WO2013148537A1

WO2013148537A1 - Substituted spirobicyclic compounds and methods of use

Info

Publication number: WO2013148537A1
Application number: PCT/US2013/033633
Authority: WO
Inventors: Ning Xi; Minxiong LI; Xuan Zhou; Yanjun Wu
Original assignee: Ning Xi
Priority date: 2012-03-29
Filing date: 2013-03-25
Publication date: 2013-10-03

Abstract

The present invention provides spirobicyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

Description

SUBSTITUTED SPIROBICYCLIC COMPOUNDS AND METHODS OF USE

[001] This application claims the benefit of U.S. Provisional Application Ser. No. 61/617,626 filed March 29, 2012, the contents of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[002] This invention relates to novel substituted spirobicyclic compounds, and salts thereof, which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. In particular, the invention relates to compounds that inhibit the protein tyrosine kinase activity, resulting in the inhibition of inter- and/or intra-cellular signaling. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

[003] Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. By adding phosphate groups to substrate proteins, they direct the activity, localization and overall function of many proteins, and serve to orchestrate the activity of many cellular processes. Kinases are particularly prominent in signal transduction and co-ordination of complex functions such as the cell cycle. Of the 518 human protein kinases, 478 belong to a single superfamily whose catalytic domains are related in sequence. These can be clustered into groups, families and sub-families, of increasing sequence similarity and biochemical function.

[004] A partial list of such kinases include abl, AATK, ALK, Akt, Axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKIO, cRafl, CSFIR, CSK, DDRl, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, MER, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX 14, TNK1, TNK2, TNNI3K, TXK, TYK2, Tyro-3, tie, tie2, TRK, Yes and Zap70.

[005] Receptor tyrosine kinases (RTKs) are a diverse group of transmembrane proteins that act as receptors for cytokines, growth factors, hormones and other signaling molecules. Receptor tyrosine kinases (RTKs) are expressed in many cell types and play important roles in a wide variety of cellular processes, including growth, differentiation and angiogenesis. Activation of the kinase is effected by binding of a ligand to the extracellular domain, which induces dimerization of the receptors. Activated receptors auto-phosphorylatetyrosine residues outside the catalytic domain via cross-phosphorylation. This auto-phosphorylation stabilizes the active receptor conformation and creates phosphotyrosine docking sites for proteins that transduce signals within the cell.

[006] Receptor tyrosine kinases (RTKs) are hyper-activated (through receptor activating mutations, gene amplification, growth factor activation, etc.) in many human solid tumors and hematological malignancies. RTK's elevated activation contributes to tumourigenesis factors such as hyperplasia, survival, invasion, metastasis and angiogenesis. Inhibition of receptor tyrosine kinases proved to be effective strategies in cancer therapy (Sharma PS; et al. "Receptor tyrosine kinase inhibitors as potent weapons in war against cancers." Curr. Pharm. Des. 2009, 15, 758).

[007] Anaplastic lymphoma kinase (ALK), a membrane associated tyrosine kinase receptor from the insulin receptor superfamily, has been implicated in oncogenesisin several human tumors.

Indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms (the most common being nucleophosmin (NPM)-ALK) in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) (Morris, S. W.; et al. "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma." Science 1994, 263, 1281).

[008] ALK fusions were also found in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). Studies suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. Moreover, studies have implicated various mutations of the ALK gene in both familial and sporadic cases of neuroblastoma. ALK mutations in neuroblastoma cells results in constitutive ALK phosphorylation and attenuation. Conversely, inhibition of ALK by sRNA and small molecule ALK inhibitors resulted in profound growth inhibition in those cell lines(Palmer, R. H.; et al. "Anaplastic lymphoma kinase: signaling in development and disease." Biochem.J. 2009, 420, 345).

[009] More recently, various isoforms of a fusion gene comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene were identified in NSCLC cells. The EML4-ALK fusion transcript was detected in approximately 3-7% of NSCLC patients examined. Experimental evidence from in vitro and in vivo studies demonstrated oncogenic transforming activity of the EML4-ALK fusion proteins and reinforced the pivotal role of EML4- ALK in the pathogenesis of NSCLC in humans (Soda, M.; et al. "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer." Nature 2007, 448, 561).

[010] Fusions of ALK have clear oncogenic potential as its aberrant tyrosine kinase activity enhances cell proliferation and survival and leads to cytoskeletal rearrangements and changes in cell shape. Oncogenic ALK transformation is mediated by interactions with downstream molecules that trigger substantial intracellular signaling cascades. Similarly to most normal and oncogenic tyrosine kinases, ALK fusions activate many different pathways that are strictly interconnected and overlapping. The most relevant and better characterized pathways are reported: the Ras-extracellular signal-regulated kinase (ERK) pathway, the Janus kinase 3 (JAK3)-STAT3 pathway and the phosphatidylinositol 3-kinase (PBK)-Akt pathway. These three pathways have many points of interaction to mediate the effects of ALK activity. Overall, the JAK3-STAT3 pathway and the PI3K-Akt pathway have been shown to be vital primarily for cell survival and phenotypic changes(Chiarle, R.; et al. "The anaplastic lymphoma kinase in the pathogenesis of cancer." Nat. Rev. CancerlOOS, 8,1 1 ; Barreca, A.; et al. "Anaplastic lymphoma kinase (ALK) in human cancer. "J. Mol. Endocrinol. 2011, 47, Rl l).

[011] The involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others has also been implicated. In a survey of a collection of human cancer cell lines, Dirks,et al. confirmed the expression of ALK transcripts in nervous system-derived lines, including retinoblastoma, and a large percentage of cell lines derived from solid cancers of ectodermal origin, including melanoma and breast carcinoma (Dirks, P. B. "Cancer's source in the peripheral nervous system." Nature Medicine 2008, 14, 373).

[012] c-Met, also referred to as hepatocyte growth factor receptor (HGFR), is expressed predominantly in epithelial cells but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. The natural ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF). In both embryos and adults, activated c-Met promotes a morphogenetic program, known as invasive growth, which induces cell spreading, the disruption of intercellular contacts, and the migration of cells towards their surroundings(Peschard P.; Park M. "From Tpr-Met to Met, tumorigenesis and tubes." Oncogene 2007, 26, 1276; Stellrecht CM; Gandhi V. "Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target." Cancer Letter2009, 280, 1). [013] A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, thyroid, colon, renal, glioblastomas and prostate, etc. c-Met is also implicated in atherosclerosis and lung fibrosis.

Invasive growth of certain cancer cells is drastically enhanced by tumor-stromal interactions involving the HGF/c-Met pathway. Thus, extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met as major targets in cancer drug development (Migliore C; Giordano S. "Molecular cancer therapy: can our expectation be MET." Eur. J. Cancer 2008, 44, 641; Benedetta Peruzzi; Donald P. Bottaro. "Targeting the c-Met Signaling Pathway in Cancer." Clinical Cancer Research 2006, 12, 3657). Agents targeting c-Met signaling pathway are now under clinical investigation (Joseph Paul Eder; et al. "Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer." Clinical Cancer Res earch2009, 15, 2207; Paolo M.; et al. "Drug development of MET inhibitors: targeting oncogene addiction and expedience." Nature Review Drug Discovery 2008, 7, 504).

[014] Many ALK and/or c-Met inhibitors are now under clinical development for the treatment of various human cancers. Crizotinib is an ATP-competitive small molecule ALK inhibitor, which also displays activity against the c-Met receptor tyrosine kinase. The FDA recently approved crizotinib (Pfizer's Xalkori^®, originally known as PF-02341066) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in which tumor cells exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene. These rearrangements of the ALK gene (EML4-ALK) constitute driver mutations that are critical for the malignant phenotype of lung adenocarcinomas that have the mutations. Thus, the inhibition of mutated kinase ALK for the treatment of cancer is validated.

[015] Crizotinib is administered 250 mg twice daily. Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8 (Xalkori^®FDA-Approved Patient Labeling, Pfizer Inc. February 2012).

[016] As seen with other targeted cancer drugs, patients with ALK-positive NSCLC eventually relapse on crizotinib. The development of acquired resistance is clearly the major hurdle preventing targeted therapies such as crizotinib from having an even more substantial impact on patients (Nature Review Drug Discovery 2011, 10, 897).

[017] There is, therefore, still a need for effective therapies for use in proliferative disease, including treatments for primary cancers, metastatic disease, and for targeted therapies, including tyrosine kinase inhibitors, such as ALK and/or c-Met inhibitors, dual inhibitors, selective inhibitors, and for potent, orally bioavailable, and efficacious inhibitors, and for inhibitors that provide optimized dosing schedule, such as once daily oral administration.

[018] The present invention provides novel compounds believed to have clinical use for treatment of cancer through inhibiting ALK and/or c-Met. Preferred compounds of the present invention are also believed to provide an improvemnet in potency, pharmacokinetic properties, and/or toxicity profile over certain other ALK and/or c-Met inhibitor compounds found in the art.

SUMMARY OF THE INVENTION

[019] The present invention provides new compounds and methods for treating cell proliferative diseases. The compounds of the invention are inhibitors of protein tyrosine kinases. Preferably, the compounds of the invention are capable of inhibiting, for example, ALK (including ALK fusions such as EML4-ALK, NPM-ALK, etc.), and c-Met receptor (hepatocyte growth factor receptor) signaling. Accordingly, the invention provides new inhibitors of protein tyrosine kinase receptor signaling, for example, ALK receptor signaling, c-Met receptor signaling.

[020] Specifically, it has been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of receptor tyrosine kinases such as ALK and c-Met. Accordingly, the invention provides compounds having the formula (I):

or stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites, prodrugs or salts thereof, wherein each R¹, R², R³, R⁴, R⁵, R⁶, X, Y and Z is as defined herein. [021] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H, D or F; each X and Y is independently C₆-ioaryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S or N, wherein the said C₆-ioaryl and 5-10 membered heteroaryl are each optionally substituted with 1 , 2, 3 or 4 substituents independently selected from D, F, CI, Br, I, -CN, -N0₂, N₃, -OR^a, -SR^a, -NR^aR^b, -C(=0)NR^aR^b, Ci_₆alkyl, Ci_₆haloalkyl, C₂_₆ alkenyl, C₂_₆alkynyl, -Ci_₄alkylene-CN, -Ci_₄alkylene-OR^a, -Ci_₄alkylene-NR^aR^b, C₆-i₀aryl or 5-10 membered heteroaryl;

Z is C₅_i₂spirobicyclyl or -(Ci_₄alkylene)-(C₅_i₂spirobicyclyl), provided that, when Z is C_5-12 spirobicyclyl, the cyclic structure directly attached to Y is a C₃_₆heterocyclic ring, wherein the C_5-12 spirobicyclyl and -(Ci_₄alkylene)-(C₅_i₂spirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, -OR^a, -NR^aR^b, -C(=0)NR^aR^b, - OC(=0)NR^aR^b, Ci_₆alkyl, Ci_₆haloalkyl, -(Ci_₄alkylene)-CN, -(Ci_₄alkylene)-OR^a or -(Ci_₄alkylene)- NR^aR^b; and each R^a and R^b is independently H, C ^aliphatic, C₃_₆cycloalkyl, -(Ci_₄alkylene)-(C₃_₆cycloalkyl), C₃_₆heterocyclyl, -(Ci_₄alkylene)-(C₃_₆heterocyclyl), C₆-ioaryl, -(Ci_₄alkylene)-(C₆_ioaryl), 5-10 membered heteroaryl or -(Ci_₄alkylene)-(5-10 membered heteroaryl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-8 membered heterocyclyl, wherein C ^aliphatic, C₃_₆cycloalkyl, -(Ci_₄alkylene)- (C₃_₆cycloalkyl), C₂_₆heterocyclyl, -(Ci_₄alkylene)-(C₂_₆heterocyclyl), C₆-ioaryl, -(Ci_₄alkylene)-(C₆_ _loaryl), 5-10 membered heteroaryl, -(Ci_₄alkylene)-(5-10 membered heteroaryl) and 3-8 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, -CN, N₃, -OH, -NH₂, Ci_₄alkoxy or Ci_₄alkylamino.

[022] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H or D.

[023] In another embodiment, X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, Br, Ci_₃alkyl or Ci_₃haloalkyl.

[024] In another embodiment, Y is phenyl or 5-6 membered heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from O, S or N, wherein the phenyl and the said 5-6 membered heteroaryl are each optionally substituted with 1 , 2, 3 or 4 substituents independently selected from D, F or CI. [025] In another embodiment, Z is Cs-iospirobicyclyl or -(Ci_₃alkylene)-(C₅-iospirobicyclyl), provided that, when Z is C₅_i₂Spirobicyclyl, the cyclic structure directly attached to Y is a C₃_₅ heterocyclic ring, wherein the C₅_iospirobicyclyl and -(Ci_₃alkylene)-(C₅_ioSpirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a, - NR^aR^b, Ci_₃alkyl, Ci_₃haloalkyl, -(Ci_₃alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

[026] In another embodiment, each R^a and R^b is independently H, Ci_₃alkyl, C₃_₆cycloalkyl or - (Ci_₃alkylene)-(C₃_₆cycloalkyl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-6 membered

heterocyclyl, wherein Ci_₃alkyl, C₃_₆cycloalkyl, -(Ci_₃alkylene)-(C₃-₆cycloalkyl) and 3-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

[027] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is H.

[028] In another embodiment, X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI or -CF₃.

[029] In another embodiment, Y is 5-6 membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O or N, wherein the said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from D or F.

[030] In another embodiment, Z is selected from the following substructures:

or a stereoisomer thereof, wherein each W and W is independently O, NH or N(Ci-C₃alkyl); Z is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a, -NR^aR^b, Ci_₃alkyl, Ci_₃haloalkyl, -(C_1-3 alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

[031] In another embodiment, each R^a and R^b is independently H or Ci_₂alkyl, or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 5-6 membered heterocyclyl, wherein the Ci_₂alkyl and 5-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

[032] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite,

pharmaceutically acceptable salt or prodrug thereof, and an optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. In certain embodiments, the compound is an inhibitor of protein tyrosine kinase. In other embodiments, the compound is an inhibitor of ALK receptor signaling and HGF receptor signaling.

[033] In some embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent. In other embodiments, the therapeutic agent is a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosisor acombination thereof.

[034] In certain embodiments, the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof.

[035] In another aspect, provided herein are methods for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient infected with the proliferative disorder, which comprises administrating a pharmaceutically effective amount of a compound disclosed herein, or the pharmaceutical composition disclosed herein to the patient.

[036] In another aspect, provided herein is use of the compound disclosed herein, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.

[037] In some embodiments, the proliferative disorder is metastatic cancer. In other embodiments, the proliferative disorder is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma or a myeloproliferative disorder. In further embodiments, the proliferative disorder is atherosclerosis or lung fibrosis.

[038] In another aspect, provided herein is a method of inhibiting or modulating the activity of protein kinase in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.

[039] In some embodiments, the protein kinases are receptor tyrosine kinases. In other

embodiments, the receptor tyrosine kinases are ALK and/or c-Met.

[040] In another aspect, provided herein is a method of inhibiting protein tyrosine kinase, the method comprises contacting the kinase with the compound disclosed herein, or with the

composition disclosed herein. In other embodiments, provided herein is a method of inhibiting ALK receptor signaling and/or HGF receptor signaling, the method comprises contacting the receptor with the compound disclosed herein, or with the pharmaceutical composition disclosed herein. [041] In some embodiments, inhibition of receptor protein kinase activity, such as ALK and/or HGF receptor signaling, can be in a cell or a multicellular organism. If in a multicellular organism, the method disclosed herein may comprise administering to the organism the compound disclosed herein, or the pharmaceutical composition disclosed herein. In some embodiments, the organism is a mammal; in other embodiments, the organism is a human. In still other embodiments, the method further comprises contacting the kinase with an additional therapeutic agent.

[042] In another aspect, provided herein is a method of inhibiting proliferative activity of a cell, wherein the method comprises contacting the cell with an effective proliferative inhibiting amount of the compound disclosed herein or the pharmaceutical composition disclosed herein. In some embodiments, the method further comprises contacting the cell with an additional therapeutic agent.

