WO2013138210A1 - Substituted cyclic compounds and methods of use - Google Patents

Substituted cyclic compounds and methods of use Download PDF

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WO2013138210A1
WO2013138210A1 PCT/US2013/030096 US2013030096W WO2013138210A1 WO 2013138210 A1 WO2013138210 A1 WO 2013138210A1 US 2013030096 W US2013030096 W US 2013030096W WO 2013138210 A1 WO2013138210 A1 WO 2013138210A1
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alkylene
mmol
cancer
etoac
heterocyclyl
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PCT/US2013/030096
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French (fr)
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Ning Xi
Tingjin WANG
Lei Yi
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Ning Xi
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to novel substituted cyclic compounds, and salts thereof, which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
  • 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.
  • 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.
  • a partial list of such kinases include abl, AATK, ALK, Akt, Axl, bmx, bcr-abl,
  • Receptor tyrosine kinases 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.
  • RTKs Receptor tyrosine kinases
  • Receptor tyrosine kinases 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).
  • ALK Anaplastic lymphoma kinase
  • NPM anaplastic large-cell lymphoma
  • 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: signalling in development and disease" Biochem.J. 2009, 420, 345).
  • EML4-ALK fusion gene comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene were identified in NSCLC cells.
  • 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" NaturelWl, 448, 561).
  • 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. Cancer200S, 8, 11 ; Barreca, A.; et al. "Anaplastic lymphoma kinase (ALK) in human cancer" J. Mol. Endocrinol. 2011, 47, Rl 1).
  • c-Met also referred to as hepatocyte growth factor receptor (HGFR)
  • HGFR hepatocyte growth factor receptor
  • HGF hepatocyte growth factor
  • SF scatter factor
  • 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.
  • 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.
  • 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.
  • 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).
  • crizotinib 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 DiscoverylQW, 10, 897).
  • 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.
  • the present invention provides new compounds and methods for treating cell proliferative diseases.
  • the compounds of the invention are inhibitors of protein tyrosine kinases.
  • 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.
  • ALK including ALK fusions such as EML4-ALK, NPM-ALK, etc.
  • c-Met receptor hepatocyte growth factor receptor
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z is as defined herein.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F;
  • each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N 3 , Ci_ 6 alkyl, Ci_ 6 haloalkyl, -CN, -OH, -OR a , - NR b R c , -(Ci_ 4 alkylene)-CN, -(C M alkylene)-OH, -(Ci_ 4 alkylene)-OR a or -(C ⁇ alkylene)- NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
  • R is Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 - 6 heterocyclyl, C6-ioaryl, C 1 -9 heteroaryl, -(Ci ⁇ alkylene)-(C 3 _ 6 cycloalkyl), -(Ci ⁇ alkylene)-(C 3 _ 6 heterocyclyl),
  • C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci_ 6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 6 alkylene)-(C 6 -ioaryl) and -(Ci_ 6 alkylene)-(Ci_ 9 heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H or D.
  • Z is
  • C 5 _i 2 fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , -(Ci_ 3 alkylene)- CN, -(Ci_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , - (Ci_ 3 alkylene)-CN, -(d_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
  • R is independently
  • each R b and R c is independently H, C3-6 cycloalkyl or -(Ci_ 3 alkylene)-(C 3 _ 6 cycloalkyl); or R b and R c , together with the nitrogen atom they are attached to, optionally form C3_ 6 heterocyclyl; wherein the C3_ 6 cycloalkyl, - (Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) and C3_ 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • X is independently O or NH
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(Ci_
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • each W and W is independently O, NH or N(Ci_ 3 alkyl)-;
  • each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(C 1-3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer herein is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)- OR a or -(Ci_ 3 alkylene)-NR b R c .
  • R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H or C 1-2 alkyl; or R b and
  • R c together with the nitrogen atom they are attached to, optionally form C3-6heterocyclyl; wherein the and C3- 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • 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.
  • the compound is an inhibitor of protein tyrosine kinase.
  • the compound is an inhibitor of ALK receptor signaling and HGF receptor signaling.
  • the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent.
  • the therapeutic agent is a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.
  • the therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol
  • kits 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.
  • 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.
  • the proliferative disorder is metastatic cancer.
  • 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.
  • the proliferative disorder is atherosclerosis or lung fibrosis.
  • a method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.
  • the protein kinase is a receptor tyrosine kinase.
  • the receptor tyrosine kinase is ALK and/or c-Met.
  • a method of inhibiting protein tyrosine kinase comprises contacting the kinase with the compound disclosed herein, or with the composition disclosed herein.
  • a method of inhibiting ALK receptor signaling and/or HGF receptor signaling comprises contacting the receptor with the compound disclosed herein, or with the pharmaceutical composition disclosed herein.
  • inhibition of receptor protein kinase activity 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.
  • a method of inhibiting proliferative activity of a cell comprising 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.
  • a method of treating a cell proliferative disease in a patient comprising 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.
  • a method of inhibiting tumor growth in a patient 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.
  • provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).
  • 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.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted”.
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • a 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.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • 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 (-CDH 2 ), two of deuterium atoms may attached to a methyl group to form a di-deuterated methyl (-CD 2 H), and three of deuterium atoms may attached to a methyl group to form a tri-deuterated methyl group (-CD 3 ).
  • N 3 denotes an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, Me s); or attached to a phenyl group to form phenyl azide (PI1N 3 ).
  • halogen means F, CI, Br or I.
  • 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.
  • alkyl radicals include, but are not limited to, methyl (Me, -CH 3 ), ethyl
  • alkyl and the prefix “alk-” as used herein, are inclusive of both straight chain and branched saturated carbon chain.
  • alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, alkylene groups include 1-10 carbon atoms. In some embodiments, alkyl groups contain 1-6 carbon atoms. In other embodiments, alkyl groups contain 1-4 carbon atoms. In still other embodiments, alkyl groups contain 1-3 carbon atoms. Examples of alkylene radicals include, but are not limited to,methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms 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), 2-propynyl (propargyl, -CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon atom through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1-20 carbon atoms. In some embodiments, alkoxy groups contain 1-10 carbon atoms. In other embodiments, alkoxy groups contain 1-8 carbon atoms. In still other embodiments, alkoxy groups contain 1-6 carbon atoms, and in yet other embodiments, alkoxy groups contain 1-4 carbon atoms.
  • alkoxy radicals include, but are not limited to, methoxy (MeO, -
  • 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, ⁇ , ⁇ -diethylamino, and the like.
  • 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.
  • Carbocycle 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.
  • cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated ring having
  • a cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments, a cycloalkyl contains 3 to 6 carbon atoms.
  • the cycloalkyl radicals are optionally substituted independently with one or more substituents described herein.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR (as in N- substituted pyrrolidinyl).
  • heterocycle 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.
  • the "heterocycle”, “heterocyclyl”, “heterocyclic ring'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 SO2, PO or PO2, with the proviso that when the ring is a 3-membered ring, there is only one heteroatm).
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, 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-dioxo
  • the heterocycle groups herein are optionally substituted independently with one or more substituents described herein.
  • aryl and "aryl ring” interchangeably used herein, refer to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3-7 ring members and that has a single point of attachment to the rest of the molecule.
  • aryl rings would include phenyl, naphthyl, anthracene, and the like.
  • heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen 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 5-7 ring members and that has a single point of attachment to the rest of the molecule.
  • heteroaryl 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
  • 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.
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO 2 H.
  • fused bicyclic “fused bicyclic”, “fused cyclic”, “fused bicyclyl” or “fused cyclyl” refer to saturated bridged ring system which has a C-C bond shared between two five-membered rings (Structure a), two six-membered rings (Structure b) and one five-membered ring and one six-membered ring (Structure c), as depicted in Structures a-c.
  • Each cyclic ring in a fused bicyclyl can be either a carbocyclic or a heterocyclic.
  • fused bicyclyl examples include hexahydrofuro[2,3-b]furan-
  • a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the rings to which it is attached.
  • Structure d represents possible substitution in any of the positions on the B ring shown in Structure e.
  • 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.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • prodrug 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 (d-C 24 ) esters, 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.
  • prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_4 alkyl)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, C 1-8 sulfonate and aryl sulfonate.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • 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, i-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • 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 -CH 2 CH 2 SO 2 PI1, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxy-methy-1, 2-(p-toluenesulfonyl) ethyl, 2-(p- nitrophenylsulfenyl)-ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • 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.
  • 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 a compound of Formula (I):
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z is as defined herein.
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F;
  • each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N 3 , Ci_ 6 alkyl, Ci_ 6 haloalkyl, -CN, -OH, -OR a , - NR b R c , -(Ci_ 4 alkylene)-CN, -(C M alkylene)-OH, -(Ci_ 4 alkylene)-OR a and -(Ci_ 4 alkylene)- NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
  • R is Ci_ 6 alkyl, C 3 _ 6 cycloalkyl, C 3 - 6 heterocyclyl, C6-ioaryl, Ci_ 9 heteroaryl, -(Ci_ 4 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci ⁇ alkylene)-(C 3 _ 6 heterocyclyl), -(Ci- 4 alkylene)- (C6-ioaryl) or Ci- 6 alkynyl, C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci ⁇ alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 4 alkylene)-(C 3 - 6 cycloalkyl), -(Ci_ 4 alkylene)-(C 6 -ioaryl) and -(Ci ⁇ alkylene)-(Ci_ 9 heteroaryl
  • each R b and R c is independently H, Ci- 6 alkyl, C 3 _ 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci_ 9 heteroaryl, -(Ci_ 6 alkylene)-(C 3 _ 6 cycloalkyl), -(Ci_ 6 alkylene)-(C 3 _ 6 heterocyclyl), -(Ci- 6 alkylene)- (C6-ioaryl) or -(Ci_ 6 alkylene)-(Ci_ 9 heteroaryl); or R b and R c , together with the nitrogen atom they are attached to, optionally form C 3 _ 6 heterocyclyl; wherein the Ci- 6 alkynyl, C 3 - 6 cycloalkyl, C 3 _ 6 heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci- 6 alkylene)-(C 3 _ 6 cycloal
  • each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H or D.
  • bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N 3 , Ci_ 3 alkyl, Ci_ 3 haloalkyl, -CN, -OH, -OR a , -NR b R c , - (Ci_ 3 alkylene)-CN, -(Ci_ 3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a and -(Ci_ 3 alkylene)-NR b R c , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
  • R is independently Ci_ 3 alkyl, Ci_ 3 alkenyl, Ci_ 3 alkynyl, C 3 _
  • Ci_ 3 alkyl, Ci_ 3 alkenyl, Ci_ 3 alkynyl, C 3 _ 6 cycloalkyl and -(Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H, Ci_ 3 alkyl, C 3 _
  • Ci_ 3 alkyl, C 3 _ 6 cycloalkyl, - (Ci- 3 alkylene)-(C 3 _ 6 cycloalkyl) and C 3 _ 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • X is independently O or NH
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, C 1-3 haloalkyl, -OH, -OR , -NR b R c , -(C 1-3 alkylene)-OH, -(Ci_ 3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c , provided that when n is 1, 2 or 3, the said Z is not substituted with one hydroxyl (OH) group, the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine.
  • Z is selected from the following structures:
  • n 0, 1, 2 or 3;
  • each W and W is independently O, NH or N(Ci_ 3 alkyl)-;
  • each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR , - NR b R c , -(d_ 3 alkylene)- OH, -(C 1 _ 3 alkylene)-OR a or -(d_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_ 3 haloalkyl, -OH, -OR , -NR b R c , -(Ci_
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, d_ 3 haloalkyl, -OR a , -NR b R c , -(d_ 3 alkylene)-OH, -(Ci -3 alkylene)-OR a or -(Ci_ 3 alkylene)-NR b R c .
  • Z is selected from the following structures:
  • each hydrogen in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_ 3 alkyl, Ci_ 3 haloalkyl, -OH, -OR a , -NR b R c , -(Ci_ 3 alkylene)- OH, -(Ci_ 3 alkylene)- OR a and -(Ci_ 3 alkylene)-NR b R c .
  • R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • each R b and R c is independently H or C 1-2 alkyl; or R b and R c , together with the nitrogen atom they are attached to, optionally form C3- 6 heterocyclyl; wherein the and C3- 6 heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
  • 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.
  • 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.
  • 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).
  • the salt is a pharmaceutically acceptable salt.
  • 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.
  • 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).
  • 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.
  • an inorganic acid such as hydrochloric acid, hydrobro
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable carrier 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.
  • 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;
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
  • 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.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • 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.
  • 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.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories 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.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • 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 low intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • the oral compositions can also include adj
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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.
  • dissolving or suspending the compound in an oil vehicle accomplishes delayed absorption of a parenterally administered compound form.
  • 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.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • 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.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • buffering agents include polymeric substances and waxes.
  • 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.
  • 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.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form 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.
  • 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.
  • 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-proliferative diseases such as cancer.
  • 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.
  • 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”.
  • additional therapeutic agents is meant to include chemotherapeutic agents and other anti-proliferative agents.
  • chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of this invention to treat proliferative disease or cancer.
  • 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 6,506,73
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • 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 (paclitaxel, taxotere), platinum derivatives (cisplatin, carboplatin, oxaliplatin), 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., antieme
  • the compounds of the present invention can be combined, with cytotoxic anti-cancer agents.
  • cytotoxic anti-cancer agents examples 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, proc
  • 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).
  • agents include, by no way of limitation, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2,2'-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, P
  • 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. Oncology2003, 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).
  • cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology2003, 21(4),
  • 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
  • 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).
  • SAHA suberoylanilide hydroxamic acid
  • 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
  • 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.
  • those additional agents may be administered separately from the compound- containing composition, as part of a multiple dosage regimen.
  • 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.
  • 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.
  • 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.
  • 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.
  • diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis and lung fibrosis.
  • neoplasm 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, gallbladder, 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, myelodysplastic syndrome and promyelocytic leukemia); tumors of lymphoid lineage (including acute and chronic myelogenous
  • 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).
  • the compounds also would be useful for treatment of ophthalmological 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.
  • 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.
  • the compounds of the present invention include the pharmaceutically acceptable derivatives thereof.
  • the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • biological sample 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.
  • an “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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
  • MS data were generally determined on an Agilent 1200 Series LCMS (Zorbax SB-C18, 2.1 x 30 mm, 4 micorn, 10 minutes run, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 0)) with UV detection at 210/254 nm and a low resonance electrospray mode (ESI).
  • Agilent 1200 Series LCMS Zorbax SB-C18, 2.1 x 30 mm, 4 micorn, 10 minutes run, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 0)
  • UV detection at 210/254 nm
  • ESI low resonance electrospray mode
  • the desired kinase inhibitor (7) disclosed hererin can be prepared in a method illustrated in Scheme 1.
  • (R)-aryl alcohol (1) 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).
  • kinase inhibtor (7) in this invention may be synthesized through the procedure depicted in Scheme 2.
  • the intermediate (5) and (Boc) 2 0 is treated with a base such as a 2 C0 3 , aHC0 3 or Et 3 N 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)Cl 2 -CH 2 Cl 2 or Pd(PPh 3 ) 2 Cl 2 in an aprotic solvent (for example, DMSO, DMF or dioxane) to afford a boronic acid derivative (9).
  • an aprotic solvent for example, DMSO, DMF or dioxane
  • the preferred bases for the coupling reaction include NaHC(3 ⁇ 4, KHC0 3 , Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , and others.
  • the reaction is preferably performed in a mixed solvent such as DME/H 0, dioxane/H 0, at a temperature ranging from 70 °C to 100 °C.
  • Boc- group and other PG group are all removed under acidic conditions, for example, trifluoroacetic acid (TFA) in DCM, or HCl in ethyl acetate or ethyl ether to afford the desired kinase inhibitor (7).
  • TFA trifluoroacetic acid
  • Step 9) N,N-bis(tert-butoxycarboxyl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- fluorotetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 10 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l -(4-fluorotetrahvdrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Step 1 4-iodo- 1 -(4-((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3 -yl)- 1 H-pyrazole
  • Step 2 N.N-bis(ter/-butoxycarbonyl)-3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- ((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 3) 4-(4-(6-amino-5-((R)-l -(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- !H-pyrazol- 1 - yl)tetrahydrofuran-3 -ol
  • Step 2) l-(tert-butoxycarbonyl)-2,5-dihvdro-lH-pyrrole
  • Step 6) 1 -( 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3 -yl)-4-iodo- 1 H-pyrazole
  • Step 7) 1 -(1 -(ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl- 1 ,3 ,2- dioxaborolan-2-yl)- IH-pyrazole
  • Step 8) 5-(l -(1 -( ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)- lH-pyrazol-4-yl)-3-( (R)- 1 -(2.6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 9) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-fluoropyrrolidin-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Step 1) 1 -CI -( ' ter?-butoxycarbonyl -4-( ' ( ' tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-3 -yl)-4-iodo- lH-pyrazole
  • Step 2 N.N-bisCter/-butoxycarbonyl)-5 -C 1 -C 1 -Cter/-butoxycarbonyl)-4-CCtetrahydro-2H-pyran-2- yl)oxy)pyrrolidin-3 -yl)- lH-pyrazol-4-yl)-3 -((R)- 1 -C2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin- 2 -amine
  • Step 3 4-(4-(6-amino-5-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l- yl)pyrroridin-3-ol
  • Step 2) ⁇ ((Syi-l-ftert-butoxycarbonyD-S-faethoxycarbonyDpyrrolidin-S-yD ⁇ -iodo-lH- pyrazole
  • Step 5 C( ' 2S)-4-( ' 4-( ' 6-amino-5-( ' ( ' R)-l-( ' 2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)- 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol
  • Step 6 ((2S)-4-(4-(6-amino-5-( ' ( ' R)-l-( ' 2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)pyrrolidin-2-yl)methanol
  • Step 2) (SV 1 -( 1 -(tert-butoxycarbonyl)pyrrolidin-3 -yl -4-iodo- 1 H-pyrazole
  • Step 5 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-3-yl)-lH- pyrazol-4- yl)pyridin-2-amine
  • Example 7 3- /?)-1- 2,6- ⁇ € ⁇ -3- ⁇ 6 ⁇ 1)6 ⁇ )-5- 1- 4,4-( ⁇ 6 ⁇ 1 ⁇ 6 ⁇ 3 ⁇ -2- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 4) l-((4,4-dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)- lH-pyrazole
  • Step 5 3-((R)- 1 -(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l -((4.4-dimethyloxetan-2-yl)methyl)- 1 H-pyrazol-4-yl)pyridin-2-amine
  • Step 2) l-(tert-butoxycarboxyl)-3-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol
  • Step 2) (S)- 1 -(( 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
  • Example 6 Step 2 by using a suspension of 4-iodo-lH-pyrazole(840mg, 7.4mmol), (5)-(l-(tert- butoxycarbonyl)pyrrolidin-2-yl)methyl methanesulfonate(1.4g) and NaH(320mg, 12mmol, 90% dispersion in mineral oil)in DMF (20 mL).
  • Step 4) 5-q -((YSV 1 -( ' tert-butoxycarbonvnpyrrolidin-2-vnmethvn- lH-pyrazol-4-vn-3 -((TO- 1 - (2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 5 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-2-yl methyl)-lH- pyrazol-4-yl)pyridin-2-amine
  • Example 6 Step 5 by using a solution of 5-(l-(((5)-l-(?ert-butoxycarbonyl)pyrrolidin-2- yl)methyl)- lH-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine (160mg, 0.29mmol) and HCl (5 mL, 1 M in EtOAc)in EtOAc to afford the title compound as a yellow solid(60mg, 46%).
  • Step4) 1 -(((2 S)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
  • Step 5 l-(((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-(4.4.5.5-tetramethyl- 1.3-dioxolan-2-yl)-lH-pyrazole
  • Step6)5 ( 1 -(((2 S)- 1 -(tert-butoxycarbonyl -4-fluoropyrrolidin-2-yl methyl - 1 H-pyrazol-4-yl - 3 - ((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-2-amine
  • Step3 ((2S -l-(tert-butoxycarboxyl -4-((tetrahydro-2H-pyran-2-yl oxy pyrrolidin-2-yl methyl methanesulfonate
  • Step4) l-(((2S)-l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yl)methyl)-4-iodo- lH-pyrazole
  • Step 1) 1 -(((2S)- 1 -( ' tert-butoxycarbonyl -4-( ' ( ' tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-2- yl)methyl)-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazole
  • Step 2) 5-(l-(((2S)- l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yPmethyl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine
  • Example 13 4- 6-amino-5- J R)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH- Pyrazol-l-yl)tetrahvdro-2H-pyran-3-ol (13 a) and
  • Step l) l -(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate
  • MsCl 8.6 g, 59 mmol
  • the reaction was stirred at rt for 2 h. then diluted with DCM (100 mL), and washed with saturated aqueous a 2 CO 3 (250 mL) followed by brine (250 mL).
  • the organic phase was dried over anhydrous a 2 S0 4 , and concentrated in vacuoto obtain the crude compound as yellow oil (14 g, 97 %), which was used for the next step without further purification.
  • Step 2) l-(tert-butoxycarboxyl)-L2,3,6-tetrahvdropyridine
  • Step 6) 1 -(tert-butoxycarboxyl)-3 -((tetrahydro-2H-pyran-2-yl)oxy)- 1 ,2,3 ,6-tetrahydropyridine
  • Step 9) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -one
  • Step 10) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -ol
  • Step 12 l-(tert-butoxycarbonyl)-3-fluoro-5-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -vDpiperidine
  • Step 13) 5-(1-(1 -(tert-butoxycarbonyl)-5-fruoropiperidin-3 -yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2 ,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 14 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(5-fluoropiperidin-3-yl)- 1H- pyrazol-4-yl)pyridin-2-amine
  • Step 1)1 -(ter/-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- !H-pyrazol- l-yl)piperidin-3-ol
  • Step 7) 5-q -(2.2 -dideuteropiperidin-4-yl - 1 H-pyrazol-4-ylV 3 -(YRV 1 -(2.6-dichloro-3 - fluorophenyl)ethoxy)pyridin-2-amine
  • Step 1) l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)piperidin-3-ol(17.1 a)
  • Step 2) 1 -(tert-butoxycarbonyl)-4-(4-iodo- 1 H-pyrazol- 1 -yl)-3 -((tetrahydro-2H-pyran-2- yl)oxy)piperidine
  • Step 3 l-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(4-(4.4.5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine
  • Step 4) 5-( 1 -(1 -(tert-butoxycarbonyl)-3 -((tetrahvdro-2H-pyran-2-yl)oxy)piperidin-4-yl)- 1 H- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 7) 3 -((R)- 1 -(2.6-dichloro-3 -fluorophenyl)ethoxy)-5-( 1 -((3 S.4RV3 -fluoropiperidin-4-yl)- 1 H- pyrazol-4-yl)pyridin-2-amine(l 7 a)
  • Step 1) 1 -(tert-butoxycarbonyl)-3 -(4-iodo- 1 H-pyrazol- 1 -yl)-4-((tetrahydro-2H-pyran-2- yl)oxy)piperidine
  • Step 2) 1 -(tert-butoxycarbonyl)-4-((tetrahvdro-2H-pyran-2-yl)oxy)-3 -(4-(4 ,4,5 ,5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-l H-pyrazol- 1-vDpiperi dine [0277]
  • the title compound was prepared according to the procedure described in Example 17 Step 3 by using a suspension of l-(tert-butoxycarbonyl)-3-(4-iodo-lH-pyrazol-l- yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine (0.6 g, 1.25 mmol), bis(pinacolato)diboron (0.9 g, 3.8 mmol), KOAc(0.25 g, 2.5 mmol) and Pd(dppf)Cl 2 -CH 2 Cl 2 (0.1 g, 0.125 mmol)
  • Step 3) 5-(l-(l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-3-yl)-lH- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
  • Step 5 3-( ' ( ' R -l-( ' 2,6-dichloro-3-fluorophenyl ethoxy -5-( ' l-( ' ( ' hexahvdrofuror2,3-/?1 furan-3- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 4) l-((3a5',65',6aR)-6-((tetrahvdro-2H-pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-4- (4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)- lH-pyrazole
  • Step 5 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((3a .65'.6aR)-6-((tetra- hydro-2H- pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 6 (3 ,3a5',6ay)-6-(4-(6-amino-5-((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-3-yl)- lH-pyrazol-l-yl)hexahydrofuro[3.2-/?]furan-3-ol
  • Example 23 4- g)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- (octahvdrocvclopenta[clpyrrol-5-yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • Step 2) 2,2'-(l-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid
  • Step 9) 4-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(octahvdrocyclopentarc1 pyrrol-5- yl)-lH-pyrazol-4-yl)pyridin-2-amine
  • 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.
  • 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.

Abstract

The present invention provides novel substituted cyclic 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 CYCLIC COMPOUNDS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
[001] This application claims the benefit of U.S. Provisional Application No.
61/610,473, filed March 14, 2012, and 61/617,626, filed March 29, 2012, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[002] This invention relates to novel substituted cyclic 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, CDK10, cRafl, CSF1R, CSK, DDR1, 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 ( PM)-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" Sciencel994, 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: signalling 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" NaturelWl, 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. Cancer200S, 8, 11 ; Barreca, A.; et al. "Anaplastic lymphoma kinase (ALK) in human cancer" J. Mol. Endocrinol. 2011, 47, Rl 1).
[01 1] 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 Medicine200S, 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 Letter 2009, 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 Research 2009, 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 DiscoverylQW, 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):
Figure imgf000006_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each R1, R2, R3, R4, R5, R6 and Z is as defined herein.
