WO2013032797A2

WO2013032797A2 - Oxetane 3,3-dicarboxamide compounds and methods of making and using same

Info

Publication number: WO2013032797A2
Application number: PCT/US2012/051790
Authority: WO
Inventors: Xiao-Tao Chen
Original assignee: New Hope R & D Bioscience, Inc.
Priority date: 2011-08-26
Filing date: 2012-08-22
Publication date: 2013-03-07
Also published as: WO2013032797A3

Abstract

A novel series of oxetane 3,3-dicarboxamide compounds modulate protein kinase activity for modulating cellular activities such as proliferation, migration, differentiation, and programmed cell death. This novel series of oxetane 3,3-dicarboxamide compounds may inhibit, regulate, and/or modulate kinase receptor, particularly c-Met, KDR (VEGFR-2) signal transduction pathways, thereby make them useful as anti-cancer agents. The pharmaceutical compositions that comprise these compounds are also useful in the treatment of diseases, other than cancers, which are associated with signal transduction pathways operating through growth factor and anti-angiogenesis receptors, such as c-Met, and KDR (VEGFR-2).

Description

OXETANE 3,3-DICARBOXAMIDE COMPOUNDS AND METHODS OF

MAKING AND USING SAME

Background

[0001] c-Met tyrosine kinase is a high-affinity transmembrane receptor for the hepatocyte growth factor (HGF, Bottaro et al. (1991) Science 251 :802-804).

Stimulation of c-Met by the ligand HGF, also known as Scatter Factor(SF), initiates numerous physiological processes, including cell proliferation, scattering, morphogenic differentiation, angiogenesis, wound healing, tissue regeneration, and embryological development (Parr et al. (2004) Clin. Cancer Res. 10(1, Pt. 1) 202- 211 ; Comoglio et al. (2002) J. Clin. Invest. 109:857-862; Maulik et al. (2002) Cytokine Growth Factor Reviews 13:41-59; Hecht et al. (2004) Cancer Res.

64(17): 6109-6118). Aberrant expression of FIGF and c-Met is associated with the development and poor prognosis of a wide range of solid tumors, including breast, prostate, thyroid, lung, stomach, colorectal, pancreatic, kidney, overian, and uterine carcinoma, malignant glioma, uveal melanoma, and osteo-and soft-tissue sarcoma (W.G. Jiang, et al.(2005) Crit. Rev. Oncol. Hematol. 53 :35-69, and references cited therein). Numerous experimental data support the role of HGF and c-Met in tumor invasion, growth, survival and progression ultimately leading to metastases. For example, deregulation or dysregulation of c-Met and/or HGF; c-Met overexpression; and c-Met mutations are implicated in uncontrolled cell proliferation and survival, and play a key role in early-stage tumorigenesis, invasive growth of cancer cells, and metastasis (Danilkovitch-Miagkova et al. (2002) J. Clin. Invest. 109(7): 863 -867; Di Renzo et al. (1994) Int. J. Cancer 58:658-662; Matsumoto et al. (1994) J. Biol.

Chem. 269:31807-31813; Tusolino et al. (1998) J. Cell Biol. 142: 1145-1156; Jeffers et al. (1996) Mol. Cell. Biol. 16: 11 15-1 125; Wong et al. (2004) Exper. Cell Res. 299(l):248-256; Konda et al. (2004) Jour, of Urology 171(6), Pt. 1 :2166-2170; Heideman et al. (2004) J. Gene Med. 6(3):317-327; Ma et al. (2003) Cancer Res. 63(19):6272-6281 ; Maulik et al. (2002) Clin. Cancer Res. 8:620-627), making c-Met an important target for anticancer drug development (Cohen, P. (2002) Nat. Rev. Drug Discovery 1 :309-315). [0002] A number of approaches have been employed to modulate the HGF-c-Met axis malfunction in animal models. For example, Cao et al. (2001, Proc. Natl. Acad. Sci. U.S.A. 98:7443-7448) reported that neutralizing monoclonal antibodies to HGF/SF displayed antitumor activity in animal model; Martens et al. (2006, Clin. Cancer Res. 12:6144-6152) disclosed that a novel one-armed anti-c-Met antibody inhibited glioblastoma growth in-vivo; Brockmann et al. (2003, Clin. Cancer Res. 9: 4578-4585) demonstrated that inhibition of intracerebral glioblastoma growth was achieved by local treatment with SF/HGF-antagoinst NK4. Small molecule c-Met kinase inhibitors are of particular interest because it is irrespective of the activation mechanism, which may benefit a different and potentially larger cancer patient population due to the existence of ligand-independent activation pathway

(Birchmeier et al. 2003, Nat. Rev. Mol. Cell Biol. 4:915-925; D'Angelo et al. 2008, J. Med. Chem. 51 :5766-5779). Both selective c-Met kinase inhibitor and nonselective c-Met kinase inhibitors were reported and were under clinical or late pre- clinical development. Underiner et al (2010, Anti-Cancer Agents Med. Chem. 10:7- 27) summarized drug discovery and drug development efforts in small molecule c- Met kinase inhibitors. There are almost 10 small molecule c-Met kinase inhibitors in different stages of clinical evaluation. INCB28060 was a selective c-Met kinase inliibitor, whose IND has been filed. ARQ197 was a selective and non-ATP- competetive c-Met kinase inhibitor in phase 2 trial. A number of other small molecule c-Met kinase inhibitors in clinic trials showed activities against other kinases. For example, MGCD265 and GSK1363089 inhibited multiple kinases. MGCD265, which inhibits c-Met, VEGFR1/R2/R3, Tie and Ron is in phase 1 clinic trial. GSK1363089, which iiihibits c-Met, Axl, VEGFR2, PDGFR, c-Kit, FLT3 and Tie-2, is inpahse 2 clinic evaluation. Other medicinal chemistry literatures described the chemistry efforts in small molecule c-Met kinase inhibitor (Zhang et al. 2011, J. Med. Chem. 54:2127-2142; D'Angelo et al. 2008, J. Med. Chem. 51 : 5766-5779; Albrecht et al. 2008, J. Med. Chem. 51 :2879-2882; Liu et al. 2008, J. Med. Chem. 51 : 3688-3691·: Schroeder et al. 2009, J. Med. Chem. 52: 1251-1254).

