazolin4-yl}oxy)phenyl]-N'-(4fluorophenyl)cyclobutane -1,1-dicarbox amide

(2R,3R)-N-[3-fluoro-4({6-(methyloxy)-7-[(3morpholin-4ylpropyl)oxy]quinazolin4-yl} oxy)phenyl]-N'-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide

N-(4-{[7-{[3(diethylamino)propyl]oxy } -6-(methyloxy)qiiinolin4-yl]oxy}-3fluorophenyl)-N'-(4fluorophenyl)cyclobutane -1,1-dicarboxamide

N-{3-fluoro-4-[(6(methyloxy)-7-{ [3-(4methylpiperazm-1yOpropyl] oxy} quinoliri-4yl)oxy]phenyl}-N'-(4fluorophenyl)cyclobutane -1,1-dicarboxamide

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Table 2

Entry Name Structure 92 (lR,2R)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6(methyloxy)quinazolin-4yl]oxy} -3-fluorophenyl)- N'-(4-fluorophenyl)-2methylcyclopropane-1,1dicarboxamide ⁹³ (lR,2R)-N-{3-fluoro-4[(6-(methyloxy)-7- {[3-(4methylpiperazin-1yl)propyl]oxy} quinazolin4-yl)oxy]phenyl} -N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide 1 94 (2R,3R)-N-(4-{[7-{[2(diethylamino)ethyl]oxy }6-(methyloxy)quinazolin4-yl]oxy}-3fluorophenyl)-N’-(4fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide k N^N 95 (2R,3R)-N-(4-{[7-{[3(diethylamino)propyl]oxy }-6(methy!oxy)quinazolin-4yl]oxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,3dimethylcyclopropane1,1-dfcarboxamide .0¾¾ A _r ' S/. 96 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3piperazin-1ylpropyl)oxy]quinazolin4-yl}oxy)phenyl]-N’-(4fluorophenyl)-2methylcyclopropane-1,1dicarboxamide Y

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Table 2

Entry Name Structure 97 (2R,3R)-N-(4-{[7-{[2(diethylamino)ethyl]oxy} 6-(methyloxy)quinolin-4yl] oxy} -3-fluorophenyl)N'-(4-fluorophenyl)-2,3dimethylcyclopropane1,1-dicarboxamide ^X° Η' 98 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[(4fluorophenyl)methyl]cycl opropane-1,1dicarboxamide F \ Ls-aL 99 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy }phenyl)-N'-(2morpholin-4ylethyl)cyclopropane-1,1dicarboxamide Ay Ό 100 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[2(piperidin-1ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide Or⁰ NH ₀ 101 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} phenyl)-N'-[2(pyrrolidin-1ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide

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Table 2

Entry Name Structure 102 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N’-[3(morpholin-4ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide __/ '— & Aa# 103 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[2(morpholin-4ylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide o iA o Λα γχΑ 104 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'phenylcyclopropane-1,1dicarboxamide 1 (j ί^Ύ° γ,χτΑ 105 N-[3- (aminomethyl)phenylj-N'(4-1[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)cyclopropa ne-1,1-dicarboxamide ,-NHs . / 0 Μ ο JL J ΝΗ_Ο ΑϊΤΥΫ ο=\ A AsJ Un Η 106 N-(4-{[6,7bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-[3(piperidin-lylmethyl)phenyl]cyclopro pane-1,1 -dicarboxamide / /· __/ 0 /j ΥΑ'χ

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Entry Name Structure 107 N-(4-{[6,7- bis(methyloxy)quinolin-4yl]oxy} pheny] )-N'-[3(pyrrolidin-1ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide rO o' θ Xa NH _o ⁰ yW M H

106. A pharmaceutical composition comprising a compound according to any one of claims 1 -105 and a pharmaceutically acceptable carrier.

107. A metabolite of the compound or the pharmaceutical composition according to any one of claims 1 - 106.

108. 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 claims 1-105.

109. The method according to claim 108, wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.

110. The method according to claim 108, wherein the kinase is at least one of c-Met, KDR, c-Kit, flt-3, and flt-4.

111. The method according to claim 110, wherein the kinase is c-Met.

112. A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the 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 claims 1 -106.

113. A method of screening for a modulator of a kinase, said kinase selected from cMet, KDR, c-Kit, flt-3, and flt-4, the method comprising combining a compound according to any one of claims 1 - 105, and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.

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114. 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 claims 1 -105 to a cell or a plurality of cells.