[043] In another aspect, provided herein is a method of treating a cell proliferative disease in a patient, wherein the method comprises administering to the patient in need of such treatment an effective therapeutic amount of the compound disclosed herein or the pharmaceutical composition disclose herein. In other embodiments, the method further comprises administering an additional therapeutic agent.

[044] In another aspect, provided herein is a method of inhibiting tumor growth in a patient, the method comprises administering to the patient in need thereof an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering an additional therapeutic agent.

[045] In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).

[046] The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS AND GENERAL TERMINOLOGY

[047] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

[048] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75^th Ed. 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are hereby incorporated by reference.

[049] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term

"substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Examples of substituent include, but are not limited to, D, F, CI, Br, I, -CN, -N0₂, N₃, alkyl, haloalkyl, alkenyl, alkynyl, -OH, -NH₂.

[050] The term "aliphatic" or "aliphatic group" as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. In some embodiments, aliphatic groups contain 1-10 carbon atoms. In other embodiments, aliphatic groups contain 1-8 carbon atoms. In still other embodiments, aliphatic groups contain 1-6 carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. For example, C ^aliphatic groups include unbranched or branched, unsubstituted or suitably substituted Ci_₆alkyl, C₂-6alkenyl, or C₂_ ₆alkynyl groups.

[051] The term "alkyl" or "alkyl group" as used herein refers to a saturated linear or branched- chain monovalent hydrocarbon radical of one to twenty carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, alkyl groups contain 1-10 carbon atoms. In other embodiments, alkyl groups contain 1-6 carbon atoms. In still other embodiments, alkyl groups contain 1-3 carbon atoms, and in yet other embodiments, alkyl groups contain 1-2 carbon atoms.

[052] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ), ethyl (Et, - CH₂CH₃), 1 -propyl («-Pr, n-propyl, -CH₂CH₂CH₃), 2-propyl (/-Pr, /-propyl, -CH(CH₃)₂), 1 -butyl (n- Bu, «-butyl, -CH₂CH₂CH₂CH₃), 2-methyl-l-propyl (/-Bu, /-butyl, -CH₂CH(CH₃)₂), 2-butyl (s-Bu, s- butyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (/-Bu, /-butyl, -C(CH₃)₃), 1-pentyl (n-pentyl, - CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)₂), 2-methyl-2- butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 3-methyl-l-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-l-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (- CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (- CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (- C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (- C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

[053] The terms "alkyl" and the prefix "alk-" as used herein, are inclusive of both straight chain and branched saturated carbon chain.

[054] The term "alkylene", as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene (-CH₂-), ethylene (-CH₂CH₂-), isopropylene (- CH(CH₃)CH₂-), and the like.

[055] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (- CH=CH₂), allyl (-CH₂CH=CH₂), and the like.

[056] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms or 2 to 8 carbons or 2 to 6 carbons or 2 to 4 carbons with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CH₂C≡CH), -C≡C-CH₃, and the like.

[057] The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" refers to alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.

[058] The term "carbocycle", "carbocyclyl", "carbocyclic ring" or "cycloaliphatic" refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic ring system. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like. The term "cycloalkyf'refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic ring system.

[059] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used interchangeably herein refers to a monocyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. One or more ring atoms are optionally substituted independently with one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl" or

"heterocyclic" group is a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0₂, PO or P0₂ or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0₂, PO or P0₂. [060] The heterocyclyl may be a carbon radical or heteroatom radical. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydro-furanyl,

tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,

morpholino, thiomorpholino, thioxanyl, piperazinyl, homo-piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,

imidazolidinyl, 1,2,3,4-tetrahydroiso-quinolinyl. Examples of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (=0) moieties are pyrimidindionyl and 1, 1-dioxo- thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein.

[061] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quatemized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N- substituted pyrrolidinyl).

[062] The term "halogen" means F, CI, Br or I.

[063] The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.

[064] The term "D" denotes a single deuterium atom. One of this radical may be attached, for example, to a methyl group to form a mono-deuterated methyl group (-CDH₂), two of deuterium atoms may attached to a methyl group to form a di-deuterated methyl (-CD₂H), and three of deuterium atoms may attached to a methyl group to form a tri-deuterated methyl group (-CD₃).

[065] The term "N3" denotes an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, MeN₃); or attached to a phenyl group to form phenyl azide (PhN₃).

[066] The term "aryl" used alone or as part of a larger moiety as in "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aryl ring." Examples of aryl rings would include phenyl, naphthyl, and anthracene.

[067] The term "heteroaryl" used alone or as part of a larger moiety as in "heteroaralkyl" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

[068] Further examples of heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5- tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2- thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5- triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=0)-.

[069] The term "alkoxy" as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") atom.

[070] The term "alkylamino" embraces "N-alkylamino" and "N, N-dialkylamino" where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.

[071] The term "arylamino" denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical. [072] The term "aminoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

[073] The term "unsaturated" as used herein, means that a moiety has one or more units of unsaturation.

[074] The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.

[075] The terms "spirocyclyl", "spirocyclic", "spiro bicyclyl" or "spiro bicyclic" refer to a ring originating from a particular annular carbon of another ring. For example, as depicted in Structure a, b, c, d whereas ring A and ring B share an atom between the two saturated ring system, which terms as a "spirocyclyl" or "spiro bicyclyl". Each cyclic ring in a spirocyclyl can be either a carbocyclic ring or a heterocyclic ring. Some non-limiting examples of spiro bicyclyl include 4- oxaspiro[2.4]heptane-6-yl, 4-azaspiro[2.4]heptane-6-yl, 7-azaspiro[4.5]decane-8-yl, 1- azaspiro[4.4]nonane-3-yl, 5-oxaspiro[3.5]nonane-7-yl, 2,7-dioxaspiro[4.5]decane-10-yl and the like.

Structure a Structure b Structure c Structure d

[076] As described herein, a bond drawn from a substituent to the center of one ring within a ring system (as shown below) represents substitution of the substituent at any substitutable position on the rings to which it is attached. For example, Structure e represents possible substitution in any of the positions on the B ring shown in Structure f.

Structure e Structure f

[077] Unless otherwise stated, structures depicted herein are also meant to include all isomeric

(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[078] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto- enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[079] Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[080] The term "prodrug" as used herein, represents a compound that is transformed in vivo into a compound of Formula (I). Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.

Prodrugs of the compounds of the invention may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic Ci_₂₄esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the invention that contains an OH group may be acylated at this position in its prodrug form. Other prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound. 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, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical

Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51 , 2328-2345, each of which is incorporated herein by reference.

[081] A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[082] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane -polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these

stereoisomers are identical except that they are mirror images of one another. A specific

stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[083] A "pharmaceutically acceptable salt" as used herein, refers to organic or inorganic salts of a compound of the invention. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977, which is incorporated herein by reference. Examples of pharmaceutically acceptable, nontoxic salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate,

benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate,/?-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci_₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, Ci_₈ sulfonate and aryl sulfonate.

[084] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

[085] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9- fluorenylmethylenoxy-carbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH₂CH₂S0₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxy-methy-1, 2-(p- toluenesulfonyl) ethyl, 2-(p-nitrophenylsulfenyl)-ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF COMPOUNDS OF THE INVENTION

[086] The present invention provides pyridine compounds, salts, and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions and disorders modulated by receptor tyrosine kinases, especially ALK and c-Met receptor. More specifically, the present invention provides compounds of Formula (I):

or stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites, prodrugs or salts thereof, wherein each R¹, R², R³, R⁴, R⁵, R⁶, X, Yand Z is as defined herein.

[087] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H, D or F; each X and Y is independently C₆-ioaryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S or N, wherein the said C₆-ioaryl and 5-10 membered heteroaryl are each optionally substituted with 1 , 2, 3 or 4 substituents independently selected from D, F, CI, Br, I, -CN, -N0₂, N₃, -OR^a, -SR^a, -NR^aR^b, -C(=0)NR^aR^b, Ci_₆alkyl, Ci_₆ haloalkyl, C₂_₆ alkenyl, C₂_₆alkynyl, -Ci_₄alkylene-CN, -Ci_₄alkylene-OR^a, -Ci_₄alkylene-NR^aR^b, C₆_io aryl or 5-10 membered heteroaryl;

Z is C₅_i₂spirobicyclyl or -(Ci_₄alkylene)-(C₅_i₂spirobicyclyl), provided that, when Z is C_5-12 spirobicyclyl, the cyclic structure directly attached to Y is a C₃_₆heterocyclic ring, wherein the C_5-12 spirobicyclyl and -(Ci_₄alkylene)-(C₅_i₂spirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, -OR^a, -NR^aR^b, -C(=0)NR^aR^b, - OC(=0)NR^aR^b, -Ci_₆alkyl, -Ci_₆haloalkyl, -(Ci_₄alkylene)-CN, -(Ci_₄alkylene)-OR^a or -(Ci_

4alkylene)-NR^aR^b; and each R^a and R^b is independently H, Ci_₆aliphatic, C₃_₆cycloalkyl, -(Ci_₄alkylene)-(C₃_₆cycloalkyl), C₃_6heterocyclyl, -(Ci_₄alkylene)-(C3_6heterocyclyl), C₆-ioaryl, -(Ci_₄alkylene)-(C6-ioaryl), 5-10 membered heteroaryl or -(Ci_₄alkylene)-(5-10 membered heteroaryl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-8 membered heterocyclyl, wherein C ^aliphatic, C₃_₆cycloalkyl, -(Ci_₄alkylene)- (C3_6cycloalkyl), C₂-6heterocyclyl, -(Ci_₄alkylene)-(C₂-6heterocyclyl), C₆-ioaryl, -(Ci_₄alkylene)-(C6_ _loaryl), 5-10 membered heteroaryl, -(Ci_₄alkylene)-(5-10 membered heteroaryl) and 3-8 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, -CN, N₃, -OH, -NH₂, Ci_₄alkoxy or Ci_₄alkylamino.

[088] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H or D.

[089] In another embodiment, X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, Br, Ci_₃alkyl or C^haloalkyl.

[090] In another embodiment, Y is phenyl or 5-6 membered heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from O, S or N, wherein the phenyl and the said 5-6 membered heteroaryl are each optionally substituted with 1 , 2, 3 or 4 substituents independently selected from D, F or CI.

[091] In another embodiment, Z is C₅_iospirobicyclyl or -(Ci_₃alkylene)-(C₅_ioSpirobicyclyl), provided that, when Z is Cs-^spirobicyclyl, the cyclic structure directly attached to Y is a C3-5 heterocyclic ring, wherein the Cs-iospirobicyclyl and -(Ci_3alkylene)-(C₅_iospirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a, - NR^aR^b, Ci_₃alkyl, Ci_₃haloalkyl, -(Ci_₃alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

[092] In another embodiment, each R^a and R^b is independently H, Ci_₃alkyl, C₃_₆cycloalkyl or - (Ci_₃alkylene)-(C₃_₆cycloalkyl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-6 membered

heterocyclyl, wherein Ci_₃alkyl, C₃_₆cycloalkyl, -(Ci_₃alkylene)-(C₃_₆cycloalkyl) and 3-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

[093] In certain embodiments, each R¹, R², R³, R⁴, R⁵ and R⁶ is H. [094] In another embodiment, X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI or -CF₃.

[095] In another embodiment, Y is 5-6 membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O or N, wherein the said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from D or F.

[096] In another embodiment, Z is selected from the following substructures:

or a stereoisomer thereof, wherein each W and W is independently O, NH or N(Ci-C₃alkyl); Z is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a, -NR^aR^b, Ci_3alkyl, Ci_3haloalkyl, -(C_1-3 alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

[097] In another embodiment, each R^a and R^b is independently H or Ci_₃alkyl, or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 5-6 membered heterocyclyl, wherein the Ci_₃alkyl and 5-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F. [098] In some embodiments, non-limiting examples of compounds disclosed herein, and their pharmaceutically acceptable salts and solvates thereof, are shown in the following:

Table 1

[099] The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of a hyperproliferative disease state and/or an angiogenesis mediated disease state, including those described previously. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of protein kinases.

[0100] The present invention comprises a pharmaceutical composition comprising a

therapeutically effective amount of a compound of Formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

[0101] The present invention also comprises a method of treating hyperproliferating and angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula

(I)-

[0102] Unless otherwise stated, all stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

[0103] In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase

"pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

[0104] The compounds of the invention also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I).

[0105] The desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p- toluenesulfonic acid or ethanesulfonic acid, or the like.

COMPOSITION, FORMULATIONS AND ADMINSTRATION OF COMPOUNDS OF THE INVENTION

[0106] According to one aspect, the invention features pharmaceutical compositions that include a compound of Formula (I), a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is such that is effective to detectably inhibit a protein kinase in a biological sample or in a patient.

[0107] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0108] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988- 1999, Marcel Dekker, New York, the contents of each of which is incorporated by reference herein, are disclosed various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. [0109] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;

buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyro gen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0110] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally,

intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. 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-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0111] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0112] The pharmaceutically acceptable compositions of this invention may be orally

administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0113] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0114] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0115] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0116] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[0117] Liquid dosage forms for oral administration include, but are not limited to,

pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0118] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0119] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be

accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, dissolving or suspending the compound in an oil vehicle accomplishes delayed absorption of a parenterally administered compound form.

[0120] Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and

poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0121] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0122] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0123] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polythylene glycols and the like.

[0124] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain pacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0125] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0126] The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0127] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 - 200 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

[0128] Compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents where the combination causes no unacceptable adverse effects. This may be of particular relevance for the treatment of hyper-pro liferative diseases such as cancer. In this instance, the compound of this invention can be combined with known cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents, as well as with admixtures and combinations thereof. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated". As used herein, "additional therapeutic agents" is meant to include chemotherapeutic agents and other antiproliferative agents.

[0129] For example, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative disease or cancer. Examples of chemotherapeutic agents or other antiproliferative agents include HDAC inhibitors including, but are not limited to, SAHA, MS-275, MGO 103, and those described in WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agents including, but not limited to, 5-aza-dC, Vidaza and Decitabine and those described in US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US

6,020,318, US 6,066,625, US 6,506,735, US 6,221,849, US 6,953,783, US 11/393,380.

[0130] In another embodiment of the present invention, for example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, for example, other therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention and include surgery, radiotherapy (in but a few examples, gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, taxanes (taxol, taxotere etc), platinum derivatives (cisplatin, carboplatin), biologic response modifiers (interferons, interleukins), tumor necrosis factor (TNF, TRAIL receptor targeting agents, to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate, pemetrexed etc), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabile, gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone), antiangio genie agents (avastin and others), monoclonal antibodies (Belimumab (Bnlysta^®), brentuximab (Adcetris^®), cetuximab (Erbitux^®), gemtuzumab (Mylotarg^®), ipilimumab (Yervoy^®), ofatumumab (Arzerra^®), panitumumab (Vectibix^®), ranibizumab (Lucertis^®), rituximab (Rituxan^®), tositumomab (Bexxar^®), trastuzumab (Herceptin^®)), kinase inhibitors (imatinib (Gleevec^®), sunitinib (Sutent^®), sorafenib (Nexavar^®), erlotinib

(Tarceva^®), gefitinib (Iressa^®), dasatinib (Sprycel^®), nilotinib (Tasigna^®), lapatinib (Tykerb^®), crizotinib (Xalkori^®), ruxolitinib (Jakafi^®), vemurafenib (Zelboraf^®), vandetanib (Caprelsa^®), pazopanib (Votrient^®), and others), and agents inhibiting or activating cancer pathways such as the mTOR, HIF (hypoxia induced factor) pathways (such as everolimus and temsirolimus) and others. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglist-rame.htm, and The Merck Manual, Eighteenth Ed. 2006, the entire contents of which are hereby incorporated by reference.

[0131] In another embodiment, the compounds of the present invention can be combined, with cytotoxic anti-cancer agents. Examples of such agents can be found in the 13th Edition of the Merck Index (2001). These agents include, by no way of limitation, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine.

[0132] Other cytotoxic drugs suitable for use with the compounds of the invention include, but are not limited to, those compounds acknowledged to be used in the treatment of neoplastic diseases, such as those for example in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include, by no way of limitation,

aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan,

diethylstilbestrol, 2¹, 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon,

medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N- phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine and vinorelbine.