[021] In certain embodiments, each R1, R2, R3, R4, R5 and R6 is independently H, D or F;
Z is
(1) C3_7heterocyclyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(CMalkylene)-CN, -(Ci_ 4alkylene)-OH, -(Ci_4alkylene)-ORa or -(Ci_4alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-deuterium- piperidin-4-yl)- 1 H-pyrazol-4-yl)pyridin-2-amine,
(2) -(Ci^alkylene)-(C3_7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(CMalkylene)-OH, -(Ci-4alkylene)-OR or -(Ci_4alkylene)-NRbRc, provided that the said -(C3_7heterocyclyl) is not substituted with one hydroxyl (OH) group,
(3) C5-12 fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently
selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_ 4alkylene)-CN, -(CMalkylene)-OH, -(CMalkylene)-ORa or -(Ci_4alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
(4)
Figure imgf000007_0001
bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, - NRbRc, -(Ci_4alkylene)-CN, -(CMalkylene)-OH, -(Ci_4alkylene)-ORa or -(C^alkylene)- NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
R is Ci_6alkyl,
Figure imgf000007_0002
C3_6cycloalkyl, C3-6heterocyclyl, C6-ioaryl, C1-9 heteroaryl, -(Ci^alkylene)-(C3_6cycloalkyl), -(Ci^alkylene)-(C3_6heterocyclyl),
Figure imgf000007_0003
(C6-ioaryl), or -(Ci^alkylene)-(Ci_9heteroaryl), wherein the Ci_6alkyl, Ci_6alkenyl, Ci_6alkynyl, C3_6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci_9heteroaryl, -(Ci^alkylene)-(C3_6cycloalkyl), -(Ci_4 alkylene)-(C3_6cycloalkyl),
Figure imgf000007_0004
and -(Ci_4alkylene)-(Ci_9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy or alkylamino; and each Rb and Rc is independently H, Ci-6alkyl, C3_6cycloalkyl, C3-6heterocyclyl, C6-ioaryl, C1-9 heteroaryl, -(Ci_6alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C3_6heterocyclyl),
Figure imgf000008_0001
(C6-ioaryl) or -(Ci_6alkylene)-(Ci_9heteroaryl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the Ci-6alkyl, Ci-6alkenyl,
Figure imgf000008_0002
C3-6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci_6alkylene)-(C3_6cycloalkyl), -(Ci_6 alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C6-ioaryl) and -(Ci_6alkylene)-(Ci_9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy or alkylamino.
[022] In another embodiment, each R1, R2, R3, R4, R5 and R6 is independently H or D.
[023] In another embodiment, Z is
(1) C3_7heterocyclyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-CN, -(Ci_3alkylene)- OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-deuterium- piperidin-4-yl)- 1 H-pyrazol-4-yl)pyridin-2-amine,
(2) -(Ci^alkylene)-(C3_7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, C1_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(C^alkylene OH, -(d_3 alkylene)-OR or -(Ci_3alkylene)-NRbRc, provided that the said -(C3_7heterocyclyl) is not substituted with one hydroxyl (OH) group,
(3) C5_i2fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)- CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
(4)
Figure imgf000008_0003
bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, - (Ci_3alkylene)-CN, -(d_3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
[024] In another embodiment, R is independently
C3_6cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); wherei
Figure imgf000008_0004
3alkynyl, C3_6cycloalkyl and -(Ci-3alkylene)-(C3_6cycloalkyl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[025] In another embodiment, each Rb and Rc is independently H,
Figure imgf000009_0001
C3-6 cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the
Figure imgf000009_0002
C3_6cycloalkyl, - (Ci-3alkylene)-(C3_6cycloalkyl) and C3_6heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[026] In another embodiment, Z is selected from the following structures:
Figure imgf000009_0003
or a stereoisomer thereof, wherein
n is 0, 1, 2 or 3;
X is independently O or NH; and
each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_3haloalkyl, -OH, -OR , -NRbRc, -(Ci_
3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, provided that
• when n is 1, 2 or 3, the said Z is not substituted with one hydroxyl (OH) group,
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- deuterium- piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine.
[027] In another embodiment, Z is selected from the following structures:
Figure imgf000010_0001
or a stereoisomer thereof, wherein
n is 0, 1, 2 or 3;
each W and W is independently O, NH or N(Ci_3alkyl)-; and
each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_3alkyl, Ci_3haloalkyl, -OH, -OR , - NRbRc, -(Ci_3alkylene)- OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc.
[028] In another embodiment, Z is selected from the following structures:
Figure imgf000010_0002
or a stereoisomer thereof, wherein
each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_3haloalkyl, -OH, -OR , -NRbRc, -(C1-3 alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc.
[029] In another embodiment, Z is selected from the following structures:
Figure imgf000011_0001
or a stereoisomer thereof, wherein
each hydrogen in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents
independently selected from D, F, Ci_3haloalkyl, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_ 3alkylene)-ORa or -(Ci_3alkylene)-NRbRc.
[030] In another embodiment, Z is selected from the following structures:
Figure imgf000011_0002
or a stereoisomer thereof, wherein
each hydrogen in Z or its stereoisomer herein is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_3alkyl, Ci_3haloalkyl, -OH, -OR , - NRbRc, -(Ci_3alkylene)- OH, -(Ci_3alkylene)- ORa or -(Ci_3alkylene)-NRbRc.
[031] In another embodiment, R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F. [032] In another embodiment, each Rb and Rc is independently H or C1-2alkyl; or Rb and
Rc, together with the nitrogen atom they are attached to, optionally form C3-6heterocyclyl; wherein the
Figure imgf000012_0001
and C3-6heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[033] 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.
[034] 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 fibrosis or a combination thereof.
[035] In certain embodiments, the therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, 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, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, tositumomab, trastuzumab, or a combination thereof.
[036] 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.
[037] 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.
[038] 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.
[039] In another aspect, provided herein is a method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.
[040] In some embodiments, the protein kinase is a receptor tyrosine kinase. In other embodiments, the receptor tyrosine kinase is ALK and/or c-Met.
[041] 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.
[042] 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.
[043] 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.
[044] 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.
[045] 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.
[046] In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).
[047] 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
[048] 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.
[049] 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 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.
[050] 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, a 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.
[051 ] The term "unsaturated" as used herein, means that a moiety has one or more units of unsaturation.
[052] The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.
[053] The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
[054] The term "D" or "2H" 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).
[055] The term "N3" denotes an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, Me s); or attached to a phenyl group to form phenyl azide (PI1N3).
[056] The term "halogen" means F, CI, Br or I.
[057] 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.
[058] Examples of alkyl radicals include, but are not limited to, methyl (Me, -CH3), ethyl
(Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2- butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-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.
[059] The terms "alkyl" and the prefix "alk-" as used herein, are inclusive of both straight chain and branched saturated carbon chain.
[060] 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. Unless otherwise specified, alkylene groups include 1-10 carbon atoms. In some embodiments, alkyl groups contain 1-6 carbon atoms. In other embodiments, alkyl groups contain 1-4 carbon atoms. In still other embodiments, alkyl groups contain 1-3 carbon atoms. Examples of alkylene radicals include, but are not limited to,methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.
[061] 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, sp2 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. [062] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms 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), 2-propynyl (propargyl, -CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.
[063] The term "alkoxy" or "alkoxy group"as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon atom through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1-20 carbon atoms. In some embodiments, alkoxy groups contain 1-10 carbon atoms. In other embodiments, alkoxy groups contain 1-8 carbon atoms. In still other embodiments, alkoxy groups contain 1-6 carbon atoms, and in yet other embodiments, alkoxy groups contain 1-4 carbon atoms.
[064] Examples of alkoxy radicals include, but are not limited to, methoxy (MeO, -
OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l- propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3- methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.
[065] The terms "haloalkyl" or "haloalkoxy" means alkyl, or alkoxy, as described herein, may be substituted with one or more halogen atoms. The examples inculed, but limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like.
[066] 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, Ν,Ν-diethylamino, and the like.
[067] 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.
[068] 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, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like.
[069] The term "cycloalkyl" refers to a monovalent or multivalent saturated ring having
3-12 carbon atoms as a monocyclic ring system. In some embodiments, a cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments, a cycloalkyl contains 3 to 6 carbon atoms. The cycloalkyl radicals are optionally substituted independently with one or more substituents described herein.
[070] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or NR (as in N- substituted pyrrolidinyl).
[071] The terms "heterocycle", "heterocyclyl", "heterocyclic ring" and "heterocyclic" as used interchangeably herein refer 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", "heterocyclic ring'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 SO2, PO or PO2, with the proviso that when the ring is a 3-membered ring, there is only one heteroatm).
[072] The heterocyclyl may be a carbon radical or heteroatom radical. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, 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, pyrazolidinyl, imidazolinyl, imidazolidinyl. 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.
[073] The terms "aryl" and "aryl ring" interchangeably used herein, refer to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3-7 ring members and that has a single point of attachment to the rest of the molecule.Examples of aryl rings would include phenyl, naphthyl, anthracene, and the like.
[074] The terms "heteroaryl","heteroaryl ring"and "heteroaromatic"used interchangeably herein refer to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen 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 5-7 ring members and that has a single point of attachment to the rest of the molecule.
[075] Further examples of heteroaryl 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), isoquinolinyl (e.g., 1 -isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), and the like.
[076] 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. [077] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO2H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=0)-.
[078] The terms "fused bicyclic", "fused cyclic", "fused bicyclyl" or "fused cyclyl" refer to saturated bridged ring system which has a C-C bond shared between two five-membered rings (Structure a), two six-membered rings (Structure b) and one five-membered ring and one six-membered ring (Structure c), as depicted in Structures a-c. Each cyclic ring in a fused bicyclyl can be either a carbocyclic or a heterocyclic.
Figure imgf000020_0001
Structure a Structure b Structure c
[079] Some non-limiting examples of fused bicyclyl include hexahydrofuro[2,3-b]furan-
3-yl, hexahydrofuro[3,2-b]furan-3-yl, octahydrocyclopenta[c]pyrrol-5-yl, octahydropentalen-2- yl, octahydro-lH-isoindol-5-yl, and the like.
[080] 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 d represents possible substitution in any of the positions on the B ring shown in Structure e.
Figure imgf000020_0002
Structure d Structure e
[081] 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.
[082] 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.
[083] 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.
[084] 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 (d-C24) esters, 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.
[085] 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.
[086] 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 L or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or L 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.
[087] 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 Sciencesl977, 66, 1-19, 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, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci_4 alkyl)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, C1-8 sulfonate and aryl sulfonate.
[088] 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.
[089] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with 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, i-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxycarbonyl (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 -CH2CH2SO2PI1, 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
[090] 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 a compound of Formula (I):
Figure imgf000024_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each R1, R2, R3, R4, R5, R6 and Z is as defined herein.
[091] In certain embodiments, each R1, R2, R3, R4, R5 and R6 is independently H, D or F;
Z is
(1) C3_7heterocyclyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(CMalkylene)-CN, -(Ci_ 4alkylene)-OH, -(Ci_4alkylene)-ORa and -(Ci_4alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-deuterium- piperidin-4-yl)- 1 H-pyrazol-4-yl)pyridin-2-amine,
(2) -(Ci^alkylene)-(C3_7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6haloalkyl, -CN,-OH, -ORa, -NRbRc, -(CMalkylene)-OH, -(Ci-4alkylene)-OR or -(Ci_4alkylene)-NRbRc, provided that the said -(C3_7heterocyclyl) is not substituted with one hydroxyl (OH) group,
(3) C5_i2fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently
selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_ 4alkylene)-CN, -(CMalkylene)-OH, -(CMalkylene)-ORa and -(CMalkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
(4)
Figure imgf000024_0002
bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, - NRbRc, -(Ci_4alkylene)-CN, -(CMalkylene)-OH, -(Ci_4alkylene)-ORa and -(Ci_4alkylene)- NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
R is Ci_6alkyl,
Figure imgf000025_0001
C3_6cycloalkyl, C3-6heterocyclyl, C6-ioaryl, Ci_ 9heteroaryl, -(Ci_4alkylene)-(C3_6cycloalkyl), -(Ci^alkylene)-(C3_6heterocyclyl), -(Ci-4alkylene)- (C6-ioaryl) or
Figure imgf000025_0002
Ci-6alkynyl, C3- 6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci^alkylene)-(C3_6cycloalkyl), -(Ci_ 4alkylene)-(C3-6cycloalkyl), -(Ci_4alkylene)-(C6-ioaryl) and -(Ci^alkylene)-(Ci_9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy and alkylamino; and,
each Rb and Rc is independently H, Ci-6alkyl, C3_6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci_ 9heteroaryl, -(Ci_6alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C3_6heterocyclyl), -(Ci-6alkylene)- (C6-ioaryl) or -(Ci_6alkylene)-(Ci_9heteroaryl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the
Figure imgf000025_0003
Ci-6alkynyl, C3-6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci-6alkylene)-(C3_6cycloalkyl), -(Ci_ 6alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C6-ioaryl) and -(Ci_6alkylene)-(Ci_9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy and alkylamino.
[092] In another embodiment, each R1, R2, R3, R4, R5 and R6 is independently H or D.
[093] In another embodiment, Z is
(1) C3_7heterocyclyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, C^alkyl, C1_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(d_3alkylene)-CN, -(d_3alkylene)- OH, -(Ci_3alkylene)-ORa and -(Ci_3alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-deuterium- piperidin-4-yl)- 1 H-pyrazol-4-yl)pyridin-2-amine,
(2) -(Ci^alkylene)-(C3_7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_ 3alkylene)-OR and -(Ci_3alkylene)-NRbRc, provided that the said -(C3_7heterocyclyl) is not substituted with one hydroxyl (OH) group, (3) C5_i2fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci-3alkyl, d_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)- CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa and -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
(4)
Figure imgf000026_0001
bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, - (Ci_3alkylene)-CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa and -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
[094] In another embodiment, R is independently Ci_3alkyl, Ci_3alkenyl, Ci_3alkynyl, C3_
6cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); wherein the Ci_3alkyl, Ci_3alkenyl, Ci_3alkynyl, C3_6cycloalkyl and -(Ci-3alkylene)-(C3_6cycloalkyl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[095] In another embodiment,each Rb and Rc is independently H, Ci_3alkyl, C3_
6cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the Ci_3alkyl, C3_6cycloalkyl, - (Ci-3alkylene)-(C3_6cycloalkyl) and C3_6heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[096] In another embodiment, Z is selected from the following structures:
Figure imgf000026_0002
or a stereoisomer thereof, wherein
n is 0, 1, 2 or 3;
X is independently O or NH; and
each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, C1-3haloalkyl, -OH, -OR , -NRbRc, -(C1-3 alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, provided that when n is 1, 2 or 3, the said Z is not substituted with one hydroxyl (OH) group, the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine.
In another embodiment, Z is selected from the following structures:
Figure imgf000027_0001
or a stereoisomer thereof, wherein
n is 0, 1, 2 or 3;
each W and W is independently O, NH or N(Ci_3alkyl)-; and
each hydrogen on carbon atoms in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_3alkyl, Ci_3haloalkyl, -OH, -OR , - NRbRc, -(d_3alkylene)- OH, -(C1_3alkylene)-ORa or -(d_3alkylene)-NRbRc.
[098] In another embodiment, Z is selected from the following structures:
Figure imgf000027_0002
or a stereoisomer thereof, wherein
each hydrogen on carbon atoms in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_3haloalkyl, -OH, -OR , -NRbRc, -(Ci_
3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc. [099] In another embodiment, Z is selected from the following structures:
Figure imgf000028_0001
or a stereoisomer thereof, wherein
each hydrogen in Z or its stereoisomer is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, d_3haloalkyl, -ORa, -NRbRc, -(d_3alkylene)-OH, -(Ci-3 alkylene)-ORa or -(Ci_3alkylene)-NRbRc.
[0100] In another embodiment, Z is selected from the following structures:
Figure imgf000028_0002
or a stereoisomer thereof, wherein
each hydrogen in Z or its stereoisomer is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, Ci_3alkyl, Ci_3haloalkyl, -OH, -ORa, -NRbRc, -(Ci_ 3alkylene)- OH, -(Ci_3alkylene)- ORa and -(Ci_3alkylene)-NRbRc. [0101] In another embodiment, R is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[0102] In another embodiment, each Rb and Rc is independently H or C1-2alkyl; or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3-6heterocyclyl; wherein the
Figure imgf000029_0001
and C3-6heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
[0103] Some non-limiting examples of the compound disclosed herein, and their pharmaceutically acceptable salts and solvates thereof, are shown in the following:
Figure imgf000029_0002
Figure imgf000030_0001

Figure imgf000031_0001
30
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
[0104] 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. 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.
[0105] 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).
[0106] 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.
[0107] 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.
[0108] 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).
[0109] 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
[0110] 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.
[0111] 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.
[0112] 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.
[01 13] 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; pyrogen-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.
[01 14] 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.
[01 15] 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.
[01 16] 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.
[01 17] 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.
[01 18] 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 low intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[01 19] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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-proliferative 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 anti-proliferative agents.
[0133] 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.
[0134] 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 (paclitaxel, taxotere), platinum derivatives (cisplatin, carboplatin, oxaliplatin), 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 (chlormethine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, etc), anti-metabolites (methotrexate, raltitrexed, pemetrexed, etc), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5- fluorouracil, cytarabine, 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), antiangiogenic 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.
[0135] 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.
[0136] 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, 2,2'-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.
[0137] 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. Oncology2003, 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).
[0138] 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, J J38877605, TKI258, GDC- 0941 (Folkes, et al.J. Med. Chem. 2008, 51 : 5522), BZE235, and others.
[0139] 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).
[0140] 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.
[0141] 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.
[0142] 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 COMPOSITIONS OF THE INVENTION
[0143] 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.
[0144] 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.
[0145] Compounds of the invention would be useful for the treatment of neoplasm 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, gallbladder, 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, myelodysplastic 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).
[0146] The compounds also would be useful for treatment of ophthalmological 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.
[0147] 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.
[0148] 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. [0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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 Ca¾. EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous a2S04 prior use.
[0160] 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.
[0161] Column chromatography was conducted using a silica gel column. Silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory. JH NMR spectra were recorded with a Bruker 400 MHz spectrometer at ambient temperature. ¾ NMR spectra were obtained as CDCI3, de-DMSO, CD3OD or i -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). [0162] Low -resolution mass spectral (MS) data were generally determined on an Agilent 1200 Series LCMS (Zorbax SB-C18, 2.1 x 30 mm, 4 micorn, 10 minutes run, 0.6 mL/min flow rate, 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).
[0163] Purities of compounds were assessed by Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm. Column was normally operated at 40 °C.
[0164] The following abbreviations are used throughout the specification:
BBr3 boron tribromide
ΒΓΝΑΡ 2,2'-bis(diphenylphosphino)-l, l'-binaphthyl
BOC, Boc butyloxycarbonyl
BSA bovine serum albumin
CDCI3 chloroform deuterated
CHCI3 chloroform
CH2CI2, DCM methylene chloride
CH3SO2CI, MsCl methanesulfonyl chloride
CS2CO3 cesium carbonate
Cu copper
Cul copper (I) iodide
DAST Diethylaminosulfur trifluoride
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DEAD dimethyl azodicarboxylate
DHP 3,4-Dihydro-2H-pyran
DIAD diisopropyl azodicarboxylate
DIBAL diisobutylaluminum hydride
DIEA, DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridine DMF dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EDCI 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride
EtOAc, EA ethyl acetate
Et20 diethyl ether
Et3N, TEA triethylamine
FBS fetal bovine serum
Fe iron
g gram
h hour
HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBr hydrobromic acid
HBTU 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HC1 hydrochloric acid
H2 hydrogen
H20 water
H202 hydrogen peroxide
HOAc, AcOH acetic acid
HOBt 1 -hydroxybenzotriazole hydrate
K2CO:, potassium carbonate
KOH potassium hydroxide
LiHMDS lithium bis(trimethylsilyl)amide
LDA Lithium diisopropylamide
MCPBA, m-CPBAmeto-chloroperbenzoic acid
MeCN, CH3CN acetonitrile Mel methyl iodide
MeOH, CH3OH methanol
2-MeTHF 2-methyl tetrahydrofuran
MgS04 magnesium sulfate mL, ml milliliter
MTBE methyl tert-butyl ether
2 nitrogen
NaBH4 sodium borohydride
NaBH?CN Sodium cyanoborohydnde
NaCl sodium chloride
aC102 sodium chlorite
NaH sodium hydride
NaHCO? sodium bicarbonate
NaH2P04 sodium biphosphate
Nal sodium iodide
NaO(7-Bu) sodium te/Y-butoxide
NaOH sodium hydroxide
Na2S04 sodium sulfate
NBS N-bromosuccinimide
NH3 ammonia
NH4C1 ammonium chloride
NIS N-iodosuccinimide
NMP N-methylpyrrolidinone
PBS phosphate buffered saline
P (7-Bu)3 tri(tert-butyl)phosphine
Pd/C palladium on carbon Pd2(dba)3 bis(dibenzylideneacetone) palladium
Pd(dppf)Cl2 l,l-bis(diphenylphosphino)ferrocene palladium chloride
Pd(OAc)2 palladium acetate
Pd(OH)2 palladium hydroxide
Pd(PPh3)4 palladium tetrakis triphenylphosphine
Pd(PPh3)2Cl2bis(triphenylphosphine)palladium(II) chloride
PE petroleum ether (60-90 °C)
POCI3 phosphorous oxychloride
PPTS pyridinium / toluenesulfonate
PyBop benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
TBAB tetrabutylammonium bromide
TBAHS04 tetrabutylammonium hydrogen sulfate
TBTU 0-benzotriazol-l-yl-N,N,N ',N '-tetramethyluronium tetrafluoroborate
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
TEAC bis(ieira-ethylammonium)carbonate
THF tetrahydrofuran
μΙ_, microliter
[0165] Representative synthetic procedures for the preparation of compounds of the disclosure are outlined below in following schemes. Unless othewise indicated, R1, R2, R3, R4, R5, R6 and Z carry the definitions set forth above in connection with Formula (I). Scheme 1
Figure imgf000055_0001
(5) (Z)
[0166] The desired kinase inhibitor (7) disclosed hererin can be prepared in a method illustrated in Scheme 1. (R)-aryl alcohol (1) 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
Figure imgf000056_0001
[0167] 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 a2C03, aHC03 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 NaHC(¾, KHC03, Na2C03, K2C03, Cs2C03, and others. The reaction is preferably performed in a mixed solvent such as DME/H 0, dioxane/H 0, 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 HCl in ethyl acetate or ethyl ether to afford the desired kinase inhibitor (7). Examples
Example 1 3- ?)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- 4-fluorotetrahvdrofuran-3- yl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000057_0001
Step 1) (R)-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine
[0168] To a solution of (R)-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 aHC03 (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
[0169] To a solution of (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (13.4 g, 40.47 mmol) in EtOH (250 mL) was added iron powder (1 1 g, 197 mmol). The mixture was heated at90°C for 20 min, followed by the addition of HCl (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] ; !H NMR (400 MHz, DMSO-i¾) 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) (R)-5-bromo-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0170] To a solution of (R)-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]+;
¾ NMR (400 MHz, DMSO-i¾) 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) (R)-5-bromo-N.N-bis(ter/-butoxycarbonyl)-3-(l-(2.6-dichloro-3-fluorophenyl)ethoxy) pyridin-2-amine
[0171] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (4.5 g, 1 1.8 mmol), DMAP (1.46 g, 1 1.8 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) (R)-NN-bis(ter?-butoxycarbonyl)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5- tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2-amine
[0172] To a suspension of (R)-5-bromo-N,N-bis(?ert-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)Ci2-CH2Ci2 (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 ¾0 (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous a2S04, 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]+; ¾ 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).
Step 6) 3,6-dioxabicyclor3.1.01hexane
[0173] To a solution of 2,5-dihydrofuran(5.3 niL, 71.3 mmol) in DCM (250 mL) was added m-CPBA (24.6 g,142.6 mmol). The reaction was stirred at rt for 48 h, then filtered through a pad of Celite, which was washed with DCM (50 mL). The filtrate was washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo to afford crude product as colorless oil (4.12 g, 67%).
GC-MS m/z:86 (M);
¾ NMR (400 MHz, CDC13) δ (ppm): 3.65-3.65 (d, J= 10.5 Hz,2H), 3.80 (s, 2H), 4.02-4.04 (d, J= 10.5 Hz, 2H).
Step 7) 4-(4-iodo-lH-pyrazol-l-yl)tetrahydrofuran-3-ol
[0174] To a solution of 4-iodo-lH-pyrazole (10.8 g, 57.6 mmol) in anhydrous THF (60 mL) was added LDA (31.2 mL, 62.4 mmol) at -78 °C.The mixture was stirred at -40 °C for 1 h, followed by the addition of a solution of 3,6-dioxabicyclo[3.1.0]hexane (4.12 g, 48 mmol) in THF (50 mL). The reaction was sitrred at rt for lh,then heated to 80 °C and continued to stir for 36 h. The solution was cooled to rt, then quenched with H20 (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified bya silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (5 g, 37%).
LC-MS (ESI, pos. ion) m/z: 281 [M + H]+;
1H NMR (400 MHz, CDC13) δ (ppm): 3.44 (s, 1H), 3.79-3.82 (dd, J= 2.8, 10.0 Hz, 1H), 4.15- 4.22 (m, 2H), 4.29-4.33 (m, 1H), 4.55 (s, 1H), 4.75-4.78 (m, 1H), 7.53 (s, 1H), 7.55 (s, 1H).
Step 8) l-(4-fluorotetrahydrofuran-3-yl)-4-iodo-lH-pyrazole
[0175] To a solution of 4-(4-iodo-lH-pyrazol-l-yl)tetrahydrofuran-3-ol (1.5 g, 5.4 mmol) in DCM (15 mL) was added DAST (1.53 mL, 10.8 mmol, 95%) slowly at -78 °C.The reaction was stired at -78 °C for 2 h, then warmed tortand continued to stirfor 40 h. The mixture was quenched with H20 (30 mL) and extracted with DCM (80 mL x 3).The combined orginc phases were washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residuewas purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to afford the title compound as yellow oil (1.1 g, 72%).