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115. A process for preparing a compound of Formula XXI,

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

XXIII

each R¹ is independently selected from halogen, -OR³, -NO₂, -NH₂, -NR³R³, -D-R³⁰ and optionally substituted Cj^alkyl;

R⁷⁰ is selected from -H, halogen, -OR³, -S(0)o.2R³, -NO2, -NH₂, -NR³R³, and optionally substituted Ci^alkyl;

J is selected from =N-, =C(H)-, =C(halogen)-, and =C(CN)-;

Z is selected from -S(O)₀.₂-, -O-, and -NR³-;

each R⁵ is independently selected from -H, optionally substituted Cp^alkyl, optionally substituted aryl, 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;

R² is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(O)0.₂R³, -SO₂NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted Chalky!;

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2020201638 05 Mar 2020 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;

two R³, together with the nitrogen to which they are attached, form a four- to sevenmembered 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, -SO2R³, -SO2NR³R³, -COaR³, -C(O)NR³R⁵, -C(O)R³, and optionally substituted lower alkyl;

B is selected from absent, -N(R¹³)-, -N(SO2R¹³)-, -O-, -S(0)o.2-, and -C(=O)-;

L is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, -SOjNfR¹³)-, -SOr, -C(=O)N(R¹³)-, -N(R¹³)-, -C(=O)Ci_2alkylN(R¹³)-, -N(R^I3)Cb2alkylC(=O)-,

-C(=0)Co.ialkylC(=0)N(R¹³)-, -C(=O)-> -C₀₄alkylene-, -C(=O)C₀₁alkylC(=O)OR³-, -C(=NR¹⁴)CwaIkylC(=O)-, -C(=0)Co.ialkylC(=0)-, and an optionally substituted four- to six-membered heterocyclyl containing between one and three annular heteroatoms and comprising at least one nitrogen;

T is selected from -H, -R¹³, -C^alkyl, -C04alkylQ, -OC0.4alkylQ, -Co^alkylOQ, -N(R^,3)Co4alkylQ, -SO₂C₀.₄alkylQ, -C(=O)C₀₄alkylQ, -Co.₄aIkylN(R^I3)Q( and -C(=0)N(R^l3)Co.4alkylQ, wherein each of the aforementioned Co.₄alkyl 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, -NO2, -NH2, -OR³, -NR³R³, -S(0)o.2R³, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Ci.6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C^alkyl;

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 -O-, -S(0)o.₂-, and -NR¹⁵-;

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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(R^e)R⁷-, -O-, -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-, -O-, -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 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, -SO₂NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -NCO₂R³, -C(O)R³, optionally substituted Ci.₆alkyl, optionally substituted

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2020201638 05 Mar 2020 aryl, optionally substituted aryl Chalky!, optionally substituted heterocyclyl, optionally substituted heterocyclyl a Ci-glkyl, and a bond to either Y orD; 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, -SO2NR³R³, -CO2R³, -C(O)NR³R³, -SO₂R³, and -C(O)R³;

R¹³ is selected from -H, -C(=O)R³, -C(=O)OR³, -C(=O)SR³, -SO₂R³, -C(=O)N(R³)R³, and optionally substituted Cj-galkyl;

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 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, -NO₂, -NH₂₎ -N(R³)R³, -CN, -OR^J, optionally substituted Ci-galkyl, optionally substituted heteroalicyclyl Ci^alkyl, optionally substituted aryl, optionally substituted aryl Chalky! and optionally substituted heteroalicyclic;

R¹⁵ is a group -M^-M³, wherein M¹ is selected from absent, -C(=S)N(R¹³)-, -C(=NR¹⁴)N(R¹³)-, -SOjNfR¹³)-, -SO2-, -C(=O)N(R¹³)-, -C<=O)C(=O)N(R¹³)-,

-Co^alkylene-, -C(=O)-, 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, -C0^a]kyl, alkoxy, -C(=0)Co-4alkylQ, -Co^alkylQ, -OCo^alkylQ-, -N(R^I3)Co4alkylQ-, and -C(=O)N(R¹³)CMa]kylQ;

R⁶⁰ is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(0)o-2R³, -SOaNRSR³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted Ci.6alkyl, optionally substituted aryl, optionally substituted heteroaryl Ci^alkyl, and optionally substituted aryl Ci^alkyl;

two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;

P¹ is a suitable leaving group; and

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P² is selected from -H, a metal, and a group removed in-situ when combining XXII and

XXIII to make XXI.

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116. The process according to claim 115, wherein Ar is para-phenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene.