[0133] Other cytotoxic anti-cancer agents suitable for use in combination with the compounds of the invention also include newly discovered cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology 2003, 21(4), 646-651), tositumomab (Bexxar), trabedectin (Vidal et al, Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3181), and the inhibitors of the kinesin spindle protein Eg5 (Wood; et al. Curr. Opin. Pharmacol. 2001, 1, 370-377).

[0134] In another embodiment, the compounds of the present invention can be combined with other signal transduction inhibitors. Examples of such agents include, by no way of limitation, antibody therapies such as trastuzumab (Herceptin^®), cetuximab (Erbitux^®), ipilimumab (Yervoy^®) and pertuzumab. Examples of such therapies also include, by no way of limitation, small-molecule kinase inhibitors such as imatinib (Gleevec^®), sunitinib (Sutent^®), sorafenib (Nexavar^®), erlotinib (Tarceva^®), gefitinib (Iressa^®), dasatinib (Sprycel^®), nilotinib (Tasigna^®), lapatinib (Tykerb^®), crizotinib (Xalkori^®), ruxolitinib (Jakafi^®), vemurafenib (Zelboraf^®), vandetanib (Caprelsa^®), pazopanib (Votrient^®), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607,

JNJ38877605,TKI258, GDC-0941 (Folkes, et alJ. Med. Chem. 2008, 51 : 5522), BZE235, and others.

[0135] In another embodiment, the compounds of the present invention can be combined with inhibitors of histone deacetylase. Examples of such agents include, by no way of limitation, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck et al, Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryan et al, Proceedings of the American Association of Cancer Research 2004, 45, abstract 2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3028) and MGCDOl 03 (US 6,897,220).

[0136] In another embodiment, the compounds of the present invention can be combined with other anti-cancer agents such as proteasome inhibitors, and m-TOR inhibitors. These include, by no way of limitation, bortezomib, and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3849). The compounds of the present invention can be combined with other anti-cancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.

[0137] Those additional agents may be administered separately from the compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another which would result in the desired activity of the agents.

[0138] The amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Normally, the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically.

USES OF THE COMPOUNDS AND COMPOSITION OF THE INVENTION

[0139] The invention features pharmaceutical compositions that include a compound of Formula (I), or a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions of the invention is such that is effective to detectably inhibit a protein kinase, such as ALK and c-Met inhibitory activity. The compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious effects of ALK and c-Met signaling.

[0140] Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of proliferative diseases, condition, or disorder in a patient by administering to the patient a compound or a composition of the invention in an effective amount. Such diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis and lung fibrosis.

[0141] Compounds of the invention would be useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer 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);

hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplasia syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and

rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).

[0142] The compounds also would be useful for treatment of ophthalmo logical conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including

neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability. [0143] The compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy. The compounds of the present invention are also useful in the reduction of blood flow in a tumor in a subject. The compounds of the present invention are also useful in the reduction of metastasis of a tumor in a subject.

[0144] Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. As used herein, the compounds of the present invention include the pharmaceutically acceptable derivatives thereof.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.

[0145] The treatment method that includes administering a compound or composition of the invention can further include administering to the patient an additional therapeutic agent

(combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an antiinflammatory agent, wherein the additional therapeutic agent is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or

composition of the invention as a single dosage form or separately from the compound or composition as part of a multiple dosage form. The additional therapeutic agent may be

administered at the same time as a compound of the invention or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

[0146] The invention also features a method of inhibiting the growth of a cell that expresses ALK or c-Met, that includes contacting the cell with a compound or composition of the invention, thereby causing inhibition of growth of the cell. Examples of a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell, or a leukemia cell.

[0147] The invention provides a method of inhibiting ALK or c-Met kinase activity in a biological sample that includes contacting the biological sample with a compound or composition of the invention. The term "biological sample" as used herein, means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibition of kinase activity, particularly ALK or c-Met kinase activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0148] In certain embodiments of the present invention an "effective amount" or "effective dose" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above.

[0149] The compounds of this invention or pharmaceutical compositions thereof may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re- narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of this invention.

[0150] Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121, the contents of each of which are incorporated by reference herein. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics into the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co- formulated with a polymer or other molecule, to provide a "drug depot" thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.

GENERAL SYNTHETIC PROCEDURES

[0151] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention.

[0152] Generally, the compounds in this invention may be prepared by methods described herein, wherein the substituents are as defined for formula(I), above, except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention. Persons skilled in the art will recognize that the chemical reactions described herein may be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

[0153] In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, Shanghai Medpep.Co Ltd, Aladdin-Shanghai Jinchun Reagents, Ltd, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent

Chemical Ltd., and Qingdao Ocean Chemical Factory.

[0154] Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH₂CI₂ and CHCI₃ were obtained by refluxing the solvent with CaH₂. EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous Na₂S0₄ prior use. [0155] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

[0156] Column chromatography was conducted using a silica gel column. Silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory. ^lH NMR spectra were recorded with a Bruker 400 MHz spectrometer at ambient temperature. ^lH NMR spectra were obtained as CDCI₃, d8-DMSO, CD₃OD or d₆-acetone solutions (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0157] Low-resolution mass spectral (MS) data were generally determined on an Agilent 1200 or Agilent 6120 Series LCMS [Column: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micorn, 6 minutes run, 0.6 mL/min flow rate. Mobile phase: 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid in H₂0)] with UV detection at 210/254 nm and a low resonance electrospray mode (ESI).

[0158] Purities of compounds were assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm. Column was normally operated at 40 °C.

[0159] The following abbreviations are used throughout the specification:

BBr₃ boron tribromide

BOC, Boc butyloxycarbonyl

BSA bovine serum albumin

CDCI₃ chloroform deuterated

CHCI₃ chloroform

CH₂C1₂, DCM methylene chloride

CH₃S0₂C1, MsCl methanesulfonyl chloride

Cs₂C0₃ cesium carbonate

Cu copper

Cul copper(I) iodide

DAST Diethylaminosulfur trifluoride DEAD dimethyl azodicarboxylate DIEA, DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

EtOAc, EA ethyl acetate

Et₂0 diethyl ether

Et₃N, TEA triethylamine

FBS fetal bovine serum

Fe iron

g gram

h hour

HBr hydrobromic acid

HC1 hydrochloric acid

H₂ hydrogen

H₂0 water

H₂0₂ hydrogen peroxide

HO Ac, AcOH acetic acid

K₂C0₃ potassium carbonate

KOH potassium hydroxide

LiHMDS lithium bis(trimethylsilyl)amide

LDA Lithium diisopropylamide

MCPBA m-CPBA weta-chloroperbenzoic

MeCN, CH₃CN acetonitrile

Mel methyl iodide

MeOH, CH₃OH methanol

2-MeTHF 2-methyl tetrahydrofuran

MgS0₄ magnesium sulfate

mL, ml milliliter

N₂ nitrogen

NaBH₄ sodium borohydride NaBH₃CN Sodium cyanoborohydride

NaCl sodium chloride

NaC10₂ sodium chlorite

NaH sodium hydride

NaHC0₃ sodium bicarbonate

NaH₂P0₄ sodium biphosphate

Nal sodium iodide

NaO(t-Bu) sodium tert-butoxide

NaOH sodium hydroxide

Na₂S0₄ sodium sulfate

NBS N-bromosuccinimide

NH₃ ammonia

NH₄C1 ammonium chloride

NMP N-methylpyrrolidinone

PBS phosphate buffered saline

P(t-Bu)₃ tri(tert-butyl)phosphine

Pd/C palladium on carbon

Pd₂(dba) bis(dibenzylideneacetone) palladium

Pd(dppf)Cl₂ l,l-bis(diphenylphosphino)ferrocene palladium chloride

Pd(OAc)₂ palladium acetate

Pd(OH)₂ palladium hydroxide

Pd(PPh )₄ palladium tetrakis triphenylphosphine

Pd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium(II) chloride

PE petroleum ether (60-90 °C)

POC l₃ phosphorous oxychloride

RT, rt, r.t. room temperature

Rt retention time

TFA trifluoro acetic acid

TEAC bis(tetra-ethylammonium)carbonate

THF tetrahydrofuran

MeTi(z-PrO)₃ Methyl titanium triisopropoxide

CyMgCl Cyclohexylmagnesium chloride DHP 3,4-dihydrogen-2H-pyrane

PPTS Pyridinium toluene-4-sulphonate

Ti(PrO)₄ Titanium tetraisopropanolate

EtMgBr ethyl magnesium bromide

t-BuCHO Trimethylacetaldehyde

EDCI 1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride

HOBt 1-Hydroxybenzotriazole

Os0₄ Osmium tetraoxide

BH₃.THF Borane-tetrahydrofuran complex

PPh₃ Triphenylphosphine

Ra(Ni) Nickel

(z^'-PrO)₃TiCl Chlorotitanium triisopropoxide

[0160] Representative synthetic procedures for the preparation of compounds of the disclosure are outlined below in following schemes. Unless othewise indicated, R¹, R², R\ R⁴, R⁵, R⁶ and Z carry the definitions set forth above in connection with Formula (I).

Scheme 1

[0161] The desired kinase inhibitor (7) desclosed hererin can be prepared in a method illustrated in Scheme 1. (7?)-aryl alcohol (T) and substituted fluoropyridine (2) is treated with a base such as NaH in aprotic solvent such as THF to give the coupled compound (3). The nitro group in (3) is then reduced to an amine (4) under acidic conditions using a reducing agent such as Fe powder. Subsequent regio-selective bromination of the pyridine ring can be accomplished with the aid of N- bromo-succinimide to furnish compound (5). Final coupling of (5) with compound (6) in the presence of a suitable Pd catalyst affords the desired kinase inhibitor (7).

Scheme 2

[0162] In another aspect, kinase inhibtor (7) in this invention may be synthesized through the procedure depicted in Scheme 2. The intermediate (5) and (Boc)₂0 is treated with a base such as Na₂C0₃, NaHC0₃ or Et₃N to give N-protected compound (8). Compound (8) is then coupled with bis(pinacolato)diboronwith the aid of an appropriate Pd catalyst such as Pd(dppf)Cl₂-CH₂Cl₂ or Pd(PPh₃)₂Cl₂ in an aprotic solvent (for example, DMSO, DMF or dioxane) to afford a boronic acid derivative (9). The subsquent Suzuki reaction of compound (9) and cyclic compound (10) in the presence of a base and a catalyst such as Pd(dppf)Cl₂-CH₂Cl₂ to furnish compound (11). The preferred bases for the coupling reaction include NaHC0₃, KHC0₃, Na₂C0₃, K₂C0₃, Cs₂C0₃, and others. The reaction is preferably performed in a mixed solvent such as DME/H₂0, dioxane/H₂0, at a temperature ranging from 70 °C to 100 °C. Finally, the Boc- group and other PG groupare all removed under acidic conditions, for example, trifluoroacetic acid (TFA) in DCM, or HC1 in ethyl acetate or ethyl ether to afford the desired kinase inhibitor (7).

EXAMPLES

Example 1 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(((S)-4-methyl-4- azaspiro[2.4]heptan-5-yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine

Step 1) (i?)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine

[0163] To a solution of (i?)-l-(2,6-dichloro-3-fluorophenyl)ethanol (10 g, 47.84 mmol) in THF (150 mL) was added NaH (2.3 g, 57.41 mmol, 60% dispersion in mineral oil) in portions at 0°C in 30 min. The mixture was stirred at rt for 2 h, followed by the dropwise addition of a solution of 3- fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in THF (80 mL) at 0°C over 20 min. The reaction was stirredat rtfor 3 h, then quenched with iced water (10 mL) and concentrated in vacuo. The residue was diluted with EtOAc (150 mL) and H₂0 (150 mL), and the seperated aqueous phase was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with saturated aqueous NaHC0₃ (400 mL) followed by brine (400 mL), dried over anhydrous Na₂S0₄ and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (13.4 g, 84.6%).

LC-MS (ESI, pos. ion) m/z: 331 [M + H]⁺.

Step 2) (R)-3-(l -(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

[0164] To a solution of (i?)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (13.4 g, 40.47 mmol) in EtOH (250 mL) was added iron powder (11 g, 197 mmol). The mixture was heated at90°C for 20 min, followed by the addition of HC1 (1 M, 8 mL) in two portions in 15 min. The reaction was continued to stir at 90°C for 2 h, then cooled down to rt, and filtered through a pad of Celite, which was washed with EtOH (80 mL x 3). The combined filtrates were concentrated in vacuo to give the title compound as a pale brown solid (12 g, 98.5%).

LC-MS (ESI, pos. ion) m/z: 301 [M + H]⁺;

1H NMR (400 MHz, DMSO- ₆) δ (ppm): 1.75 (d, J= 6.6 Hz, 3H), 5.67 (brs, 2H), 5.97-5.92 (q, J = 6.6 Hz, 1H), 6.38-6.35 (dd, J= 5.0 Hz, 7.7 Hz, 1H), 6.61 (d, J= 7.1 Hz, 1H), 7.47-7.42 (m, 2H), 7.56-7.52 (dd, J= 5.0 Hz, 7.7 Hz, 1H).

Step 3) (i?)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

[0165] To a solution of (i?)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (12 g, 39.8 mmol) in MeCN (250 mL) was added NBS (9.2 g, 51.7 mmol) in portions at 0°C in 20 min. The reaction was stirred at 0°C for 1 h, then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a pale brown solid (10 g, 66%).

LC-MS (ESI, pos. ion) m/z: 379 [M + H]⁺;

1H NMR (400 MHz, DMSO-d₆) δ (ppm): 1.82 (d, J= 6.6 Hz, 3H), 4.82 (brs, 2H), 6.01-5.96 (q, J = 6.6 Hz, 1H), 6.83 (d, J= 1.8 Hz, 1H), 7.10-7.06 (t, J= 8.0 Hz, 1H), 7.33-7.30 (dd, J= 4.8 Hz, 8.9 Hz, 2H), 7.66(d, J= 5.0 Hz, 1.8 Hz, 1H).

Step 4) (i?)-5-bromo-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy) pyridin-2-amine

[0166] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (4.5 g, 11.8 mmol), DMAP (1.46 g, 11.8 mmol) and (Boc)₂0 (7.33 g, 35.4 mmol) in THF (100 mL) was added Et₃N (3.65 g, 36 mmol). The reaction was stirred at 70 °C overnight, then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as vicious liquid (6 g, 87.28%).

Step 5) (i? -N.N-bis(tert-butoxycarbonvn-3-(l-(2.6-dichloro-3-fluorophenvnethoxy -5-(4.4.5.5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-amine

[0167] To a suspension of (i?)-5-bromo-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl) ethoxy)pyridin-2-amine (6 g, 11.8 mmol), bis(pinacolato)diboron (3.6 g, 14.6 mmol) and CH₃COOK (3.54 g, 35.4 mmol) in DMSO(150 mL) was added Pd(dppf)Cl₂-CH₂Cl₂ (0.48 g, 0.59 mmol) in a nitrogen atmosphere. The reaction was stirred at 80 °C for 5 h, then cooled to rt, diluted with H₂0 (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na₂S0₄, and concentrated in vacuo. The resulted residue was purified by a silica column chromatography (PE/EtOAc (v/v) = 6/1) to afford the title compound as colorless oil (5.8 g, 89.25%).

LC-MS (ESI, pos. ion) m/z: 627 [M + H]⁺;

1H NMR (400 MHz, CDC1₃) 5(ppm): 8.37 (s, 1H), 7.52 (s, 1H), 7.06-7.02 (m, 1H), 6.13-6.08 (q,lH, J= 6.64 Hz), 1.80-1.78 (q,3H, J= 6.68 Hz), 1.34-1.32 (m, 18H), 1.26 (s, 12H).

Step6) (S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

[0168] To a mixture of (S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol, Aldrich) and DHP (1.46 g, 17.4 mmol, Alfa) in 20 mL of dichloromethane was added PPTS (0.437 g, 1.74 mmol, Aldrich) in portions. The reaction mixture was stirred at rt for 4 hrs, and was quenched with 20 mL of saturated NaHC0₃ aqueous solution. The resulted mixture was extracted with dichloromethane (25 mL><2). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound (as a diastereomer mixture) as colorless oil (0.9 g, 52 %).