[0003] Normal angiogenesis plays a vital role in a variety of processes, such as embryonic development, wound healing, and several components of female reproductive function. Undesirable or pathological angiogenesis had been associated with disease states including Kaposi's sarcoma, haemangioma, and other solid tumors (Fan et al, 1995, Trend Pharmacol. Soc. 16: 57-66; Folkman, 1995, Nature Medicine 1 :27-31). VEGF (vascular endothelial growth factor) is one of the major regulators of angiogenesis. VEGFR (vascular endothelial growth factor receptor) binds to VEGF. VEGFR-2 belongs to a VEGF receptor family, and it is also known as kinase insert domain containing receptor (KDR) (Mustonen et al, 1995, J. Cell Biol. 129:895-898; Waltenberger et al, 1994, J. Biol. Chem. 269:

26988-26995).

[0004] In vivo, VEGF plays a central role in vasculogenesis and induces angiogenesis and permeabilization of blood vessels. Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability process. Regulation of the VEGF- mediated signal transduction cascade will therefore provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes. Small molecule VEGFR-2 inhibtors may intercept VEGF-mediated signal travsduction cascade and have a benefit for inhibition of aberrant angiogenesis (Traxler et al, 2004, Cancer Res. 64:4931-4941; Boyer et al, 2002, Curr. Top. Med. Chem. 2: 973- 1000). A number of small molecule VEGFR-2 inhibitors are or have been in clinical trials (Ivy et al, 2009, Nature Reviews Clinical Oncology, 6:569-579).

Summary

[0005] In one embodiment, a compound has Formula I:

Formula I or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

Ai, A₂, A₃, A4, and A₅ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl) and CO(alky); Only one null is allowed among A1-A5 in any instance; Any two adjacent Ai to A₅ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;

B] and B₂ are independently selected from the following groups: CH₂, CH(alkyl) and C(alkyl)₂;

D_1; D₂, D₃, and D₄ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl) and CO(alkyl);

X=CH₂, NH, O or S; and

Z is selected from the following structures Mi to M₆:

[0006] In the structures Mi to M₆, An, A₁₂, A₁₃, A14, A₁₅ and A₁₆ are

independently selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; adjacent two An and A₁₆may combine to form a membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S and/or N. 0007] Y is selected from the following groups Y_\ to Y₆:

In Yi to Y₆, n is a integer of 0 to 4, and m is a integer of 0 to 16;

A₂i, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle; such substituted heterocycles include substituted pyrrolidine and piperidine;

Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0 and S0₂NH;

W₂ is selected from O, S, NH and N(alkyl).

[0008] Alkanoyl mentioned above is selected from formyl, acetyl and propanoyl.

[0009] The abundant isotopes ^!H and ¹²C in the structures may be replaced with the stable isotopes of hydrogen ( H) and carbon ( C), respectively. [0010] I

Formula I I or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein:

Aj, A₂, A₃, A4, and A5 are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alky); Only one null is allowed among Ai-A₅ in any instance; Any two adjacent A] and A₅ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;

D_ls D₂, D₃, and D₄ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alkyl);

Z is selected from the following structures Mi to M₆:

[0011] In the structures M_\ to M₆, An, A₁₂, A₁₃, A₁₄, A₁₅ and A₁₆ are

independently .selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN,

C(alkyl), CO(alkyl), and CY; the adjacent two A] i and Ai may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S, and/or N.

0012] Y is selected from the following groups Yi to Y₆:

[0013] In Yi to Y₆, n is an integer of 0 to 4, and m is an integer of 0 to 16;

A₂i, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle; such substituted lieterocycles include substituted pyrrolidine and piperidine;

Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0, and S0₂NH;

W₂ is selected from O, S, NH, and N(alkyl).

[0014] Alkyl mentioned above is selected from methyl, ethyl, propyl, i-propyl, i- butyl, s-butyl, t-butyl, allyl;

Alkanoyl mentioned above is selected from formyl, acetyl and propanoyl.

[0015] The abundant isotopes H and C in the structures may be replaced with the stable isotopes of hydrogen ( H) and carbon ( C), respectively. [0016] In yet another embodiment, a compound has Formula III:

Formula III

[0017] or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein:

A3 is selected from the following groups: CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alky);

D2 is selected from the following groups: CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alkyl);

Z is selected from the following structures Ml

M_fi [0018] In the structures Mi to M₆, A_{l ls} A_l2, A₁₃, A₁₄, A₁₅ and Α_ϊ6 are

independently selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; the adjacent two An and A₁₆ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S, and/or N.

0019] Y is selected from the following groups

[0020] In Yi to Y₆, n is an integer of 0 to 4, and m is an integer of 0 to 16;

A₂₁, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle; such substituted heterocycles include substituted pyrrolidine and piperidine; one example of the substituted heterocycles is (3S,4 )-l-ethyl-3- fluoropiperidin-4-yl.

[0021] Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0, S0₂NH;

[0022] W₂ is selected from O, S, NH, N(alkyl).

[0023] Alkanoyl mentioned above is selected from formyl, acetyl and propanoyl,

[0024] The abundant isotopes H and C in the structures may be replaced with the stable isotopes of hydrogen (²H) and carbon (¹³C), respectively. [0025] A method for preparing a compound of formula (I), (II) or (III) includes: a) oxidizing a 3,3-hydroxymethyloxetane compound A-1 to A-2:

A"¹ A-2 _and b) reacting A-2 with a first and second aromatic amine Ar'NH₂ and

Ar"NH₂L:

solvent, base/no base

A-2 B-1

[0026] In addition, a pharmaceutical composition comprises a therapeutically effective amount of the compound described herein, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

[0027] A method of treating a cancer comprises administering to a person in need thereof a therapeutically effective amount of the compound described herein.

[0028] Further, a method of treating a cancer comprises administering to a person in need thereof a pharmaceutical composition comprising the compound described herein. Detailed Description

[0029] Described are compounds of Formulas I, II, and III defined above, pharmaceutical compositions containing such compounds, method of making and methods of using such compounds.