117. The process according to claim 116, wherein Z is either -O- or -NR⁵-.

118. The process according to claim 117, wherein -B-L-T is selected from the following:

R¹³ _R13 I I V'A ⁿ'_r ¹⁴ _R13 r13 ^{1 1} i \θ-3 N_x P R¹⁴ / \l-2 1 Ψ ^x Y o r—Μ¹’² J. Ji / \0-3 0 o ,_____£A°'² i ⁽r ΧγΑ/⁰ 0 R¹³ Ya-v /^q L/fL R¹³ Z^Q LA r13 I _R13 ^X I T ^-2 N^V J o o r13 I . ,0-4 y^ 2/V 0 0 _R13 vYY o o _R1S YA O 0 R¹³ I v Y K₃ 0 o_x p 0 ΛΥ R¹³ J P X Jet³ R¹³ AX 0 vⁿt%'= 0

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□θ'³ 0 —r /γ^Νν 0 _(l/Y° γ r® 0 Lf^{3 qJ}Y _f ^Ύ Y ^R13 0 r13 _R13 s R¹³ R¹³ I I / 10-3 vV-A S 0 ^)-^{2 x} Y S ___zd-2 i \l , 10-3 -N. (Λ Y Ίί ^Q s o f-Y ΎγΥ³ s X-, -hk -N- A Y R¹³ s R¹³ 0 R¹³ I / \0-4 υΎ 0 f ($ 0 o R¹³ , A² I ' Po-3 ,N. Ju x j| ^SH 0 R¹³ ( -T^Q 1 ' Po-3 -N. Ju Ά JX OH 0 R¹³ ( I ' Po-3 _r13 -N- Ju Ά >r N II η 0 .tL T '^RK 0 R¹³ o o [-(f Y o θι P V f J³ „ R’³ %-Λ<Μ J. 0 0 O_x P R¹³ %// t \l-2 1 /.y, R¹³ 0 R¹³ 0 o R¹³ R¹³ I I / \0-3 0 0 R¹³ vW 0 OR³

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R¹³ I , ,0-1 . .0-3 Y I θ ^N^3 OR³ R¹³ R¹³ XT'· R¹³ ’ / t^{0 2} C7

wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from -O-, -N(R¹³)-, -CH2, and -S(0)o.2-; M is selected from -O-, -N(R¹³)-, -CH2-, and -C(=O)N(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, -NO2, -NH2, -OR³, -NR³R³, -S(O)0.₂R³, -SOzNR^³, -CO₂R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO2R³, -C(O)R³, optionally substituted aryl, optionally substituted aryl Ci^alkyl, heteroaryl Ci-ealkyl, and optionally substituted Chalky]; two of R²⁵, together with the 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.

119. The process according to claim 118, wherein there is one of R¹ that is -D-R⁵⁰ and another of R¹ that is -OR^3a.

120. The process according to claim 119, wherein D is -O-.

121. The process according to claim 120, wherein -O-R⁵⁰ and -OR³* are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula XXI.

122. The process according to claim 121, wherein -OR^3a is selected from -OH, -OSi(R⁵)(R⁵)R⁵, and optionally substituted -OCi-galkyl.

123. The process according to claim 122, wherein J is =N- or =C(H)-.

124. The process according to claim 123, wherein -B-L-T is selected from:

R¹³ O O R¹³ R¹³ R¹³ I I / ,0-3 s 0 _R13 _R13 o o

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R¹³ I , ,1-2 i ,0-3 YA 0 (R®°)0-4 r13 AY Α/γΑ T3-2 R¹³ iSA R¹³ I , ,0-4 0 R¹³ 0 0 _R13 _R13 ¹ / \0-i 1 V W 'fl” 0 0 ^r13 O 0 (R⁶°)0-4 M-(r%4 )0-2 R¹³ AY 4 Ο (Ηθ°)04 ^{0 Nx}OR³

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, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR³, -NR³R³, -S(O)0_2R³, -SO₂NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO_zR³, -C(O)R³, Optionally substituted aryl, optionally substituted aryl C^alkyl, heteroaryl Ci-galkyl, and optionally substituted Chalky!; two of R²³, together with the carbon or carbons to which they are attached, can combine to form a three- to seven membered optionally substituted alicyclic or heteroalicyclic.

125. The process according to claim 124, 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.

126. The process according to claim 125, wherein -B-L-T is either of formula XXV or formula XXVI,

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XXV _Rl3a q

(R²°)0-4

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, -NO2, -NH2, -OR³, -NR^R³, -S(OX2R³, -SO₂NR³R³, -CO2R³, -C(O)NR³R³, -N(R³)SO2R³, -N(R³)C(O)R³, -N(R³)CO₂R³, -C(O)R³, and optionally substituted Chalky!; and R^3a and R^3b are each independently selected from -H and optionally substituted Chalky!.