MS (ESI, pos. ion) m/z: 199.9 (M+l);

1H NMR (400 MHz, CDC1₃) 5(ppm): 1.69 - 1.88 (m, 6H), 2.25 - 2.28 (m, 2H), 2.32 - 2.35 (m, 2H), 3.23 (m, 1H), 3.48 - 3.55 (m, 2H), 3.78 - 3.85 (m, 2H), 4.58 (m, 1H).

Step7) (S)- 1 -methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

[0169] To a mixture of NaH (0.48 g, 12 mmol, 60 % mineral oil, Aldrich) in 15 mL of DMF was added a solution of (S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl) pyrrolidin-2-one (2 g, 10 mmol) in 5 mL of DMF via a syringe at -40 °C. The reaction was stirred at -40 °C for 1 hr. CH₃I (0.9 mL, 12 mmol, Shanghai Jingchun Reagent Ltd.) was added dropwise via a syringe. The reaction was continued to stir at -40 °C for 4 hrs, and was quenched with 10 mL of saturated NaHS0₃ aqueous solution. The mixture was extracted with ethyl acetate (50 mL><3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired product as colorless oil (1.98 g, 92 %).

MS (ESI, pos. ion) m/z: 214.0 (M+l);

1H NMR (400 MHz, CDC1₃) 5(ppm): 1.69 - 1.88 (m, 6H), 1.93 - 2.17 (m, 2H), 2.33 - 2.47 (m, 2H),

2.90 (3H, s), 3.40 - 3.52 (m, 2H), 3.80 - 3.90 (m, 2H), 3.78 (m, 1H), 4.60 (m, 1H).

Step8) (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane

[0170] To a mixture of (S)-l-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-pyrrolidin-2-one

(0.6 g, 2.82 mmol) in 20 mL of THF was added Ti(z-PrO)₄ (2.56 mL, 8.45 mmol, d = 0.937 g/L,

Aldrich) via a syringe under nitrogen at rt. After stirring at rt for 30 min, EtMgBr (5.63 mL, 16.9 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 3 hrs. The reaction was continued to stir at rt overnight, and then quenched with a mixture of 20 mL of water and 30 mL of ethyl acetate. After stirring for 20 min, the mixture was filtered through a celite pad. The filtrate was extracted with ethyl acetate (30 mL><3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (50: l(v/v) CH₂C1₂ / CH₃OH) to give the desired product as pale yellow oil (64 mg, 10 %).

MS (ESI, pos. ion) m/z: 226.0 (M+l);

1H NMR (400 MHz, CDCI3) 5(ppm): 0.23 (m, 1H), 0.46 (m, 1H), 0.63 (m, 1H), 0.86 (m, 1H), 1.58 - 1.90 (m, 10H), 2.13 (s, 3H), 2.85 (m, 1H), 3.37 - 3.50 (m, 2H), 3.72 - 3.89 (m, 2H), 4.62 (m, 1H). Step9) (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.41heptane

[0171] To a mixture of (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4- azaspiro[2.4]heptane (64 mg, 0.284 mmol) in 10 mL of methanol was added 4-methyl- benzenesulfonic acid (97.8 mg, 0.568 mmol, Aldrich). The reaction mixture was stirred at 50 °C overnight, and then concentrated in vacuo. The residue was treated with 10 mL of saturated Na₂C0₃ aqueous solution, and extracted with dichloromethane (20 mL><3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo to give the desired product as yellow oil (32 mg, 80 %).

Step 10) ((5S)-4-methyl-4-azaspiro[2.41heptane-5-yl)methyl methanesulfonate

[0172] A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2 g, 1.42 mmol) and triethylamine (0.287g, 2.84 mmol, Shantou Xilong chemical factory) in 5 mL of

dichloromethane was stirred at 0 °C for 30 min. To the mixture was added methanesulfonyl chloride

(0.325 g, 2.84 mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixture was stirred at 0 °C for 4 hrs and quenched with a mixture of 5 mL of saturated Na₂C0₃ aqueous solution and 5 mL of water. The resulted mixture was extracted with dichloromethane (20 mL><3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo to give ((5S)-4-methyl-4- azaspiro[2.4]heptane-5-yl)methyl methanesulfonate as yellow oil (150 mg, 48 %).

Step 11) (S)-5-((4-iodo-lH-pyrazol-l-yl)methyl)-4-methyl-4-azaspiro[2.4]heptane

[0173] To the cooled solution of 4-Iodopyrazole (154 mg, 0.79 mmol) in dry DMF (5 mL) was added NaH (60% in mineral oil, 53 mg, 1.32 mmol) in one portion. The resulting mixture was stirred at 0 °C for lh. Then a solution of ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate (145 mg, 0.66 mmol) in DMF (3 mL) was added via a syringe. The resulting mixture was stirred at 100 °C for 16h, poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA (v/v) =1/1) to give the title compound as an light yellow oil (140 mg, 67%).

MS (ESI, pos. ion) m/z: 318 (M+l).

Step 12) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(((S)-4-methyl-4-azaspiro[2.41heptan- 5-yl)methyD- 1 H-pyrazol-4-yl)pyridin-2-amine

[0174] To the mixture of (S)-5-((4-iodo-lH-pyrazol-l-yl)methyl)-4-methyl-4-azaspiro[2.4]heptane (140 mg, 0.44 mmol) and (i?)-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-amine (332 mg,0.53 mmol) in DME (15 mL) was added a solution of Na₂C0₃ (148 mg, 1.4 mmol) in water (3 mL). The resulting mixture was degassed with nitrogen, then Pd(dppf)Cl₂-CH₂Ci₂ (35 mg, 0.05 mmol) was added and degassed again. The resulting mixture was stirred at 95 °C for 16 h, concentrated in vacuo, diluted with water (15 mL), and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA=1/1) to give a crude product which was redissolved in DCM (20 mL), and a soluton of HC1 in EA (4M, 2 mL) was added after cooling to 0 °C. The resulting mixture was stirred for 12h, concentrated in vacuo, redissolved in water, and adjusted to pH=10 with saturated aqueous Na₂C0₃ solution. The resulting basic aqueous mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were dried over Na₂S0₄, filtered, and concentrated in vacuo. The residue was reslurried with Et₂0 (5 mL) to give the title compound as yellow solid (110 mg, 51%).

MS (ESI, pos. ion) m/z: 490 (M+l).

Example 2 5-(l-(2-((R)-l,7-diazaspiro[4.4]nonan-7-yl)ethyl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6- dichloro- -fluoro henyl)ethoxy)pyridin-2-amine

Step 1) (3RJaS)-3-(tert-butyl)tetrahydro-lH,3H-pyrrolo[l,2-cloxazol-l-one

[0175] A suspension of L-proline (10.0 g, 86.8 mmol) and t-BuCHO (11.2 g, 130 mmol) in chloroform (250 mL) were stirred at 80 °C for overnight with a reverse Dean-Stark trap. The solution was washed with water (100 mL x 2) and the organic layer was dried over Na₂S0₄ and concentrated in vacuo to give the tittle compound as white solid (12.9 g, 81%). The crude product was used directly in the next step without further purification.

MS (ESI, pos. ion) m/z: 184 (M+l).

Step 2) (3R aR)-7a-allyl-3-(tert-butyl)tetrahydro-lH3H-pyrrolo[l,2-cloxazol-l-one

[0176] To the solution of (3R,7aS)-3-(tert-butyl)tetrahydro-lH,3H-pyrrolo[l,2-c]oxazol-l-one

(11.0 g, 60.0 mmol) in dry THF (300 mL) was added LDA (1.0 M in THF, 90 mL, 90.0 mL) at -78

°C over 20 min. The mixture was stirred for a further 30 min, then allyl bromide (15.6 mL, 180.0 mmol) was added drop wise over 30 min. The resulting solution was stirred for another 6h, quenched with water (15 mL) and concentrated in vacuo. The residue was partitioned between water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na₂S0₄, filtered and concentrated to in vacuo. The residue was purified by column chromatography (PE/EA

(v/v) = 6/1) afforded the tittle compound as as a light orange oil (7.5 g, 56%).

MS (ESI, pos. ion) m/z: 224 (M+l).

Step 3) (R)-2-allylpyrrolidine-2-carbo xylic acid

[0177] To the solution of (3R,7aR)-7a-allyl-3-(tert-butyl)tetrahydro-lH,3H-pyrrolo[l,2-c]oxazol- 1-one (6.7 g, 30 mmol) in MeOH/H₂0 (v/v, 2: 1, 60 mL) was added silica gel (1.0 g). The resulting suspension was stirred at rt for 24h. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was used directly in the next step without further purification.

MS (ESI, pos. ion) m/z: 156 (M+l).

Step 4) (R)-2-allyl-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0178] To the solution of (R)-2-allylpyrrolidine-2-carboxylic acid (4.7 g, 30 mmol) in water (60 mL) cooled to 0°C was added 10% NaOH (14.4 mL) followed by a solution of Boc₂0 (16.4 g, 75.0 mmol) in dioxane (60 mL). The reaction was allowed to warm to room temperature and stirred for overnight. The mixture was washed with Et₂0, and the aqueous layer was acidified with AcOH to pH 4. The mixture was then extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH (v/v) = 20/1) to give the tittle compound as white solid (5.2 g, 68%o for two steps). MS (ESI, neg. ion) m/z: 254 (M-l).

Step 5) tert-butyl (R)-2-allyl-2-((2-methoxy-2-oxoethyl)carbamoyl)pyrrolidine-l-carboxylate

[0179] The mixture of (R)-2-allyl-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.2 g, 20.4 mmol), Glycine methyl ester hydrochloride (2.6 g, 20.4 mmol), EDCI (3.9 g, 20.4 mmol), HOBt (2.8 g, 20.4 mmol), and TEA (2.7 mL, 20.4 mmol) in dry DCM (50 mL) was stirred at room temperature under N₂ for overnight. The mixture was partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated and washed with 1 M NaHC0₃, 10% citric acid, and brine. The organic layer was dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (PE/EA (v/v) = 3/1) to give the tittle compound as a colorless oil (6.1 g, 92%).

MS (ESI, pos. ion) m/z: 327 (M+l);

1H NMR (400 MHz, CDC1₃) 5(ppm): 1.33 and 1.36 (s, 9H), 1.54-1.81 (m, 3H), 2.00-2.15 and 2.41-

2.44 (m, 1H), 2.57-2.64 (m, 1H), 2.85-2.98 (m, 1H), 3.15-3.25 (m, 1H), 3.40-3.45 (m, 1H), 3.62 (s,

3H), 3.81-3.97 (m, 2H), 5.01-5.06 (m, 2H), 5.49-5.58 (m, 1H), 6.55 and 7.89 (br, 1H).

Step 6) tert-butyl (5R)-8-hydroxy-7-(2-methoxy-2-oxoethyl)-6-oxo-l,7-diazaspiro[4.41nonane-l- carboxylate

[0180] To a solution of tert-butyl (R)-2-allyl-2-((2-methoxy-2-oxoethyl)carbamoyl)pyrrolidine- 1 - carboxylate (6.1 g, 18.7 mmol) in THF/H₂0 (v/v = 2: 1, 45mL) was added Os0₄ (100 mg). The mixture was stirred at room temperature under N₂ for 10 min, and then finely powdered NaI0₄ (12.0 g, 56.1 mmol) was added. After 2 h, the light yellow mixture was poured into brine (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by chromatography (PE/EA (v/v) = 1/2) to give the tittle compound as white solid (2.3 g, 37%>).

Step 7) tert-butyl (R)-7-(2-hydroxyethyl)-l,7-diazaspiro[4.4]nonane-l -carboxylate

[0181] To the solution of tert-butyl (5R)-8-hydroxy-7-(2-methoxy-2-oxoethyl)-6-oxo- 1 ,7- diazaspiro[4.4]nonane-l -carboxylate (2.3 g, 7.0 mmol) in dry THF (50 mL) at 0 °C was added BH₃ ^»THF (1.0 M, 70 mL, 70.0 mmol) dropwise. The resulting mixture was stirred at 80 °C for overnight. The mixture was cooled to 0 °C and added MeOH (50 mL) dropwise, then heated to reflux for lh. Concentrated in vacuo, and the residue was partitioned between water (50 mL) and DCM (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic extracts were dried over Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH (v/v) = 10/1) to give a yellow oil (660 mg, 35%).

MS (ESI, pos. ion) m/z: 271 (M+l);

Step 8) tert-butyl (R)-7-(2-((methylsulfonyl)oxy)ethyl)-l,7-diazaspiro[4.41nonane-l-carboxylate

[0182] A mixture of tert-butyl (R)-7-(2-hydroxyethyl)-l,7-diazaspiro[4.4]nonane-l-carboxylate (660 mg, 2.4 mmol) and triethylamine (486 mg, 4.8 mmol) in 15 mL of dichloromethane was stirred at 0 °C for 30 min. To the mixture was added MsCl (550 mg, 4.8 mmol) via a syringe. The reaction mixture was stirred at 0 °C for 4 hrs and quenched with a mixture of 10 mL of saturated Na₂C03 aqueous solution and 10 mL of water. The resulted mixture was extracted with dichloromethane (50 mLx3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo to give the tittle compound as yellow oil (794 mg, 95 %).

Step 9) tert-butyl (R)-7-(2-(4-iodo- 1 H-pyrazol- 1 -yDethyl)- 1 ,7-diazaspiro [4.4]nonane- 1 -carboxylate

[0183] To the cooled solution of 4-Iodopyrazole (349 mg, 1.8 mmol) in dry DMF (10 mL) was added NaH (60% in mineral oil, 72 mg, 1.8 mmol) in one portion. The resulting mixture was stirred at 0 °C for lh. Then a solution of tert-butyl (R)-7-(2-((methylsulfonyl)oxy)ethyl)-l,7- diazaspiro[4.4]nonane-l -carboxylate (523 mg, 1.5 mmol) in DMF (5 mL) was added via a syringe. The resulting mixture was stirred at 100 °C for 16h, concentrated in vacuo and the residue was dissolved in water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the title compound as white solid (469 mg, 70%).

MS (ESI, pos. ion) m/z: 447 (M+l).

Stepl0 5-(l-(2-((R -lJ-diazaspiror4.41nonan-7-vnethvn-lH-pyrazol-4-vn-3-((R -l-(2.6-dichloro- 3-fluorophenyl)ethoxy)pyridin-2-amine

[0184] To the mixture of tert-butyl (R)-7-(2-(4-iodo- 1 H-pyrazol- 1 -yl)ethyl)- 1 ,7- diazaspiro[4.4]nonane-l -carboxylate (241 mg, 0.54 mmol) and (i?)-N,N-bis(tert-butoxycarbonyl)-3-

(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- amine (284 mg,0.45 mmol) in DME (15 mL) was added a solution of Na₂C03 (148 mg, 1.4 mmol) in water (3 mL). The resulting mixture was degassed with nitrogen, then Pd(dppf)Cl₂-CH₂Cl₂ (35 mg, 0.05 mmol) was added and degassed again. The resulting mixture was stirred at 95 °C for 16 h, concentrated in vacuo, extracted with DCM (50 mL x 3), and washed with brine (50 mL). The organic phase was dried over Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA (v/v) = 1/2) to give a crude product which was redissolved in DCM (30 mL), and a soluton of HC1 in EA (4M, 3 mL) was added after cooling to 0 °C. The resulting mixture was stirred for 12h, concentrated in vacuo, redissolved in water, adjusted to pH=10 with saturated aqueous Na₂C03 solution, and extracted with DCM/MeOH (v/v = 8/1, 50 mL x 4). The combined organic phases were dried over Na₂S0₄, filtered, and concentrated in vacuo The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) =7/1) to give the title compound as yellow solid (96 mg, 41%).

MS (ESI, pos. ion) m/z: 260 (M+2)/2.