[0030] Listed below are definitions of various terms used in the instant invention.

[0031] The term "alkyl" herein alone or as part of another group refers to a monovalent radical derived from alkane (hydrocarbon) containing from 1 to 12 carbon atoms unless otherwise defined. Preferred alkyl groups have from 1 -to 6 carbon atoms. In one embodiment, the alkyl group is optionally substituted straight, branched or cyclic saturated hydrocarbon group. Alkyl groups may be substituted at any available point of attachment. An alkyl group substituted with another alkyl group is also referred to as a "branched alkyl group". Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, 4,4- dimethylpentyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents include but are not limited to one or more of the following groups: alkyl, aryl, alkoxy, alkylthio, hydroxyl, carbocxy(-COOH), alkyloxycarbonyl(-C(0)R), alkylcarbonyloxy (-OCOR), amino (-NH₂), carbamoyl (-NHCOOR or OCONHR), urea (-NHCONHR) or thiol (-SH).

[0032] The term "anticancer" agent includes any agent that is useful for the treatment of cancers including 17. alpha. -Ethinylestradiol, Diethylstilbestrol,

Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,

TesLolacLone, JVlegesLrolacetale, MeLhylprednisolone, Methyi-leslosLerone,

Prednisolone, Triamcinolone, chlorotrianisene, Hydroxyprogesterone,

Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex, matrix metalloproteinase inliibitors, vascular endothelial growth factor (VEGF) inhibitors, anti-VEGF antibodies such as Avastin. Small molecules such as ZD6474 and SU6668, vatalanib, BAY-43-9006, SUI 1248, CP-547632, and CEP-7055 are also included. Anti-Her2 antibodies from Genentech (such as Herceptin) may also be utilized. Suitable EGFR inhibitors include gefitinib, erlotinib, and cetuximab. Pan Her inliibitors include canertinib, EKB-569, and GW- 572016. Also included are Src inliibitors, dasatinib (BMS-354825) as well as Casodex.RTM. (bicalutamide, Astra Zeneca), Tamoxifen, MEK-1 kinase inhibitors, MAPK kinase inliibitors, PI3 inhibitors, and PDGF inhibitors, such as imatinib.

Also included are anti-angio genie and antivascular agents which, by interrupting blood flow to solid tumors, render cancer cells quiescent by depriving them of nutrition. Castration, which also renders androgen dependent carcinomas nonproliferative, may also be utilized. Also included are IGFIR inliibitors, inhibitors of non-receptor and receptor tyrosine kinases, and inliibitors of integrin signaling.

Additional anticancer agents include microtubule- stabilizing agents such as paclitaxel (also known as Taxol.RTM.), docetaxel (also known as Taxotere.RTM.), 7-O-methylthiomethylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176), 4-desacetyl- 4-methylcarbonatepaclitaxel, 3 '-tert-butyl-3 '-N-tert-butyloxycarbonyl-4-deacetyl-3 '- dephenyl-3 -N-debe- nzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in U.S. Ser. No. 09/712,352 filed on Nov. 14, 2000), C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxycpothilonc B, [1S-[1R*,3R*(E),7R*, 10S*, 11R*, 12R*, 16S*]]^'-7-l l-dihydroxy-8,8,10,12,16- pentamethyl-3-[l-methyl-2-(2-methyl-4~ thiazolyl)ethenyl]-4-aza-l 7 oxabicyclo [14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514), [1S-[1R*,3R*(E),7R*, 10S*, 11R*, 12R*, 16S^!l!]]-3-[2-[2-(aminomethyl)-4-thiazol]-l-methylethenyl]-7,l l- dihydroxy-8- ,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,9- dione (disclosed in U.S. Pat. No. 6,262,094) and derivatives thereof; and

micro tubule-disruptor agents. Also suitable are CDK inhibitors, an antiproliferative cell cycle inhibitor, epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis- platin and carboplatin; biological response modifiers; growth inhibitors;

antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.

[0033] Additional cytotoxic agents include, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, topotecan, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, and interleukins.

[0034] As used herein, the term "patient" encompasses all mammalian species including humans and animals.

[0035] The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formulas I, II and III. The compounds of formulas 1, II and III that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare

pharmaceutically acceptable acid addition salts of such basic compounds of formulas I, II and III are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride,

hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, malate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'- methylene-bis-(2-hydroxy-3 -naphthoate)] salts.

[0036] In one embodiment, a compound has Formula I:

Formula I or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein:

A_1} A₂, A₃, A4, and A₅ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alky); Only one null is allowed among Ai-A₅ in any instance; Any two adjacent Ai to A₅ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;

B_\ and B₂ are independently selected from the following groups: CH₂, CH(alkyl), and C(alkyl)₂;

D_l5 D₂, D₃, and D₄ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alkyl);

X=CH₂, NH, 0, or S; Z is selected from the following structures Mi to M₆:

[0037] In the structures Mi to M₆, An, A₁₂, A₁₃, A₁₄, A₁₅ and A₁₆ are independently selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; the adjacent two An to Aj₆ may combine to form a membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S, and/or N.

0038] Y is selected from the following groups Yi to Y₆:

[0039] In Yi to Y₆, n is an integer of 0 to 4, and m is an integer of 0 to 16;

Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0, and S0₂NH;

W₂ is selected from O, S, NH, and N(alkyl).

[0040] The stable isotopes of hydrogen (²H), carbon (¹³C) are allowed to replace the abundant isotopes (1H and ¹²C) respectively.