LC-MS (ESI, pos. ion) m/z: 283 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 4.07-4.25 (m, 3H), 4.33-4.37 (m, 1H), 4.95-5.02 (m, 1H), 5.26-5.27 (d, J= 3.6 Hz, 0.5H), 5.39-5.40 (d, J= 3.8 Hz, 0.5H), 7.52 (s, 1H), 7.58(s, 1H).
Step 9) N,N-bis(tert-butoxycarboxyl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- fluorotetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
[0176] To a solution of (R)-N,N-bis(?ert-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (266 mg, 0.43 mmol), l-(4-fluorotetrahydrofuran-3-yl)-4-iodo-lH-pyrazole (0.1 g, 0.35mmol) and Na2C03 (150 mg, 1.42 mmol) in DME/H20 (3 mL/0.7 mL) was added Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in a nitrogen atmosphere. The reaction was stirred at 90 °C for 16 h, then cooled to rt, diluted with EtOAc (60 mL), and filtered through a Pad of celite. The filtrate was washed with brine (20 mL x 2), concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as a yellow solid (136 mg, 59%).
LC-MS (ESI, pos. ion) m/z: 655 [M + H]+;
1H MR (400 MHz, CDC13) δ (ppm): 1.30-1.53 (m, 18H), 1.82-1.84 (d, J= 6.7 Hz, 3H), 4.1 1- 4.29 (m, 3H), 4.78-4.42 (m, 1H), 4.98-5.05 (m, 1H), 5.30-5.46 (m, lH), 6.02-6.07 (q, J= 6.6 Hz, 1H), 7.05-7.09 (t, J= 8.6 Hz, 1H), 7.15-7.16 (t, J= 1.8 Hz, 1Η),7.70-7.73 (m, 3H), 8.17 (d, J = 1.8 Hz, 1H).
Step 10) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l -(4-fluorotetrahvdrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
[0177] To a solution of N,N-bis(tert-butoxycarboxyl)-3-((R)-l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5 -( 1 -(4-fluorotetrahydrofuran-3 -yl)- 1 H-pyrazol-4-yl)pyridin-2-amine (136mg, 0.2 mmol) in DCM (5 mL) was added a solution of HC1 in EtOAc (3M, 1.5mL) slowly at 0 °C. The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was dissolved in H20 (10 mL) and adjusted to pH 10 with saturated aqueous a2C03, and then extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na2S04, concentrated in vacuo, and then purified by a silica column chromatography (PE/EtOAc (v/v) = 1/1) to afford the title compound as a white solid (90 mg, 95%).
LC-MS (ESI, pos. ion) m/z: 455 [M + H]+; ¾ NMR (400 MHz, CDC13) δ (ppm): 1.85-1.87(d, J= 6.6 Hz, 3H), 4.09-4.27 (m, 3H), 4.36-4.40 (m, 1H), 4.83(s, 2H), 4.95-5.00 (m, 1H), 5.30-5.43 (m, lH), 6.04-6.09 (q, J= 6.4 Hz, 1H), 6.84(s, 1H), 7.03-7.07 (m, 1H), 7.29-7.32 (m, 1H), 7.54 (s, 1H), 7.60 (s, 1H), 7.75 (s, 1H).
Example 2 4-(4-(6-3ηΐίηο-5-((/? -1-(2,6-(ϋ€Η1θΓθ-3-ΑυοΓορΗ6ην1 6ίΗοχν ρνΓί(ϋη-3-ν1 -1^ pyrazol-l-yl)tetrahydrofuran-3-ol
Figure imgf000061_0001
Step 1 ) 4-iodo- 1 -(4-((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3 -yl)- 1 H-pyrazole
[0178] To a suspension of 4-(4-iodo-lH-pyrazol-l-yl)tetrahydrofuran-3-ol (lg, 3.57mmol), PPTS (1 13 mg, 0.43 mmol) in DCM (46 mL) was added DHP (788 mg, 9.4 mmol). The reaction was stirred at rt for 48 h, then 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 colorless oil (1.3 g, 100%).
LC-MS (ESI, pos. ion) m/z: 365 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 1.50-1.65 (m, 4H), 1.71-1.80 (m, 2H), 1.80-1.84 (m, 2H), 3.47-3.51 (m, 1H), 3.77-3.89 (m, 2H), 4.1 1-4.27 (m, 3H), 4.47-4.58 (m, 1H), 4.59-4.75 (m, 1H), 4.79-5.04 (m, 1H), 7.53 (s, 1H), 7.54 (s, 1H).
Step 2) N.N-bis(ter/-butoxycarbonyl)-3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4- ((tetrahvdro-2H-pyran-2-yl)oxy)tetrahvdrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
[0179] The title compound was prepared according to the procedure described in Example 1 Step 9 by using a suspension of (R)-N,N-bis(/er/-butoxycarbonyl)-3-(l-(2,6- dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- amine(224 mg, 0.357 mmol), 4-iodo- l-(4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-3- yl)-lH-pyrazole(100 mg, 0.275 mmol),Na2C03 (1 17 mg, 1.1 mmol) and Pd(PPh3)2Cl2 (21.6 mg, 0.031 mmol) in DME/H20 (2.5 mL/0.6 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/l) to afford the desired product as a white solid(87 mg, 44%).
LC-MS (ESI, pos. ion) m/z: 737[M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.35-1.50 (m, 18H), 1.50-1.60 (m, 4H), 1.71-1.85 (m, 5H), 3.45-3.54 (m, 1H), 3.77-3.93 (m, 2H), 4.17-4.33 (m, 3H), 4.52-4.79 (m, 2H), 4.82-5.06 (m, 1H), 6.02-6.07 (q,J= 6.6 Hz, 1H), 7.04-7.08 (t,J= 8.2 Hz, 1H), 7.15 (s, 1H), 7.29-7.33 (m, 1H), 7.69- 7.73 (m, 2H), 8.17 (d, J = 1.5 Hz, 1H).
Step 3) 4-(4-(6-amino-5-((R)-l -(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- !H-pyrazol- 1 - yl)tetrahydrofuran-3 -ol
[0180] The title compound was prepared according to the procedure described in Example 1 Step 10 by using a solution of N,N-bis(?ert-butoxycarbonyl)-3-((R)-l-(2,6-dichloro- 3-fluorophenyl)ethoxy)-5-(l-(4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine(264 mg, 0.36 mmol) in DCM (12mL) and a solution of HCl in EtOAc (3.5 mL, 3M). The crude product was purified by a silica gel column chromatography (100% EtOAc) to afford the desired product as a yellow solid (131 mg, 80%).
LC-MS (ESI, pos. ion) m/z: 453 [M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.85-1.86 (d, J= 6.6 Hz, 3H), 3.83-3.86 (m, 1H), 4.18-4.26 (m, 2H), 4.32-4.38 (m, 1H), 4.58-4.61 (m, 1H), 4.71-4.79 (m, 1H), 4.85 (s, 2H), 6.01-6.09 (m, 1H), 6.83 (s, 1H), 6.98-7.07 (m, 1H), 7.29-7.33 (m, 1H), 7.49-7.51 (d, J= 8.6 Hz, 1H), 7.57 (s, 1H), 7.67 (s, 1H).
Example 3 S-rr^-l-ri^-dichloro-S-fluorophenvDethoxy S-d-^-fluoropyrrolidin-S-vD-lH- pyrazol-4-yl)pyridin-2-amine
Figure imgf000062_0001
Step 1) Tert-butyl carbamate
[0181] A solution of di -tert-butyl dicarbonate (10 g, 45.8 mmol) in MeOH (200 mL) was charged with a stream of NH3 at 0°C. The mixture was stirred at 0°C for 2 h, then warmed up to rt and continued to stir for 5 h. The mixture was concentrated in vacuo, and diluted with n- hexane (100 mL). The resulted mixture was heated to 65°C and maintained at this temperature for 30 min. After cooling the mixture to room temperature, the mixture was filtered, washed with n-hexane to give the title compound as a white solid (5 g, 94%).
¾ NMR (400 MHz, CDC13) δ (ppm): 4.48 (brs, 2H), 1.46(s, 9H).
Step 2) l-(tert-butoxycarbonyl)-2,5-dihvdro-lH-pyrrole
[0182] To a solution of tert-butyl carbamate (5 g, 42.5 mmol) in DMF (50 mL) was added NaH (3.1 g, 106 mmol) in portions at 0°C in 15 min. The mixture was stirred at 0°C for 1 h, followed by the dropwise addtion of cis-l,4-dichloro-2-butene (8 mL). The reaction was stirred at 80°C for 5 h, then cooled to rt, quenched with H20 (150 mL), and extracted with EtOAc (150 mL x 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous a2S04, concentrated in vacuo to give the crude product as yellow oil (6.5 g), which was used for the next step without further purification.
Step 3) 4-bromo-l-(tert-butoxycarbonyl)pyrrolidin-3-ol
[0183] To a solution of l-(tert-butoxycarbonyl)-2,5-dihydro-lH-pyrrole (6.4 g, 37.8 mmol) in DMSO/H20 (30 mL/3 mL)was added NBS (8 g, 45.4 mmol) in portions at 0°C. The reaction was stirred at rt for 2 h, then quenched with H20 (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2S04, and 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 white solid (5 g, 60%).
'H NMR (400 MHz, CDC13) δ (ppm): 4.47-4.46 (t, J= 1.94 Hz, 1H), 4.18-4.16 (t, J= 2.36 Hz, 1H), 4.05-4.01 (dd, J= 4.86 Hz, 1H), 3.88-3.70 (m, 2H), 3.40 (t, J= 13.2 Hz, 1H), 3.03 (brs, 1H), 1.47 (s, 9H).
Step 4) 3-(tert-butoxycarbonyl)-6-oxa-3-azabicvclo[3.1.01hexane
[0184] A solution of 4-bromo-l-(tert-butoxycarbonyl)pyrrolidin-3-ol (2.5 g, 9.4 mmol) in 2 M NaOH/THF (20 mL/10 mL) was stirred at rt for 2 h. The mixture was diluted with H20 (40 mL), and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as yellow oil (1.6 g, 98%). ¾ NMR (400 MHz, CDC13) δ (ppm): 3.83-3.72 (dd, J= 12.8 Hz, 2H), 3.67-3.66 (m, 2H), 2H 3.44-3.30 (dd, J= 5.1 Hz, 12.8 Hz, 2H), 1.45 (s, 9H).
Step 5) 1 -(tert-butoxycarbonvD- 4-(4-iodo- 1 H-pyrazol- 1 -yl pyrrolidin-3 -ol
[0185] The title compound was prepared according to the procedure described in Example 1 Step 7 by using a solution of 4-iodo- IH-pyrazole (1.8 g, 9.7 mmol), LDA(5.2 mL, 1 M in THF) and 3-(tert-butoxycarbonyl)-6-oxa-3-azabicyclo[3.1.0]hexane (1.5 g, 8 mmol) in THF (20 mL).The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the desiredproduct as a white solid (2 g, 67%).
'H NMR (400 MHz, CDCI3) δ (ppm): 7.54 (s, 1H), 7.48 (s, 1H), 4.64-4.60 (m, 2H), 3.99-3.97 (m, 1H), 3.80-3.72 (m, 2H), 3.40-3.35 (m, 2H), 1.47 (s, 9H).
Step 6) 1 -( 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-3 -yl)-4-iodo- 1 H-pyrazole
[0186] To a solution of l-(tert-butoxycarbonyl)-4-(4-iodo-l H-pyrazol- l-yl)pyrrolidin-3-ol (1 g, 2.5 mmol) in DCM (20 mL) was added a solution of DAST (3 mmol, 1.5 mL) in DCM (2 mL) dropwise at -78°C. The mixture was stirred at -78°C for 1 h, then warmed up to room temperature and continued to stir overnight. The mixture was concentrated in vacuo. The residue was diluted with 1 M NaHC03 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (70mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as yellow oil (0.5 g, 50%).
¾ NMR (400 MHz, CDC13) δ (ppm): 7.54 (s, 1H), 7.48 (s, 1H), 5.34-5.21 (m, 1H), 4.93-4.91 (m, 1H), 3.96-3.68 (m, 4H), 1.47 (s, 9H).
Step 7) 1 -(1 -(ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl- 1 ,3 ,2- dioxaborolan-2-yl)- IH-pyrazole
[0187] A suspension of l-(l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-iodo-lH- pyrazole (0.5 g, 1.3 mmol), bis(pinacolato)diboron (0.4 g, 1.5 mmol), Pd(dppf)Ci2 (60 mg, 0.13 mmol) and CH3COOK (3.9 mmol, 0.38 g) in DMSO (10 mL) was stirred at 75°C for 2 h in a nitrogen atmosphere. Then The reaction was cooled to rt, quenched with ¾0 (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (70 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as yellow oil (0.4 g, 80%). LC-MS (ESI, pos. ion) m/z: 382[M + H .
Step 8) 5-(l -(1 -( ter?-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)- lH-pyrazol-4-yl)-3-( (R)- 1 -(2.6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0188] A suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (1.26 mmol, 0.48 g), l-(l-(?ert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.4 g, 1.05 mmol), Pd(OAc)2 (0.37 mmol, 84 mg), (?-Bu)3P (0.925 mmol, 1 M in toluene) and Cs2C03 (2.63 mmol, 0.86 g) in DME (20 mL) was stirred at 87°C for 36 h. The reaction was quenched with H20 (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous a2S04, concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to provide the title compound as a yellow solid (0.16 g, 32%).
'H NMR (400 MHz, CDC13) δ (ppm): 7.74 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.33-7.30 (m, 1H), 7.07-7.04 (m, 1H), 6.84 (s, 1H), 6.09-6.04 (t, J = 6.64 Hz, 1H), 5.37-5.24 (m, 1H), 4.94-4.85 (m, 3H), 3.92-3.72 (m, 4H), 2.18-2.15 (d, J = 6.64 Hz, 3H), 1.49 (s, 9H).
Step 9) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(4-fluoropyrrolidin-3-yl)-lH- pyrazol-4-yl)pyridin-2-amine
[0189] To a solution of 5-(l-(l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-lH- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.16 g, 0.29 mmol) in EtOAc (5 mL) was added HC1 (5 mL, 1 M in EtOAc). The reaction was stirred at 40°C for 1 h, then treated with 2 M Na2C03 (5 mL) followed by H20 (20 mL), andthe resulted solution was extracted with EtOAc (20 mL x 3).The combined organic phases were washed with brine (60 mL), dried overanhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a yellow solid (0.1 g, 78%).
LC-MS (ESI, pos. ion) m/z:227.6 (M+2)/2;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.56 (s, 1H), 7.53-7.31 (m, 2H), 7.30-7.26 (s, 1H), 7.08- 7.04 (m, 1H), 6.85 (s, 1H), 6.09-6.04 (t, J= 6.64 Hz, 1H), 5.38-5.22 (m, 1H), 4.85-4.74 (m, 3H), 3.58-3.21 (m, 4H), 1.87-1.85(d, J = 6.64 Hz, 3H).
Example 4 4-(4-(6-3ΐηίηο-5-((/? -1-(2,6-(ϋ€Η1θΓθ-3-ΑυοΓορΗ6ην1 6ίΗοχν ρνΓί(ϋη-3-ν1 -1^ pyrazol-l-yl)pyrrolidin-3-ol
Figure imgf000066_0001
Step 1) 1 -CI -('ter?-butoxycarbonyl -4-('('tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-3 -yl)-4-iodo- lH-pyrazole
[0190] To a solution of l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)pyrrolidin-3-ol (1 g, 2.6mmol) in DCM (20 niL) was added DHP (1 mL) and PPTS (0.065 g, 0.26 mmol). The reaction was stirred at rt for 12 h, then concentrated in vacuo. The residuewas purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compoundas a white solid (1.1 g, 92%).
LC-MS (ESI, pos. ion) m/z: 464[M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.54(s, 1H), 7.48(s, 1H), 4.70-4.50(m, 3H), 3.94-3.73(m, 3H), 3.66-3.40 (m, 3H), 1.77-1.60 (m, 3H), 1.62-1.5 l(m, 3H), 1.47(s, 9H).
Step 2) N.N-bisCter/-butoxycarbonyl)-5 -C 1 -C 1 -Cter/-butoxycarbonyl)-4-CCtetrahydro-2H-pyran-2- yl)oxy)pyrrolidin-3 -yl)- lH-pyrazol-4-yl)-3 -((R)- 1 -C2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin- 2 -amine
[0191] To a solution of (R)-N,N-bis(/er/-butoxycarbonyl)-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.6g, 1.1 mmol), l-(l-(/er/-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-3-yl)-4-iodo- lH-pyrazole (0.5g, 1.05 mmol)and Na2C03 (0.22 g, 2.1 mmol) in DME/H2O(30mL/2mL) was added Pd(dppf)Cl2-CH2Cl2 (0.075 g, 0.01 mmol) in a nitrogen atmosphere. The reaction was stirred at 87°C for 12h,then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compoundas a pale yellow solid (250 mg, 92%).
LC-MS (ESI, pos. ion) m/z: 836[M + H]+; !H NMR (400 MHz, CDC13) δ (ppm): 8.16 (s, 1H), 7.32-7.12 (m, 1H), 7.65 (s, 1H), 7.33-7.30 (m, 1H), 7.16 (m, 1H), 7.09-7.04 (m, 1H), 6.07-6.02 (t, J=6.64 Hz, 1H), 3.99-3.61 (m, 3H), 3.58-3.41 (m, 3H), 1.83-1.81 (d, J=6.64 Hz, 1H), 1.52-1.48 (2H, m), 1.48-1.44(m, 13H).
Step 3) 4-(4-(6-amino-5-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l- yl)pyrroridin-3-ol
[0192] To a solution of N,N-bis(tert-butoxycarbonyl)-5-(l-(l-(tert-butoxycarbonyl)-4- ((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-3 -yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 - fluorophenyl)ethoxy)pyridin-2-amine (0.23 g, 0.275 mmol) in EtOAc (lOmL) was added HCl(10mL, 1 M in EtOAc). The reaction was stirred at 40°C for 3 h, then cooled to rt, and diluted with H20 (20 mL). The seperated aqueous phase waswashed with EtOAc (20 mL x 2),thentreatedwith 2 M a2C03 (10 mL), and the resulted mixture was extracted with EtOAc (20 mL x 3).The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as a white solid (70 mg, 62%).
LC-MS (ESI, pos. ion) m/z: 452 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.50 (s, 1H), 7.47 (s, 1H), 7.30-7.29 (m, 1H), 7.29-7.28 (m, 1H), 7.03-6.99 (m, 1H), 6.85-6.84 (m, 1H), 6.09-6.04 (t, J=6.64 Hz, 1H), 4.87 (s, 2H), 4.56-4.54 (m, 2H), 3.56-3.52(m, 1H), 3.46-3.41 (dd, J=5.5 Hz, 1H), 3.34-3.3 l(dd, J= 4.2 Hz, 1H), 3.01- 2.97 (m, 1H), 1.87-1.86 (d, J=6.64 Hz, 1H).
Example 5 ((2 -4-(4-(6-3ηΐίηο-5-((/? -1-(2,6-(ϋ€Η1θΓθ-3-ΑυοΓορΗ6ην1 6ίΗοχν ρνΓί(ϋη-3-ν1 - lH-Pyrazol-l-yl)pyrrolidin-2-yl)methanol
Figure imgf000067_0001
Step 1) (3R,5S)-l-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl methanesulfonate
[0193] To a solution of (3R,5S)-l-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin- 3-ol (0.50 g, 2.04 mmol) in DCM (20 mL) was added DMAP (3 mg, 0.02 mmol) and Et3N (0.28 mL, 2.04 mmol). The mixture was cooled down to 0 °C, followed by the dropwise addition of MsCl (0.16 mL, 2.04 mmol). The reaction was stirred at 0 °C for 1 h, then warmed to rt and continued to sitr for 24 h. The mixture was concentrated in vacuo to afford the crude product as yellow sticky liquid (0.64 g, 100%), which was used for the next step without further purification.
LC-MS (ESI, pos. ion) m/z:224.0[(M + H)+ - C4H8].
Step 2) ^((Syi-l-ftert-butoxycarbonyD-S-faethoxycarbonyDpyrrolidin-S-yD^-iodo-lH- pyrazole
[0194] To a solution of 4-iodo-lH-pyrazole (0.35 g, 1.80 mmol) in anhydrous DMF (6 mL) was added NaH (0.15 g, 3.75 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by the addition of a solution of (3R,5S)-l-(tert- butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.64 g, 1.98 mmol) in anhydrous DMF (4 mL). The reaction was stirred at 100 °C for 12 h, then cooled to rt, quenched with H2O (40 mL), and extracted with DCM (30 mL x 4). The combined organic phases were washed with 5% LiCl (100 mL x 2) followed by brine (100 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 afford the title compound as a yellow solid (0.58 g, 76%).
LC-MS (ESI, pos. ion) m/z:365.9 [(M + H)+ - C4H8].
Step 3) ((2S)-l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)pyrrolidin-2-yl)methanol
[0195] To a solution of l-((55)-l-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3- yl)-4-iodo-lH-pyrazole (0.46 g, 1.09 mol) in THF (10 mL) was added LiBH4 (0.12 g, 5.46 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 30 min, then warmed to rt and continued to stir overnight. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (30 mL x 4). The combined organic phases were washed with brine (30 mL), dried over anhydrous s2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as sticky liquid (0.21 g, 28%).
LC-MS (ESI, pos. ion) m/z:338.0 [(M + H)+ - C4H8]; ¾ NMR (400 MHz, CDC13) δ (ppm): 7.53 (s, 1H), 7.49 (s, 1H), 4.68-4.82 (m, 1H), 4.00-4.18 (m, 2H), 3.52-3.82 (m, 3H), 2.50-2.68 (m, 1H), 2.11-2.38 (m, 1H), 1.47 (s, 9H).
Step 4) ((2S)-l-(tert-butoxycarbonyl)-4-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH- pyrazol- 1 -yl)pyrrolidin-2-yl)methanol
[0196] To a solution of ((2S)-l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l- yl)pyrrolidin-2-yl)methanol (0.50 g, 1.27 mmol) in DMSO (12 mL) was added bis(pinacolato)diboron (0.48 g, 1.91 mmol), followed by Pd(dppf)2Cl2-CH2Cl2 (0.10 g, 0.13 mmol) and CH3COOK (0.50 g, 5.09 mmol) in a nitrogen atmosphere. The reaction was stirred at 90 °C overnight, then cooled down to rt, diluted with H20 (40 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dired over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as sticky yellow liquid (0.38 g, 76%).
LC-MS (ESI, pos. ion) m/z:394.2 [M+H];
¾ NMR (400 MHz, CDC13) δ (ppm): 7.79 (s, 1H), 7.74 (s, 1H), 4.70-4.82 (m, 1H), 4.04-4.18 (m, 2H), 3.55-3.85 (m, 3H), 2.52-2.66 (m, 1H), 2.12-2.30 (m, 1H), 1.46 (s, 9H), 1.30 (s, 12H).
Step 5) C('2S)-4-('4-('6-amino-5-('('R)-l-('2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)- 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol
[0197] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (0.30 g, 0.79 mmol) and ((2S)-l-(tert-butoxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)pyrrolidin-2-yl)methanol (0.46 g, 1.18 mmol) in DME (10 mL) were added Cs2C03 (0.77 g, 2.37 mmol), Pd(dppf)Cl2-CH2Cl2 (64 mg, 0.08 mmol) and H20 (2 mL) in a nitrogen atmosphere. The reaction was heated at reflux overnight, then cooled down to rt, diluted with H20 (30 mL), and extracted with DCM (40 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as a yellow solid (0.26 g, 58%).
LC-MS (ESI, pos. ion) m/z: 566.2 [M+H];
¾ NMR (400 MHz, CDC13) δ (ppm): 7.71 (d, J = 1.7 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.28- 7.34 (dd, J= 8.8 Hz, 4.8 Hz, 1H), 7.01-7.08 (t, J = 8.0 Hz, 1H), 6.84 (d, J= 1.6 Hz, 1H), 6.02- 6.10 (q, J = 6.7 Hz, 1H), 4.91 (s, 2H), 4.69-4.82 (m, 1H), 4.04-4.18 (m, 2H), 3.60-3.80 (m, 2H), 2.52-2.79 (m, 2H), 2.12-2.30 (m, 1H), 1.84 (d, J= 6.7 Hz, 3H), 1.47 (s, 9H).
Step 6) ((2S)-4-(4-(6-amino-5-('('R)-l-('2.6-dichloro-3-fluorophenvnethoxy)pyridin-3-vn-lH- pyrazol- 1 -yl)pyrrolidin-2-yl)methanol
[0198] To a solution of ((2S)-4-(4-(6-amino-5-((R)-l-(2,6-dichloro-3 -fluorophenyl) ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 -yl)- 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol (0.26 g, 0.46 mmol) in DCM (10 mL) was added HC1 (3 mL, 3 M in EtOAc). The reaction was stirred at rt overnight, and then concentrated in vacuo to afford the residue, which was diluted with saturated aqueous a2C03 (10 mL) and EtOAc (10 mL). The mixture was stirred at rt for 10 min, and then the seperated aqueous phase was extracted with EtOAc/MeOH (v/v, 10/1, 30 mL x 3). The combined organic phases were washed with brine (40 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM MeOH (v/v) = 8/1) to give the title compound as a yellow solid (84 mg, 39%).
LC-MS (ESI, pos. ion) m/z: 466.2 [M+H];
¾ NMR (400 MHz, CDC13) δ (ppm): 7.71 (d, J = 1.4 Hz, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.27- 7.32 (dd, J= 8.8 Hz, 4.8 Hz, 1H), 6.99-7.07 (t, J = 8.5 Hz, 1H), 6.83 (d, J= 1.4 Hz, 1H), 6.01- 6.09 (q, J= 6.7 Hz, 1H), 4.90 (br, 2H), 4.77-4.85 (m, 1H), 3.81-3.87 (m, 1H), 3.74 (m, 1H), 3.64 (m, 1H), 3.44-3.53 (m, 1H), 3.27 (m, 2H), 2.42-2.53 (m, 1H), 2.08-2.19 (m, 1H), 1.82 (d, J= 6.7 Hz, 3H).