Example 3 5-a-(4-oxaspiror2.41heptan-6-yl)-lH-pyrazol-4-yl)-3-qR)-l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

Step 1) 1 -(3 -hydroxy-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)cyclopropanol

[0185] To a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)dihydrofuran-2(3H)-one (10 g, 53.7 mmol) and Ti(0 -Pr)₄ (6.4 mL, 21.5mmol) in THF (179 mL) was added EtMgBr (46.6 mL) at 15°C over 4 h. The reaction was continued to stir at 15°C for aditional lh,then quenched with saturated NH₄C1 (60 mL).The mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100%) EtOAc) to give the title compound as yellow oil(9.18 g, 79%>).

MS (ESI, pos. ion) m/z 239 [M + Na]⁺.

Step 2) 6-((tetrahydro-2H-pyran-2-yl)oxy)-4-oxaspiro[2.4]heptane

[0186] To a solution of l-(3-hydroxy-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)cyclopropanol (5.4 g, 24.97 mmol) and PPh₃ (9.9 g, 37.5 mmol) in THF (125 mL) was added DEAD (5.9 mL, 37.5 mmol) dropwise at rt under N₂. The reaction was stirred at rt overnight, then quenched with H₂0 (70 mL). The mixture was extracted with EtOAc (250 mL). The organic phase was washed with water (300 mL), dried over Na₂S0₄ andconcentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 20: 1 to 10: 1) to give the title compound as yellow oil (8.3 g, 95%).

MS (ESI, pos. ion) m/z 221 [M+Na]⁺.

Step 3) 4-oxaspiro|^"2.4^"|heptan-6-ol

[0187] To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)-4-oxaspiro[2.4]heptane (1.5 g, 7.6 mmol) in MeOH (80 mL) was added PPTS (0.19 g, 0.8 mmol). The reaction was stirred at 40°C overnight, then concentrated in vacuo. The residue was purified by a silica gel column

chromatography (PE/EtOAc = 1 : 1) to give the title compound as colorless oil (0.8 g, 93%).

MS (ESI, pos. ion) m/z 115 [M + H]⁺.

Step 4) 4-oxaspiro[2.4]heptan-6-yl methanesulfonate

[0188] To a solution of 4-oxaspiro[2.4]heptan-6-ol (1 g, 8.8 mmol) and DMAP (10 mg, 0.09 mmol) in DCM (20 mL) was added Et₃N (1.9 mL, 13.1 mmol) at 0°C, followed by a solution of MsCl (0.8 mL, 10.5 mmol) in DCM (5 mL). The reaction was stirred at rt for 3.5 h, then quenched with water (8 mL). The mixture was extracted with DCM (20 mL x 3). The combined organic phases were washed with H₂0 (20 mL x 3), dried over anhydrous Na₂S0₄ and concentrated in vacuo to givethe title compoundas yellow oil (1.98 g, >100%>).

Step 5) 4-iodo-l-(4-oxaspiro[2.4]heptan-6-yl)-lH-pyrazole

[0189] To a solution of 4-iodo-lH-pyrazole (2 g, 10.5 mmol) in DMF (175 mL) was added NaH (394 mg, 13.1 mmol, 80% in mineral oil) in portions at 4°C. The reaction was stirred at 4°C for 1 h,followed by the additon of 4-oxaspiro[2.4]heptan-6-yl methanesulfonate (1.7 g, 8.8 mmol). The reaction was heated atl00°C overnight, then cooled to rt and quenched with H₂0 (30 mL). The resulted mixture was concentrated in vacuo, diluted with H₂0 (300 mL) and extracted with EtOAc (200 mL x 4). The combined organic phases were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 10: 1) to give the title compound as colorless oil (2.4 g, 96%).

MS (ESI, pos. ion) m/z 313 [M + Na]⁺;

1H NMR (400 MHz, CDC1₃) 5(ppm): 0.49-0.59 (m, 1H), 0.62-0.72 (m, 1H), 0.88-0.96 (m, 1H),

0.99-1.09 (m, 1H), 2.32 (dd, J=13.5, 3.7 Hz, 1H), 2.55 (dd, J=13.5, 8.4 Hz, 1H), 4.06 (dd, J=9.6, 3.3

Hz, 1H), 4.16 (dd, J=9.6, 3.5 Hz, 1H), 5.07-5.20 (m, 1H), 7.51 (s, 1H), 7.63 (s, 1H);

¹³C NMR (100 MHz, CDC1₃)5 10.6, 10.9, 39.2, 56.7, 63.6, 72.8, 132.0, 144.3.

Step 6) l-(4-oxaspiro[2.4]heptan-6-yl)-4-(4^,5,5-tetramethyl-13,2-dioxaborolan-2-yl)-lH-pyrazole [0190] To a solution of 4-iodo-l-(4-oxaspiro[2.4]heptan-6-yl)-lH-pyrazole(2.4 g, 8.4 mmol) in 35 mL of DMSO was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3 g, 11.7 mmol) and CH₃COOK (3.3 g, 33.5 mmol). The mixture was purged with N₂. Catalyst Pd(PPh₃)₂Cl₂ (294 mg, 0.42 mmol) was then added under N₂ and the reaction was heated to 80°C for 3.5 h. The mixture was cooled to rt, then filtered through a Celite pad. The organic phase was washed with brine (40 mL x 3), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 5: 1 to 1 : 1) to give the title compound as yellow oil (2.4 g, 95%).

MS (ESI, pos. ion) m/z 313 [M + Na]⁺;

1H NMR (400 MHz, CDCI₃) 5(ppm): 0.49-0.59 (m, 1H), 0.62-0.72 (m, 1H), 0.82-0.94 (m, 1H), 0.99-1.09 (m, 1H), 1.32 (s, 12H), 2.39 (dd, J=13.4, 4.3 Hz, 1H), 2.53 (dd, J=13.4, 8.5 Hz, 1H), 4.08 (dd, J=9.4, 3.9 Hz, 1H), 4.18 (dd, J=9.4, 6.4 Hz, 1H), 5.10-5.22 (m, 1H), 7.80 (s, 1H), 7.88 (s, 1H); ¹³C NMR (100 MHz, CDC1₃) δ 10.5, 10.9, 25.0, 39.1, 62.5, 63.6, 72.7, 83.4, 134.4, 145.5.

Step 7) 5-(l-(4-oxaspiro Γ2.41 heptan-6-vn-lH-pyrazol-4-vn-3-((i? -l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

[0191] To a solution of (i?)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy) pyridine-2- amine (3.8 g, 10.1 mmol) and l-(4-oxaspiro[2.4]heptan-6-yl)-4-(4,4,5,5- tetra-methyl- 1,3,2-dioxaborolan- 2-yl)-lH-pyrazole (2.4 g, 8.4 mmol) in DME (34 mL) was added a solution of Na₂C0₃ (2.7 g, 25.1 mmol) in H₂0 (8.5 mL). The mixture was purged with N₂for 20 minutes, followed by the addition of Pd(PPh₃)₂Cl₂(294 mg, 0.42 mmol). The reaction was heated at 87°C for 16 h, then cooled to rt and diluted with EtOAc (20 mL). The resulted mixture was filtered through a Celite pad. The organic phase was washed with brine (50 mL), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 1 : 1 to 1 :3) to give the title compound as a yellow solid (1.55g, 40%).

MS (ESI, pos. ion) m/z 464 [M + H]⁺;

1H NMR (400 MHz, CD₃OD) 5(ppm): 0.49-0.59 (m, 1H), 0.62-0.72 (m, 1H), 0.79-0.90 (m, 1H), 0.92-1.03 (m, 1H), 1.81 (d, J=6.6 Hz, 3H), 2.36 (dd, J=13.4, 3.8 Hz, 1H), 2.53 (dd, J=13.4, 8.3 Hz, 1H), 4.04 (dd, J=9.4, 3.4 Hz, 1H), 4.15 (dd, J=9.4, 6.2 Hz, 1H), 4.93 (s, 1H), 5.08-5.18 (m, 1H), 6.05 (q, J=6.6 Hz, 1H), 6.86 (s, 1H), 7.06-7.18 (m, 1H), 7.28-7.40 (m, 1H), 7.60 (s, 1H), 7.73 (s, 1H), 7.80 (s, 1H). ^1JCNMR (100 MHz, CD₃OD) δ(ρρηι): 11.0, 11.4, 19.3, 39.6, 64.1, 64.7, 73.6, 73.9, 116.2, 118.0, 118.2, 119.6, 121.7, 122.8, 123.0, 125.3, 130.3, 135.6, 136.9, 138.1, 141.2, 150.9.

Example 4 5-( l-((R)-4-oxaspiro Γ2.41 heptan-5-ylmethyl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

Step 1) (S)-tetrahydro-5-oxofuran-2-carboxylic acid

[0192] To a solution of L-glutamic acid (10.07 g, 0.068 mol, J&K CHEMICA) in 20 ml of coned. HC1 and 40 mL H₂0 was added a solution of NaN0₂ (7.0 g, 0.102 mol, Shantou Xilong chemical factory) in H₂0 (20 mL) slowly at -5 °C. The mixture was continued to stir for 12 hrs at room temperature. The reaction mixture was evaporated in vacuo below 50 °C to give yellow oil, which was dissolved in EtOAc. The solid formed was filtered and washed with EtOAc. The filtrate and washing solution were combined, dried over Na₂S0₄. The solvent was concentrated in vacuo to give (S)-tetrahydro-5-oxofuran-2-carboxylic acid as pale yellow oil (8.1 g, 91.6 %).

MS (ESI, pos. ion) m/z: 130.9 (M+l);

1H NMR (400MHz, CDCI₃) 5(ppm): 2.27 - 2.41 (m, 1H), 2.44 - 2.65 (m, 3H), 5.09 (m, 1H), 9.12 - 9.55 (m, 1H).

Step 2) (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one

[0193] To a solution of (S)-5-oxo-tetrahydrofuran-2-carboxylic acid (0.6 g, 0.0046 mol) in 10.8 mL of THF was added BH₃ Me₂S solution (2.76 mL, 0.0055 mol, 2 M in THF, Aldrich) dropwise via a syringe at -20 °C. The mixture was stirred for 12 hrs at room temperature. The reaction was then quenched with aqueous NH₄C1 and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂S0₄, and concentrated in vacuo to furnish the crude product as light yellow oil. (S)-5-(Hydroxymethyl)-dihydrofuran-2(3H)-one was obtained as colorless oil (0.253 g, 47 %) after a silica gel column chromatography purification (CHC1₃ / MeOH (v/v) = 100/1).

MS (ESI, pos. ion) m/z: 116.9 (M+l); 1H NMR (400MHz, CDCI3) δ(ρρηι): 2.11 - 2.15 (m, 1H), 2.20 - 2.29 (m, 1H), 2.46 - 2.51 (m, 2H),

3.63 (t, 2H), 3.83 - 3.86 (d, J=14.8Hz, 1H), 4.58 - 4.63 (m, 1H).

Step 3) (5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one

[0194] To a mixture of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (1.78 g, 0.0153 mol) and 3,4-dihydro-2H-pyran (2.62 g, 0.0312 mol, Alfa) in 40 mL of CH₂C1₂ was added PPTS (0.391 g, 0.00156 mol, Aldrich) slowly. After stirring at rt overnight, the reaction mixture was quenched with 5 mL of water. The mixture was extracted with EtOAc (50 mL><2). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo to give pale yellow oil. The crude product was purified by a silica gel column chromatography (PE / EtOAc (v/v) = 3/1) to afford the title compound as colorless oil (2.7 g, 88 %).

MS (ESI, pos. ion) m/z: 200.8 (M+l);

1H NMR (400 MHz, CDCI₃) 5(ppm): 1.41 - 1.62 (m, 4H), 1.64 - 1.75 (m, 2H), 2.11 - 2.19 (m, 1H), 2.22 - 2.31 (m, 1H) , 2.39 - 2.49 (m, 1H), 2.51 - 2.62 (m, 1H), 3.41 - 3.48 (m, 1H), 3.58 - 3.62 (dd, Ji=3.2 Hz, J₂=14.6 Hz, 1H), 3.74 - 3.79 (m, 1H), 3.85 - 3.92 (dd, Ji=3.2 Hz, J₂=14.4 Hz, 1H), 4.55 - 4.72 ( m, 2H).

Step 4) 1 -((S)-3 -hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol

[0195] To a mixture of Ti( -PrO)₄ (0.33 mL, 0.001 mol, Ardrich) and (5S)-5-((tetrahydro-2H- pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one (1.0 g, 0.005 mol) in 18.7 mL of THF was added a solution of 3M EtMgBr in Et₂0 (4.3 mL, 0.0125 mol, Aldrich) via a syringe over 3 hrs at 15 °C.

After stirring for additional one hour at 15 °C, the reaction was quenched with 20 mL of saturated

NH₄C1 solution, filtered and extracted with EtOAc (50 mL><2). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography to afford l-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol as colorless oil (0.853 g, 74 % ).

MS (ESI, pos. ion) m/z: 253.0 (M+23);

1H NMR (400 MHz, CDC1₃) 5(ppm): 0.4 - 0.5 (s, 1H), 0.67 - 0.87 (m, 3H), 1.4 - 1.9 (m, 12H), 3.38 - 3.44 (m, 1H), 3.53 - 3.60 (m, 1H), 3.75 - 3.78 (m, 1H), 3.87 - 3.96 (m, 1H), 4.57 (d, J=2.4 Hz, 1H). Step 5) (5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane

[0196] To a solution of l-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)- cyclopropanol (1.73 g, 0.0075 mol) and PPI13 (2.95 g, 0.0113 mol, Richjoint) in 32 mL of anhydrous THF at rt under N₂ was added DEAD (1.96 g, 0.0113 mol, Aladdin) dropwise via a syringe. The reaction was stirred at 60 °C for 12 hours. The solvent was concentrated in vacuo. The red oil was purified by a silica gel column chromatography (n-hexane / EtOAc (v/v) = 8/1) to give the title compound as colorless oil (1.1 g, 64 %).

MS (ESI, pos. ion) m/z: 213.0 (M+l);

1H NMR (400 MHz, CDC1₃) 5(ppm): 0.4 - 0.6 (m, 2H), 0.75 - 0.95 (s, 2H), 1.4 - 1.9 (m, 10H), 3.45 - 3.52 (m, 2H), 3.73 - 3.79 (m, 1H), 3.80 - 3.90 (m, 1H), 4.23 - 4.28 (m, 1H), 4.63 - 4.69 (s, 1H). Step 6) (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane

[0197] To a mixture of (5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane (101 mg, 0.48 mmol) in 5 mL of MeOH was added PPTS (12.1 mg, 0.048 mol, Aldrich) at room temperature. The reaction mixture was stirred at 40 °C overnight and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH₂C1₂) to give the title compound as colorless oil (55 mg, 89 %).

1H NMR (400 MHz, CDC1₃) 5(ppm): 0.4 - 0.6 (m, 2H), 0.75 - 0.95 (m, 2H), 1.84 - 1.91 (m, 1H), 1.94 - 1.98 (m, 2H), 2.07 - 2.13 (m, 1H), 2.27 (s, 1H), 3.56 - 3.70 (m, 2H), 4.16 - 4.18 (m, 1H). Step 7) ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate

[0198] To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg, 0.9 mmol) and Et₃N (183.8 mg, 1.82 mmol, Shantou Xilong chemical factory) in dry CH₂C1₂ (6 mL) at -10 °C under N₂, was added MsCl (203 mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe. After stirring for 2 hrs at rt, the reaction was quenched with water ice (3 mL), and the water phases were extracted with CH₂C1₂ (20 mLx2). The combined organic phases were dried over Na₂S0₄, and concentrated in vacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl

methanesulfonate as pale yellow oil (171 mg, 92%).

Step 8) (R)- 1 -(4-oxaspiro[2.4]heptan-5-ylmethyl)-4-iodo- lH-pyrazole

[0199] To the cooled solution of 4-Iodopyrazole (194 mg, 1.00 mmol) in dry DMF (10 mL) was added NaH (60% in mineral oil, 60 mg, 1.5 mmol) in one portion. The resulting mixture was stirred at 0 °C for lh. Then a solution of ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (171 mg, 0.83 mmol) in DMF (5 mL) was added via a syringe. The resulting mixture was stirred at 100 °C for 16h, poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA (v/v) =3/1) to give the title compound as an light yellow oil (185 mg, 75%).