[0041] In a further embodiment, in Formula (I), Bi=B₂= CH₂, and X=0. In another embodiment, in Formula (I), Bi=B₂= CH₂, X=0, A₁=A₂=A₄=A₅= CH, and 0^03=04= CH. In yet another embodiment, in Formula (I), A₃=CF; D₂=CH or CF; Z is

[0042] In still another embodiment, in Formula (I), A₃=CF; D₂=CH or CF; Z is

[0043] In another embodiment, a compound has Formula IT:

Formula II

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein:

A], A₂, A₃, A₄, and A₅ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alky); Only one null is allowed among Ai-A₅ in any instance; Any two adjacent A₁ to A₅ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;

Di, D₂, D₃, and D₄ are independently selected from the following groups: null, S, O, N, CII, CF, CCl, CBr, CCN, C(alkyl), and CO(alkyl); Z is selected from the following structures Mi to M₆:

M,

[0044] In the structures Mi to M₆, An, An, A₁₃, A₁₄, A₁₅ and A₁₆ are independently selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; the adjacent two An to Aj₆ may combine to form a membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S, and/or N.

0045] Y is selected from the following groups Y_\ to Y₆:

[0046] In Yi to Y₆, n is an integer of 0 to 4, and m is an integer of 0 to 16;

A₂₁, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle; such substituted heterocycles include substituted pyrrolidine and piperidine;

Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0, and S0₂NH; W₂ is selected from O, S, NH, and N(alkyl).

[0047] Alkyl mentioned above is selected from methyl, ethyl, propyl, i-propyl, i- butyl, s-butyl, t-butyl, and allyl.

[0048] Alkanoyl mentioned above is selected from formyl, acetyl and propanoyl.

[0049] The stable isotopes of hydrogen (2H), carbon (13C) are allowed to replace the abundant isotopes (1H and 12C) respectively. [0050]

Formula III or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein:

A₃ is selected from the following groups: CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alky);^'

D₂ is selected from the following groups: CH, CF, CCl, CBr, CCN, C(alkyl), and CO(alkyl);

Z is selected from the following structures Mi to M₆:

M,

M₅

[0051] In the structures Mi to M₆, An, A₁₂, A₁₃, A₁ , A₁₅ and A₁₆ are

independently selected from O, N, NH, N(alkyl), S, CH, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; the adjacent two An to Ai₆ may combine to form a membered or 6-membered carbocyclic or heterocyclic ring, while such a ring contains no more than 2 heteroatoms of O, S, and/or N.

0052] Y is selected from the following groups Yi to Y₆:

Y,

[0053] In Yi to Y₆, n is an integer of 0 to 4, and m is an integer of 0 to 16;

A₂₁, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle; such substituted heterocycles include substituted pyrrolidine and piperidine; one example of the substituted heterocycles is (3S,4R)-l-ethyl-3- fluoiOpiperidin-4-yl;

Wi is independently selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0, and S0₂NH;

W₂ is independently selected from O, S, NH, and N(alkyl).

[0054] The stable isotopes of hydrogen (²H), carbon (¹³C) are allowed to replace the abundant isotopes ( H and C) respectively. [0055] Also described are methods for treating a proliferative disease, such as cancer, by administering to a patient in need of such treatment a therapeutically effective amount of a compound described herein. These methods may further include an additional step of administering at least one other anticancer agent (either in combination or sequentially), to the patient.

[0056] Further described are pharmaceutical compositions comprising a

therapeutically effective amount of a compound described herein in a

pharmaceutically acceptable carrier.

[0057] In one embodiment the compounds described herein are useful in the treatment of a variety of cancers, including, but not limited to, the following:

a) carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;

b) hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;

c) hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; d) tumors of mesenchymal origin, including fibrosarcoma and

rhabdomyosarcoma;

e) tumors of the central and peripheral nervous system, including

astrocytoma, neuroblastoma, glioma and schwannomas; and

f) other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[0058] In a further embodiment, methods are provided for treating cancers in a patient in need of such treatment comprising administering to the patient a compound having Formula I or II, wherein the cancer is a cancer of the bladder, breast, colorectal, gastric, head and neck, kidney, liver, lung, pancreatic, gall bladder, prostate, MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma,

glioblastoma/astrocytomas, or melanoma. [0059] Due to the key role protein kinases in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neuro- fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,

glomerulonephritis, restenosis following angioplasty or vascular surgery,

hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endo toxic shock, and fungal infections.

In one embodiment, the compounds described herein or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof have an IC50 value of less than 5 uM. In a further embodiment, the compounds described herein or an enantiomer,

diastereomer, or pharmaceutically acceptable salt thereof have an IC50 value of less than 1 uM.

[0060] The compounds described herein as modulators of apoptosis, will be expected to be useful in the treatment of cancers (including but not limited to those types mentioned herein above), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated

glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

[0061] The compounds described herein may modulate the level of cellular RNA and DNA synthesis. These agents would therefore be expected to be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

[0062] The compounds described herein may be expected to be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the

development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.

[0063] The compounds described herein may also be expected to be useful in inhibiting tumor angiogenesis and metastasis.

[0064] The present inventor has found that some compounds described herein inhibit protein kinases other than Met, such as those in the Trk family of protein kinases.

[0065] The compounds described herein may also be expected to be useful in combination (administered together or sequentially) with other anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inliibitors, such as etoposide; topoisomerase 1 inhibitors such as CPT-1 L or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolities, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors;

VEGF inhibitors; CDK inhibitors; SRC inhibitors; c-Kit inhibitors; Herl/2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2).

[0066] The pharmaceutical compositions containing the compounds described herein as an active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the

gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl- methylcellulose or hydroxypropyl-cellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.

[0067] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyetliyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0068] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylenc sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0069] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisol or alpha-tocopherol.

[0070] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0071] The pharmaceutical compositions may also be in the form of an oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.

Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.

[0072] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant. [0073 J The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.

[0074] The sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.

[0075] The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be

advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS.TM. model 5400 intravenous pump.

[0076] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous

administration. This suspension may be formulated according to any known technique in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0077] The compounds described herein may also be administered in the form of a suppository, for example, for rectal administration of the compound. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

[0078] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I, II or III are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)

[0079] The compounds described herein can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0080] When a compound described herein is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.

[0081] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent or treatment within its approved dosage range. The compounds described herein may also be administered sequentially with other anticancer or cytotoxic agent(s) when a combination formulation is inappropriate. The present invention is not limited in the sequence of administration and the compounds described herein may be administered either prior to or after

administration of the other anticancer or cytotoxic agent(s).