127. The process according to claim 126, wherein a compound of formula XXIIa is combined with a compound of formula XXIIIa to make a compound of formula XXIa,

wherein -B-L-T, Z, J, R³⁰, and R² are as defined above; R⁷⁰ is selected from -H, -NO2, -NH2, and -NR³R³; provided when Z is -N(R³)- that R⁵ is selected from -H, Ci^alkyl, and aryl Ci.3alkyl; P¹ is selected from halogen, optionally substituted aIkyl-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.

128. The process according to claim 127, wherein P² is selected from -H, lithium, sodium, potassium, cesium, copper, palladium, and titanium.

129. The process according to claim 128, wherein Z is -O-.

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130. The process according to claim 129, wherein P¹ is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate.

131. The process according to claim 130, wherein R is-H.

132. The process according to claim 131, wherein J is =C(H)-.

133. The process according to claim 132, wherein R² is selected from Ci^ alkyl, perfluoro Ci-e alkyl, and halogen.

134. The process according to claim 133, wherein XXIIa and XXIIIa are heated together, optionally with a base, optionally with microwave radiation, to form XXIa.

135. The process according to claim 134, wherein the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base.

136. The process according to claim 135, wherein the base is selected from 2,6-lutidine, 4-N,N-dimethylaminopyridine, and a metal carbonate.

137. The process according to claim 136, wherein 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.

138. The process according to claim 137, wherein the solvent is an organic solvent.

139. The process according to claim 138, wherein one molar equivalent of XXIIa is combined with between about one quarter and four molar equivalents of XXIIIa.

140. The process according to claim 139, wherein one molar equivalent of XXIIa is combined with more than one but less than two molar equivalents of XXIIIa.

141. The process according to claim 140, 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 200°C for between about one and ten hours to form la.

142. The process according to claim 141, wherein the aromatic solvent is an optionally substituted benzene.

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143. The process according to claim 142, wherein the aromatic solvent is bromobenzene.

144. The process according to claim 143, wherein the base is 4-N,Ndimethylaminopyridine.

145. Hie process according to claim 144, wherein said mixture is heated to reflux for between about three and seven hours.

146. The process according to claim 145, wherein said mixture is heated to reflux for between about four and six hours.

147. The process according to claim 140, wherein XXIIa is combined with XXIHa 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.

148. The process according to claim 147, wherein the non-aromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.

149. The process according to claim 148, wherein the non-aromatic solvent is N,Ndimethylacetamide.

150. The process according to claim 149, wherein the base is potassium carbonate.

151. The process according to claim 150, wherein said mixture is heated to about 50°C between about ten and twenty hours.

152. The process according to claim 151, wherein the aromatic solvent is an optionally substituted pyridine.

153. The process according to claim 152, wherein the aromatic solvent is 2,6-lutidine.

154. The process according to claim 153, wherein the base is 2,6-lutidine.

155. The process according to claim 154, wherein said mixture is heated to reflux for between about three and seven hours.

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156. The process according to claim 155, wherein said mixture is heated to reflux for between about four and six hours.

157. The process according to claim 139, wherein one molar equivalent of XXIIIa is combined with more than one but less than two molar' equivalents of XXIIa.

158. The process according to claim 157, 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 1OO⁰C and 200°C for between about ten and twenty hours to form XXIa,

159. The process according to claim 158, wherein the aromatic solvent is an optionally substituted pyridine.

160. The process according to claim 159, wherein the aromatic solvent is 2,6-lutidine.

161. The process according to claim 160, wherein the base is 2,6-lutidine.

162. The process according to claim 161, wherein said mixture is heated to between about 150°C and 200°C for between about fifteen and twenty hours.

163. The process according to any of claims 134 - 162, wherein a compound of formula XXIIb is substituted for the compound of formula XXIIa, and either a compound of formula XXIIIb or a compound of formula XXHIc is substituted for the compound of formula XXIIIa, in order to make a compound of formula XXIb or a compound of formula XXIc, respectively,

XXIIb

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XXIb

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

164. The process according to claim 163, wherein R², if present, is halogen.

165. The process according to claim 164, wherein R², if present, is fluorine.

166. The process according to claim 165, wherein R², if present, is up to two fluorines ortho to the oxygen of the phenylene to which R² is attached.

167. The process according to claim 115, used to make a compound listed in either

Table 1 or Table 2.

168. The process according to any of claims 115 - 167, further comprising converting said compound to a pharmaceutically acceptable salt, hydrate, or prodrug thereof.