MS (ESI, pos. ion) m/z: 305 (M+l);

Step 9) 5-(l-((R -4-oxaspiror2.41heptan-5-ylmethvn-lH-pyrazol-4-vn-3-((R -l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

[0200] To the mixture of (R)-l-(4-oxaspiro[2.4]heptan-5-ylmethyl)-4-iodo-lH-pyrazole (185 mg, 0.61 mmol) and (i?)-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-amine (320 mg, 0.51 mmol) in DME (15 mL) was added a solution of Na₂C03 (159 mg, 1.5 mmol) in water (3 mL). The resulting mixture was degassed with nitrogen, then Pd(dppf)Cl₂-CH₂Cl₂ (35 mg, 0.05 mmol) was added and degassed again. The resulting mixture was stirred at 95 °C for overnight, concentrated in vacuo, diluted with water (15 mL), and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA=1/1) to give a crude product which was redissolved in DCM (20 mL), and a soluton of HC1 in EA (4M, 2 mL) was added after cooling to 0 °C. The resulting mixture was stirred for overnight, concentrated in vacuo, redissolved in water, and adjusted to pH=10 with saturated aqueous Na₂C0₃ solution. The resulting basic aqueous mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was reslurried with Et₂0 (5 mL) to give the title compound as yellow solid (129 mg, 53%).

MS (ESI, pos. ion) m/z: 477 (M+l).

Example 5 5-a- S)-5-azaspiror2.41heptan-6-ylmethyl)-lH-pyrazol-4-yl)-3- R)-l-q,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

Step 1) (S)-5-tert-butyl 6-methyl 5-azaspiro[2.41heptane-5,6-dicarboxylate [0201 ] To the solution of (S)- 1 -tert-butyl 2-methyl 4-methylenepyrrolidine- 1 ,2-dicarboxylate (2.41 g, 10.0 mmol) in toluene (20 mL) was then added 30 mL of 1.0 M diethylzinc in toluene (3.71 g, 30.0 mmol) over 15 minutes at -25 °C, followed by addition of chloroiodomethane (8.82 g, 50.0 mmol) dropwise over 10 min. The resulting mixture was stirred at -25 °C for 8h, and then cooled to 0 °C. Saturated aqueous NH₄C1 (50 mL) was added dropwise at this temperature, and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography (PE/EA (v/v) = 6/1) to give the tittle compound as an light yellow oil (943 mg, 37%).

MS (ESI, pos. ion) m/z: 304 (M+l-56).

Step 2) (S)-tert-butyl 6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate

[0202] To a solution of (S)-5 -tert-butyl 6-methyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate (943 mg, 3.7 mmol) in THF (30 mL) at 0 °C was added L1BH₄ (403 mg, 18.5 mmol) in portions. The suspension was stirred at room temperature for overnight, cooled to 0 °C and AcOH (0.5 mL) was added, then the mixture was poured onto 100 mL of brine. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over Na₂S0₄, filtered and

concentrated in vacuo to afford title compound (818 mg, 97%) as an yellow oil.

MS (ESI, pos. ion) m/z: 228 (M+l);

1H NMR (400 MHz, CDC1₃) 5(ppm): 4.73 (m, 1H), (3.78 (m, 1H), 3.55 (m, 1H), 3.33 (m, 1H), 2.95 (m, 1H), 2.11 (m, 1H), 1.64 (m, 1H), 1.40 (s, 9H), 0.53 (m, 4H).

Step 3) (S)-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-5-azaspiro[2.41heptane-5-carboxylate

[0203] A mixture of (S)-tert-butyl 6-(hydroxymethyl)-5-azaspiro[2.4]heptane-5-carboxylate (500 mg, 2.2 mmol) and triethylamine (444 g, 4.4 mmol) in 10 mL of dichloromethane was stirred at 0 °C for 30 min. To the mixture was added a solution of methanesulfonyl chloride (378 mg, 3.3 mmol) in dichloromethane via a syringe. The reaction mixture was stirred at 0 °C for 4 hrs and quenched with a mixture of 10 mL of saturated Na₂C03 aqueous solution and 10 mL of water. The resulted mixture was extracted with dichloromethane (30 mL><3). The combined organic phases were dried over

Na₂S0₄ and concentrated in vacuo to give the tittle compound as yellow oil (550 mg, 82 %>).

Step 4) (S)-tert-butyl 6-((4-iodo-lH-pyrazol-l-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate

[0204] To the cooled solution of 4-Iodopyrazole (233 mg, 1.2 mmol) in dry DMF (10 mL) was added NaH (60% in mineral oil, 96 mg, 2.4 mmol) in one portion. The resulting mixture was stirred at 0 °C for lh. Then a solution of (S)-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-5- azaspiro[2.4]heptane-5-carboxylate (305 mg, 1.0 mmol) in DMF (5 mL) was added via a syringe. The resulting mixture was stirred at 100 °C for 16h, poured into brine (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA (v/v) = 3/1) to give the title compound as an white solid (274 mg, 68%).

MS (ESI, pos. ion) m/z: 404 (M+l);

Step 5) 5-(l-((S -5-azaspiror2.41heptan-6-ylmethvn-lH-pyrazol-4-vn-3-((R -l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

[0205] To the mixture of (S)-tert-butyl 6-((4-iodo-lH-pyrazol-l-yl)methyl)-5- azaspiro[2.4]heptane-5-carboxylate (242 mg, 0.6 mmol) and(i?)-N,N-bis(tert-butoxycarbonyl)-3-(l- (2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- amine ( (314 mg, 0.50 mmol) in DME (15 mL) was added a solution of Na₂C0₃ (159 mg, 1.5 mmol) in water (3 mL). The resulting mixture was degassed with nitrogen, then Pd(dppf)Cl₂-CH₂Cl₂ (35 mg, 0.05 mmol) was added and degassed again. The resulting mixture was stirred at 95 °C for overnight, concentrated in vacuo, diluted with water (15 mL), and extracted with DCM (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na₂S0₄, and

concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EA (v/v) = 4/1) to give a crude product which was redissolved in DCM (25 mL), and a soluton of HC1 in EA (4M, 3 mL) was added after cooling to 0 °C. The resulting mixture was stirred for overnight, concentrated in vacuo, redissolved in water, and adjusted to pH=10 with saturated aqueous Na₂C0₃ solution. The resulting aqueous mixture was extracted with EtOAc (70 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was reslurried with Et₂0 (5 mL) to give the title compound as light yellow solid (114 mg, 48%).

MS (ESI, pos. ion) m/z: 476 (M+l).

Example 6 5-a- R)-4-azaspiror2.41heptan-6-yl)-lH-pyrazol-4-yl)-3- R)-l-q,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

Step 1) (46 -4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-one

[0206] To a mixture of (5)-4-hydroxypyrrolidin-2-one (2 g, 19.78 mmol) in DCM (400 mL) was added DHP (3.33 g, 39.56 mmol) and PPTS (0.5 g, 1.98 mmol). The reaction was stirred at 35°C for 48 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100% EtOAc to EtOAc/MeOH (v/v) = 20/1) to give the title compound as a white solid (4.58 g, 63%).

MS (ESI, pos. ion) m/z 186 [M + H]⁺;

1H NMR (400 MHz, CDC1₃) 5(ppm): 6.68 (br, 1H), 4.69-4.65 (d, 1H), 4.55 (s, 1H), 3.87-3.82 (t, 1H), 3.69-3.58 (m, 1H), 3.54-3.55 (m, 2H), 2.66-2.33 (m, 2H), 1.83-1.72 (m, 2H), 1.55 (s, 4H); ¹³CNMPv (100 MHz, CDC1₃) 5(ppm): 19.3, 19.6, 25.3, 30.7, 30.8, 37.2, 38.3, 48.6, 49.7, 62.6, 62.9, 71.2, 71.6, 97.5, 98.0, 176.4, 177.0.

Step 2) (AS)- 1 -benzyl -4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-one

[0207] To a solution of NaH (363 mg, 12.1 mmol, 80%> dispense in oil) in DMF (60 mL) was added a solution of (45)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-one (1.5 g, 8.1 mmol) in DMF (10 mL) at -15°C. The reaction was stirred at 0°C for 1 h, followed by the addition of BnBr (1.44 mL, 12.1 mmol). The reaction was stirredat rtfor additional 4 h, then quenched with saturated NaHC0₃ aqueous solution (20 mL). The mixture was concentrated in vacuo andthe residue was extracted with EtOAc (20 mL x 3).The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂S0₄, andconcentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as yellow oil (1.36 g, 61%>).

MS (ESI, pos. ion) m/z 276 [M + H]⁺;

1H NMR (400 MHz, CDC1₃) 5(ppm): 1.39-1.87 (m, 6H), 2.48-2.60 (m, 1H), 2.67-2.74 (m, 1H), 3.21-3.34 (m, 1H), 3.38-3.56 (m, 2H), 3.66-3.88 (m, 1H), 4.36-4.67 (m, 4H), 7.18-7.39 (m, 5H); ¹³C NMR (100 MHz, CDCI3) δ(ρρηι): 19.2, 19.4, 25.2, 30.6, 30.7, 38.1, 39.0, 46.0, 46.1, 52.4, 53.7, 62.4, 62.6, 68.2, 69.0, 97.1, 98.0, 127.5, 127.9, 128.0, 128.6, 136.1, 136.2, 172.3, 172.8.

Step 3) (66 -4-benzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-4-azaspiro[2.41heptane

[0208] To a solution of (45)-l-benzyl-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-one (4 g, 14.5 mmol) in THF (145 mL) was added MeTi(0 -Pr)₃ (14.5 mL, 14.5 mmol) at 15°C, followed by EtMgBr (9.7 mL, 29.1 mmol) over 2 h at 15°C. The reaction was stirred at rt overnight and then quenched with saturated NH₄CI aqueous solution (10 mL). The resulted mixture was filtered through a Celite pad. The aqueous phase was extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine (80 mL), dried over Na₂S0₄, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as yellow oil (1.49 g, 36%).

MS (ESI, pos. ion) m/z 288 [M + H]⁺;

¹HNMR (400 MHz, CDC1₃) 5(ppm): 7.31-7.19 (m, 5H), 4.60-4.51 (m, 1H), 4.48-4.44 (m, 1H), 3.85- 3.75 (m, 1H), 3.49-3.33 (m, 3H), 2.98-2.71 (m, 2H), 2.16-1.90 (m, 2H),1.81-1.65 (m, 2H), 1.56-1.45 (m, 4H), 0.89-0.84 (m, 1H), 0.77-0.73 (m, 1H), 0.54-0.47 (m, 1H), 0.36-0.32 (m, 1H).

Step 4) (S)-tert-bvA.y\ 6-hydroxy-4-azaspiro[2.4]heptane-4-carboxylate

[0209] To a solution of (65)-4-benzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-4-azaspiro[2.4] heptane (1 g, 3.48 mmol) in MeOH (100 mL) was added HCOOH(16.1 g, 348 mmol) and Pd/C (1 g, 10% Pd content). The reaction was stirred at rt for 7 h, then filtered through a Celite pad. The filtrate was treated with IN HC1 (5 mL) and stirred at rtfor 24 h. The resulted solution was titrated with 2N NaOH aqueous solution to pH= 10, followed by the addition of (Boc)₂0 (4.6 g, 20.88 mmol). The reaction was continued to stir at rt overnight, then quenched with 20 mL of H₂0 and extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na₂S0₄and

concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to givethe title compound as yellow oil (0.47g, 63.3%>).

MS (ESI, pos. ion) m/z 236 [M +Na]⁺.

¹HNMR (400 MHz, CDC1₃) 5(ppm): 4.36 (s, 1H), 3.67-3.63 (q, 1H), 3.55-3.52 (d, 1H), 2.75 (s, 1H), 2.30-2.18 (q, 1H), 1.81-1.78 (d, 1H), 1.68-1.51 (m, 2H), 1.42 (s, 9H), 0.59-0.54 (m, 1H), 0.42-0.37 (m, 1H).

Step 5) (i?)-tert-butyl 6-(4-iodo-lH-pyrazol-l-yl)-4-azaspiro[2.4]heptane-4- carboxylate [0210] To a solution of (S)-tert-bvAy\ 6-hydroxy-4-azaspiro[2.4]heptane-4-carboxylate (0.47g, 2.2 mmol), DMAP (3 mg, 0.02 mmol) and Et₃N (0.48 mL, 3.31 mmol) in DCM (5 mL) was added a solution of MsCl (0.21 mL, 2.64 mmol) in DCM (1 mL) slowly at 0°C. The reaction was stirred at rt for 2 h, then quenched with 20 mL of water andextracted with DCM (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na₂S0₄ and concentrated in vacuo to give (S)-tert-butyl 6-((methylsulfonyl)oxy)-4-azaspiro[2.4]- heptane-4-carboxylateas brown oil (702 mg, 109%). The compound was used in the next step without further purification.

[0211] To a stirred solution of 4-iodo-lH-pyrazole(513 mg, 2.64 mmol) in anhydrous DMF (45 mL) was added NaH (99 mg, 3.31 mmol) in portions at 4°C. The mixture was stirred at 4°Cfor 1 h, followed by the addition of (S)-tert- vXy\ 6-((methylsulfonyl)oxy)-4-azaspiro[2.4]-heptane-4- carboxylate (642 mg, 2.2 mmol). The reaction was heated atl00°C for 17 h, then cooled to rt.The mixture was quenched with water (20 mL) and concentrated in vacuo. The residue was diluted with H₂0 (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 10: 1) to givethe title compound as colorless oil (656 mg, 77%).

MS (ESI, pos. ion) m/z 412 [M +Na]⁺;

¹HNMR (400 MHz, CDCI3) 5(ppm): 0.41-0.56 (m, 2H),0.78-1.02 (m, 2H), 1.43 (s, 9H), 2.30-2.49 (m, 2H), 3.83 (dd, J=11.5, 4.1 Hz, 1H), 3.98 (dd, J=11.9, 6.8 Hz, 1H), 4.87-4.97 (m, 1H), 7.52 (s, 1H), 7.56 (s, 1H).

Step 6) (R)-tgrt-butyl 6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)-4- azaspiro[2.4]heptane-4-carboxylate

[0212] To a solution of (R)-tert-bvA.y\ 6-(4-iodo-lH-pyrazol-l-yl)-4-azaspiro[2.4]heptanes-4- carboxylate (656 mg, 1.69 mmol) in DMSO (7 mL) was added 4,4,4',4',5,5,5',5'- octamethyl-2,2'- bi(l,3,2-dioxaborolane) (0.6 g, 2.36 mmol) and CH3COOK (662 mg, 6.74 mmol). The mixture was purged with N₂for 10 minutes, followed the addition of Pd(PPh₃)₂Cl₂ (59 mg, 0.08 mmol). The reaction was heated at 80°C for 2 h, then cooled to rt and filtered through a Celite pad. The filtrate was diluted with brine (20 mL) and then extracted with EtOAc (10 mL x 3). The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc = 5: 1) to give the title compound as a white solid (462 mg, 70%). MS (ESI, pos. ion) m/z 412 [M + Na] ;

¹HNMR (400 MHz, CDC1₃) δ(ρρηι): 0.40-0.60 (m, 2H),1.32 (s, 12H), 1.43 (s, 9H), 1.55-1.85 (m, 2H), 2.33 (dd, J=12.7, 6.5 Hz, IH), 2.50 (dd, J=12.8, 6.8 Hz, IH), 3.85 (dd, J=11.6, 5.6 Hz, IH), 4.03 (dd, J=11.6, 7.1 Hz, IH), 4.88-5.00 (m, IH), 7.80 (s, IH), 7.81 (s, IH).

Step 7) (7?)-fert-butyl 6-(4-(6-amino-5-((i?)-l-(2,6-dichloro-3-fluorophenyl)ethoxy) pyridine-3-yl)- lH-pyrazol- 1 -yl)-4-azaspiro[2.4]heptane-4-carboxylate

[0213] To a solution of (i?)-5-bromo-3-(l-(2,6-dichloro-3-fiuorophenyl)ethoxy)pyridin-2-amine (217 mg, 0.56 mmol) and (R)-tert- vXy\ 6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)-4-azaspiro[2.4]heptane-4-carboxylate (318 mg, 0.84 mmol) in DME (5 mL) was added a solution of Na₂C0₃ (177 mg, 1.67 mmol) in 2 mL of H₂0. The solution was purged with N₂ for 10 minutes, followed the addition of Pd(PPh₃)₂Cl₂ (20 mg, 0.03 mmol).The reaction was stirred at 90°C for 16h under N₂,thencooled to rt. The mixture was diluted with EtOAc (20 mL) and filtered through a Celite pad. The filtrate was washed with brine (5 mL) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a yellow solid (0.21 g, 67%).