Example 6 3-rrgVl-r2.6-dichloro-3-nuorophenvnethoxyV5-n-rrS)-pyrrolidin-3-ylVlH- pyrazol-4-yl)pyridin-2-amine
Figure imgf000070_0001
Step 1) (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate
[0199] To a mixture of (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-ol (lg, 5.3mmol) and Et3N(1.2mL) in DCM (15mL) was added MsCl(0.62mL) dropwise at 0°C. The reaction was stirred at rt for 2h, then concentrated in vacuo. The residue was diluted with H20(35mL)and extracted with EtOAc (25mL x 3). The combined organic phases were washed with 1M KHSO4(20 mL) followed by H20 (20mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the crude compound as yellow oil (1.4 g), which was used for the next step without further purification.
Step 2) (SV 1 -( 1 -(tert-butoxycarbonyl)pyrrolidin-3 -yl -4-iodo- 1 H-pyrazole
[0200] To a solution of 4-iodo-lH-pyrazole(840mg, 7.4mmol) in DMF (15 mL) was added NaH(320mg, 12mmol, 90% dispersion in mineral oil) in portions at 0°C. The mixture was stirred at 0°C for lh, then a solution of (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (1.4g) in DMF (5 mL) was added.The reaction was sitrred at 70°C for 6h, then coole to rt, diluted with Ι¾0 (50 mL), and extracted with EtOAc(30mL x 3). The combined organic phases were washed with brine(20mL), dried over anhydrous Na2S04, and concentrated in vacuum. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as colorless oil (1.6 g, 80%).
LC-MS (ESI, pos. ion) m/z: 308[M + H - 56]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.52(s, 1H), 7.47(s, 1H), 4.89-4.85(m, 1H), 3.84-3.51(m, 4H), 2.36-2.32(m, 2H).
Step 3) (S)-l-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan- 2-yl)-lH-pyrazole
[0201] A suspension of (5)-l-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-iodo-lH- pyrazole (lg,2.75mmol), bis(pinacolato)diboron(0.8g, 3.32mmol), Pd(dppf)Cl2-CH2Cl2(0.22g, 0.275mmol) and CH3COOK(0.53g, 5.3mmol) in DMSO(15mL)was stirred at 80°C for 2h in a nitrogen atmosphere. Then the reaction was cooled to rt, diluted with H2O(30mL), and extracted with EtOAc(25mL x 3).The combined organic phases were washed with brine(75mL), 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 desired product as a white solid (800 mg, 80%).
LC-MS (ESI, pos. ion) m/z: 364 [M + H]+.
Step 4) 5-q -(CS 1 -(tert-butoxycarbonvnpyrrolidin-S -ylV 1 H-pyrazol-4-viy 3 -(YRV 1 -C2.6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine [0202] A suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (500mg, 1.32mmol), (5')-l-(l-(ieri-butoxycarbonyl)pyrrolidin-3-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole(500mg, 1.32mmol), Pd(PPh3)2Cl2(108mg, 0.15 mmol) and Na2C03(2.64mmol, 280mg) in DME/H20 (15mL/1.5mL) was stirred at 87 °C for 16h in a nitrogen atmosphere. Then the reaction was concentrated in vacuo, and the resulted residue waspurified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a brown solid (300 mg, 42.4%).
LC-MS (ESI, pos. ion) m/z: 536 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.74(s, 1H,), 7.59-7.57(m, 1H), 7.52-7.48(m, 1H), 7.47- 7.29(m, 2H), 7.07-7.03(t, J =8.4Hz, lH), 6.85(s, 1H), 6.09-6.04(q, J =6.64Hz, 1H), 4.88-4.83(m, 3H), 3.85-3.54(m, 3H), 2.39-2.37(m, 2H), 1.86(d, J =6.64Hz, 3H), 1.66(s, 9H).
Step 5) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-3-yl)-lH- pyrazol-4- yl)pyridin-2-amine
[0203] To a solution of 5-(l-((5)-l-(/er/-butoxycarbonyl)pyrrolidin-3-yl)-lH-pyrazol-4- yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine(280mg, 0.523mmol) in EtOAc (5mL) was added HC1 (5 mL, 1 M in EtOAc). The reaction was stirred at 40°C for lh, then cooled to rt, diluted with H20 (35 mL), and washed with EtOAc (20mL). The mixture wastreated with2 M Na2C03(3mL), and then extracted with EtOAc (containing 1% MeOH, 15mL x 3). The combined organic phases were washed with brine(40mL),dried over anhydrous Na2S04, and concentrated in vacuo to give the title compound as a yellow solid(180mg, 80%).
LC-MS (ESI, pos. ion) m/z:436 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.75(s, 1H), 7.54-7.5 l(m, 2H), 7.31-7.28(m, 1H), 7.07- 7.03(t,J= 8.4Hz, 1H), 6.09-6.04(q, J= 6.64Hz, 1H), 4.80-4.73(m, 3H), 3.33-3.24(m, 3H), 3.19- 3.15(m, 1H), 2.33-2.09(m, 2H), 1.87(d, J= 6.64Hz, 3H).
Example 7 3- /?)-1- 2,6-άί€ΜθΓθ-3-ΑυοΓθρΗ6ην1)6ίΗοχν)-5- 1- 4,4-(ϋηΐ6ίΗν1οχ6ί3η-2- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000073_0001
Step 1) 2-methylpent-4-en-2-ol
[0204] Allylmagnesium bromide (20 mL, 0.02 mol, 2 M in Et20) was placed in a two- neck round-bottom flask in a protective argon atmosphere and cooled using an ice bath. Then acetone (1.7 mL, 0.02 mol) was added dropwise to the bromide at 0 °C in 10 min. The solution was refluxed for 2 h, then quenched with H20 (10 mL) while cooling, followed by drop wise addition of HCl (3 mL, 6 M) at 0 °C until pH 2. The seperated aqueous phase was extracted with ether (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous MgS04, and concentrated in vacuo to give the crude product as colorless oil (lg, 50%).
LC-MS (ESI, pos. ion) m/z: 101 [M + H]+;
1HNMR (400 MHz, CDC13) δ (ppm): 1.20 (s, 6H),2.21-2.23 (d, J= 7.5 Hz, 2H), 5.07-5.04 (m, 2H), 5.81-5.93 (m, 1H).
Step 2) 4-(iodomethyl)-2,2-dimethyloxetane
[0205] To a solution of2-methylpent-4-en-2-ol(510 mg, 5.1 mmol), 12(1.81 g, 7.14 mmol) in DCM (43mL) was added bis(sym-collidine)silber(I)perchlorate (3.5g, 7.14 mmol) in a nitrogen atmosphere.The reaction was stirred at rt for 24 h, then filtered through a pad of Celite, which was washed with EtOAc (50 mL).The filtrate was washed with 10% aS2S03 (10 mL x2) followed by 10% HCl (50 mL x2), and then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/DCM (v/v) = l/2)to give the title compound as colorless oil (629 mg, 55%).
LC-MS (ESI, pos. ion) m/z: 226[M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.41 (s, 3H),1.45 (s, 3H), 2.05-2.09 (m, 1H), 2.44-2.49 (m, 1H), 3.22-3.27 (m, 1H), 3.34-3.38 (m, 1H), 4.57-4.64 (m, 1H). Step 3) l-('('4,4-dimethyloxetan-2-yl methyl -4-iodo-lH-pyrazole
[0206] To a solution of 4-iodo-lH-pyrazole(1.13 g, 5.85 mmol) in anhydrous DMF (32 mL)was added NaH (296 mg, 1 1.7 mmol, 95%) in portions at 0°C. The mixture was stirred at rt for 1.5h, followed by the addtition of 4-(iodomethyl)-2,2-dimethyloxetane(1.32g, 5.85 mmol). The reaction was stirredat 90°C for 19 h, then cooled to rt,quenched withsaturated aqueous NH4CI (20 mL), and extracted with EtOAc (80 mL x2). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified bya silica gel column chromatography (PE/EtOAc (v/v) = 4/l)the title compound as colorless oil (890 mg, 53%).
1HNMR (400 MHz, CDC13) δ (ppm): 1.19 (s, 3H), 1.45 (s, 3H), 2.17-2.22 (m, 1H), 2.36-2.41 (m, 1H), 4.30 (d, J= 4.5 Hz, 2H), 4.84-4.90 (m, 1H), 7.52 (s, 1H), 7.58 (s, 1H).
Step 4) l-((4,4-dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)- lH-pyrazole
[0207] To a solution of bis(pinacolato)diboron (995 mg, 3.9 mmol) in DMSO (22 mL) was added l-((4,4-dimethyloxetan-2-yl)methyl)-4-iodo-lH-pyrazole (880 mg, 3.0 mmol) andCH3COOK (1.22 g, 12 mmol), followed by Pd(PPh3)2Cl2 (218 mg, 0.3 mmol) in a nitrogen atmosphere. The reaction was stirred at 80°C for 3 h, then cooled to rt, and filtered through a pad of Celite, which was washed with EtOAc (100 mL). The filtrate was washed with brine (50 mL x2), dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as colorless oil (650 mg, 74%).
LC-MS (ESI, pos. ion) m/z:293 [M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.21(s, 3H), 1.31(s, 12H), 1.45 (s, 3H), 2.21-2.26 (m, 1H), 2.37-2.42 (m, 1H), 4.32(d,J=4.9Hz,2H),4.87-4.92(m, lH),7.79(s, lH),7.81(s, lH).
Step 5) 3-((R)- 1 -(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l -((4.4-dimethyloxetan-2-yl)methyl)- 1 H-pyrazol-4-yl)pyridin-2-amine
[0208] To a suspensionof(R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin- 2-amine(1.27 g, 3.3 mmol), l-((4,4-dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole(650 mg, 2.2 mmol) and Pd(OAc)2 (50 mg, 0.22mmol)in DME (20 mL) was added a solution of a2C03 (707 mg, 6.7 mmol) in H20 (3.25 mL), followed by (t- Bu)3P(0.7 mL, 1 M in toluene) in a nitrogen atmosphere. The reaction was stirred at 90 °C for 16h, then cooled to rt, diluted with EtOAc (30 mL), and filtered through a pad of Celite, whichwas washed with EtOAc (50 mL). The filtrate was washed with brine (20 mL x2), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gelcolumn chromatography (PE/EtOAc (v/v) = 1/1) to afford the title compound as a yellow solid(370 mg, 36%).
LC-MS (ESI, pos. ion) m/z:465 [M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.37(s, 3H), 1.40 (s, 3H), 1.84-1.86 (d, J= 6.7 Hz, 3H), 2.18-2.29 (m, 2H), 2.17 (d, J= 4.5 Hz, 2H), 4.80 (s, 2H), 4.87-4.93 (m, 1H), 6.05-6.10 (q, J = 6.5 Hz, 1H), 6.88 (d, J= 1.3 Hz, 2H), 7.02-7.07 (m, 1H), 7.29-7.32 (m, 1H), 7.57-7.60 (m, 2H), 7.77 (s, 1H).
Example 8 S- ^-l- i^-dichloro-S-fluorophenvDethoxy S- i- S-fluoropyrrolidin-S- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000075_0001
Step 1) 5-(tert-butoxycarboxyl)-l-oxa-5-azaspiro|"2.4"|heptane
[0209] To themixture of trimethylsulfoxonium iodide (2.57 g, 11.7 mmol) in DMSO (8.8 mL) was added NaH (351 mg, 80% dispersion in mineral oil) at 10°C. The mixture was stirred at rt for 2 h, then a solution of l-(tert-butoxymethyl)pyrrolidin-3-one (2.00 g, 10.8 mmol) in DMSO (3.0 mL) was added. The reaction was continued to stir for 3 h, then quenched with ice water (50 mL)followed by brine (50 mL), and then extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, and concentrated in vacuo to yield viscous brown oil, which was used for the next step without further purification.
Step 2) l-(tert-butoxycarboxyl)-3-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol
[0210] To asolution of 4-iodo-lH-pyrazole (2.1 g, 10.8 mmol) in DMF (20 mL) was added NaH (390 mg, 80% dispersion in mineral oil) at 0°C. The resulted suspension was stirred at 0 °C for lh, then a solution of 5-(tert-butoxycarboxyl)-l-oxa-5-azaspiro[2.4]heptane (2.1 g, 10.8 mmol) in DMF (10 mL) was added. The reaction was heated at 70 °C for 36 h, then cooled to rt, quenched with H20 (10 mL), and concentrated in vacuo. The residue was partioned between DCM (100 mL) and H20 (100 mL).The seperated organic phase was washed with brine (50 mL), dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =3/1) to give the title compound as colorless oil (1.15 g, 27 %, for two steps).
LC-MS (ESI, pos. ion) m/z:338 [M + H - 56]+;
¾ NMR (400 MHz, DMSO-i¾) δ (ppm): 1.38 (s, 9H), 1.57-1.73 (m, 1H), 1.74-1.90 (m, 1H), 3.05-3.13 (m, 1H), 3.21-3.32 (m, 3H), 4.23 (d, J=3.6 Hz, 2H), 5.16 (d, J=1.6 Hz, 2H), 7.54 (s, 1H), 7.82 (d, J=2.9 Hz, 2H).
Step 3) l-((l-(ter/-butoxycarboxyl)-3-fluoropyrrolidin-3-yl)methyl)-4-iodo-lH-pyrazole
[0211] To a solution of DAST (0.5 mL, 4 mmol) in DCM (30 mL) was added a solution of l-(tert-butoxycarboxyl)-3-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol (786 mg, 2.0 mmol) in DCM (10 mL) dropwise at -78 °C. The reaction was stirred atrt for 6h, then diluted with DCM (50 mL), and washed with H20 (20 mL)followed by brine (20 mL). The solution was dried over anhydrousNa2S04, 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 colorless oil (600 mg, 76%).
LC-MS (ESI, pos. ion) m/z:340 [M + H - 56]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 1.45 (s, 9H), 1.96-2.03 (m, 2H), 3.40-3.70 (m, 4H), 3.97- 4.20 (m, 1H), 4.38-4.55 (m, 2H), 7.45-7.60 (m, 2H).
Step 4) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((3-fluoropyrrolidin-3-yl) methyl)- 1 H-pyrazol-4-yl)pyridin-2-amine
[0212] To a mixture of l-((l-(?ert-butoxycarboxyl)-3-fluoropyrrolidin-3-yl)methyl)-4- iodo-lH-pyrazole (215 mg, 0.54 mmol) and (R)-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 (40 mL) was added a solution of Na2C03 (148 mg, 1.4 mmol) in H20 (10 mL), followed byPd(dppf)Cl2-CH2Cl2 (35 mg, 0.05 mmol) in a nitrogen atmosphere. The reaction was stirred at 88 °C for 16 h, and then concentrated in vacuo. The residue waspartioned between DCM (60 mL) and H2O(60 mL), and then the seperated organic phase was washed with brine (30 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the crude product, which was dissolved in DCM (40 mL), and a soluton of HCl (8 mL, 1 M in EtOAc) was added at 0 °C. The reaction was stirred for 12h, and then concentrated in vacuo. The residue was redissolved in H20 (lOOmL), then adjusted to pHlOwith saturated aqueous a2C03, and extracted with DCM/MeOH (8/1, 50 mL x 3). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (DCM/MeOH (v/v) =7/1) to give the title compound as a yellow solid (75 mg, 31%).
LC-MS (ESI, pos. ion) m/z: 234.5 (M+2)/2;
¾ NMR (400 MHz, DMSO-i¾) δ (ppm): 1.79 (d, J=6.6 Hz, 3H), 1.80-2.05 (m, 3H), 2.82-3.13 (m, 4H), 4.47 (s, 1H), 4.52 (s, 1H), 5.67 (s, 2H), 6.09 (q, J=6.6 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 7.40-7.47 (m, 1H), 7.52-7.58 (m, 1H), 7.59 (s, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.84 (s, 1H).
Example 9 3-((/? -1-(2,6-(ϋ€ΜθΓθ-3-ΑυοΓορΗ6ην1 6ίΗοχν -5-(1-(( -ρνΓΓθ1ί(ϋη-2-ν1ηΐ6ίΗν1 - lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000077_0001
Stepl) (S)-(l-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl methanesulfonate
[0213] The title compound was prepared according to the procedure described in Example 6 Step 1 by using a solution of (S)-(l-(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol (lg, 4.9mmol), MsCl(0.6mL) and Et3N(l. lmL) in DCM (15mL) to afford the crude product as yellow oil(1.4g), which was used for the next step without further purification.
Step 2) (S)- 1 -(( 1 -(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
[0214] The title compound was prepared according to the procedure described in
Example 6 Step 2 by using a suspension of 4-iodo-lH-pyrazole(840mg, 7.4mmol), (5)-(l-(tert- butoxycarbonyl)pyrrolidin-2-yl)methyl methanesulfonate(1.4g) and NaH(320mg, 12mmol, 90% dispersion in mineral oil)in DMF (20 mL).The crude product was purified by a silica gel column chromatography(PE/EtOAc (v/v) = 5/1) to give the desired compound as colorless oil(1.6g, 89%).
LC-MS (ESI, pos. ion) m/z:378.1 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.40(1H, s), 7.31(1H, s), 4.26-3.96(3H, m), 3.30-3.06(2H, m), 2.80-1.64(4H, m), 1.42(9H, s).
Step 3) (S)-l-((l-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)- 1 H-pyrazole
[0215] The title compound was prepared according to the procedure described in Example 6 Step 3 by using asuspension of (5)-l-((l-(tert-butoxycarbonyl)pyrrolidin-2- yl)methyl)-4-iodo- 1 H-pyrazole ( 1 g,2.65mmol), bis(pinacolato)diboron(3.9mmol, 1 g), Pd(dppf)Cl2-CH2Cl2 (0.2g, 0.265mmol) and CH3COOK(0.53g, 5.3mmol) in DMSO (15mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to givethe desired compoundas a white solid (800mg, 80%).
LC-MS (ESI, pos. ion) m/z:378.1 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.69(1H, s), 7.58(1H, s), 4.29-4.07(3H, m), 3.31-3.07(2H, m), 2.00-1.66(4H, m), 1.43(9H, s), 1.18(12H, s).
Step 4) 5-q -((YSV 1 -('tert-butoxycarbonvnpyrrolidin-2-vnmethvn- lH-pyrazol-4-vn-3 -((TO- 1 - (2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0216] The title compound was prepared according to the procedure described in Example 6 Step 4 by using a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (500mg, 1.32mmol), (5)-l-((l-(tert-butoxycarbonyl) pyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (500mg, 1.32mmol), Pd(PPh3)2Cl2(108mg, 15.3 mmol)and Na2C03(2.64mmol, 280mg) in DME/H20 (15mL/1.5mL).The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the desired compound as a brown solid (200mg, 27%).
LC-MS (ESI, pos. ion) m/z:550 [M + H]+.
Step 5) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((S)-pyrrolidin-2-yl methyl)-lH- pyrazol-4-yl)pyridin-2-amine
[0217] The title compound was prepared according to the procedure described in
Example 6 Step 5 by using a solution of 5-(l-(((5)-l-(?ert-butoxycarbonyl)pyrrolidin-2- yl)methyl)- lH-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine (160mg, 0.29mmol) and HCl (5 mL, 1 M in EtOAc)in EtOAc to afford the title compound as a yellow solid(60mg, 46%).
LC-MS (ESI, pos. ion) m/z:225.7 (M+2)/2;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.74(s, 1H), 7.55-7.52(m, 2H), 7.32-7.30(m, 2H), 7.07- 6.86(m, 1H), 6.07 (q,J= 6.64Hz, 1H), 4.85(s, 2H), 4.28-4.23(dd, J=4.4Hz, lH), 4.13-4.08(dd, J = 7.4Hz, lH), 3.73-3.68(m, 1H), 3.04-3.02(m, 2H), 1.86-1.84(m, 2H), 1.81(d,J= 6.64Hz, 3H), 1.49-1.47(m, 2H).
Example 10 3-((/? -1-(2,6-άί€ΜθΓθ-3-ΑυοΓορΗ6ην1 6ίΗοχν -5-(1-(((2 -4-ΑυοΓορνΓΓθ1ί(ϋη-2- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000079_0001
Stepl) (2S)-methyl l-(tert-butoxymethyl)-4-fluoropyrrolidine-2-carboxylate
[0218] The title compound was prepared according to the procedure described in Example 1 Step 8 by using a solution of (2S)-methyl 1 -(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylate (1 g, 4.1 mmol) and DAST (1.1 mL, 8.2 mmol)in DCM (5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the desired compound as yellow oil (0.93 g, 93%).
LC-MS (ESI, pos. ion) m/z:248 [M + H]+.
Step2) ((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methanol
[0219] To a solution of (2S)-methyl l-(tert-butoxymethyl)-4-fluoropyrrolidine-2- carboxylate (0.95 g, 3.85 mmol) in THF (18 mL) was added LiBH4 (126 mg, 5.78 mmol) at 0°C. The reaction was stirred at rt overnight, then quenched with HOAc (0.5 mL in 60 mL of water), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with 1 M aHC03 (50 mL) followed by brine (50 mL), dried over 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 thick yellow oil (0.82 g, 97%).
LC-MS (ESI, pos. ion) m/z:242 [M + Na]+.
Step3) ((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl methanesulfonate
[0220] To a solution of ((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methanol (0.41 g, 1.87 mmol) and DMAP (22.8 mg, 0.1 mmol) in DCM (6 mL) at 0°C was added Et3N (0.52 mL, 3.74 mmol), followed by CH3S02C1 (0.23 mL, 2.81 mmol) slowly. The reaction was stirred at rt for 2.5 h, then quenched with 1 M NaHC03 (25mL), and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (25 mL), dried over anhydrous a2S04, and concentrated in vacuo to give the residue, which was used for the next step without further purification.
Step4) 1 -(((2 S)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
[0221] To a solution of 4-iodo-lH-pyrazole (513 mg, 2.64 mmol) in dry DMF (45 mL) was added NaH (169 mg, 7.0 mmol) in portions at 0°C. The mixture was stirred at 0°C for 8 h and warmed to rt. ((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl methanesulfonate was then added to the mixture, which was subsequently heated at 100°C for 8 h. The reaction was quenched with aqueous NH4C1 (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (25 mL), dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as colorless oil (700 mg, 95%).
LC-MS (ESI, pos. ion) m/z:396 [M + H]+;
'tlNMR (400 MHz, CDC13) δ (ppm): 1.46 (s, 9H), 1.56-2.39 (m, 2H), 3.49-3.75 (m, 2H), 4.14- 4.58 (m, 3H), 5.18-5.32 (m, 1H), 7.42 (s, 1H), 7.53 (s, 1H).
Step5) l-(((2S)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-(4.4.5.5-tetramethyl- 1.3-dioxolan-2-yl)-lH-pyrazole
[0222] The title compound was prepared according to the procedure described in Example 7 Step 4 by using a suspension of l-(((2S)-l-(tert-butoxycarbonyl)-4- fluoropyrrolidin-2-yl)methyl)-4-iodo-lH-pyrazole(700 mg, 1.77 mmol), bis(pinacolato)diboron (675 mg, 2.66 mmol), CH3COOK (695 mg, 7.08 mmol) and Pd(PPh3)2Cl2 (62 mg, 0.09 mmol)in DMSO (10 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as yellow oil (0.66 g, 94%).
LC-MS (ESI, pos. ion) m/z:398 [M + H]+; 'ΗΝΜΡν (400 MHz, CDC13) δ (ppm): 1.30 (s, 12H), 1.46 (s, 9H), 2.01-2.31 (m, 2H), 3.52-3.79 (m, 2H), 4.09-4.15 (m, 1H), 4.32-4.37 (m, 1H), 4.45-4.60 (m, 1H), 5.16-5.29 (m, 1H), 7.67 (s, 1H), 7.79 (s, 1H).
Step6)5 -( 1 -(((2 S)- 1 -(tert-butoxycarbonyl -4-fluoropyrrolidin-2-yl methyl - 1 H-pyrazol-4-yl - 3 - ((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-2-amine
[0223] The title compound was prepared according to the procedure described in Example 7 Step 5 by using a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy) pyridin-2-amine (540 mg, 1.436 mmol), l-(((2S)-l-(tert-butoxycarbonyl)- 4-fluoropyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)-lH-pyrazole(376 mg, 0.957 mmol), Pd(OAc)2 (21.5 mg, 0.0957 mmol), Na2C03 (304 mg, 2.87 mmol) and (t-Bu)3P (49 mg, 0.24 mmol) in DME/H2O (6 mL/1.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to afford the title compound as a yellow solid (500 mg, 55%).
LC-MS (ESI, pos. ion) m/z:569 [M + H]+;
'tlNMR (400 MHz, CDCI3) δ (ppm): 1.46 (s, 9H), 1.84-1.86 (d, J= 6.6 Hz, 3H), 2.04-2.45 (m, 2H), 3.49-3.76 (m, 2H), 4.09-4.14 (m, 1H), 4.30-4.36 (m, 1H), 4.43-4.59 (m, 1H), 4.77 (s, 2H), 5.16-5.32 (m, 1H), 6.04-6.09 (q, J = 6.6 Hz, 1H), 6.85 (s, 1H), 7.03-7.07 (m, 1H), 7.28-7.32 (m, 1H), 7.41 (s, 1H), 7.54-7.58 (m, 1H), 7.75-7.76 (d, J= 1.6 Hz, 1H).