[0082] The compounds described herein may generally be prepared according to the following Schemes A-C. The compounds are synthesized readily using synthetic methods laiown to one skilled in the art. Tautomers and solvates (e.g., hydrates) of the compounds are also within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds may be in a free or hydrate form, and may be obtained by methods exemplified by the following schemes below.

[0083] In general, an oxetane-3,3-dicarboxic acid (or its substituted analogs) can be prepared according to Scheme A. Scheme A: Oxidation of 3,3-hydroxymethyloxetane or its derivatives

A-1 A-2

[0084] The oxidation of 3,3-dihydroxymethyloxetane or its derivatives can be accomplished by TEMPO/Bleach (R. Ciriminna et al (2003), Adv. Synth. Catal.

345(3), 383); HN0₃ can also be used for oxidation A-1 to A-2 following a procedure described by A.R. Evans et al. (1987) JCS, Perkin Trans .1 (7), 1635; NaI0₄/RuCl₃ oxidizes A-1 to A-2 following a procedure described by B. Trost at al. (2007), J.

Amer. Chem. Soc. 129(38), 11781; N₂0₄/CHC1₃ can also be employed for the oxidation in this instance (D. Seebach et al. (1990), Liebig Aim. Chem. (4), 379);

And KMn0₄ can also oxidize A-1 to A-2 following a procedure similar to the one described by N. Katagiri et al (1988), Chem. & Pharm. Bulletin (Japan), 36(10), 3867.

[0085] In general, the compounds described herein can be prepared in one-pot- two steps (Scheme B) by coupling A-2 with two distinct aromatic amines using standard coupling reagents known to a skilled person in the art. The coupling

reagent/activation reagent can be one of these described by M. Bradley et al. (2009), Chem. Soc. Rev. 38, 606. For example, the coupling reagent that can be one of the following HATU, DCC/HOAt, EDC/HOAt, TATU, BOP, PyBOP, but not limited to the listed. Any coupling reagent can be used for amide formation can be potentially used for preparing the compounds described herein.

Scheme B: Preparation of oxetane-3,3-dicarboxamide (or its derivative)

See Formulas I, II, or II [0086] Also, the compounds described herein can be prepared stepwise from A-2 (Scheme C) using coupling reagent or activation reagent (such as acyl chloride, mixed anhydride, activated ester and others). For example, acyl chloride can be prepared by reacting A-2 with oxalyl chloride, thionyl chloride, and other method (G. Luo et al. (2002), Tetrahedron Lett. 43(49), 8909.

Scheme C: Preparation of oxetane-3,3-dicarboxamide (or its derivative)

[0087] Activation of the carboxylic acid can be achieved by coupling reagents, such as acylchloride, thionyl chloride, etc. Act, and Act' can be halogen, or other good leaving groups generally used in amide synthesis and known to one skilled in the art.

[0088] Specific non-limiting examples are provided below.

Example 1

3 -Ν'- {4- [(6,7-dimethoxyquinolin-4-yl)oxy]phenyl} -3 -N-(4-fluorophenyl)oxetane-

3 ,3 -dicarboxamide

[0089] 1A) oxetane-3,3-dicarboxylic acid

[0090] To a solution of (hydiOxymethyl)oxetan-3-yl]metlianol (355 mg, 3.0 mmol) in 10 niL of H₂0 were subsequently added KBr (24 mg, 0.2 mmol), TEMPO (31 mg, 0.2 mmol) and Na₂C0₃ (1.0 g, 9.4 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 10 minutes, and then 6% bleach (5 mL) was added. The reaction was stirred at room temperature for 2 days. The solvent (H₂0) was removed under reduced pressure and neutralized at 0 °C with 2N HCl ( 8 mL) to pH to 1.0. Water was removed again under reduced pressure. The solid was then triturated with a mixture of solvents (EtOH : DCM) (40 mL, 1 : 1). After filtration, the solid was triturated with EtOH (10 mL x 2) and filtered. The combined organics were combined and concentrated to dryness to provide crude product (oxetane-3,3- dicarboxylic acid) (500 mg, contaminated with inorganic salts and incomplete oxidation impurities). The methyl group of oxetane in 1A showed a singlet at 5.00 ppm in D₂0. The crude material was directly used in the next step.

[0091] IB) 3-[(4-fluorophenyl)carbamoyl]oxetane-3-carboxylic acid

[0092] The crude material from step 1A and 4-fluoroaniline (2.4 mmol, 0.23 mL) were dissolved in 10 mL of acetonitrile. To the solution was added HATU (1 .14 g, 3 mmol) and N,N-diisopropylehtylamine (1.0 g, 6 mmol). The solution was stirred overnight at rt. The solution was diluted with 50 mL of EtOAc, washed with 2 N NaOH (5 mL, 3 mL x 2). The combined aq. layer was extracted with EtOAc (5 mL). The aq. layer was then neutralized with 6N HCl to pH to 1.0. The aq. layer was then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine ( 5 mL). After filtration through a phase separator and concentration, the residue was dissolved in 5 mL of MeOH and purified by HPLC to give the fractions with the desired product. The fractions were pooled together and concentrated. The residue was then lyophilized to give fine powder: 3-[(4- fluorophenyl)carbamoyl]oxetane-3-carboxylic acid (150 mg, 21 % yield in two steps).