MS (ESI, pos. ion) m/z 564 (M +1);

Step 8 5-(l-((i? -4-azaspiror2.41heptan-6-vn-lH-pyrazol-4-vn-3-((i? -l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

[0214] To a solution of (R)-tert- vXy\ 6-(4-(6-amino-5-((i?)-l-(2,6-dichloro-3-fluorophenyl) ethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)-4-azaspiro[2.4]heptane-4-carboxylate (0.21g, 0.37 mmol) in DCM (10 mL) was added HC1 in EtOAc (3N, 2.5 mL) at 0°C. The reaction was stirred at rt overnight and then concentrated in vacuo. The residue was diluted with water (50 mL) and adjusted to pH 10 with saturated Na₂C0₃ aqueous solution. The resulted mixture was extracted with DCM (50 mL x3) and the combined organic phases were washed with brine, dried over Na₂S0₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography

(DCM/MeOH/Et₃N (v/v/v) = 500/20/1) to give the title compound as a pink solid (118 mg, 69%). MS (ESI, pos. ion) m/z 464 [M +H]⁺;

¹HNMPv (400 MHz, CDC1₃) 5(ppm): 0.48-0.59 (m, IH), 0.66-0.82 (m, 2H), 0.89-0.99 (m, IH), 1.86 (d, J=6.6 Hz, 3H), 2.29 (d, J= 6.3 Hz, 2H), 2.48 (br, IH), 3.29 (dd, J=12.4, 3.4 Hz, IH), 3.37 (dd, J=12.4, 3.4 Hz, 1H), 4.80 (s, 2H), 4.90-5.03 (m, 1H), 6.07 (q, J=6.6 Hz, 1H), 6.86 (s, 1H), 7.00-7.10 (m, 1H), 7.27-7.35 (m, 1H), 7.54 (s, 1H), 7.58 (s, 1H), 7.76 (s, 1H);

¹³CNMR (100 MHz, CDCl₃) 5(ppm): 1.2, 13.9, 18.9, 41.0, 42.2, 54.5, 64.3, 72.4, 114.8, 116.6, 116.8, 119.1, 120.1, 122.1, 123.9, 128.9, 135.6, 136.2, 136.9, 139.8, 148.9.

Example 7 ^ )-5-a- - ,8-diazaspiror4.51decan-8-yl)ethyl)-lH-pyrazol-4-yl)-3-a-q,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

Step 1) Ethyl 2-(triphenylphosphoranylidene)acetate

[0215] To a solution of triphenylphosphine (36.00 g, 137.26 mmol) dissolved in EtOAc (300 ml) was added ethyl bromoacetate (22.92g, 137.26 mmol) at rt. After 24h, white precipitate was collected which was washed with EtOAc (100 ml), dried in high vacuo to give wittig salt (52.0 g, 88%). The wittig salt (27.6 g) dissolved in CH₂C1₂ (150 ml) was vigorously shaked with 1M NaOH aq. in separation funnel, the aqueous was extracted with CH₂C1₂ (50 ml x2), the combined organic phase were concentrated in vacuo to give the title compound as white solid (21.36 g , 95%).

Step 2) Tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-l-carboxylate

[0216] To a mixture of tert-butyl 4-oxopiperidine-l-carboxylate (10 g, 50.19 mmmol) and ylide (17.7 g,62.25 mmol) in Toluene (200 ml) were refluxed for 24 h. cooled to rt, concentrated in vacuo, the residue was purified by silica gel column chromatographic (PE/EtOAc=6/l) to give the title compound (10.8 g, 80%>) as white solid.

MS (ESI, pos. ion) m/z: 270 [M+l]

Step 3) Tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine-l-carboxylate

[0217] To a solution of tert-butyl 4-(2-ethoxy-2-oxoethylijidene)piperidine-l-carboxylate (10.5 g, 38.98 mmol) in nitromethane (120 ml) was added 1,1,3,3-tetramethylguanidine (TMG) (1.35 g, 11.70 mmol). The suspension was stirred at 100°C for 24 h. cooled to rt, concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound (10.8 g ,83%) as white solid.

Step 4) Tert-butyl 3-oxo-2,8-diazaspiro[4.51decane-8-carboxylate

[0218] To a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine - 1 - carboxylate (10.0 g, 30.27 mmol) in EtOH (70 mL) was added Ra(Ni) (1.5 mL). The suspension system was stirred at rt under hydrogen atmosphere for 3 days. The catalyst was removed and the solvent was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (3.7 g, 48%) as white solid.

MS (ESI, pos. ion) m/z: 255 [M+l].

Step 5) Tert-butyl 2-benzyl-3-oxo-2,8-diazaspiro|^"4.5^"|decane-8-carboxylate

[0219] To a suspension of NaH (60%, 640 mg, 16.00 mmol) in DMF (50 ml) was added tert-butyl 3-0X0-2, 8-diazaspiro[4.5]decane-8-carboxylate (3.7 g, 14.55 mmol) at 0°C under N₂ atmosphere. After 30 min., And then added (bromomethyl)benzene (2.99 g, 17.46 mmol) dropwise. The resulted suspension was stirred at 0°C for 4h., quenched with 2 ml and concentrated in vacuo, the residue was diluted with 100 ml EtOAc, and washed with water for twice, the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1 to 1/1) to give the title compound ( 3.7 g, 74%) as little yellowish colloid.

MS (ESI, pos. ion) m/z: 345 [M+l]

Step 6) Tert-butyl 2-benzyl-2,8-diazaspiro[4.5]decane-8-carboxylate

[0220] To a solution of tert-butyl 2-benzyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (3.5 g, 10.16 mmol) in anhydrous THF (100 ml) was added BH₃ in THF (1M, 41.0 ml, 41.00 mmol) under N₂ atmosphere. The reaction was refluxed for overnight, cooled to rt, quenched with 20 ml H₂0 carefully, concentrated in vacuo, the residue was dissolved in 100 ml EtOAc, and then washed with saturated brine (50 ml x 2), the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 6/1) to give the title compound (1.4 g, 40%) as light yellowish oil.

MS (ESI, pos. ion) m/z: 331 [M+l],

Step 7) 2-Benzyl-2,8-diazaspiro[4.5]decane

[0221] To a solution of tert-butyl 2-benzyl-2,8-diazaspiro[4.5]decane-8-carboxylate (1.0 g, 3.03 mmol) in EtOAc (30 ml) was added HC1 in EtOAc (4 M, 8 ml, 32 mmol) at 0°C, the reaction was stirred at rt for overnight, concentrated in vacuo, the residue was dissolved in DCM/MeOH (20 ml/2 ml) which was added NaHC0₃ (508 mg, 6.05 mmol) powder, the resulted system was stirred at rt for another 4h. concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1 to 1/1 ) to give the title compound as light yellowish oil ( 0.63 g, 90%).

MS (ESI, pos. ion) m/z: 231 [M+1],

Step 8) 2-(2-Benzyl-2,8-diazaspiro[4.51decan-8-yl)ethanol

[0222] To a suspension of NaH (60%, 115 mg, 2.87 mmol) in DMF (25 ml) was added 2-benzyl- 2,8-diazaspiro[4.5]decane (0.6 g, 2.60 mmol) at 0°C under N₂ atmosphere. After 30 min., And then added 2-chloroethanol (252 mg, 3.13 mmol) dropwise. The reaction was stirred at 100°C for overnight, cooled to rt, quenched with 3 ml H₂0, concentrated in vacuo, the residue was diluted with 100 ml EtOAc, and washed with water (50 ml x 2), the organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, the residue was purified by silica gel column

chromatography (PE/EtOAc (v/v) = 4/1 to 1/1) to give the title compound (0.5 g, 70%>) as colorless oil.

MS (ESI, pos. ion) m/z: 275 [M+l],

Step 9) 2-(2,8-Diazaspiro[4.51decan-8-yl)ethanol

[0223] To a solution of 2-(2-benzyl-2,8-diazaspiro[4.5]decan-8-yl)ethanol (1 g, 3.64 mmol) in EtOH (20 ml) was added Pd/C (5 wt%>, 10 mg). The reaction was stirred at rt under H₂ atmosphere for overnight, the catalyst was removed and the solvent ws concentrated in vacuo, the residue was purified by silica gel column chromatography (DCM/MeOH = 100/1 to 100/3) to give the title compound (0.63 g, 94%>) as colorless oil.

MS (ESI, pos. ion) m/z: 185 [M+l],

Step 10) Tert-butyl 8-(2-hydroxyethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0224] To a solution of 2-(2,8-diazaspiro[4.5]decan-8-yl)ethanol (0.6 g, 3.26 mmol) in THF (10 ml) was added Na₂C0₃ aq.(0.65 mol/L, 10 ml) and then was added (Boc)₂0 (0.9 ml, 4.23 mmol) drop wise. The reaction was stirred at rt for overnight, the aqueous was extracted with EtOAc (30 ml x 2), the combined organic phase was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 5/1 to 2/1) to give the title compound (0.84g, 90%>) as colorless oil.

MS (ESI, pos. ion) m/z: 185 [M+l],

Step 11) Tert-butyl 8-(2-((methylsulfonyl)oxy)ethyl)-2,8-diazaspiro[4.5]decane-2- carboxylate

[0225] To a solution of tert-butyl 8-(2-hydroxyethyl)-2,8-diazaspiro[4.5]decane-2- carboxylate

(0.8 g, 2.81 mmol) in DCM (20 ml) was added Et₃N (0.80 ml, 5.63 mmol) and then was added MsCl (0.32 ml, 4.22 mmol) at 0°C drop wise, the raction was stirred at rt for overnight, quenched with 3 ml saturated NH₄C1 aq., the organic phase was concentrated in vacuo, to give the title compound (0.84g, 82%) as white solid.

Step 12) Tert-butyl 8-(2-(4-iodo-lH-pyrazol-l-yl)ethyl)-2,8-diazaspiro[4.51decane-2- carboxylate

[0226] To a solution of 4-iodo-lH-pyrazole (0.4 g, 2.06 mmol) in DMF (10 ml) was added NaH (99 mg, 2.47 mmol) portion wise at 0°C under N₂ atmosphere. The resulting mixture was stirred at 0°C for lh. And then was added tert-butyl 8-(2-((methylsulfonyl)oxy)ethyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (0.82 g, 2.27 mmol). The resulting mixture was stirred at 100°C for overnight, cooled to rt, quenched with 2 ml H₂0, concentrated in vacuo, the residue was dissolved in 100 ml EtOAc, and then was washed with saturated brine (50 ml x 3), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 10/1 to 5/1) to give the title compound (0.57 g, 60%) as white solid. MS (ESI, pos. ion) m/z: 406 [M+l-55],

Step 13 (RV5-(l-(2-(2,8-diazaspiror4.51decan-8-vnethvn-lH-pyrazol-4-ylV3- (l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine

[0227] To a mixture of (i?)-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-amine (500 mg, 0.79 mmol), tert-butyl 8-(2-(4-iodo-lH-pyrazol-l-yl)ethyl)-2,8-diazaspiro[4.5]decane-2- carboxylate (403 mg, 0.87 mmol) and Na₂C0₃ (169 mg, 1.59 mmol) in DME/H₂0 (10 ml/0.5 ml) was added Pd(dppf)Cl₂.DCM (64 mg, 0.08 mmol) under N₂ atmosphere. The reaction was stirred at refluxing temperature for overnight, cooled to rt, diluted with 10 ml EtOAc, filtered through a celite pad, and the filtration was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1 to 3/1) to give the title compound (398 mg, 60%>) as colorless colloid. The compound obtained above was dissolved in EtOAc (4 ml) was added HC1 in EtOAc (4M, 8 ml, 32 mmol) at 0°C. The reaction was stirred at rt for overnight, concentrated in vacuo, the residue was dissolved in DCM/MeOH (10 ml/1 ml) which was added NaHC0₃ powder (123 mg, 1.44 mmol), the resulting mixture was stirred for another 3 h, concentrated in vacuo, the residue was purified by silica gel column chromatography (DCM/MeOH/NH₄OH (v/v/v) = 100/1/0 to 10/1/0.1) to give the title compound (136 mg, 53 >) as off- white solid.

MS (ESI, pos. ion) m/z: 533[M+1]

Example 8 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((4-methyl-4-azaspiro [2.41 heptan-l-yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine

Step 1) l-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-azaspiro[2.41heptane

[0228] To a solution of l-methylpyrrolidin-2-one (1 g, 10.09 mmol), (allyloxy)(tert- butyl)dimethylsilane (1.74 g, 10.09 mmol) and (z^'-PrO)₃TiCl (11.3 ml, 1M, 11.30 mmol) in THF (100 ml) was added CyMgCl (19.6 ml, 2M, 39.3 mmol) slowly at rt over 60 min. under N₂ atmosphere. The reaction mixture was stirred for an additional 1 h and poured into water. The organic layer was separated, and the aqueous layer was extracted three times with DCM (50 ml). The combined extracts were dried over MgS0₄ and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound (0.95 g, 37%) as pale yellowish oil.

Step 2 (4-methyl-4-azaspiro[2.4]heptan-l-yl)methanol

[0229] To a solution of l-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-azaspiro [2.4]heptane (0.9 g, 3.52 mmol) in EtOAc (20 ml) was added HC1 in EtOAc (4 M, 9 ml, 36 mmol) at 0°C. The reaction was stirred at rt for overnight, concentrated in vacuo, the residue dissolved in DCM/MeOH (20 ml/2 ml) was added NaHC0₃ powder (300 mg, 3.52 mmol), the resulting mixture was stirred at rt for 2 h., concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 5/1) to give the title compound (0.43 g, 86%) as colorless oil.

Step 3) (4-methyl-4-azaspiro[2.4]heptan-l-yl)methyl methanesulfonate

[0230] To a solution of (4-methyl-4-azaspiro[2.4]heptan-l-yl)methanol (0.4 g, 2.83 mmol) and Et₃N (0.8 ml, 5.67 mmol) in DCM (25 ml) was added MsCl (0.33 ml, 4.25 mmol) drop wise at 0°C, the reaction was stirred at rt for overnight, quenched with 1 ml saturated NH₄C1 aq. the organic phase was washed with 10 ml saturated brine, dried over anhydrous Na₂S0₄, concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 6/1) to give the title compound (0.48 g, 78%) as white solid.

Step 4) l-((4-iodo-lH-pyrazol-l-yl)methyl)-4-methyl-4-azaspiro[2.4]heptane

[0231] To a solution of 4-iodo-lH-pyrazole (0.3 g, 1.55 mmol) in DMF (10 ml) was added NaH

(74 mg, 1.86 mmol) portion wise at 0°C under N₂ atmosphere. The resulting mixture was stirred at 0°C for lh. And then was added (4-methyl-4-azaspiro[2.4]heptan-l-yl)methyl methanesulfonate (0.37 g, 1.70 mmol). The resulting mixture was stirred at 100°C for overnight, cooled to rt, quenched with 2 ml H₂0, concentrated in vacuo, the residue was dissolved in 100 ml EtOAc, and then was washed with saturated brine (50 ml x 3), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc = 10/1 to 5/1) to give the title compound (0.31 g, 64%) as white solid.