Step7) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(((25)-4-fluoropyrrolidin- 2- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
[0224] The title compound was prepared according to the procedure described in Example 1 Step 10 by using a solution of 5-(l-(((2S)-l-(tert-butoxycarbonyl)-4- fluoropyrrolidin-2-yl)methyl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 - fluorophenyl)ethoxy) pyridin-2-amine (400 mg, 0.524 mmol) and HC1 (5 mL, 3 M in EtOAc) in DCM (15 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) = 200/20/1) to afford the title compound as a yellow solid (294 mg, 90%).
LC-MS (ESI, pos. ion) m/z:468 [M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.80-2.05 (m, 1H), 1.84 (d, J= 6.0 Hz, 3H), 2.05-2.24 (m, 1H), 2.95-3.08 (m, 1H), 3.30-3.39 (m, 1H), 3.64-3.68 (m, 1H), 4.12-4.18 (m, 1H), 4.21-4.26 (m, 1H), 4.78 (s, 2H), 5.14-5.30 (m, 1H), 6.05-6.10 (q, J= 6.7 Hz, 1H), 6.86-6.87 (d, J= 1.5 Hz, 1H), 7.03-7.07 (t, J= 1.7 Hz, 1H), 7.29-7.32 (m, 1H), 7.54 (s, 1H), 7.58 (s, 1H), 7.76-7.77 (d, J= 1.7 Hz, 1H).
Example 11 3- R)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- S)-4,4-difluoropyrrolidin- 2-yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000082_0001
Stepl) (2S)-methyl l-(tert-butoxycarboxyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2- carboxylate
[0225] To a suspension of (2S)-methyl l-(tert-butoxycarboxyl)-4-hydroxypyrrolidine-2- carboxylate (2.0g, 8.15mmol) in DCM (100 niL) was added DHP (1.71g, 20.4mmol) and PPTS (246mg, 0.978 mmol). The reaction was stirred at 35 °Cfor 36h,then concentrated in vacuo and purified by a silica gel columnchromatography(PE/EtOAc (v/v) = 4/1) to give the title compound as colorless oil(2.65 g, 99%).
!HNMR (400 MHz, CDC13) δ (ppm): 1.41-1.46(d, 9H), 1.50-1.63 (m, 5H), 1.64-1.75 (m, 1H), 1.75-1.86 (m, 1H), 2.01-2.18 (m, 2H), 2.23-2.51 (m, 1H), 3.39-3.72 (m, 3H), 3.73(s, 3H), 3.78- 3.90 (m, 1H), 4.28-4.46(m, 2H), 4.61-4.69(m, 1H).
Step2) ((2S)-l-(tert-butoxycarboxyl)-4-((tetrahvdro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol
[0226] To a solution of (2S)-methyl l-(tert-butoxycarboxyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidine-2-carboxylate (l.Og, 3.0 mmol) in THF (15 mL) cooled in an iced-bath was added LiBH4 (94.5mg,4.5mmol). The reaction was heatedat 35°Covernight, thencooled in an iced-bath, quenched with saturated aqueous NH4C1(20 mL) slowly, and extracted with EtOAc (60 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated in vacuo.The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound ascolorless oil (850 mg, 94%).
LC-MS (ESI, pos. ion) m/z:324 [M + Na]+; !HNMR (400 MHz, CDC13) δ (ppm): 1.47(s, 9H), 1.49-1.75 (m, 6H), 1.75-1.87 (m, 1H), 1.87- 2.02 (m, 1H), 2.05-2.24 (m, 1H), 3.25-3.79 (m, 5H), 3.79-3.86(m, 1H), 3.78-3.90 (m, 1H), 4.22- 4.39(m, 1H), 4.61-4.69(m, lH),4.82-5.02(m, 1H).
Step3) ((2S -l-(tert-butoxycarboxyl -4-((tetrahydro-2H-pyran-2-yl oxy pyrrolidin-2-yl methyl methanesulfonate
[0227] The title compound was prepared according to the procedure described in Example 10 Step 3 by using a solution of ((2S)-l-(tert-butoxycarboxyl)-4-((tetrahydro-2H- pyran-2-yl)oxy)pyrrolidin-2-yl)methanol(1.0g, 3.3 mmol), MsCl (0.38 mL, 4.95 mmol) DMAP (40 mg, 0.33mmol) and Et3N (0.92 mL, 6.6 mmol)in DCM (10 mL).The crude product (1.25g, 100%)was used for the next step without purification.
Step4) l-(((2S)-l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yl)methyl)-4-iodo- lH-pyrazole
[0228] To a solution of 4-iodo-lH-pyrazole(704.2 mg, 3.63 mmol) in anhydrous DMF (15 mL)was added NaH (7.6 mmol, 192 mg, 95%) in portions at 0°C. The suspension was stirred at 0°C for 8 h,then warmed to rtand stirred for 1.5 h. A solution of ((2S)-l-(tert-butoxycarbonyl)- 4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl methanesulfonate (1.25g, 3.3 mmol) in DMF (3 mL) was added to the suspension, and the reaction was heated at 100 °Cfor 13 h. The mixture was cooled to rt, quenched with saturated aqueous NH4C1 (30mL), and then extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (25mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to givethe title compound as a white solid (1.3g, 83%).
LC-MS (ESI, pos. ion) m/z:478 [M + H]+;
!HNMR (400 MHz, CDCI3) δ (ppm): 1.40-1.59 (m, 13H), 1.60-1.70 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 3.02-3.72 (m, 3H), 3.73-3.86(m, 1H), 3.80-4.02 (m, 1H), 4.05-4.39(m, 3H), 4.45-4.69(m, 2H), 7.35-7.40(m, 1H), 7.48 (s, 1H).
Step5) (5S)-l-(tert-butoxycarbonyl)-5-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol
[0229] To a suspension of l-(((2S)-l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2- yl)oxy)pyrrolidin-2-yl)methyl)-4-iodo-lH-pyrazole(200mg, 0.42mmol) in THF/H2O (5 mL/5 mL) was added HOAc (lmL, 16.8 mmol). The reaction was heated at 70 °C for 16 h, then cooled to rt. The mixture was adjusted to pH 10 with saturated aqueous a2C03, and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gelcolumn chromatography (PE/EtOAc (v/v) = 1/1) to afford the title compound as colorlessoil(157 mg,95%).
LC-MS (ESI, pos. ion) m/z:394 [M + H]+.
Step6) (S)-l-(tert-butoxycarbonyl)-5-((4-iodo-lH-pyrazol-l-yl)methyl)pyrrolidin-3-one
[0230] To a suspension of (5S)-l-(tert-butoxycarbonyl)-5-((4-iodo-lH-pyrazol-l- yl)methyl)pyrrolidin-3-ol(1.39g, 3.54mmol) in DCM (44 mL) was added Dess-Martin Oxidant (3 g, 7.07mmol). The reaction was stirred at rt for 16 h, then filtered. The filtrate was concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/1) to afford the title compound as a white soli d( 1.2 g, 87%).
!HNMR (400 MHz, CDC13) δ (ppm): 1.49 (s, 9H), 2.60-2.90 (m, 2H), 2.90-3.29 (m, 1H), 3.50- 3.98 (m, 1H), 4.20-4.27 (m, 1H), 4.61 (s, 2H), 7.34(s, 1H), 7.49 (s, 1H).
Step7) (S)- 1 -(( 1 -(tert-butoxycarboxyl)-4,4-difluoropyrrolidin-2-yl)methyl)-4-iodo- 1 H-pyrazole
[0231] To a solution of (S)-l-(tert-butoxycarbonyl)-5-((4-iodo-lH-pyrazol-l- yl)methyl)pyrrolidin-3-one(100mg, 0.26 mmol) in DCM (3 mL) was added DAST (95%,0.15 mL, 1.04 mmol) at -78°C. The reaction was stirred at -40°C for 2 h, then warmed to rt and continued to stir for 21 h. The mixture was concentrated in vacuo, and the residue was diluted with H2O(30 mL), then extracted with DCM(30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous a2S04, 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 yellow oil (100 mg, 93 %).
LC-MS (ESI, pos. ion) m/z:414 [M + H]+;
'tlNMR (400 MHz, CDC13)8 (ppm): 1.49 (s, 9H), 2.29-2.70 (m, 2H), 3.25-3.60 (m, 1H), 3.60- 3.98 (m, 1H), 4.12-4.55 (m, 3H), 7.44(s, 1H), 7.51 (s, 1H).
Step8) (S)-l-((l-(tert-butoxycarbonyl)-4.4-difluoropyrrolidin-2-yl)methyl)-4-(4.4.5.5- tetramethyl-L3-dioxolan-2-yl)-lH-pyrazole
[0232] To a solution of bis(pinacolato)diboron (128mg, 0.504 mmol) in DMSO (3 mL) was added (S)- 1 -(( 1 -(tert-butoxycarboxyl)-4,4-difluoropyrrolidin-2-yl)methyl)-4-iodo- 1 H- pyrazole (80mg, 0.194 mmol) and CH3COOK (76mg, 0.776mol), followed by Pd(PPh3)2Cl2 (16.3mg, 0.023 mmol) under N2 atmosphere. The reation was heated at 80°C for 3h, thencooled to rt, diluted with H2O(30 mL) and extracted with EtOAc (30 mL x 3).The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as yellow oil (30 mg, 37.5 %).
LC-MS (ESI, pos. ion) m/z:414 [M + H]+.
Step9) 5-(l-(((S)-l-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)-lH-pyrazol-4-yl)- 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0233] To a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine(195mg, 0.51 mmol), (S)-l-((l-(tert-butoxycarboxyl)-4,4-difluoropyrrolidin-2- yl)methyl)-4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)-lH-pyrazole (141 mg, 0.34mmol)and Pd(OAc)2(7.7mg,0.034mmol)in DME/H20 (3/0.5mL) was added a solution of Na2C03 (145mg, 1.37 mmol) in H20 (0.5 mL), followed by (t-BubP (0.15mL, lM in toluene) in a nitrogen atomsphere. The reactionwas heated at 90 °Cfor 13h, then cooled to rt and diluted with EtOAc (40 mL). The mixture was filtered through a pad of Celite, which was washed with EtOAc (40 mL). The filtrate was washed with brine (30 mL x 2), concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to afford the title compound as a yellow solid(80mg, 44%).
LC-MS (ESI, pos. ion) m/z:586[M + H]+.
Step 10) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(((S)-4.4-difluoropyrrolidin-2- vDmethyl)- 1 H-pyrazol-4-yl)pyridin-2-amine
[0234] The title compound was prepared according to the procedure described in Example 1 Step 10 by using a solution of 5-(l-(((S)-l-(tert-butoxycarbonyl)-4,4- difluoropyrrolidin-2-yl)methyl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3- fluorophenyl) ethoxy)pyridin-2-amine (140mg, 0.24 mmol) and HC1 (2 mL, 3 M in EtOAc) in DCM (6 mL). The crude product was purified by a silica gel column chromatography (EtOAc/MeOH (v/v) =20/1) to afford the title compound as a yellow solid (80mg,69%).
LC-MS (ESI, pos. ion) m/z: 243 (M+l/2).
¾ NMR (400 MHz, CDC13) δ (ppm): 1.85-1.87 (d, J=6.5Hz, 3H), 1.95-2.10(m, 1Η),2.32-2.45 (m, 1H), 3.12-3.35 (m, 2H), 3.75-3.86 (m, 1H), 4.06-4.18 (m, 1H), 4.19-4.29(m, 1H), 4.84 (s, 2H), 6.05-6.10 (q, J=6.3 Hz, 1H), 6.86(s, 1H), 7.03-7.08 (t, J=8.4 Hz, 1H), 7.28-7.33 (m, 1H), 7.51 (s, 1H),7.57 (s, lH),7.75(s, 1H). Example 12 5S)-5- 4- 6-amino-5- R)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- lH-pyrazol-l-yl)methyl)pyrrolidin-3-ol
Figure imgf000086_0001
Step 1) 1 -(((2S)- 1 -('tert-butoxycarbonyl -4-('('tetrahvdro-2H-pyran-2-yl oxy pyrrolidin-2- yl)methyl)-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazole
[0235] The title compound was prepared according to the procedure described in Example 11 Step 8 by using a suspension of l -(((25)- l-(tert-butoxycarbonyl)-4-((tetrahydro- 2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)-4-iodo-lH-pyrazole(100mg, 0.21 mmol), bis (pinacolato)diboron (140mg, 0.54 mmol), Pd(PPh3)2Cl2 (16 mg, 0.23 mmol) and CH3COOK (82mg, 0.84mol) in DMSO (3 mL). The crude product was purified by a silica gel coloumn chromatography (PE/EtOAc (v/v)= 1/4) to give the desired product as a white solid (80 mg, 80%).
LC-MS (ESI, pos. ion) m/z:477[M + H]+;
'HNMP (400 MHz, CDCI3) δ (ppm): 1.25-1.27 (m, 12H), 1.40- 1.59 (m, 13H), 1.60-1.85 (m, 3H), 1.95-2.05 (m, 1H), 2.05-2.22 (m, 1H), 2.98-3.72 (m, 3H), 3.73-3.86 (m, 1H), 3.80-4.02 (m, 1H), 4.05-4.30 (m, 2H), 4.3 1-4.42 (m, 1H), 4.43-4.62 (m, 2H), 7.62-7.70 (s, 1H), 7.75-7.76 (m, 1H).
Step 2) 5-(l-(((2S)- l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2- yPmethyl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine
[0236] The title compound was prepared according to the procedure described in Example 11 Step 9 by using a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine(96 mg, 0.25 mmol), 1 -(((25)- 1 -(/er/-butoxymethyl)-4- ((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl- l,3,2- dioxaborolan-2-yl)- lH-pyrazole(100 mg, 0.21 mmol),Pd(OAc)2(4.7 mg, 0.021 mmol),Na2C03 (89 mg, 0.84mmol) and (t-Bu)3P(0.06 mL, lM in toluene) in DME/H20 (3 mL/0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to afford the desired product as a yellow solid (60 mg, 44%). LC-MS (ESI, pos. ion) m/z:650[M + H] ;
'tlNMR (400 MHz, CDC13) δ (ppm): 1.45-1.59 (m, 13H), 1.60-1.70 (m, 2H), 1.70-1.95 (m, 1H), 1.95-2.20 (m, 2H), 3.02-3.25 (m, 1H), 3.25-3.52 (m, 2H), 3.52-4.02 (m, 2H), 4.15-4.39 (m, 3H), 4.45-4.69 (m, 2H), 4.79 (s, 2H), 6.05-6.10 (q, J= 6.6 Hz, 1H), 6.84-6.87 (m, 1H), 7.03-7.07 (t, J = 8.7 Hz, 1H), 7.29-7.33 (m, 1H), 7.35-7.45 (m, 1H), 7.52-7.60 (m, 1H), 7.74 (d, J= 1.5 Hz, 1H).
Step 3) (5S)-5-((4-(6-amino-5-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH- pyrazol-l-yl)methyl)pyrrolidin-3-ol
[0237] The title compound was prepared according to the procedure described in Example 1 Step 10 by using a solution of 5-(l-(((2S)-l-(tert-butoxycarbonyl)-4-((tetrahydro- 2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3- fluorophenyl) ethoxy)pyridin-2-amine (250 mg, 0.385 mmol) and HCl (3.5 mL, 3 M in EtOAc) in DCM (12 mL). The crude product was purified by a silica gel column chromatography (EtOAc/MeOH(v/v) = 5/1) to afford the title compound as a yellow solid (120 mg, 67%).
LC-MS (ESI, pos. ion) m/z:233 (M+l/2);
1H NMR (400 MHz, CDC13) δ (ppm): 1.41-1.50 (m, 1H), 1.59-1.65 (m, 1H), 1.80 (d, J=6.6 Hz, 3H), 1.89 (s, lH),2.62-2.65 (m, 1H), 2.84-2.89 (m, 1H), 3.55-3.62 (m, 1H), 3.96-3.96 (d, J= 6.2 Hz, 2H),4.11-4.18 (m, 1H), 4.57 (s, 1H), 5.65 (s, 2H), 6.06-6.1 1 (q, J=6.6 Hz, 1H), 6.87-6.88 (d, J=1.6 Hz, 1H), 7.42-7.47 (t, J= 8.8 Hz, 1H), 7.51 (s, 1H), 7.55-7.59 (m, 1H), 7.73-7.74 (d, J=1.7 Hz, 1H), 7.87 (s, 1H).
Example 13 4- 4- 6-amino-5- JR)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH- Pyrazol-l-yl)tetrahvdro-2H-pyran-3-ol (13 a) and
3- 4- 6-amino-5- JR)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l-yl) tetrahvdro-2H-pyran-4-ol (13 b)
Figure imgf000087_0001
(13 a) (13 b) Step 1) 3,6-dihvdro-2H-pyran
[0238] To a solution of tetrahydro-2H-pyran-4-ol (20.4 g, 0.2 mol) and Et3N (36.2 mL, 0.26 mol) in DCM (200 mL) was added MsCl (17 mL, 0.22 mol) dropwise at 0 °C. The reation was stirred at rt for 3 h, then poured into H20 (100 mL). The separated organic phase was washed with brine (100 mL x 2), dried over anhydrous a2S04, and concentrated in vacuo to give orange oil. The oil was heated to 50 °C, followed by the dropwise addtion of DBU (40 mL). The mixture was stirred at 100 °C for 2 h. The residue was purified by distillation (92- 93°C) to give the title compound as colorless liquid (10.0 g, 60%).
GC-MS m/z: 84 (M).
Step 2) 3.7-dioxabicyclo|"4.1.0"|heptane
[0239] To a suspension of m-CPBA (25.6 g, 296 mmol) in DCM (200 mL) was added 3,6-dihydro-2H-pyran (8.3 g, 98.7 mmol) dropwise at 0 °C. The reation was stirred at rt overnight, then concentrated in vacuo, and the residue was diluted with DCM (30 mL). The mixture was cooled to 0 °C and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil (7.5 g, 76%).
GC-MS m/z: 100 (M).
Step 3) 3-(4-iodo-lH-pyrazol-l-yl)tetrahydro-2H-pyran-4-ol (13.3 a)
4-(4-iodo-lH-pyrazol-l-yl)tetrahvdro-2H-pyran-3-ol (13.3 b)
Figure imgf000088_0001
(13.3 a) (13.3 b)
To a suspention of NaH (1.6 g, 40.0 mmol, 60% dispersion in mineral oil) in DMF (30 mL) was added 4-iodo-lH-pyrazole (5.8 g, 30.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 2.5 h, then a solution of 3,7-dioxabicyclo[4.1.0]heptane (2.0 g, 20.0 mmol) in DMF (5 mL) was added. The reaction was stirred at 100 °C for 18 h, thenconcentrated in vacuo. The residue was partitioned between EtOAc (300 mL) and H20 (150 mL), and the seperated aqueous phase was extracted with EtOAc (300mL). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give a mixture of (13.3 a) and (13.3 b) as yellow oil (4.2 g, 36%).
LC-MS (ESI, pos. ion) m/z:295[M + H]+. Step 4)
4-(4-(6-amino-5-((R)- 1 -(2 ,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 - yl)tetrahydro-2H-pyran-3 -ol(13 a)
3 -(4-(6-amino-5-((R)- 1 -(2 ,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 - yl)tetrahydro-2H-pyran-4-ol(13 b)
[0240] To a mixture of (13.3 a) and (13.3 b) (530 mg, 1.8 mmol) in DME (25 mL) were added (R)-3 -( 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)-5 -(4,4,5 ,5 -tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pyridin-2-amine (941 mg, 1.5 mmol) and a solution of CS2CO3 (1467 mg, 4.5 mmol) in H20 (5 mL), followed by the addition of Pd(dppf)Cl2-CH2Cl2 (122 mg, 0.15 mmol) in a nitrogen atmosphere.The reaction was stirred at 90 °C for 18 h, then poured into brine (50 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give an off-white solid, which was dissovled in DCM (20 mL). The solution was cooled to 0 °C, followed by the addition of HC1 (3 mL, 3 M in EtOAc). The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was diluted with H20 (15 mL), and the mixture was adjusted to pH 10 with saturated aqueous Na C(¾; and then extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2S04, concentrated in vacuo, and then washed with Et20 (5 mL) to give a mixture of (13 a) and (13 b) as tan solids (55 mg, 7%).
LC-MS (ESI, pos. ion) m/z:467[M + H]+.
Example 14 S- ^-l- i^-dichloro-S-fluorophenvDethoxy^-S- i- S-fluoropiperidin-S-vD-lH- pyrazol-4-yl)pyridin-2-amine
Figure imgf000089_0001
Step l) l -(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate [0241] To a solution of l-(tert-butoxycarbonyl)piperidin-4-ol (10 g, 49.3 mmol) and Et3 (10 g, 74 mmol) in DCM (150 mL) was added MsCl (8.6 g, 59 mmol) dropwise at 0°C. The reaction was stirred at rt for 2 h. then diluted with DCM (100 mL), and washed with saturated aqueous a2CO3(250 mL) followed by brine (250 mL). The organic phase was dried over anhydrous a2S04, and concentrated in vacuoto obtain the crude compound as yellow oil (14 g, 97 %), which was used for the next step without further purification.
Step 2) l-(tert-butoxycarboxyl)-L2,3,6-tetrahvdropyridine
[0242] A solution ofl-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate(14 g, 48 mmol) in DBU (80 mL) was heated to 80 °C and stirred for 16 h. Then the mixture was cooled to rt, diluted with H20 (200 mL) and extracted with EtOAc(150 mL x 3). The combined organic phases were washed with 1 M HC1 (450 mL x 3), followed by saturated aqueous a2CO3(450 mL x 2). The solution was dried over anhydrous a2S04, and concentrated in vacuo to obtain the title compound as brown oil (8 g, 100 %), which was used forthe next step without further purification.
LC-MS (ESI, pos. ion) m/z: 128[(M + H)+ - C4H8];
¾ NMR (400 MHz, CDC13) δ (ppm): 5.83-5.80 (m, 1H), 5.66 (m, 1H), 3.87 (m, 2H), 3.49-3.47 (t, J= 5.2 Hz, 2H), 2.13 (m, 2H), 1.47 (s, 9H).
Step 3) 3-(tert-butoxycarboxyl)-7-oxa-3-azabicyclo[4.1.0]heptane
[0243] To a solution of m-CPBA (20 g, 87.4 mmol) in DCM (150 mL) was added l-(tert- butoxycarboxyl)-l,2,3,6-tetrahydropyridine (8 g, 43.7 mmol) dropwise at 0 °C.The reaction was stirred at rt for 14 h,then filtered. The filter cake was washed with DCM (50 mL x 2), and the combined filtrates were washed with saturated aqueous a2C03 (300 mL x 2). The solution was dried over anhydrous Na2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as colorless oil (8 g, 93 %).
¾ NMR (400 MHz, CDC13) δ (ppm): 3.92-3.82 (m, 1H), 3.71 (m, 1H), 3.44 (m, 1H), 3.29-3.28 (m, 1H), 3.21-3.10 (m, 2H), 2.04 (m, 1H), 1.95-1.88 (m, 1H), 1.45 (s, 9H).
Step 4) l-(tert-butoxycarboxyl)-4-iodopiperidin-3-ol
[0244] To a solution of 3-(tert-butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (lOOmg, 0.5mmol) in DMF (5 mL) cooled in an iced-bath was added ISiMe3 (0.078mL, 0.55mmol). The reaction was stirred at rt overnight, then diluted with EtOAc (50 mL) and washed with 1 M HC1 (25 mL x 2), followed by saturated aqueous Na2CO3(20 mL x 2). The solution was dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatogrphy (PE/EtOAc (v/v) =4/1) to give the title compound as yellow oil (60mg, 37%).
LC-MS (ESI, pos. ion) m/z:350[M + Na , 254[(M + H)+ - C4H8 - H20];
!HNMR (400 MHz, CDC13) δ (ppm): 1.46(s, 9H),2.05-2.16 (m, 1H), 2.33-2.39(m, 1H), 2.59- 3.00 (m, 3H), 3.65-3.87(m, 2H),4.05-4.11(m, 1H), 4.17-4.21(m, 1H).
Step 5) l-(tert-butoxycarbonyl)-4-iodo-3-((tetrahvdro-2H-pyran-2-yl)oxy)piperidine
[0245] To a suspension ofl-(tert-butoxycarboxyl)-4-iodopiperidin-3-ol (lg, 3.1mmol), PPTS (77mg, 0.31mmol) in DCM (20mL) was added DHP (0.56mL, 9.4mmol). The reaction was stirred at rt overnight, then 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 colorlessoil (1.0g, 80%).
LC-MS (ESI, pos. ion) m/z:434[M + Na]+;
'tlNMR (400 MHz, CDCI3) δ (ppm): 1.45(s, 9H), 1.54-1.82(m, 4H), 1.82-2.14(m, 2H), 2.27- 2.41(m, 1H), 2.80-3.05(m, 1H), 3.30-3.59(m, 3H), 3.59-3.78(m, 1H), 3.79-3.95(m, 2H), 3.98- 4.15(m, 1H), 4.15-4.39(m, 1H), 4.81-4.96 (m, 1H).
Step 6) 1 -(tert-butoxycarboxyl)-3 -((tetrahydro-2H-pyran-2-yl)oxy)- 1 ,2,3 ,6-tetrahydropyridine
[0246] To a solution of l-(tert-butoxycarboxyl)-4-iodo-3-((tetrahydro-2H-pyran-2- yl)oxy)piperidine (7.7g, 18.7mmol)was added DBU (50 mL). The reaction was stirred at 80°C for 27h, then cooled to rt, and diluted with EtOAc (50 mL).The mixture was washed with 1M HCl (50 mL x 3) followed by saturated aqueous a2CO3(50 mL x 2), then dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography(PE/EtOAc (v/v) =15/1) to give the title compound as colorless oil (4.2g, 72%).