[0093] MS: (m/z) 240.1 observed [M+l]⁺; MW=239.20

[0094] 1 C) 3-N'-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl} -3-N-(4- fluorophenyl)oxetane-3,3-dicarboxamide

[0095] To a solution of 3-[(4-fluorophenyl)carbamoyl]oxetane-3-carboxylic acid (50 mg, 0.21 mmol) in 3 mL of THF were subsequently added 4-[(6,7- dimethoxyquinolin-4-yl)oxy]aniline (60 mg, 0.20 mmol), HATU (76 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days. The crude reaction mixture was directly purified on reverse phase HPLC to afford fractions containing the desired product. The fractions were pooled and concentrated to remove acetonitrile. The residue was basified with IN NaOH (10 mL) and extracted with 10% EtOAc in DCM (50 ml, 20 mL x 2). The combined organics were washed with IN NaOH ( 5 mL x2) and followed by brine (10 mL). The organic layer was then filtered through a phase separator and the filtrate was concentrated to provide 3-N'-{4-[(6,7- dimethoxyquinolin-4-yl)oxy]phenyl}-3-N-(4-fluoiOphenyl)oxetane-3,3- dicarboxamide (52 mg, 50% yield). MS (m/z): 517.9 [M+l]. 1H NMR (400 MHz, CDC13) δ 10.00 (s, 1H), 9.63 (s, 1H), 8.35 (d, J=6.3 IIz, Hi), 7.93 (m, 3H), 7.66 (m, 3H), 7.12 (d, J=8.9Hz, 2H), 6.95 (dd, J=14.4, 5.8 Hz, 2H), 6.58 (d, J=6.6 Hz, 1H), 5.24 (m, 4H), 4.13 (s, 3H), 4.10 (s, 3H).

Example 2

3-N'-{4-[(6,7-dimethoxyquinolin-4-yl)oxyJ-3-fluoiOphenyl}-3-N-(4- fluorophenyl)oxetane-3 ,3 - dicarboxamide

[0096] To a solution of 3-[(4-fluorophenyl)carbamoyl]oxetane-3-carboxylic acid

(50 mg, 0.21 mmol) in 3 mL of THF were subsequently added 4-[(6,7- dimethoxyquinolin-4-yl)oxy]-3-iluoroaniline (63 mg, 0.20 mmol), HATU (76 mg,

0.2 mmol) and N,N-diisopropylethylamine (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days. The crude reaction mixture was directly purified on reverse phase HPLC to afford fractions containing the desired product. The fractions were pooled and concentrated to remove acetonitrile. The residue was basified by IN NaOII (10 mL) and extracted with 10% EtOAc in DCM (50 ml, 20 mL x 2). The combined organics were washed with IN NaOH ( 5 mL x2) and followed by brine (10 mL). The organic layer was then filtered tlirough a phase separator and the filtrate was concentrated to provide 3-N'- {4- [(6,7-dimethoxyquinolin-4-yl)oxy] -3 -fluorophenyl } -3 -N-(4- iluorophenyi)oxetane-3, 3 -dicarboxamide (25 mg, 23% yield). MS (m/z): 535.9

[M+1]. IH NMR (400 MHz, CDC13) δ 10.34 (s, IH), 9.82 (s, IH), 8.39 (d, J=6.5 Hz, IH), 7.92 (m, 2H), 7.69 (m, 4H), 7.20 (m, IH), 6.95 (m, 2H), 6.60 (d, J=6.5 Hz, IH), 5.23 (dd, J=14.9, 6.9 Hz, 4H), 4.11 (s, 3H), 4.10, (s, 3H). Example 3

3 -N-(4-fluorophenyl)-3-N'-{4-[(2- { [2-(morpholin-4-yl)ethyl] carbamoyl} - 1 H- pyrrolo [2,3 -b]pyridin-4~yl)oxy]phenyl} oxetane-3 ,3 -dicarboxamide

[0097] Following a procedure similar to 1C, coupling between 4-(4- amiiioplienoxy)-N- [2-(morpholin-4-yl)ethyl] - 1 H-pyrrolo [2,3 -b]pyridine-2- carboxamide and 3- [(4- fluorophenyl)carbamoyl] oxetane-3 -carboxylic acid provides 3-N-(4-fluoi phenyl)-3-N'-{4-L(2-{[2-(morphoiin-4-yl)ethyl]carbamoyl}-lH- pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}oxetane-3,3-dicarboxamide.

Example 4

3 -N'- { 3 -fluoro-4- [(2- { [2-(morpholin-4-yl)ethyl] carbamoyl} - 1 H-pyrrolo L2,3 - b]pyridin-4-yl)oxy]phenyl}-3-N-(4-fluorophenyl)oxetane-3,3-dicarboxamide

[0098] Following a procedure similar to 1 C, coupling between 4-(4-amino-2- fluorophenoxy)-N- [2-(morpholin-4-yl)ethyl] - 1 H-pyrrolo [2,3 -b]pyridine-2- carboxamide and 3-[(4-fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3 -N-(4-fluorophenyl)-3-N'- {4- [(2- { [2-(morpholin-4-yl)ethyl] carbamoyl} - 1 H- pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}oxetane-3,3-dicarboxamide. Example 5

3 -N- [3 -fluoro-4-( { 6-methoxy-7- [3 -(morpholin-4-yl)propoxy] quinolin-4- yl} oxy)phenyl] -3-N'-(4-fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0099] Following a procedure similar to 1C, coupling between 3-fluoro-4-({6- methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline and 3-[(4- fluoi phenyl)carbamoylJoxetane-3-carboxylic acid provides 3-N-[3-fluoro-4-({6- methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)phenyl]-3-N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide.

Example 6

3-N'-(4-fluoi phenyl)-3-N-[4-({6-metlioxy-7-[3-(morpholin-4-yl)piOpoxy]quinolin- 4-yl} oxy)phenyl]oxetane-3 ,3 -dicarboxamide

[0100] Following a procedure similar to 1C, coupling between 4-({6-methoxy-7- [3-(morpholin-4-yl)propoxy]quinolin-4-yl}oxy)aniline and 3-[(4- fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3-N'-(4-fluorophenyl)- 3-N-[4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinolin-4- yl} oxy)phenyl] oxetane-3 ,3 -dicarboxamide. Example 7

3 -N- [2,5-difluoiO-4-( { 6-methoxy-7- [3 -(morpholin-4-yl)propoxy] quinolin-4- yl } oxy)phenyl] -3 -N'-(4-fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0101] Following a procedure similar to 1C, coupling between 2,5-difluoro-4-({6- methoxy-7- [3 -(morpholin-4-yl)propoxy] quinolin-4-yl} oxy)aniline and 3 - [(4- fluoiOphenyl)carbamoylJoxetane-3-carboxylic acid provides 3-N-L2,5-di luoro-4- ( { 6-methoxy-7- [3 -(morpholin-4-yl)propoxy] quinolin-4-yl } oxy)phenyl] -3 -N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide.