Step 5) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((4-methyl-4-azaspiro[2.41 heptan-1- yDmethyl)- 1 H-pyrazol-4-yl)pyridin-2-amine

[0232] To a mixture of (i?)-N,N-bis(tert-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin-2-amine (500 mg, 0.79 mmol), l-((4-iodo-lH-pyrazol-l-yl)methyl)-4-methyl -4-azaspiro[2.4]heptane (278 mg, 0.87 mmol) and Na₂C0₃ (169 mg, 1.59 mmol) in DME/H₂0 (10 ml/0.5 ml) was added Pd(dppf)Cl₂DCM (64 mg, 0.08 mmol) under N₂ atmosphere. The reaction was stirred at refluxing temperature for overnight, cooled to rt, diluted with 10 ml EtOAc, filtered through a celite pad, and the filtration was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1 to 3/1) to give the title compound (250 mg, 45%) as colorless colloid. The compound obtained above was dissolved in EtOAc (4 ml) was added HC1 in EtOAc (4M, 8 ml, 32 mmol) at 0°C. The reaction was stirred at rt for overnight, concentrated in vacuo, the residue was dissolved in DCM/MeOH (10 ml/1 ml) which was added NaHC0₃ powder (93 mg,l .08 mmol), the resulting mixture was stirred for another 3 h, concentrated in vacuo, the residue was purified by silica gel column chromatography (DCM/MeOH = 100/1 to 20/1) to give the title compound (100 mg, 56%>) as off-white solid.

MS (ESI, pos. ion) m/z: 490 [M+l]. BIOLOGICAL TESTING

[0233] The LC/MS/MS system used in the analysis consists of an Agilent 1200 Series vacuum degasser, binary pump, well-plate autosampler, thermostattedcolumn compartment, the Agilent G6430 TripleQuadrupole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.

Table A MRM: 490.2→383.1

Fragmentor 230 V

CE 55 V

Drying Gas Temp 350 °C

Nebulize 40 psi

Drying Gas Flow 10 L/min

[0234] An Agilent XDB-C18, 2.1 x 30 mm, 3.5 μΜ column was used for the analysis. 5 of the samples were injected. Analysis condition: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acidin methanol (B). The flow rate was 0.4 mL/min. And the gradient of Mobile phase was in the Table B.

Table B

[0235] Alternatively, an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis. An ESI source was used on the LC/MS/MS spectrometer. The analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution. A Capcell MP-C18 100x4.6 mm I.D., 5 μΜ column (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase was 5mM ammonia acetate, 0.1% MeOH in water (A): 5mM ammonia acetate, 0.1% MeOH in acetonitrile (B) (70:30, v/v). The flow rate was 0.6 mL/min. Column was maintained at ambient temperature. 20 μΐ_^ of the samples were injected.

Example A: Compound Stability In Human And Rat Liver Microsomes

[0236] Human or rat liver microsomes incubations were conducted in duplicate in polypropylene tubes. The typical incubation mixtures consisted of human (or rat) liver microsomes (0.5 mg protein/mL), compounds of interest (5 μΜ) and NADPH (1.0 mM) in a total volume of 200 μΐ_^ potassium phosphate buffer (PBS, 100 mM, pH7.4). Compounds were dissolved in DMSO and diluted with PBS such that the final concentration of DMSO was 0.05%. The enzymatic reactions were commenced with the addition of protein after a 3-min preincubation and incubated in a water bath open to the air at 37°C. Reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) by adding equal volume of ice-cold acetonitrile. The samples were stored at -80°C until LC/MS/MS assays.

[0237] The concentrations of compounds in the incubation mixtures of human (or rat) liver microsomes were determined by a LC/MS/MS method. The ranges of the linearity in the

concentration range were determined for each tested compounds.

[0238] A parallel incubation was performed using denatured microsomes as the negative control, and reactions were terminated at various time points (0, 15, 60 min) after incubation at 37°C.

Dextromethorphan (70 μΜ) was selected as the positive control, and reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) after incubation at 37°C. Both positive and negative control samples were included in each assay to ensure the integrity of the microsomal incubation system.

[0239] Alternatively, the stability of some of the compounds disclosed herein in human (or rat) liver microsomes were also conducted in the following protocol. The incubations were conducted in duplicate in polypropylene tubes. The typical incubation mixtures consisted of human (or rat) liver microsomes (final concentration: 0.5 mg protein/mL),compounds (final concentration: 1.5 μΜ) in a total volume of 30 K-buffer (contain 1.0 mM EDTA, 100 mM, pH7.4). Compounds were dissolved in DMSO and diluted with K-buffer such that the final concentration of DMSO was 0.2%. The enzymatic reactions were commenced with the addition of 15 μΐ_^ NADPH(fmal concentration: 2 mM)afterl0 min preincubation and incubated in a 37°C incubator. Reactions were terminated at various time points (0, 15, 30, 60 min) by adding 135 μΙ_, acetonitrile (contain IS). Protein is removed by centrifugation with 4000rpm, 10 min. Supernatant was collected for LC-MS/MS analysis

[0240] In the above protocol, ketanserin (1 μΜ) was selected as the positive control, and reactions were terminated at various time points (0, 15, 30, 60 min) after incubation at 37°C. Both positive control samples were included in each assay to ensure the integrity of the microsomal incubation system. Data Analysis

[0241] The concentrations of compounds in human liver microsomes incubations were plotted as a percentage of the relevant zero time point control for each reaction. The in vivo CLj_nt were extrapolated (ref : Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.

Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324.)

[0242] The compounds disclosed herein exhibited desirable half-life (T ) when the compounds were incubated in human and rat liver microsomes.

Example B: Evaluation of Pharmacokinetics After Intravenous and Oral Administration of The Compounds Disclosed Herein In Mice, Rats, Dogs And Monkeys

[0243] Compounds disclosed herein were assessed in pharmacokinetic studies in mice, rats, dogs or monkeys. The compounds were administered as a water solution, 2%HPMC + 1% Tween-80 in water solution, 5%DMSO + 5% solutol in saline, 4%MC suspension or capsule. For the intravenous administration, the animals were generally given at 1 or 2 mg/kg dose. For the oral (p.o.) dosing, mice and rats were generally given 5 or 10 mg/kg dose, and dogs and monkeys were generally given 10 mg/kg dose. The blood samples (0.3 mL) were drawn at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h time points or 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h time points and centrifuged at 3,000 or 4000 rpm for 2 to 10 min. The plasma solutions were collected, stored at -20°C or -70°C until analyzed by LC/MS/MS as described above.

[0244] Table 2 lists pharmacokinetic data obtained from rats administered intravenously and orally.

Table 2 Pharmacokinetic profiles in rats

* The oral bioavailabi ity for Examples 3 - 6 was determined at dose of lOmg/kg in rats Example C: Kinase Assays

33

[0245] Kinase assays can be performed by measurement of incorporation ofy- P ATP into immobilized myelin basic protein (MBP). High binding white 384 well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubation of 60 μΕ/well of 20 μg/mL MBP in Tris-buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4°C. Plates are washed 3x with 100 TBS. Kinase reactions are carried out in a total volume of 34 μΐ_^ in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #1-5506), 10 mM MgCl₂, 1 mM DTT, 0.02% TritonX-100). Compound dilutions are performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point is measured in duplicate, and at least two duplicate assays are performed for each individual compound determination. Enzyme is added to final concentrations of 10 nM or 20 nM, for example. A mixture of unlabeled ATP and

γ-³³Ρ ATP is added to start the reaction (2 x 10⁶ cpm ofy-³³P ATP per well (3000 Ci/mmole) and 10 μΜ unlabeled ATP, typically. The reactions are carried out for 1 h at rt with shaking. Plates are washed 7x with TBS, followed by the addition of 50 μΕΛνεΙΙ scintillation fluid (Wallac). Plates are 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.

[0246] The above assay procedure can be used to determine the IC₅₀ for inhibition and/or the inhibition constant, K;The IC₅₀ is defined as the concentration of compound required to reduce the enzyme activity by 50% under the condition of the assay. The IC₅₀ value is estimated by preparing a 10 point curve using a ½ log dilution series (for example, a typical curve may be prepared using the following compound concentrations: 10 μΜ, 3 μΜ, 1 μΜ, 0.3 μΜ, 0.1 μΜ, 0.03 μΜ, 0.01 μΜ, 0.003 μΜ, 0.001 μΜ and 0 μΜ).

[0247] The kinase assays described herein were performed at Millipore UK Ltd, Dundee

Technology Park, Dundee DD2 1SW, UK

ALK (h) Kinase Assay

[0248] ALK (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ

KKKSPGEYVNIEFG, 10 mM MgAcetate and [γ-³³Ρ-ΑΤΡ] (specific activity aprrox. 500 pcm/pmol, concentration as required (10 μΜ)). The reaction is initiated by the addition of the MgATO mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μί of the reaction is then spotted onto a P30 filter mat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. c-Met (h) Kinase Assay

[0249] Met (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ

KKKSPGEYVNIEFG, 10 mM MgAcetate and [γ-³³Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol, concentration as required (10 μΜ)). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μΐ_^ οΐ the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.

[0250] The compounds disclosed herein exhibited potent activities in the ALK and c-Met(h) assays. Table 3 listed the IC₅oS of some examples described herein in the ALK and c-Met(h) assays.

Table 3 Kinase inhibition data

Example D: Tumor Xenograft Models

[0251] The efficacy of compounds disclosed herein was evaluated in a standard murine model of tumorigenesis. Human tumor cells (such as U87MG glioblastoma cells, MKN45 Gastric

Adenocarcinoma cells,MDA-MB-231 breast adenocarcinoma cells, or Caki-1 renal carcinoma cells, all from ATCC) were expended in culture, harvested, and injected subcutaneously onto the rear flank of 6-7 week old female athymic nude mice (BALB/cA nu/nu, Shanghai SLAC Laboratory

Animal, Co.) (n = 10 for vehicle group, n = 8 for each dosing group). When tumors reached a volume of 100-250 mm , animals were randomly divided into vehicle control (for example, 2% HPMC+1% Tween-80 in water) and compound groups. Subsequent administration of compound by oral gavage (for example, 3-50 mpk/dose, dissolved in 2% HPMC+1%> Tween-80 in water) begins anywhere from day 0 to day 15 post tumor cell challenge and generally continues with once a day for the duration of the experiment.

Tumor Growth Inhibition (TGI) Analysis

[0252] Progression of tumor growth is assessed by tumor volumes and recorded as a function of time. The long (L) and short (W) axes of the subcutaneous tumors were measured with calipers twice weekly, and the tumor volume (TV) calculated as (L x W )/2). TGI was calculated from the difference between the median tumor volumes of vehicle-treated and drug-treated mice, expressed as a percentage of the median tumor volume of the vehicle-treated control group, by the following relation:

[0253] Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe psot hoc testing for multiple comparisons. Vehicle alone (2% HPMC+1% Tween-80, or the like) is the negative control.

[0254] The compouds described herein were also administrated orally (p.o.) once a day (QD), for 13-21 days in U87MG xenograft animal model. At doses of 60 mg/kg, the compouds produced statistically significant inhibition of growth of certain tumors grown subcutaneously in athymic nude mice.

[0255] Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive and the invention is not be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims. All publications and patents cited herein are incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein: each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H, D or F; each X and Y is independently C₆-ioaryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S or N, wherein the said C₆-ioaryl and 5- 10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, Br, I, -CN, -N0₂, N₃, -OR^a, -SR^a, -NR^aR^b, - C(=0)NR^aR^b, Ci_₆alkyl, Ci_₆haloalkyl, C₂_₆alkenyl, C₂_₆alkynyl, -Ci_₄alkylene-CN, -CM alkylene-OR^a, -Ci_₄alkylene-NR^aR^b, C₆-ioaryl or 5-10 membered heteroaryl;

Z is C₅-i₂spirobicyclyl or -(Ci_₄alkylene)-(C₅-i₂spirobicyclyl), provided that, when Z is C₅- i₂spirobicyclyl, the cyclic structure directly attached to Y is a C₃_₆heterocyclic ring, wherein the C₅_i₂spirobicyclyl and -(Ci_₄alkylene)-(C₅_i₂spirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, - OR^a, -NR^aR^b, -C(=0)NR^aR^b, -OC(=0)NR^aR^b, Ci_₆alkyl, Ci_₆haloalkyl, -(Ci_₄alkylene)- CN, -(Ci_₄alkylene)-OR^a or -(Ci_₄alkylene)-NR^aR^b; and each R^a and R^b is independently H, Ci_₆aliphatic, C₃_₆cycloalkyl, -(Ci_₄alkylene)-(C₃_ ₆cycloalkyl), C₃_₆heterocyclyl, -(Ci_₄alkylene)-(C₃_₆heterocyclyl), C₆-ioaryl, -(Ci_ ₄alkylene)-(C6_ioaryl), 5-10 membered heteroaryl or -(Ci_₄alkylene)-(5-10 membered heteroaryl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-8 membered heterocyclyl, wherein Ci_₆aliphatic, C₃-₆cycloalkyl, -(Ci_₄alkylene)-(C₃-₆cycloalkyl), C₂_ 6heterocyclyl, -(Ci_₄alkylene)-(C₂_6heterocyclyl), C₆-ioaryl, -(Ci_₄alkylene)-(C6-ioaryl), 5- 10 membered heteroaryl, -(Ci_₄alkylene)-(5-10 membered heteroaryl) and 3-8 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, -CN, N₃, -OH, -NH₂, Ci_₄alkoxy or Ci_₄alkylamino.

2. The compound according to claim 1, wherein each R¹, R², R³, R⁴, R⁵ and R⁶ is independently H or D.

3. The compound according to claim 1, wherein X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, Br, -Ci_ ₃alkyl or -Ci_₃haloalkyl.

4. The compound according to claim 1, wherein Y is phenyl or 5-6 membered heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from O, S or N, wherein the phenyl and the said 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F or CI.

5. The compound according to claim 1, wherein Z is C₅_iospirobicyclyl or -(Ci_₃ alkylene)-(C₅_ioSpirobicyclyl), provided that, when Z is C₅_iospirobicyclyl, the cyclic structure directly attached to Y is a C₃_5heterocyclic ring, wherein the Cs-iospirobicyclyl and -(Ci_₃alkylene)-(C5-iospirobicyclyl) are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a,-NR^aR^b, Ci_₃alkyl, Ci_₃haloalkyl, - (Ci_₃alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

6. The compound according to claim 1, wherein each R^a and R^b is independently H, Ci_₃alkyl, C₃_₆cycloalkyl or -(Ci_₃alkylene)-(C₃-₆cycloalkyl), or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 3-6 membered heterocyclyl, wherein Ci_₃alkyl, C₃_₆ cycloalkyl, -(Ci_₃alkylene)-(C₃_₆cycloalkyl) and 3-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

7. The compound according to claim 1, wherein each R¹, R², R³, R⁴, R⁵ and R⁶ is H.

8. The compound according to claim 1, wherein X is phenyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI or -CF₃.

9. The compound according to claim 1, wherein Y is 5-6 membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O or N, wherein the said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from D or F.

10. The compound according to claim 1, wherein Z is selected from the following substructures:

or a stereoisomer thereof, wherein each W and W is independently O, NH or N(Ci-C₃alkyl); Z is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, -OR^a, -NR^aR^b, Ci_₃ alkyl, Ci_₃haloalkyl, -(Ci_₃alkylene)-OR^a or -(Ci_₃alkylene)-NR^aR^b.

11. The compound according to claim 1 , wherein each R^a and R^b is independently H or Ci_₃ alkyl, or, when R^a and R^b are attached to the same nitrogen atom, R^a and R^b, together with the nitrogen atom they are attached to, optionally form a 5-6 membered heterocyclyl, wherein the Ci_₃alkyl and 5-6 membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

12. The compound of claim 1 having one of the following structures:

84

claims 1 to 12 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

14. The pharmaceutical composition according to claim 13 further comprising a therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.

15. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof.

16. A method of preventing, managing, treating or lessening the severity of a proliferative disorder in a patient with the compound according to any one of claims 1 to 12 or the pharmaceutical composition according to any one of claims 13 to 15.

The compound according to any of claims 1 to 12 or the pharmaceutical composition according to any of claims 13 to 15 for use in preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.

17. The method according to claim 16, wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.

The compound or pharmaceutical composition for use according to claim 16, wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.

18. A method of inhibiting or modulating protein kinase activity in a biological sample comprising contacting a biological sample with the compound according to any of claims 1 to 12 or the pharmaceutical composition according to any of claims 13 to 15.

19. The method of claim 18, wherein the protein kinases are receptor tyrosine kinases.

20. The method of claim 19, wherein the receptor tyrosine kinases are ALK and c-Met.