LC-MS (ESI, pos. ion) m/z:306 [M + Na]+;
'HNMR (400 MHz, CDCI3) δ (ppm): 1.47(s, 9H), 1.50-1. 68(m, 4H), 1. 69-1.79(m, 1H), 1.79- 1.90(m, 1H), 3.30-4.15(m, 6H), 4.15-4.32(m, 1H), 4.70-4.85 (m, lH),5.82-5.93(m, 2H)„
Step7) l-(tert-butoxycarboxyl)-1.2.3.6-tetrahydropyridin-3-ol
[0247] To a solution ofl-(tert-butoxycarboxyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)- 1,2,3,6-tetrahydropyridine (500mg, 1.64mmol) was in DCM/MeOH (25mL/5mL) cooled atO °C was added HCl (11 mL, 3 M in EtOAc) slowly. The reaction was stirred at rtovemight, then concentrated in vacuo to give the crude product, which was dissolved in THF/H20 (76mL/60 mL). The solution was adjusted to pH 10 with saturated aqueous a2C03, followed by the addition of (Boc)20(1.5mL). The reaction was stirred at rt overnight,thendiluted with EtOAc/H20 (30 mL/30 mL).The seperated aqueous phase was extracted with EtOAc (80 mL x 2). The combined organic phases were dried over anhydrous a2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as colorless oil (0.30g, 92%).
LC-MS (ESI, pos. ion) m/z: 126[(M + H)+ - C4H8 - H20].
Step 8) l-(tert-butoxycarbonyl)-L6-dihvdropyridin-3(2H)-one
[0248] To a solution of l-(tert-butoxycarboxyl)-l,2,3,6-tetrahydropyridin-3-ol (350mg, 1.76 mmol) in DCM (12mL) was added Dess-Martin Oxidant (1.5 g, 3.52mmol). The reaction was stirred at rt for 2h, then filtered.The filtrate was washed with saturated aqueous a2CO3(50 mL), and concentrated in vacuo. The resulted residue was purified bya silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as colorless oil(340mg, 98%).
LC-MS (ESI, pos. ion) m/z: 142[(M + H)+ - C4H8],220[M + Naf;
'tlNMR (400 MHz, CDC13) δ (ppm): 1.48(s, 9H), 4.11 (s, 2H), 4.24 (s, 2H), 6.16-6.20(m, 1H), 7.04 (s, 1H).
Step 9) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -one
[0249] To a solution of 4-iodo- lH-pyrazole (389.9mg, 2.01mmol) in MeCN (6mL) was added l-(tert-butoxycarbonyl)-l,6-dihydropyridin-3(2H)-one(260mg, 1.34 mmol). The reaction was stirred at 80°C overnight, then cooled to rt, diluted with H20 (20 mL), and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over anhydrous Na2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as a white solid (1 lOmg, 21%).
LC-MS (ESI, pos. ion) m/z:336[(M + H)+ - C4H8],414[M + Naf;
'tlNMR (400 MHz, CDCI3) δ (ppm): 1.39(s, 9H), 2.86-2.92(m, 1H), 2.80-3.05(m, 1H), 3.09- 3.15(m, 1H), 3.50-4.42(m, 4H), 4.78-4.82(m, 1H), 7.49(s, 1H), 7.51 (s, 1H).
Step 10) 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -ol
[0250] To a solution of 1 -(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-3 -one (3.45g, 8.82mmol) in MeOH(50mL) was addedNaBH4 (670mg, 17.64mmol)at 0°C. The reaction was stirred atrt for lh, then quenched with saturated aqueous NH4C1 (50 mL), and extracted with EtOAc (100 mL x 2). The combined organic phases were dried over anhydrous Na2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound asa white solid (2.1g, 60.7%).
LC-MS (ESI, pos. ion) m/z:394[M + H]+.
Step 11) l-(tert-butoxycarboxyl)-3-fluoro-5-(4-iodo-lH-pyrazol-l-yl)piperidine
[0251] The title compound was prepared according to the procedure described in Example 11 Step 7 by usinga solution of l-(tert-butoxycarbonyl)-5-(4-iodo-lH-pyrazol-l- yl)piperidin-3-ol (240mg, 0.61 mmol) and DAST (95%,0.15 mL, 1.04 mmol)in DCM (5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as a yellow solid (900 mg, 45%).
LC-MS (ESI, pos. ion) m/z:340[M + H - 56]+.
Step 12) l-(tert-butoxycarbonyl)-3-fluoro-5-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -vDpiperidine
[0252] The title compound was prepared according to the procedure described in Example 11 Step 8 by usinga suspension of l-(tert-butoxycarboxyl)-3-fluoro-5-(4-iodo-lH- pyrazol-l-yl)piperidine (900mg, 2.07 mmol), bis(pinacolato)diboron (1.04g, 4.14 mmol) and CH3COOK (608mg,6.21mol)in DMSO (50mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as yellow oil (650 mg, 72 %).
LC-MS (ESI, pos. ion) m/z:396[M + H]+.
Step 13) 5-(1-(1 -(tert-butoxycarbonyl)-5-fruoropiperidin-3 -yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2 ,6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0253] The title compound was prepared according to the procedure described in Example 11 Step 9 by usinga suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (195mg, 0.5139 mmol), l-(tert-butoxycarbonyl)-3-fluoro- 5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine (521.5 mg, 1.32mmol),Pd(OAc)2(35.5mg,mmol), Na2C03 (560mg, 5.28mmol)and(?-Bu)3P (0.15 mL, 1M in toluene) in DME/H20 (15 mL/4mL).The crude product waspurified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to afford the title compound as a yellow solid (350mg, 47%).
LC-MS (ESI, pos. ion) m/z:568[M + H]+.
Step 14) 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(5-fluoropiperidin-3-yl)- 1H- pyrazol-4-yl)pyridin-2-amine
[0254] The title compound was prepared according to the procedure described in
Example 1 Step 10 by using a solution of 5-(l-(l-(tert-butoxycarboxyl)-5-fluoropiperidin-3- yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine (35 Omg, 0. 62 mmol) and HC1 (4 mL, 3 M in EtOAc) in DCM (6 mL). The crude product was purified by a silica gel column chromatography (EtOAc/MeOH (v/v) =6/1) to afford the title compound as a yellow solid (235mg,81%).
LC-MS (ESI, pos. ion) m/z: 234.5(M+l/2);
¾ NMR (400 MHz, CDC13) δ (ppm): 1.86-1.88 (d, J=6.6Hz, 3H),2.16-2.24(m, 1Η),2.59-2.75 (m, 1H), 2.90-3.00 (m, 1H), 3.25-339 (m, 2H), 4.20-4.32 (m, 1H), 4.53-4.75(m, 1H), 4.83 (s, 2H), 6.06-6. l l(q, J=6.5 Hz, 1H), 6.88(s, 1H), 7.04-7.08 (t, J=8.4 Hz, 1H), 7.28-7.33 (m, 1H), 7.54 (s, 1H), 7.58 (s, 1H) ,7.77(s, 1H).
Example 15 5- 4- 6-3ΐηίηο-5- /?)-1- 2,6-άί€ΜθΓθ-3-ΑυοΓθρΗ6ην1)6ίΗοχν)ρνΓί(ϋη-3-ν1)-1^ pyrazol-l-vDpiperidin-3-ol
Figure imgf000094_0001
Step 1)1 -(ter/-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- !H-pyrazol- l-yl)piperidin-3-ol
[0255] To a solution of l-(tert-butoxycarbonyl)-5-(4-iodo-lH-pyrazol-l-yl)piperidin-3-ol (1.5 g, 3.81 mmol) and bis(pinacolato)diboron (1.94 g, 7.62 mmol) in DMSO (20 mL) was added CH3COOK (1.5 g, 15.24 mmol), followed by Pd(dppf)Cl2-CH2Cl2 (310 mg, 0.38 mmol) in a nitrogen atmosphere. The reaction was stirred at 90°C for 12 h, then cooled to rt, and poured into H20/EtOAc (100 mL/300 mL). The seperated organic phase was washed with brine (100 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as abrown solid (720mg, 48%).
LC-MS (ESI, pos. ion) m/z: 394.20[M + H]+.
Step 2)5-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol-l- yl)-l-(tert-butoxycarbonyl)piperidin-3-ol
[0256] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (515 mg, 1.36 mmol) and l-(?ert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidin-3-ol (800mg, 2.03 mmol) in DME (25 mL) was added a solution of CS2CO3 (1.33 g, 4.08 mmol) in H20 (5 mL), followed by Pd(dppf)Cl2 -CH2Ci2 (1 14 mg, 0.14 mmol) in a nitrogen atmosphere. The reaction was stirred at 90°C for 12h,then cooled down to rt, diluted with H20 (20 mL), and extracted with DCM (50 mL x 3). The combined organic phases werewashed with brine (100 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 60/1) to give the title compound as yellow oil (400 mg, 52%).
LC-MS (ESI, pos. ion) m/z:566.20[M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm):7.72 (s, 1H), 7.50-7.54 (m, 2H), 7.28-7.32 (m, 1H), 7.02- 7.07 (m, 1H), 6.85 (s, 1H), 6.02-6.10 (m, 1H), 4.96 (s, 2H), 4.31-4.34 (m, 1H), 3.86 (s, 1H), 3.76-3.80 (m, 1H), 3.64-3.67 (m, 1H), 3.52-3.60 (m, 1H), 3.42-3.47 (m, 1H), 2.38-2.41 (m, 1H), 2.15-2.21 (m, 1H), 1.84-1.86 (d, J= 6.6 Hz, 3H), 1.36 (s, 9H).
Step 3) 5-(4-(6-amino-5-((R)-l -(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- lH-pyrazol- 1 - yl)piperidin-3-ol
[0257] The title compound was prepared according to the procedure described in Example 1 Step 10 by using a solution of 5-(4-(6-amino-5-((R)-l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-3 -yl)- lH-pyrazol- 1 -yl)- 1 -(tert-butoxycarbonyl)piperidin-3 -ol(350 mg, 0.62 mmol) and HC1 (4 mL, 3 M in EtOAc) in DCM (5 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 40/1) to afford the title compound as a brown yellow solid (60 mg, 21%).
LC-MS (ESI, pos. ion) m/z:466.20 [M + H]+; ¾ NMR (400 MHz, DMSO-d6) δ (ppm):7.92 (s, 1H), 7.75 (s, 1H), 7.54-7.58 (m, 1H), 7.52 (s, 1H), 7.41-7.45 (m, 1H), 6.89 (s, 1H), 6.04-6.10 (m, 1H), 5.63 (s, 2H), 4.87 (s, 1H), 4.07-4.16 (m, 1H), 3.46-3.58 (m, 4H), 3.05-3.10 (m, 1H), 2.96-3.01 (m, 1H), 2.26-2.31 (m, 1H), 2.13-2.19 (m, 1H), 1.78-1.81 (d, J= 6.6 Hz, 3H).
Example 16 S-d-ri^-dideuteropiperidin^-vD-lH-pyrazo -vD-S-r^-l-ri^-dichloro-S- fluorophenyl)ethoxy)pyridin-2-amine
Figure imgf000096_0001
Step 1) 4-hydroxypiperidin-2-one
[0258] To a solution of piperidine-2,4-dione (1 g, 8.8 mmol) in MeOH (25 mL) was added NaBH4 (1 g, 26.55 mmol) at 0°C. The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 5/1) to give the title compound as ayellow solid (960 mg, 87%).
LC-MS (ESI, pos. ion) m/z: 138[M + Na]+.
Step 2) 4-((tetrahvdro-2H-pyran-2-yl)oxy)piperidin-2-one
[0259] To a suspension of 4-hydroxypiperidin-2-one (1.4 g, 12.18 mmol),PPTS (367 mg, 1.462 mmol) in DCM (200 mL) was added DHP(4.1 g, 48.72 mmol). The reaction was stirred at 35°C for 48h, and then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a whitesoild (2.16 g, 89%).
LC-MS (ESI, pos. ion) m/z:200[M + H]+;
!HNMR (400 MHz, CDC13) δ (ppm): 1.50-1.70 (m,4H), 1.71-1.80 (m, 1H), 1.80-2.10 (m, 4H), 2.40-2.71 (m, 3H), 3.21-3.35 (m, 1H), 3.36-3.62 (m, 2H), 3.80-3.95 (m, 1H), 4.11-4.20 (m,lH), 4.65-4.79 (m,lH), 6.50 (s, 1H).
Step 3) l-(tert-butoxycarbonyl)-2,2-dideuteropiperidin-4-ol [0260] To a solution of4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-2-one (1.17 g, 5.88 mmol)in THF (33.3mL) cooled in an ice bath was added LiAlD4 (272 mg, 6.47 mmol). The reaction was stirred at 70 °C overnight, then cooled in an ice bath again, and quenched with saturated aqueous NH4C1 (50 mL) slowly.The mixture was extracted with EtOAc (50 mL x 2), and the combined organic phases were dried over anhydrous a2S04, and concentrated in vacuoto give crude product, which was used w situ.
LC-MS (ESI, pos. ion) m/z: 188[M + H]+.
[0261] To a solution of 2,2-dideutero-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine in DCM/MeOH (45 mL/9 mL) was added HC1 (26 mL, 3 M in EtOAc) at 0 °C.The reaction was stirred at rtovernight, then concentrated in vacuo.
[0262] To a solution of the resulted residueand Na2CO3(16.80g, 158.5 mmol)in THF/H20 (76 mL/60 mL) was added (Boc)20(5 mL). The reaction was stirred at rt overnight, then pardoned between EtOAc (50 mL) and H20 (50 mL).The seperated aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over anhydrous Na2S04, concentrated in vacuo, and then purifiedby a silica gel column chromatography(PE/EtOAc (v/v) = 2/1) to give the title compound as a whitesoild (0.52 g, 17%).
LC-MS (ESI, pos. ion) m/z: 149[(M + H)+ - C4H8];
'FfNMR (400 MHz, CDC13)8 (ppm): 1.46 (s, 9H), 1.73 (s, 2H), 1.82-1.86 (m, 2H), 2.99-3.06 (m, 1H), 3.81-3.87 (m, 2H).
Step 4) l-(tert-butoxycarbonyl)-2,2-dideutero-4-(4-iodo-lH-pyrazol-l-yl)piperidine
[0263] To a solution of l-(tert-butoxycarbonyl)-2,2-dideuteropiperidin-4-ol (490 mg, 2.41 mmol) and DMAP (29.4 mg, 0.241mmol) in DCM (15 mL) was added Et3N (0.67 mL, 4.82 mmol) at 0°C, followed by the dropwise addition of MsCl (0.223 mL, 2.897 mmol). The reaction was stirred at rt for 5 h, thenquenched with 1 M aHC03 (25 mL), and extracted with DCM (50 mL x2). The combined organic phases were washed with brine (25mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the residue, which was used w situ.
[0264] To a solution of 4-iodo-lH-pyrazole (467.5 mg, 2.41 mmol) in anhydrous DMF (8 mL)was added NaH (193 mg, 4.82 mmol, 60% dispersion in mineral oil) in portions at 0°C. The mixture was stirred atrt for 2 h, then a solution of the above residue in DMF (4 mL) was added. The reaction was stirred at 100 °C for 12 h, then cooled to rt, quenched with saturated aqueous NH4CI (50 mL), and extracted with EtOAc (50 mL x2). The combined organic phases were washed with brine (25mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to givethe title compound as ayellow solid (620 mg, 68%).
LC-MS (ESI, pos. ion) m/z:324[(M + H)+ - C4H8];
¾ NMR (400 MHz, CDC13) δ (ppm): 1.47 (s, 9H), 1.83-1.89 (m, 2H), 2.07-2.1 1 (m, 2H), 2.85- 2.90 (m, 1H), 4.23-4.30 (m, 2H), 7.46 (s, 1H), 7.51 (s, 1H).
Step 5) l-(ter/-butoxycarbonyl)-2,2-dideutero-4-(4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- yl)- lH-pyrazol- 1 -yPpiperidine
[0265] The title compound was prepared according to the procedure described in Example 11 Step 8 by using a suspension of l-(tert-butoxycarbonyl)-2,2-dideutero-4-(4-iodo- lH-pyrazol-l-yl)piperidine(300mg, 0.792 mmol), bis(pinacolato)diboron(281.6 mg, 1.1 1 mmol), CH3COOK (310.5 mg, 3.17 mol) and Pd(PPh3)2Cl2(33.36 mg, 0.0475 mmol) in DMSO (6 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compoundas a white solid (250 mg, 83%).
LC-MS (ESI, pos. ion) m/z:380[M + H]+.
Step 6) 5-(l-(l-(ter?-butoxycarbonyl)-2,2-dideuteropiperidin-4-yl)-lH-pyrazol-4-yl)-3-((R)-l- (2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0266] To asolution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine(300.8 mg, 0.792 mmol), l-(?er?-butoxycarbonyl)-2,2-dideutero-4-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine(250 mg, 0.66 mmol)andNa2C03 (245 mg, 2.31 mmol)in DME/H20 (6 mL/1 mL) was added Pd(PPh3)2Cl2 (37 mg, 0.053 mmol)in a nitrogen atmosphere. The reaction was stirred at 90 °C for 14 h, then cooled to rt, and diluted with EtOAc (150 mL). The mixture was filtered through a pad of Celite, which was washed with EtOAc (50 mL). Thecombind filtrates were washed with brine (50 mL x 2),concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as a yellow solid(180 mg, 50%).
LC-MS (ESI, pos. ion) m/z: 552[M + H]+.
Step 7) 5-q -(2.2 -dideuteropiperidin-4-yl - 1 H-pyrazol-4-ylV 3 -(YRV 1 -(2.6-dichloro-3 - fluorophenyl)ethoxy)pyridin-2-amine
[0267] The title compound was prepared according to the procedure described in Example 1 Step 10 by usinga solution of 5-(l-(l-(?ert-butoxycarbonyl)-2,2-dideuteropiperidin- 4-yl)- lH-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine(440 mg, 0.80 mmol)and HCl (5 mL, 3 M in EtOAc) in DCM (20mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) = 100/20/1) to give the title compoundas a white solid (180 mg, 50%).
LC-MS (ESI, pos. ion) m/z:226.6 (M+2/2);
¾ NMR (400 MHz, CDC13) δ (ppm): 1.85-1.86 (d, J=6.7 Hz, 3H),1.86-1.95 (m, 2H),2.13-2.18 (m, 2H), 2.76-2.81 (t, J= 10.6 Hz, 1H), 3.24-3.28 (m, 1H), 4.18-4.24 (m, 1H), 4.78 (s, 2H), 6.05- 6.10 (q, J=6.6 Hz, 1H), 6.87 (s, 1H), 7.03-7.07 (t, J=8.5 Hz, 1H), 7.27-7.32 (m, 1H), 7.50 (s, 1H),7.56 (s, 1H) ,7.76 (s, 1H).
Example 17
3-rrRVl-r2.6-dichloro-3-nuorophenvnethoxyV5-ri-rr3S.4RV3-nuoropiperidin-4-ylVlH- pyrazol-4-vDpyridin-2-amine (17 a)
3-rrRVl-r2.6-dichloro-3-nuorophenvnethoxyV5-ri-rr3R.4SV3-nuoropiperidin-4-ylVlH- pyrazol-4-yl)pyridin-2-amine (17 b)
Figure imgf000099_0001
(17 a) (17 b)
Step 1) l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)piperidin-3-ol(17.1 a)
1 -(tert-butoxycarbonyl)-3 -(4-iodo- 1 H-pyrazol- 1 -yl)piperidin-4-ol(l 7.1 b)
Figure imgf000099_0002
(17.1 a) (17.1 b)
[0268] To a solution of 4-iodo- lH-pyrazole(3 g, 16 mmol) in THF (20 mL) was added LDA(10 mL, 2 M in THF) dropwise in 30 min at -78 °C. The mixture was stirred for 3 h, then a solution of 3-(tert-butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (3 g, 14 mmol) in THF (20 mL) was added to the mixture dropwise in 20 min. The reaction was stirred at rt for 1 h, then heated to 70 °C and continued to stir for 12 h. The mixture was cooled down to rt, quenched with H20 (4 mL), and concentrated in vacuo. The resulted residue waspurified by a silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give (17.1 a) (2.5 g, 41%) and(17.1 b) (1 g, 17%) as white solids.
(17.1 a):
LC-MS (ESI, pos. ion) m/z: 394[M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.56 (s, 1H), 7.24 (s, 1H), 4.39-4.04 (m, 2H), 4.02-3.99 (m, 1H), 3.87 (m, 1H), 2.82-2.70 (m, 2H), 2.12-2.04 (m, 1H), 2.00-1.95 (m, 1H), 1.46 (s, 9H).
(17.1 b):
LC-MS (ESI, pos. ion) m/z: 394[M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.55 (s, 2H), 4.34-4.16 (m, 3H), 3.95-3.89 (m, 1H), 3.08 (m, 2H), 2.88-2.82 (t, J=12Hz, 1H), 2.07-2.03 (m, 1H), 1.65-1.56 (m, 1H), 1.47 (s, 9H).
Step 2) 1 -(tert-butoxycarbonyl)-4-(4-iodo- 1 H-pyrazol- 1 -yl)-3 -((tetrahydro-2H-pyran-2- yl)oxy)piperidine
[0269] To a solution of l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)piperidin-3-ol (0.5 g, 1.27 mmol) and PPTS (0.032 g, 0.127 mmol) in DCM (20 mL) was added DHP (0.5 mL). The reaction was stirred at rt for 3 h,then 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 pale yellow oil (0.5 g, 84 %).
LC-MS (ESI, pos. ion) m/z: 478 [M + H]+.
Step 3) l-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(4-(4.4.5.5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine
[0270] A suspension of l-(tert-butoxycarbonyl)-4-(4-iodo-lH-pyrazol-l-yl)-3-
((tetrahydro-2H-pyran-2-yl)oxy)piperidine (0.5 g, 1 mmol), bis(pinacolato)diboron (0.8 g, 3 mmol), CH3COOK(0.2 g, 2 mmol) andPd(dppf)Ci2-CH2Cl2(0.08 g, 0.1 mmol) in DMSO (15 mL) was stirred at 50 °C for 4h in anitrogen atmosphere. Then the mixture was cooled to rt, diluted with ¾0 (40 mL) and extracted with EtOAc (30 mL x 3).The combined organic phases were washed with brine (80 mL x 2), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residuewas purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a white solid (0.45 g, 90 %).
LC-MS (ESI, pos. ion) m/z: 478 [M + H]+.
Step 4) 5-( 1 -(1 -(tert-butoxycarbonyl)-3 -((tetrahvdro-2H-pyran-2-yl)oxy)piperidin-4-yl)- 1 H- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0271] To a suspension of l-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4- (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine (0.45 g, 0.94 mmol), (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine(0.4 g, 1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol) and Na2C03 (0.22 g, 2 mmol) in DME/H20 (20 mL/lmL) was added (?-Bu)3P (0.25 mL, 1 M in toluene)in a nitrogen atmosphere. The reaction was stirred at 100 °C for 36 h, then concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale brown solid (0.38 g, 61%).
LC-MS (ESI, pos. ion) m/z: 650[M + H]+;
!H NMR (400 MHz, CDC13) δ (ppm): 7.75-7.73 (m, 1H), 7.67 (s, 1H), 7.61-7.50 (m, 1H), 7.31- 7.29 (m, 1H), 7.07-7.02 (m, 1H), 6.88-6.86 (m, 1H), 6.10-6.05 (t, J=6.64 Hz, 1H), 4.80 (s, 2H), 4.70-4.18 (m, 2H), 4.12-3.65 (m, 4H), 3.57-2.98 (m, 1H), 2.91-2.45 (m, 2H), 2.40-1.92(4H, m), 1.86-1.84(d, J=6.64 Hz, 3H), 1.78-1.45(m, 13H).
Step 5)
(3R,4R)-4-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH-pyrazol- 1 -vD- 1 -(tert-butoxycarbonyl)piperidin-3 -old 7.5a)
(3 S,4S)-4-(4-(6-amino-5 -((R)- 1 -(2 ,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- 1 -vD- 1 -(tert-butoxycarbonyl)piperidin-3 -old 7.5b)
Figure imgf000101_0001
(17.5 a) (17.5 b) [0272] A solution of 5-(l-(l-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2- yl)oxy)piperidin-4-yl)- 1 H-pyrazol-4-yl)-3 -((R)- 1 -(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin- 2-amine (1 g, 1.54 mmol) and PPTS (0.12 g, 0.46 mmol) in MeOH (30 mL)was stirred at 75 °C for 30 h. Then the mixture was concentrated in vacuo, diluted with water (40 mL) and extracted with DCM (30 mL x 3).The combined organic phases were washed with brine (90 mL), dried over anhydrous a2S04, concentrated in vacuo. The resulted residuewas purified by a silica gel column chromatography (DCM/MeOH (v/v) = 40/1) to give a mixture of (17.5a) and (17.5b) as brown solids (0.6 g, 71%).
LC-MS (ESI, pos. ion) m/z: 565 [M + H]+;
Step 6) 5-(l-((3S.4R)-l-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)-3-((R)- 1 -(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (17.6a)
5-(l-((3R.4S)-l-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)-3-((R)-l-(2.6- dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine(17.6b)
Figure imgf000102_0001
(17.6 a) (17.6 b)
[0273] To a solution of (17.5a) and (17.5b) (0.6 g, 1 mmol) in DCM (15 mL)was added a solution of DAST (0.34 g, 2 mmol) in DCM (5 mL)dropwise at -78 °C. The reaction was sitrred at -78 °C for 30min, then warmed to -40 °C and continued to stir for 4h. The mixture was quenched with 1 M NaHC03 (30 mL), and extracted with DCM (30 mL x 3).The combined organic phases were washed with H20 (90 mL) followed by brine (90 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 40/1) to give a mixture of (17.6a) and (17.6b) as brown solids (0.28 g, 47%).
LC-MS (ESI, pos. ion) m/z: 568 [M + H]+.