Example 8

3-N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-2,5-difluorophenyl}-3-N'-(4- fTuorophenyl)oxetane-3 ,3 -dicarboxamide

[0102] Following a procedure similar to 1C, coupling between 4- [(6,7- dimethoxyquinolin-4-yl)oxy]-2,5-difluoroaniline and 3-[(4- fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3-N-{4-[(6,7- dimethoxyquinolin-4-yl)oxy]-2,5-difluorophenyl}-3-N^l-(4-fluoiOphenyl)oxetane- 3,3-dicarboxamide. Example 9

3 -N- {4- [(2-aminopyridin-4-yl)oxy]phenyl} -3 -N'-(4-fluorophenyl)oxetane-3 ,3- dicarboxamide

[0103] Following a procedure similar to 1C, coupling between 4-(4- aminophenoxy)pyridin-2-amine and 3 - [(4-fluorophenyl)carbamoyl] oxetane-3 - carboxylic acid provides 3-N-{4-[(2-aminopyridin-4-yl)oxy]phenyl}-3-N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide.

Example 10

3 -N- {4-[(2-aminopyridin-4-yl)oxy] -3 -fluorophenyl} -3 -N'-(4-fluoiOphenyl)oxetane-

3 ,3 -dicarboxamide [0104] Following a procedure similar to 1 C, coupling between 4-(4-amino-2- fluorophenoxy)pyridin-2-amine and 3 - [(4-fluoiOphenyl)carbamoyl] oxetane-3 - carboxylic acid provides 3-N-{4-[(2-aminopyridin-4-yl)oxy]-3-fluorophenyl}-3-N'- (4-fluoiOphenyl)oxetane-3,3-dicarboxamide. Example 11

3-N-{4-[(2-aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-3-N^l-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0105] Following a procedure similar to 1C, coupling between 4-(4-amino-2,5- difluorophenoxy)pyridin-2-amine and 3 - [(4-fluorophenyl)carbamoyl] oxetane-3 - carboxylic acid provides 3-N-{4-[(2-aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-3- N'-(4-fluorophenyl)oxetane-3,3-dicarboxamide.

Example 12

3 -N- {4- [(2-amino-3 -chloropyridin-4-yl)oxy]phenyl } -3 -N'-(4-fluorophenyl)oxetane-

3 ,3 -dicarboxamide [0106] Following a procedure similar to 1 C, coupling between 4-(4- aminophcnoxy)-3-chloropyridin-2-aminc and 3-[(4- iluorophenyl)carbamoylJ oxetane-3 -carboxylic acid provides 3-N-{4-[(2-amino-3- chloropyridin-4-yl)oxy]phenyl}-3-N'-(4-fluoroplienyl)oxetane-3,3-dicarboxamide. Example 13

3 3-N- {4-[(2-amino-3 -chloropyridin-4-yl)oxy] -3 -fluorophenyl} -3 -N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0107] Following a procedure similar to 1C, coupling between 4-(4-amino-2- fluorophenoxy)-3-chloropyridin-2 -Amine and 3-[(4- fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3 3-N-{4-[(2-amino-3- chloropyridin-4-yl)oxy] -3 -fluorophenyl} -3 -N'-(4-fluoi phenyi)oxetane-3 ,3 - dicarboxamide.

Example 14

3 -N- {4- [(2-amino-3 -chloropyridin-4-yl)oxy] -2,5-difluorophenyl } -3 -N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0108] Following a procedure similar to 1C, coupling between 4-(4-amino-2, difluorophenoxy)-3-chloropyridin-2-amine and 3-[(4- fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3-N-{4-[(2-amino chloropyridin-4-yl)oxy]-2,5-difluorophenyl}-3-N'-(4-fluoiOphenyl)oxetane-3,3 dicarboxamide. Example 15

3 -N- {4- [(2-acetamidopyridin-4-yl)oxy]phenyl } -3 -N'-(4-fluorophenyl)oxetane-3 ,3 - dicarboxamide

[0109] Following a procedure similar to 1C, coupling between N-[4-(4- aminophenoxy)pyridin-2-yl] acetamide and 3 - [(4-fluorophenyl)carbamoyl] oxetane- 3-carboxylic acid provides 3-N-{4-[(2-acetamidopyridin-4-yl)oxy]phenyl}-3-N'-(4- fluorophenyl)oxetane-3,3-dicarboxamide.

Example 16

3-N-{4-[(2-acetamidopyridin-4-yl)oxy]-3-fluorophenyl}-3-N'-(4- fluorophenyl)oxetane-3,3-dicarboxamide [0110] Following a procedure similar to 1 C, coupling between N-[4-(4-amino-2- fluorophenoxy)pyridin-2-yl] acetamide and 3 - [(4-fluorophenyl)carbamoyl] oxetane- 3-carboxylic acid provides 3-N-{4-[(2-acetamidopyridin-4-yl)oxy]-3-fluorophenyl}- 3 -N'-(4-fluorophenyl)oxetane-3 ,3 -dicarboxamide.

3-N-{4-[(2-acetamidopyridin-4-yl)oxy]-2,5-difluoiOphenyl}-3-N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide

[0111] Following a procedure similar to 1C, coupling between N-[4-(4-amino-2,5- difluorophenoxy)pyridin-2-yl]acetamide and 3-[(4-fluorophenyl)carbamoyl]oxetane- 3-carboxylic acid provides 3~N-{4-[(2-acetamidopyridin-4-yl)oxy]-2,5- di fluorophenyl } -3 -N'-(4-fluorophenyl)oxetane-3 ,3 -dicarboxamide.