Step 7) 3 -((R)- 1 -(2.6-dichloro-3 -fluorophenyl)ethoxy)-5-( 1 -((3 S.4RV3 -fluoropiperidin-4-yl)- 1 H- pyrazol-4-yl)pyridin-2-amine(l 7 a)
3 -((R)- 1 -(2.6-dichloro-3 -fluorophenyl)ethoxy)-5-( 1 -(Y3 R.4SV3 -fluoropiperidin-4-yl)- 1 H- pyrazol-4-yl)pyridin-2-amine(l 7 b)
[0274] HC1 (10 mL, 1 M in EtOAc) was added dropwise to amixture of (17.6 a) and (17.6b) (0.28 g, 0.49 mmol). The reaction was stirred at rt for 2 h, then concentrated in vacuo. The residuewas treated with 2 M a2C03 (20 mL), and then extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH/NH4OH (v/v/v) = 50/1/1) to give a mixture of (17a) and (17b) as pale yellow solids (0.15 g, 75 %).
LC-MS (ESI, pos. ion) m/z: 234.7 (M+2)/2;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.77 (s, IH), 7.62 (s, IH), 7.58-7.52 (m, IH), 7.32-7.29(dd, J=4.80 Hz, IH), 7.07-7.03 (t, J=8.60 Hz, IH), 6.88 (s, IH), 6.10-6.05 (t, J=6.68 Hz, IH), 4.80 (s, 2H), 4.69-4.60 (m, IH), 4.23-4.13 (m, IH), 3.52-3.47 (m, IH), 3.19-3.15 (m, IH), 2.74-2.70 (m, 2H), 2.20-2.16 (m, 2H), 1.86-1.84(d, J=6.68 Hz, 3H).
Example 18 (3R,4R)-4-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3- yl)-lH-pyrazol-l-yl)piperidin-3-ol (18 a)
(3S,4S)-4-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-nuorophenyl)ethoxy)pyridin-3-yl)-lH- pyrazol-l-yl)piperidin-3-ol (18 b)
Figure imgf000103_0001
(18 a) (18 b)
[0275] HC1 (5 mL, 1 M in EtOAc) was added dropwise to 5-(l-(l-(tert-butoxycarbonyl)- 3-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-4-yl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (0.25 g, 0.38 mmol).The reaction was stirred at rt 2 h, then diluted with ¾0 (20 mL), and washed with EtOAc (20 niL x 2). The mixture was treatedwith2 M a2C03 (10 mL), and then extracted with EtOAc (20 mL x 3).The combined organic phases were washed with brine (60 mL), dried over anhydrous a2S04, and concentrated in vacuo to give the title compound as a white solid (0.12 g, 70 %).
LC-MS (ESI, pos. ion) m/z: 233.7 (M+2)/2;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.75 (d, J=1.68 Hz, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.33- 7.29 (m, 1H), 7.07-7.04(t, J=7.92 Hz, 1H), 6.86 (s, 1H), 6.10-6.05 (t, J=6.64 Hz, 1H), 4.78 (s, 2H), 3.99-3.95 (m, 2H), 3.41-3.19 (m, 2H), 2.78-2.59 (m, 2H), 2.19-1.97 (m, 2H), 1.86-1.84(d, J=6.64 Hz, 3H).
Example 19 (3R,4R)-3-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3- vD-lH-pyrazol-l-yl)piperidin-4-ol (19 a)
(3S,4S)-3-(4-(6-amino-5-((R)-l-(2,6-dichloro-3-nuorophenyl)ethoxy)pyridin-3-yl)-lH- pyrazol-l-vDpiperidin-4-ol (19 b)
Figure imgf000104_0001
(19 a) (19 b)
Step 1) 1 -(tert-butoxycarbonyl)-3 -(4-iodo- 1 H-pyrazol- 1 -yl)-4-((tetrahydro-2H-pyran-2- yl)oxy)piperidine
[0276] The title compound was prepared according to the procedure described in Example 17 Step 2 by using a solution of l-(tert-butoxycarbonyl)-3 -(4-iodo- 1 H-pyrazol- 1- yl)piperidin-4-ol (1 g, 2.6 mmol), PPTS (0.064 g, 0.26 mmol) and DHP (1 mL)in DCM (30 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to afford the title compoundas pale yellow oil (0.5 g, 84 %).
LC-MS (ESI, pos. ion) m/z: 478 [M + H]+.
Step 2) 1 -(tert-butoxycarbonyl)-4-((tetrahvdro-2H-pyran-2-yl)oxy)-3 -(4-(4 ,4,5 ,5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-l H-pyrazol- 1-vDpiperi dine [0277] The title compound was prepared according to the procedure described in Example 17 Step 3 by using a suspension of l-(tert-butoxycarbonyl)-3-(4-iodo-lH-pyrazol-l- yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine (0.6 g, 1.25 mmol), bis(pinacolato)diboron (0.9 g, 3.8 mmol), KOAc(0.25 g, 2.5 mmol) and Pd(dppf)Cl2-CH2Cl2(0.1 g, 0.125 mmol) in DMSO (20 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to afford the title compound as a yellow solid (0.58 g, 94 %).
LC-MS (ESI, pos. ion) m/z: 478 [M + H]+.
Step 3) 5-(l-(l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-3-yl)-lH- pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0278] The title compound was prepared according to the procedure described in Example 17 Step 4 by using a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine(0.6 g, 1.58 mmol), 1 -(tert-butoxycarbonyl)-4-((tetrahydro- 2H-pyran-2-yl)oxy)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine (0.58 g, 1.2 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), Na2C03 (0.26 g, 2.5 mmol) and (/-Bu)3P (0.38 mL, 1 M in toluene)in DME/H20 (30 mL/lmL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to afford the title compound as a pale brown solid (0.5 g, 60 %).
LC-MS (ESI, pos. ion) m/z: 650[M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.75-7.40 (m, 1H), 7.62-7.60 (m, 1H), 7.53-7.51 (m, 1H), 7.34-7.28 (m, 1H), 7.08-7.02 (dd, J=8.02 Hz, 1H), 6.87-6.86 (m, 1H), 6.10-6.05 (t, J=6.64 Hz, 1H), 4.48-4.01 (m, 3H), 3.95-3.80 (m, 3H), 3.41-3.37 (m, 1H), 3.01-2.78 (m, 1H), 2.15-2.12 (m, 1H), 1.86-1.84(d, J=6.64 Hz, 3H), 1.66-1.62(m, 3H), 1.58-1.36 (m, 13H).
Step 4) (3R.4R)-3-(4-(6-amino-5-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-lH- pyrazol-l-yl)piperidin-4-ol (19 a)
(3 S,4S)-3 -(4-(6-amino-5 -((R)- 1 -(2 ,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-3 -yl)- 1 H-pyrazol- l-yl)piperidin-4-ol (19 b)
[0279] The title compound was prepared according to the procedure described in Example 18 by using 5-(l-(l-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy) piperidin-3-yl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.25 g, 0.38 mmol) and HCl (5 mL, 1 M in EtOAc). The desired product was obtained as a white solid (0.09 g, 50 %). LC-MS (ESI, pos. ion) m/z: 233.7 (M+2)/2;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.74 (s, 1H), 7.60 (s, 1H), 7.50-7.49 (d, J=3.2 Hz, 1H), 7.32-7.28(m, 1H), 7.07-7.03 (m, 1H), 6.85 (s, 1H), 6.09-6.04 (t, J=6.64 Hz, 1H), 4.78 (s, 2H), 4.15-4.08 (m, 1H), 3.96-3.90 (m, 1H), 3.42-3.38 (m, 1H), 3.18-3.15 (m, 1H), 3.00-2.93 (m, 1H), 2.77-2.70 (m, 1H), 2.17-2.13 (m, 1H), 1.86-1.84(d, J=6.64 Hz, 3H).
Example 20 S- ^-l- i^-dichloro-S-fluorophenvDethoxy^-S- i- hexahydrofurofl^- 61furan-3-yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000106_0001
Step 1) (2R,3»Sy2-(allyloxy)-3-iodotetrahvdrofuran
[0280] To a suspension of S (15.1 g, 66.6 mmol) in DCM (150 mL) was added a solution of dihydrofuran (5.1 mL, 66.6 mmol) and allyl alcohol (6.8 mL, 100 mmol) in DCM (50 mL)dropwise at 0°C in 30 min. The reaction was stirred at 0°C for 3 h, then warmed up to rt, and diluted with ¾0 (200 mL). The mixture was continued to stirfor 1 h, then extracted with DCM (200 mL). The organic phase was washed with brine (400 mL), dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 9/1) to give the title compound as yellow oil (15.53 g, 91.8%).
'H NMR (400 MHz, CDC13) δ (ppm): 5.88 (m, 1H), 5.39 (s, 1H), 5.29 (m, 1H), 5.23 (m, 1H), 4.20-3.95 (m, 5H), 2.63 (m, 1H), 2.21 (m, 1H).
Step 2) 3-(iodomethyl)hexahydrofuro[2,3- ?lfuran
[0281] To a mixture of (2R,35)-2-(allyloxy)-3-iodotetrahydrofuran (2 g, 7.87 mmol) in H2O (100 mL) was added Et3B (0.7 mL, 1 M in THF) in a nitrogen atmosphere. The reaction was stirred at rt for 3 h, and then extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous a2S04, and concentrated in vacuo to give the title compound as yellow oil (1.6 g, 80%), which was used for the next step without purification.
LC-MS (ESI, pos. ion) m/z:254 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 5.78 (d, J= 4.92 Hz, 1H), 4.05-4.02 (m, 1H), 3.92-3.88 (m, 2H), 3.48-3.43 (dd, J= 8.6 Hz, 1H), 3.19-3.15 (dd, J= 7.68 Hz, 1H), 3.10-3.05 (dd, J= 8.46 Hz, 1H), 2.93-2.76 (m, 2H), 1.94-1.80 (m, 2H).
Step 3) l-((hexahydrofuror2.3-/?lfuran-3-yl)methyl)-4-iodo-lH-pyrazole
[0282] To a solution of 4-iodo-lH-pyrazole (2 g, 9.48 mmol) in anhydrous DMF (30 mL) was added NaH (0.7 g, 23.7 mmol, 80% dispersion in mineral oil) in portions at 0°C, followed by a solution of 3-(iodomethyl)hexahydrofuro[2,3-£]furan (1.6 g, 7.9 mmol) in DMF (10 mL). The reaction was stirred at 80°C for 10 h, then cooled to rt, quenched with H20 (80 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous a2S04, and 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 yellow oil (1.5 g, 60%).
LC-MS (ESI, pos. ion) m/z: 321 [M + H]+;
1H MR (400 MHz, CDC13) δ (ppm): 7.47 (s, 1H), 7.40 (s, 1H), 5.70 (d, J = 4.8 Hz, 1H), 4.28- 4.23 (dd, J= 7.32 Hz, 1H), 4.16-4.11 (dd, J= 7.7 Hz, 1H), 3.95-3.85 (m, 3H), 3.63-3.58 (dd, J = 8.64 Hz, 1H), 2.91-2.79 (m, 2H), 1.93-1.88 (m, 2H).
Step 4) l-((hexahydrofuror2,3-/?1furan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-L3,2- dioxaborolan- 2-vD- lH-pyrazole
[0283] To a solution of l-((hexahydrofuro[2,3-/?]furan-3-yl)methyl)-4-iodo-lH-pyrazole (1.2 g, 3.75 mmol), bis(pinacolato)diboron (1.14 g, 4.5 mmol) and CH3COOK (1.1 g, 11.25 mmol) in DMSO (25 mL)was added Pd(dppf)Ci2-CH2Ci2(153 mg, 0.19 mmol) in a nitrogen atmosphere. The reaction was stirred at 80°C for 3 h, then cooled to rt, diluted with H20 (60 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (120 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as yellow oil (0.6 g, 50%).
¾ NMR (400 MHz, CDC13) δ (ppm): 7.78 (s, 1H), 7.67 (s, 1H), 5.73 (d, J= A3 Hz, 2H), 4.29- 4.26 (m, 1H), 4.20-4.14 (m, 1H), 3.98-3.88 (m, 3H), 3.67-3.65 (m, 1H), 1.97-1.93 (m, 2H), 1.32 (s, 6H), 1.25(m, 6H). Step 5) 3-('('R -l-('2,6-dichloro-3-fluorophenyl ethoxy -5-('l-('('hexahvdrofuror2,3-/?1 furan-3- yl)methyl)-lH-pyrazol-4-yl)pyridin-2-amine
[0284] To a solution of (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2- amine (0.8 g, 1.8 mmol), l-((hexahydrofuro[2,3-/?]furan-3-yl)methyl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.8 g, 2 mmol) and Na2C(¾ (0.4 g, 3.6 mmol) in DME/H20 (20 mL/0.2 mL) was added Pd(OAc)2 (40 mg, 0.18 mmol), followed by (/-Bu)3P (0.15 mL, 1 M in toluene) in a nitrogen atmosphere. The reaction was stirred at 100°C for 16 h, then cooled to rt and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc/MeOH (v/v/v) = 10/10/1) to give the title compound as a white solid (0.3 g, 25%).
LC-MS (ESI, pos. ion) m/z:493 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.74 (d, J = 1.76 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.30- 7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.85 (dd, J = 1.52 Hz, 1H), 6.10-6.05 (q, J= 2.66 Hz, 1H), 5.76 (d, J = 4.84 Hz, 1H), 4.85 (s, 2H), 4.13-4.11 (m, 1H), 4.01-3.88 (m, 3H), 3.70-3.65 (m, 1H), 2.96-2.84 (m, 2H), 1.99-1.95 (m, 2H), 1.86 (d, J= 2.66 Hz, 3H).
Example 21 (3S,3aS,6aS)-6-(4-(6-amino-5-((g)-l-(2,6-dichloro-3-nuorophenyl)
ethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)hexahydrofuro[3,2-61furan-3-ol
Figure imgf000108_0001
Step 1) (3R,3aR,65,,6ay)-6-hvdroxyhexahvdrofuror3,2-/?1furan-3-yl 4-methylbenzene
sulfonate(21.1 a)
(35'.3aR.6R.6a5f)-6-hydroxyhexahydrofuro[3.2-/?lfuran-3-yl 4-methylbenzene
sulfonate^!.1 b)
(3R,3aR,6£,6aR)-hexahydrofuror3,2-&1furan-3,6-diyl bis(4-methylbenzene
sulfonate)(21.1 c)
Figure imgf000109_0001
(21.1 a) (21.1 b) (21.1 c)
[0285] To a solution of isosorbide (5 g, 34.2 mmol) in H20 (20 mL) was added a solution of TsCl (7.34 g, 38.5 mmol) in toluene (25 mL) at 0°C, followed by a solution of KOH (2.5 g, 44.6 mmol) in H20 (9 mL). The reaction was stirred at 5°C for 4 h, then warmed up to rt and continued to stir overnight. The mixture was quenched with H20 (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous a2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give a mixture of (21.1 a) and (21.1 b) (2.8 g, 28%) and (21.1 c) (0.6 g, 5%) as white solids.
LC-MS (ESI, pos. ion) m/z:301 [M + H]+.
Step 2) (3R.3aR.65'.6ay)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuror3.2-/?l furan-3-yl 4- methylbenzenesulfonate
[0286] To a solution of DHP (1.6 mL, 18 mmol) in DCM (20 mL) cooled in an ice-salt bath was added PPTS (0.2 g, 0.9 mmol), followed by a solution of (21.1 a) and (21.1 b) (2.7 g, 9 mmol) in DCM (20 mL)in a nitrogen atmosphere. The reaction was stirred at 0°C for 30 min, then warmed up to rtand continued to stir overnight. The mixture was concentrated in vacuo. The residue was diluted with H20 (50 mL)and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as colorless oil (3.1 g, 88.5%).
LC-MS (ESI, pos. ion) m/z:407 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.84 (d, J= 1.36 Hz, 2H), 7.82 (d, J= 1.44 Hz, 2H), 4.67- 4.64 (m, 1H), 4.53-4.51 (m, 2H), 4.44-4.39 (dd, J= 4.28 Hz, 2H), 4.22-4.2 (m, 1H), 3.88-3.73 (m, 4H), 3.52-3.33 (m, 2H), 2.43 (s, 3H), 1.72-1.43 (m, 6H).
Step 3) 4-iodo-l-((3a5',65',6aR)-6-((tetrahvdro-2H-pyran-2-yl)oxy)hexahvdrofuro[3,2 - ?]furan-3- vD-lH-pyrazole
[0287] To a solution of 4-iodo-lH-pyrazole(0.89 g, 4.5 mmol) in anhydrous DMF (15 mL) was added NaH (0.3 g, 9 mmol, 80% dispersion in mineral oil) in portions at 0°C. The mixture was stirred at 0°C for 1 h, then a solution of (3R,3aR,6,S,6a,S)-6-((tetrahydro-2H-pyran- 2-yl)-oxy)hexahydrofuro[3,2-&]furan-3-yl 4-methylbenzenesulfonate (1.6 g, 5.2 mmol) in DMF (10 mL) was added to the mixture. The reaction was stirred at 0°C for 30 min, then heated to 80°C and continued to stir for 10 h. The mixture was quenched with H20 (70 mL) and extracted with EtOAc (70 mL x 3). The combined organic phases were washed with brine (180 mL), dried over anhydrous a2S04, 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 yellow solid (0.9 g, 50%).
LC-MS (ESI, pos. ion) m/z:429 [M + Na]+.
Step 4) l-((3a5',65',6aR)-6-((tetrahvdro-2H-pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-4- (4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)- lH-pyrazole
[0288] To a solution of 4-iodo-l-((3a5',65,,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy) hexahydro furo[3,2-Z?]furan-3-yl)-lH-pyrazole (0.9 g, 2.2 mmol), bis(pinacolato)diboron (1.5 g, 6.6 mmol) and CH3COOK (646 mg, 6.6 mmol) in DMSO (20 mL) was added Pd(dppf)Cl2 (179 mg, 0.22 mmol) in a nitrogen atomsphere. The reaction was stirred at 60°C for 2 h, then cooled to rt, diluted with H2O (50 mL), and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (0.6 g, 67%).
LC-MS (ESI, pos. ion) m/z:407 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.93 (s, 1H), 7.80 (s, 1H), 5.12-4.92 (m, 1H), 4.81-4.68 (m, 3H), 4.44-4.41 (m, 2H), 4.36-3.73 (m, 4H), 3.54-3.53 (m, 1H), 2.05-1.50 (m, 6H), 1.25 (s, 12H).
Step 5) 3-((R)-l-(2.6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((3a .65'.6aR)-6-((tetra- hydro-2H- pyran-2-yl)oxy)hexahvdrofuror3,2-/?1furan-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
[0289] To a mixture of l-((3a5',65,,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy) hexahydrofuro [3,2-/?]furan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (857 mg, 2.3 mmol), (R)-5-bromo-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2-amine (0.77 g, 1.89 mmol) and Na2C03 (0.4 g, 3.78 mmol) in DME/H20 (25 mL/2 mL) were added Pd(OAc)2 (43 mg, 0.19 mmol) and followed by (i-BubP (0.57 mL, 2 N in toluene) in a nitrogen atmosphere. The reaction was stirred at 87°C for 18 h, thencooled rt, and concentrated in vacuo.The resulted residue was purified by a silica gel column chromatography (PE/EtOAc/MeOH (v/v/v) = 10/10/1) to give the title compound as a yellow solid (0.7 g, 54%). LC-MS (ESI, pos. ion) m/z:579 [M + H] ;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.75 (s, 1H), 7.69 (d, J = 6.04 Hz, 1H), 7.58 (s, 1H), 7.29- 7.27 (m, 1H), 7.05-7.01 (m, 1H), 6.08-6.03 (q, J = 6.64 Hz, 1H), 4.97-4.91 (m, 1H), 4.85 (m, 2H), 4.82-4.69 (m, 3H), 4.46-4.33 (m, 2H), 4.18-3.98 (m, 3H), 3.86-3.78 (m, 1H), 3.56-3.52 (m, 1H), 1.84 (d, J = 6.64 Hz, 3H), 1.58-1.23 (m, 6H).
Step 6) (3 ,3a5',6ay)-6-(4-(6-amino-5-((R -l-(2,6-dichloro-3-fluorophenyl ethoxy pyridin-3-yl)- lH-pyrazol-l-yl)hexahydrofuro[3.2-/?]furan-3-ol
[0290] To a solution of 3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-((3a5, 65", 6aR)-6- ((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-/?]furan-3-yl)-lH-pyrazol-4-yl) pyridin-2-amine (0.5 g, 0.86 mmol) in MeOH (25 mL) was added 2 M HC1 (2 mL). The reaction was stirred at 45°C for 1 h, then concentrated in vacuo. The residue was diluted with DCM (30 mL), H20 (30 mL) and 2 M Na2C03 (5 mL). The resulted mixture was extracted with DCM (30 mL x 2), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc/MeOH (v/v/v) = 10/10/1) to give the title compound as a yellow solid (0.3 g, 70%).
LC-MS (ESI, pos. ion) m/z:495 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.77(d, J= 1.4 Hz, 1H), 7.69(d, J= 6.04 Hz, 1H), 7.59 (s, 1H), 7.31 (s, 1H), 7.07-7.03 (m, 1H), 6.86 (d, J = 1.4 Hz, 1H), 6.08-6.03 (q, J= 6.68 Hz, 1H), 4.99-4.95 (m, 1H), 4.81 (s, 2H), 4.73-4.71 (m, 2H), 4.44-4.40 (m, 2H), 4.19-4.14 (t, J= 8.84 Hz, 2H), 3.98-3.95 (dd, J = 5.76 Hz, 1H), 3.80-3.77 (dd, J= 5.76 Hz, 1H), 1.85 (d, J = 6.68 Hz, 3H).
Example 22 3-((g)-l-(2,6-dichloro-3-nuorophenyl)ethoxy)-5-(l-q3aS,6g,6ag)-6- fluorohexahvdrofuro[3,2-61furan-3-yl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000111_0001
[0291] To a solution of (35,3a5,6a5)-6-(4-(6-amino-5-((R)-l-(2,6-dichloro-3- fluorophenyl) ethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)hexahydrofuro[3,2-/?]furan-3-ol (0.14 g, 0.28 mmol) in DCM (4 mL) was added a solution of DAST (70 mg, 0.43 mmol) in DCM (1 mL) dropwise at -78°C. The reaction was stirred at -78°C for 1 h, then warmed up to rt and continued to stir overnight. The mixture was concentrated in vacuo, and the resulted residue was purified by a silica gel column chromatography (PE/EtOAc/MeOH (v/v/v) = 20/20/1) to give the title compound as a brown solid (40 mg, 28.5%).
LC-MS (ESI, pos. ion) m/z: 497 [M + H]+;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.75(d, J= 1.68 Hz, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.33- 7.28 (s, 1H), 7.08-7.03 (m, 1H), 6.86 (d, J= 1.48 Hz, 1H), 6.09-6.04 (q, J= 6.68 Hz, 1H), 5.24- 5.10 (dd, J= 2.8 Hz, 1H), 4.98-4.93 (m, 4H), 4.84-4.82 (m, 1H), 4.34-4.32 (m, 1H), 4.26-3.97 (m, 3H), 1.87-1.85 (d, J= 6.68 Hz, 3H).
Example 23 4- g)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- (octahvdrocvclopenta[clpyrrol-5-yl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000112_0001
Step 1) 2-(tert-butoxycarbonyl)-2,3,3aA7 Ja-hexahvdro-lH-isoindole
[0292] To a solution ofLiAlH4 (3.04 g, 80 mmol) in THF (80 mL) was added 3a,4,7,7a- tetrahydro-lH-isoindole-l,3(2H)-dione (5.26 g, 34.8 mmol) in portions. The reaction was stirred at 60°C for 21 h, then cooled to rt, diluted with EtOAc (25 mL), and quenched with ¾0(3 mL)followed by 15% ΚΟΗ (3 mL). The mixture was stirred at rt for 1 h, and then filtered through a Celite pad, which was washed with DCM (40 mL).The filtrate was concentrated in vacuo to afford 2,3,3a,4,7,7a-hexahydro-lH-isoindole as yellow oil.
[0293] To a solution of 2,3,3a,4,7,7a-hexahydro-lH-isoindole (3.89 g, 31.3 mmol) in DCM (40 mL) was added (Boc)20 (10.3 g, 47 mmol) at 0°C. The reaction was stirred at 0°C for 0.5 h, then warmed up to rt and continued to stir for 21 h. The mixture was concentrated in vacuo and the residue was diluted with EtOAc (80 mL). The resulted solution was washed with 1M citric acid (17 mL x 2), ¾0 (17 mL x 2), then saturated aqueous aHCC (17 mL x 2) and brine (17 mL). The organic phase was dried over anhydrous a2S04, concentrated in vacuo, and then purifiled by a silica gel column chromatography (hexane/EtOAc (v/v) = 85/15) to give the title compound as orange red oil (4.7 g, 54.5%).
LC-MS (ESI, pos. ion) m/z: 168.2 [(M + H)+ - C4H8];
¾ NMR (400MHz, CDC13) δ (ppm): 5.64 (s, 2H), 3.40 (m, 2H), 3.16 (m, 1H), 3.07 (m, 1H), 2.25 (m, 4H), 1.90 (m, 2H), 1.46 (s, 9H).
Step 2) 2,2'-(l-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid
[0294] To a solution of 2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-lH-isoindole (4.7 g, 21 mmol) in CCl4/MeCN/H2O(50 mL/50 mL/75 mL) was added NaI04 (18 g, 84.2 mmol), followed by catalytic Ru02 (0.16 g, 1.2 mmol). The reaction was stirred at rt for 24 h, then diluted with DCM (60 mL), and filtered through a Celite pad.The filtrate was extracted with DCM (50 mL). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (100% DCM) to give the title compound as yellow oil (3 g, 49.6%).
LC-MS (ESI, pos. ion) m/z:232.2 [(M + H)+ - C4H8];
¾ NMR (400 MHz, CDC13) δ (ppm): 3.53 (m, 2H), 3.04 (m, 2H), 2.80 (m, 2H), 2.44 (m, 4H), 1.43 (s, 9H).
Step 3) 2-(tert-butoxycarbonyl)hexahydrocyclopenta[c]pyrrol-5(lH)-one
[0295] To a solution of 2,2'-(l-(/er/-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (3 g, 10.4 mmol) in acetic anhydride(30 mL) was added CH3COONa (0.79 g, 9.6 mmol). The reaction was stirred at 120°C for 3 h, then cooled to rt and filtered. The filter cake was washed with EtOAc (20 mL x 2) and the filtrate was concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v) = 1/1) to give the title compound as orange yellow oil (0.55 g, 23.4%).
!H NMR (400MHz, CDC13) δ (ppm): 3.69 (m, 2H), 3.00 (m, 4H), 2.61 (dd, J= 8.2, 18.4 Hz, 2H), 2.29 (dd, J= 5.8, 18.4 Hz, 2H), 1.43 (s, 9H).
Step 4) 2-(tert-butoxycarbonyl)octahvdrocvclopenta[c1pyrrol-5-ol
[0296] To a solution of 2-(tert-butoxycarbonyl)hexahydrocyclopenta[c]pyrrol-5(lH)-one
(0.9 g, 4 mmol) in EtOH (20 mL) was added NaBH4 (0.82 g, 21.7 mmol) in portions. The reaction was stirred at rt for 4.5 h, then concentrated in vacuo. The residue was diluted with
EtOAc (50 mL), then washed with H20 (50 mL) followed by brine (50 mL). The resulted solution was dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as yellow oil (0.99 g, 100%), which was used for the next step without purification.
Step 5) 2-(tert-butoxycarbonyl octahydrocvclopentarc1pyrrol-5-yl methanesulfonate
[0297] To a solution of 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-ol (0.91 g, 3.56 mmol) in DCM (8 mL) at 0°C was added Et3N (0.8 mL, 5.74 mmol), followed by a suspnesion of MsCl (0.35 mL, 4.52 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (2 mL). The reaction was stirred at rt for 16 h, then washed with H20 (15 mL) followed by brine (15 mL). The resulted solution was dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as yellow oil (1.3 g, 100%),which was used for the next reaction without purification.
Step 6) 2-(tert-butoxycarbonyl)-5-(4-iodo-lH-pyrazol-l-yl)octahydrocvclopentarc1pyrrole
[0298] To a solution of 4-iodo- lH-pyrazole (1.16 g, 6.0 mmol) in anhydrous DMF (10 mL) was added NaH (538 mg, 17.9 mmol, 80% dispersion in mineral oil) in portions at 0°C. The mixture was stirred at 0°C for 1 h, then a solution of 2-(tert- butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl methanesulfonate (1.22 g, 4 mmol) in DMF (5 mL) was added to the mixture. The reaction was stirred at 100°C for 21 h, then cooled to rt and diluted with EtOAc (30 mL). The mixture was washed with H20 (20 mL x 3) followed by brine (20 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a pale yellow solid (1.37 g, 85.1%).
LC-MS (ESI, pos. ion) m/z: 348.0 [(M + H)+ - C4H8];
¾ NMR (400MHz, CDC13) δ (ppm): 7.50 (s, 1H), 7.45 (s, 1H), 4.82 (m, 1H), 3.55 (brs, 2H), 3.23 (brs, 2H), 2.92 (m, 2H), 2.33 (m, 2H), 2.05 (brs, 2H), 1.47 (s, 9H).
Step 7) 2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazol- l-yl)octahydrocvclopenta[c1pyrrole
[0299] To a solution of 2-(tert-butoxycarbonyl)-5-(4-iodo-lH-pyrazol-l-yl) octahydrocyclopenta[c]pyrrole (0.48 g, 1.2 mmol) and bis(pinacolato)diboron (0.36 g, 1.44 mmol) in DMSO (8 mL) was added CH3COOK (0.35 g, 3.6 mmol), followed by Pd(dppf)Cl2 (98 mg, 0.12 mmol) in a nitrogen atmosphere. The reaction was stirred at 80°C for 1 h, then quenched with H20 (10 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as yellow oil (256 mg, 53.3%).
LC-MS (ESI, pos. ion) m/z: 404.3 [M + H]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.79 (s, 1H), 7.71 (s, 1H), 4.84 (m, 1H), 3.56 (brs, 2H), 3.23 (brs, 2H), 2.93 (brs, 2H), 2.34 (m, 2H), 2.08 (brs, 2H), 1.47 (s, 9H), 1.27 (s, 12H).
Step 8) 5-(l-(2-(tert-butoxycarbonyl)octahydrocyclopentarclpyrrol-5-yl)-lH-pyrazol-4-yl)-4- ((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0300] To a solution of 2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)octahydrocyclopenta[c]pyrrole (256 mg, 0.64 mmol) and (R)-5-bromo-4-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (326 mg, 0.95 mmol) in DME (8 mL) was added added 1.2 M Na2C03(2 mL, 1.91 mmol), followed by Pd(dppf)Cl2 (104 mg, 0.13 mmol) in a nitrogen atmosphere. The reaction was stirred at 100°C for 8 h, then cooled to rt, diluted with H20 (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a yellow solid (157 mg, 42.9%).
LC-MS (ESI, pos. ion) m/z: 576.2 [M + H]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.74 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.30 (m, 1H), 7.05 (t, J= 8.0 Hz, 1H), 6.85 (d, J= 1.4 Hz, 1H), 6.07 (m, 1H), 4.82 (m, 3H), 3.57 (brs, 2H), 3.25 (brs, 2H), 2.95 (brs, 2H), 2.35 (m, 2H), 2.05 (brs, 2H), 1.85 (d, J= 6.7 Hz, 1H), 1.47 (s, 9H).
Step 9) 4-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-(octahvdrocyclopentarc1 pyrrol-5- yl)-lH-pyrazol-4-yl)pyridin-2-amine
[0301] To a solution of 5-(l-(2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)- lH-pyrazol-4-yl)-4-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (157 mg, 0.27 mmol) in DCM (10 mL) was added HC1 (4 mL, 3 M in EtOAc) slowly. The reaction was stirred at rt for 2 h and then concentrated in vacuo. The residue was diluted with H20 (30 mL) and DCM (50 mL), then adjusted to pH 10 with saturated aqueous Na2C03 and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/MeOH/Et3N (v/v/v) = 500/50/1) to give the title compound as a yellow solid (0.1 g, 76.9%). LC-MS (ESI, pos. ion) m/z: 476.1 [M + H] ;
¾ NMR (400 MHz, CDC13) δ (ppm): 7.72 (d, J = 1.6 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.30 (m, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.85 (d, J= 1.4 Hz, 1H), 6.07 (m, 1H), 4.91 (s, 2H), 4.88 (m, 1H), 3.66 (s, 1H), 3.29 (m, 2H), 3.03 (m, 2H), 2.43 (m, 2H), 2.11 (m, 2H), 2.07 (d, J= 17.2 Hz, 2H), 1.85 (d, J= 6.7 Hz, 1H).
Example 24 3- R)-l- 2,6-dichloro-3-fluorophenyl)ethoxy)-5- i- octahvdro-lH-isoindol-5- yl)-lH-pyrazol-4-yl)pyridin-2-amine
Figure imgf000116_0001
Step 1) 2-(tert-butoxycarbonyl)octahvdro-lH-isoindol-5-ol
[0302] To a solution of 2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-lH-isoindole (3.16 g, 14.2mmol) in anhydrous THF (35 niL) was added BH3-DMS (1.5 mL,10 Min THF, 15.0 mmol) dropwise at 0°C in a nitrogen atmosphere. The reaction was stirred at rt overnight, then cooled to 0°C.The mixture was quenched with MeOH (8 mL), followed by a mixture of 3 M NaOH (5 mL) and 30%H2O2(5 mL). The resulted suspension was stirred at60°C for 1.5 h, then cooled to rt, diluted withEt2O/H2O(30 mL/30 mL), and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo to give orange oil (2.46 g, 71.7%), which was used for the next step without purification.
LC-MS (ESI, pos. ion) m/z: 186.2[M + H - 56]+;
¾ NMR (400MHz, CDC13) δ (ppm): 3.89 (m, 1H), 3.35 (m, 2H), 3.22 (m, 2H), 2.47 (m, 1H), 2.10 (m, 1H), 1.82 (m, 4H), 1.62 (m, 1H),1.54 (m 2H), 1.46 (s, 9H).
Step 2) 2-(tert-butoxycarbonyl)octahydro-lH-isoindol-5-yl methanesulfonate
[0303] The title compound was prepared according to the procedure described in Example 23 Step 5 by using a suspension of 2-(tert-butoxycarbonyl)octahydro-lH-isoindol-5- ol(4.51 g, 18.69 mmol), Et3N (4 mL, 28.70 mmol), MsCl (2.2 mL, 28.41 mmol) and DMAP (34.3 mg, 0.28 mmol) in DCM (50 mL). The crude product was obtained as brown oil (5.30 g, 88.8%), which was used for the next step without further purification.
LC-MS (ESI, pos. ion) m/z: 264.0[M + H - 56]+.
Step 3 ) 2-(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1 -vDoctahydro- 1 H-isoindole
[0304] The title compound was prepared according to the procedure described in Example 23 Step 6 by using a suspension of 2-(tert-butoxycarbonyl)octahydro-lH-isoindol-5- yl methanesulfonate(5.30 g, 16.6 mmol), 4-iodo- lH-pyrazole (4.83 g, 24.9 mmol) and NaH (2.26 g, 56.4 mmol, 60% dispersion in mineral oil)in anhydrous DMF (60 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give the title compound as a white solid (2.67 g, 38.6%).
LC-MS (ESI, pos. ion) m/z: 362.2[M + H - 56]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.50 (d, J= 4.1 Hz, 1H), 7.46 (s, 1H), 3.32 (m, 4H), 2.30 (brs, 1H), 2.28 (m, 1H), 2.02 (m, 2H), 1.73 (m, 5H), 1.46 (d, J= 6.8 Hz, 9H).
Step 4) 2-(tert-butoxycarbonyl)-5-(4-(4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-yl)- lH-pyrazol- 1 -vDoctahydro- 1 H-isoindole
[0305] The title compound was prepared according to the procedure described in Example 23 Step 7 by using a suspension of 2-(tert-butoxycarbonyl)-5 -(4-iodo- 1 H-pyrazol- 1- yl)octahydro-lH-isoindole(2.67 g, 6.40 mmol),bis(pinacolato)diboron (1.95 g, 7.68 mmol), CH3COOK (1.88 g, 19.20 mmol) and Pd(dppf) Cl2 ( 523 mg, 0.64 mmol)in DMSO (50 mL).The crude product was purified by a silica gel column chromatography(PE/EtOAc (v/v) = 4/1) to give the title compound as orange oil (1.34 g, 50.2%).
LC-MS (ESI, pos. ion) m/z: 418.1[M + H]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.78 (d, J= 2.3 Hz, 1H), 7.74 (s, 1H), 3.36 (m, 4H), 2.42 (br. s, 1H), 2.28 (m, 1H), 2.05 (m, 2H), 1.84 (m, 5H), 1.46 (d, J= 8.0 Hz, 9H), 1.32 (d, J= 5.4 Hz, 12H).
Step 5) 5-(l-(2-(tert-butoxycarbonyl)octahydro-lH-isoindol-5-yl)-lH-pyrazol-4-yl)-3-((R)-l- (2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine
[0306] The title compound was prepared according to the procedure described in
Example 23 Step 8 by using a suspension of (R)-5-bromo-4-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (1.83 g, 4.82 mmol), 2-(tert-butoxycarbonyl)-5-(4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)octahydro-lH-isoindole(l.34 g, 3.21 mmol), Pd(dppf)Cl2 (524 mg, 0.642 mmol) and 1.2 M Na2C03 (8 mL, 9.63 mmol) in DME (40 mL). The crude product was purified by a silica gel column chromatography(PE/EtOAc (v/v) = 1/2) to give the title compound as an orange solid (230 mg, 12.1%).
LC-MS (ESI, pos. ion) m/z:590.0[M + H]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.74 (s, 1H), 7.55 (d, J = 4.2 Hz, 1H), 7.48 (s, 1H), 7.30 (m, 1H), 7.05 (t, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.07 (m, 1H), 4.90 (s, 2H), 3.41 (m, 2H), 3.33 (m, 2H), 2.44 (br. s, 1H), 2.31 (m, 1H), 2.04 (m, 2H), 1.86 (d, J= 6.7 Hz, 3H), 1.71 (br. s, 5H), 1.46 (d, J= 7.6 Hz, 9H).
Step 6)3 -((Pv)- 1 -(2 ,6-dichloro-3 -fluorophenyl)ethoxy)-5 -( 1 -(octahydro- 1 H-isoindol-5 -yl)- 1 H- pyrazol-4-yl)pyridin-2-amine
[0307] The title compound was prepared according to the procedure described in Example 23 Step 9 by usinga solution of 5-(l-(2-(tert-butoxycarbonyl)octahydro-lH-isoindol- 5-yl)-lH-pyrazol-4-yl)-3-((R)-l-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.23 g, 0.39 mmol) and HC1 (4 mL, 3 Min EtOAc)in DCM (10 mL). The crude product was purified by a silica gel column chromatography(DCM/MeOH/Et3N (v/v/v) = 250/50/1) to give the title compound as a yellowsolid (100 mg, 52.4%).
LC-MS (ESI, pos. ion) m/z:489.9[M + H]+;
¾ NMR (400MHz, CDC13) δ (ppm): 7.75 (d, J= 1.7 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.30 (m, 1H), 7.05 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.07 (m, 1H), 4.78 (s, 2H),4.10 (m, 1H), 3.66 (m, 2H), 3.18 (m, 1H), 3.07 (m, 2H), 2.88 (d, J= 11.0 Hz, 1H), 2.37 (br. s, 1H), 2.30 (m, 1H), 2.04 (m, 2H), 1.95 (br. s, 5H), 1.85 (d, J= 6.7 Hz, 3H).
BIOLOGICAL TESTING
[0308] 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
[0309] An Agilent XDB-C18, 2.1 x 30 mm, 3.5 μΜ column was used for the analysis. 5 μΕ 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
Figure imgf000119_0001
[0310] 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 ID., 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 μϊ^ of the samples were injected. Example A: Compound Stability In Human And Rat Liver Microsomes
[0311] Human or rat liver microsomes incubations were conducted in duplicate in polypropylene tubes. The typical incubation mixtures consisted of human 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.
[0312] The concentrations of compounds in the incubation mixtures of human 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.
[0313] 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.
[0314] 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.
[0315] 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 liver microsomes (final concentration: 0.5 mg protein/mL),compounds (final concentration: 1.5 μΜ) in a total volume of 30 μΐ, 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 μϊ^ of NADPH(final 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 μϊ^ acetonitrile(contain IS). Protein is removed by centrifugation with 4000rpm, 10 min. Supernatant was collected for LCMS/MS analysis
[0316] 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. The positive control samplewas included in each assay to ensure the integrity of the microsomal incubation system.
Data Analysis
[0317] The concentrations of compounds in human liver microsome incubations were plotted as a percentage of the relevant zero time point control for each reaction. The in vivo CLint 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 DispositionlMl, 29: 1316-1324.)
[0318] The compounds disclosed herein exhibited desirable half-life (Ti/2) when the compounds were incubated in human and rat liver microsomes.
Table 1
Figure imgf000121_0001
Example B: Evaluation of Pharmacokinetics After Intravenous and Oral Administration of The Compounds Disclosed Herein In Mice. Rats. Dogs And Monkeys
[0319] Compounds disclosed herein are assessed in pharmacokinetic studies in mice, rats, dogs or monkeys. The compounds are 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 are generally given at 1 or 2 mg/kg dose. For the oral (p.o.) dosing, mice and rats are generally given 5 or 10 mg/kg dose, and dogs and monkeys are generally given 10 mg/kg dose. The blood samples (0.3 mL) are 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 are collected, stored at -20°C or -70°C until analyzed by LC/MS/MS as described above.
[0320] The compounds disclosed herein exhibited optimized pharmacokinetic properties with desirable clearance (CI), half- life (Ti¾) and excellent oral bioavailability when the compounds were administered intravenously or orally.
Example C:Kinase Assays
[0321] Kinase assays can be performed by measurement of incorporation ofy-33P 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 KC1) for 24 h at 4°C. Plates are washed 3x with 100 μϊ^ TBS. Kinase reactions are carried out in a total volume of 34 μϊ^ 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 andy-33P 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.
[0322] The above assay procedure can be used to determine the IC50 for inhibition and/or the inhibition constant, ¾. 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).
[0323] The kinase assays described herein were performed at Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK.
ALK (h) Kinase Assay [0324] ALK (h) is incubated with 8 niM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ KKKSPGEYV IEFG, 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 μΐ, 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
[0325] 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^ of 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.
[0326] The compounds disclosed herein exhibited potent activities in the ALK (h) and c- Met (h) assays. Table 2 Used the IC50S of some examples described herein in the ALK (h) andc- Met(h) assays.
Table 2
Figure imgf000123_0001
Ex. 9 29 5 Ex. 21 2 /
Ex. 10 9 / Ex. 22 12 /
Ex. 1 1 37 4 Ex. 23 9 5
Ex. 12 14 4
Example D: Tumor Xenograft Models
[0327] The efficacy of compounds disclosed herein is evaluated in a standard murine model of tumorigenesis. Human tumor cells (i.e., U87MG glioblastoma cells) are 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 tumor reaches a volume of 100-250 mm3, animals are randomly divided into vehicle control (for example, 5% PEG400+5% Solutol HS 15in water or 5% EtOH+5% CremophorEL+1% HC1 (1 1.7%), pH 2.2 in water) and compound groups. Subsequent administration of compound by oral gavage (for example, 6-60 mpk/dose, dissolved in 5% PEG400+5% Solutol HS 15 in water or 5% EtOH+5% CremophorEL+1% HC1 (1 1.7%), pH 2.2 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
[0328] 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 are measured with calipers twice weekly, and the tumor volume (TV) calculated as (L x W2)/2). TGI is 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:
Figure imgf000124_0001
[0329] 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. [0330] 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. Exemplary xenograft study results from Examples 2, 3, 19, 21 and 23 are listed in Table 3.
Table 3
Figure imgf000125_0001
[0331] 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):
Figure imgf000126_0001
or a stereoisomer, a geometric isomer, a tautomer, an N-oide, 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;
Z is
(1) C3_7heterocyclylsubstituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(d_4alkylene)-CN, -(CMalkylene)-OH, -(Ci_4alkylene)-ORaor -(Ci_4alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-
(4-deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine,
(2) -(Ci-4alkylene)-(C3-7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_4alkylene)-OH, -(CMalkylene)-ORa or -(Ci_4alkylene)-NRbRc, provided that the said -(C3-7heterocyclyl) is not substituted with one hydroxyl (OH) group,
(3) C5_i2fused bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(CMalkylene)-CN, -(Ci_4alkylene)-OH, -(CMalkylene)-ORa or -(Ci_4alkylene)-NRbRc, and
1 each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring, or
(4) -(Ci_4alkylene)-(C5_i2fused bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, CI, Br, I, N3, Ci_6alkyl, Ci_6haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_4alkylene)-CN, -(Ci_4alkylene)-OH, -(Ci_4alkylene)-ORa or -(C alkylene)-NRbRc , and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring;
Ra is Ci-6alkyl, Ci-6alkenyl, Ci_6alkynyl, C3_6cycloalkyl, C3-6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci_4alkylene)-(C3_6cycloalkyl), -(Ci_4alkylene)-(C3_6heterocyclyl),
-(Ci-4alkylene)-(C6-ioaryl) or -(Ci_4alkylene)-(Ci_9heteroaryl), wherein the Ci-6alkyl, Ci-6alkenyl, Ci-6alkynyl, C3_6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl,
-(Ci-4alkylene)-(C3-6cycloalkyl), -(Ci_4alkylene)-(C3_6cycloalkyl), -(Ci_4alkylene)-(C6-ioaryl) and -(Ci_4alkylene)-(Ci_9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy or alkylamino; and each Rb and Rc is independently H, Ci-6alkyl, C3_6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci_6alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C3_6heterocyclyl),
-(Ci-6alkylene)-(C6-ioaryl) or -(Ci_6alkylene)-(Ci_9heteroaryl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the Ci-6alkyl, Ci_6alkenyl, Ci-6alkynyl, C3_6cycloalkyl, C3_6heterocyclyl, C6-ioaryl, Ci-gheteroaryl, -(Ci-6alkylene)-(C3-6cycloalkyl), -(Ci_6alkylene)-(C3_6cycloalkyl), -(Ci_6alkylene)-(C6-ioaryl) and -(Ci-6alkylene)-(Ci-9heteroaryl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CI, N3, -CN, -OH, -NH2, alkoxy or alkylamino.
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 Z is
(1) C3_7heterocyclyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(d_3alkylene)-CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, provided that
• when the C3_7heterocyclyl is an N containing heterocyclyl, the said N is attached to a
2 hydrogen (H), and
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l- (4-deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine,
(2) -(CMalkylene)-(C3_7heterocyclyl) substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, d_3haloalkyl, -CN.-OH, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORaor -(Ci_3alkylene)-NRbRc, provided that the said -(C3_7heterocyclyl) is not substituted with one hydroxyl (OH) group,
(3) Civilised bicyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, Ci_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring,or
(4) -(Ci-4alkylene)-(C5-i2fused bicyclyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, N3, Ci_3alkyl, d_3haloalkyl, -CN, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-CN, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORaor -(Ci_3alkylene)-NRbRc, and each of the cyclic structures in bicyclyl can be either a carbocyclic ring or a heterocyclic ring.
4. The compound according to claim 1, wherein Ra is independently
Ci-3alkynyl, C3_6cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); wherein th
Figure imgf000128_0001
Ci-3alkynyl, C3_6cycloalkyl and -(Ci-3alkylene)-(C3_6cycloalkyl) are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
5. The compound according to claim 1, wherein each Rb and Rc is independently H,
Figure imgf000128_0002
C3_6cycloalkyl or -(Ci_3alkylene)-(C3_6cycloalkyl); or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the
Figure imgf000128_0003
C3_6cycloalkyl, -(Ci-3alkylene)-(C3-6cycloalkyl) and C3_6heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
6. The compound according to claim 1, wherein Z is selected from the following structures:
Figure imgf000128_0004
3
Figure imgf000129_0001
or a stereoisomer thereof, wherein n is 0, 1, 2 or 3; X is O or H; and each hydrogen on carbon atoms in Z or its stereoisomers is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_3haloalkyl, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORaor -(Ci_3alkylene)-NRbRc, provided that
• when n is 1, 2 or 3, the said Z is not substituted with one hydroxyl (OH) group,
• the compound is not (R)-3-(l-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(l-
(4-deuteriumpiperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine.
7. The compound according to claim 1, wherein Z is selected from the following structures:
Figure imgf000129_0002
or a stereoisomer thereof, wherein n is 0, 1, 2 or 3; each W and W is independently O, NH or N(Ci_3alkyl); and each hydrogen on carbon atoms in Z or its stereoisomersis optionally substituted with 1, 2, 3, 4 or 5 substituents, which isindependently selected from D, F, Ci_3alkyl, Ci_3haloalkyl, -OH, -ORa, -NRbRc, -(Ci_3alkylene)- OH, -(Ci_3alkylene)- ORaor -(Ci_3alkylene)-NRbRc.
8. The compound according to claim 6, wherein Z is selected from the following structures:
Figure imgf000130_0001
or a stereoisomer thereof, wherein each hydrogen on carbon atoms in Z or its stereoisomers is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, C1-3haloalkyl, -OH, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORa or -(Ci_3alkylene)-NRbRc.
9. The compound according to claim 6, wherein Z is selected from the following structures:
Figure imgf000130_0002
or a stereoisomer thereof, wherein each hydrogen in Z or itsstereoisomers is substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Ci_3haloalkyl, -ORa, -NRbRc, -(Ci_3alkylene)-OH, -(Ci_3alkylene)-ORaor -(Ci_3alkylene)-NRbRc.
10. The compound according to claim 7, wherein Z is selected from the following structures:
Figure imgf000130_0003
Figure imgf000131_0001
or a stereoisomer thereof, wherein each hydrogen in Z or its stereoisomers is optionally substituted with 1, 2, 3, 4 or 5 substituents, which is independently selected from D, F, d_3alkyl, Ci_3haloalkyl, -OH, -ORa, -NRbRc,
-(Ci_3alkylene)- OH, -(Ci_3alkylene)- ORa or -(Ci_3alkylene)-NRbRc.
11. The compound according to claim 1, wherein Ra is
Figure imgf000131_0002
optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
12. The compound according to claim 1, wherein each Rb and Rc is independently H or Ci_2alkyl; or Rb and Rc, together with the nitrogen atom they are attached to, optionally form C3_6heterocyclyl; wherein the
Figure imgf000131_0003
and C3_6heterocyclylare each optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.
13. The compound of claim 1 having one of the following structures:
6
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
15. The pharmaceutical composition according to claim 14 further comprising an additional 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.
16. The pharmaceutical composition according to claim 15, wherein the additional therapeutic
12 agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, 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, alemtuzumab, bevacizumab, brentuximabvedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, tositumomab, trastuzumab, or a combination thereof.
17. 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 13 or the pharmaceutical composition according to any one of claims 14 to 16.
The compound according to any of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 16 for use in preventing, managing, treating or lessening the severity of a proliferative disorder in a patient.
18. The method according to claim 17, 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 17, wherein the
13 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.
19. A method of inhibiting or modulating the the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 16.
20. The method according to claim 19, wherein the protein kinase is a receptor tyrosine kinase.
21. The method according to claim 20, wherein the receptor tyrosine kinase is ALK, c-Met, or a combination thereof.
14
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