Example 18

3 -N- {4- [(3 - { [(3 S,4R) - 1 -ethyl-3 -fluoropiperidin-4-yl] amino } - 1 H-pyrazolo [3 ,4- b]pyridin-4-yl)oxy]-3-fluoi phenyl}-3-N'-(4-fluoiOphenyl)oxetane-3,3- dicarboxamide

[0112] Following a procedure similar to 1C, coupling between 3-N-{4-[(3- { [(3 S,4R)-1 -ethyl-3 -fluoropiperidin-4-yl] amino} -1 H-pyrazolo [3, 4-b]pyridin-4- yl)oxy]-3-fluoiOaniline and 3-[(4-iluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3 -N- { 4- [(3 - { [(3 S,4R)- 1 -ethyl-3 -fluoropiperidin-4-yl] amino } - 1 H- pyrazolo[3,4-b]pyridin-4-yl)oxy]-3-fluoiOphenyl}-3-N'-(4-fluoi phenyl)oxetane- 3,3-dicarboxamide. Example 19

3 -N- {4- [(3 - { [(3 S ,4R) - 1 -ethyl-3 -fluoropiperidin-4-yl] amino } - 1 H-pyrazolo [3 ,4- b]pyridin-4-yl)oxy]-2,5-difluorophenyl}-3-N'-(4-fluorophenyl)oxetane-3,3- dicarboxamide

[0113] Following a procedure similar to 1C, coupling between 3-N-{4-[(3- { [(3 S,4R)- 1 -ethyl-3 -fluoropiperidin-4-yl] amino } - 1 H-pyrazolo [3 ,4-b]pyridin-4- yl)oxy]-2,5-difluoroaniline and 3-[(4-fluorophenyl)carbamoyl]oxetane-3-carboxylic acid provides 3 -N- {4- [(3 - { [(3 S,4R)- 1 -ethyl-3 -fluoropiperidin-4-yl] amino } - 1 H- pyrazolo[3,4-b]pyridin-4-yl)oxy]-2,5-difluorophenyl} -3-N'-(4- fluorophenyl)oxetane-3 ,3 -dicarboxamide.

Biological Assay of c-Met kinase inhibition

[0114] Elisa Kinase Assay: Following a protocol described by Zhang et al 201 1, J. Med. Chem. 54: 2127-2142, the inhibition rate (%) is determined and IC50 values are calculated from the inhibition curve.

[0115] Human c-Met Kinase Assay:

[0116] The effects of compounds on the activity of the human c-Met kinase were quantified by measuring the phosphorylation of the substrate Ulight- CAGAGAIETDKEYYTVKD (JAK1) using a human recombinant enzyme expressed in insect cells and the LANCE® detection method (Dardelli et al 1998, Proc. Natl. Acad. Sci. U.S.A. 95: 14379-14383).

[0117] Human KDR Kinase Assay (VEGFR-2):

[0118] The effects of compounds on the activity of the human KDR kinase were quantified by measuring the phosphorylation of the substrate Ulight- CAGAGA1ETDKEYYTVKD (JAK1 ) using a human recombinant enzyme expressed in Sf9 cells and the LANCE® detection method (Itokawa et al 2002, Mol. Cancer Ther. 1 : 295-302).

[0119] Biological data:

[0120] All of the above-mentioned references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.

[0121] While the foregoing describes in detail a preferred an article including identification information for use in an electrically heated smoking system with reference to a specific embodiment thereof, it will be apparent to one skilled in the art that various changes and modifications may be made to the article, which do not materially depart from the spirit and scope of the foregoing description.

Accordingly, all such changes, modifications, and equivalents that fall within the spirit and scope of the appended claims are intended to be encompassed thereby.

Claims

We claim:

1. A compound having formula I

Ai, A₂, A₃, A4, and A₅ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl) and CO(alky); only one null is allowed among A1-A5 in any instance; any two adjacent A_\ to A₅ may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;

Bl and B2 are independently selected from the following groups: C¾, CH(alkyl) and C(alkyl)₂;

D_1} D₂, D₃, and D₄ are independently selected from the following groups: null, S, O, N, CH, CF, CCl, CBr, CCN, C(alkyl) and CO(alkyl);

X=CH₂, NH, O or S; and

Z is selected from the following structures Mi to M₆:

in the structures Mi to M₆, A_lls A₁₂, A₁₃, A₁₄, Aj₅ and A₁₆ are independently selected from 0, N, NH, N(alkyl), S, CII, CF, CCl, CBr, CCN, C(alkyl), CO(alkyl), and CY; adjacent two An and A₁₆may combine to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, the ring containing no more than 2 heteroatoms of O, S and/or N,

Y is selected from the following groups Yi to Y₆:

In Yi to Y₆, n is a integer of 0 to 4, and m is a integer of 0 to 16;

A₂₁, and A₂₂ are independently selected from H, alkyl, alkanoyl, and a substituted heterocycle;

Wi is selected from O, NH, N(alkyl), S, CO, C(0)NH, C(0)0 and S0₂NH;

W₂ is selected from O, S, NH and N(alkyl),

wherein the abundant isotopes H and C in the structures may be replaced with the stable isotopes of hydrogen (²H) and carbon (¹³C), respectively. 2. The compound according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein the substituted heterocycle comprises a substituted pyrrolidine and piperidine.

3. The compound according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein

CH₂, and X=0.

4. The compound according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein Bi=B₂= C¾, X=0,

A,=A₂=A₄=A₅= CH, and Di=D₃=D₄= CH. 5. The compound according to claim 4, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, where A₃=CF; D₂=CH or CF; Z is

6. The compound according to claim 4, or an enantiomer, diastereomer, pharmaceutically acceptabl or CF; Z is

7. The compound according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, having an IC50 value of less than 5 uM.

8. The compounds according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, having an IC₅₀ value of less than 1 uM.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

A process for preparing the compound according to claim 1, comprising: a) oxidizing a 3,3-hydroxymethyloxetane compound A-l to A-2:

A-1 A-2 wherein Bi and B₂ have the same definitions as in Formula I, and

b) reacting A-2 with a first and second aromatic amine Ar'N]¾ and Ar"N¾:

1) coupling reagent or activation reagent,

A-2

wherein Ar' represents , and Ar" represents

A] to A₅, Di to D₄, X and Z having the same definitions as in

Formula I.

11. A method of treating a cancer comprising administering to a person in need thereof a therapeutically effective amount of the compound according to claim 1.

12. A method of treating a cancer comprising administering to a person in need thereof the pharmaceutical composition according to claim 9.