US20160355527A1 - Compounds as tyrosine kinase modulators - Google Patents

Compounds as tyrosine kinase modulators Download PDF

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US20160355527A1
US20160355527A1 US14/989,943 US201614989943A US2016355527A1 US 20160355527 A1 US20160355527 A1 US 20160355527A1 US 201614989943 A US201614989943 A US 201614989943A US 2016355527 A1 US2016355527 A1 US 2016355527A1
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amino
fluoro
carbonyl
thieno
phenoxy
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Xialing Guo
Zhen Zhu
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Allergan Inc
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Allergan Inc
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Priority claimed from US12/875,223 external-priority patent/US8809534B2/en
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Priority to US15/599,333 priority patent/US10221192B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides

Definitions

  • the present invention is directed to novel compounds with multiple aromatic components capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • the present invention is also directed to methods of prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including but not limited to, cell growth disorders, metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases and immune disorders.
  • PTKs Protein tyrosine kinases
  • RTKs receptor tyrosine kinases
  • RTKs signal transduction mediated by receptor tyrosine kinases
  • RTKs receptor tyrosine kinases
  • Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
  • tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine phosphorylation sites
  • Several intracellular substrate proteins that associate with RTKs have been identified and are divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack a catalytic domain but serve as adapters and associate with catalytically active molecules.
  • the specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue.
  • the RTKs comprise a large family of transmembrane receptors with diverse biological activities.
  • the intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
  • RTK subfamilies At present, at least nineteen distinct RTK subfamilies have been identified.
  • One RTK subfamily, designated the HER subfamily is believed to be comprised of EGFR, HER2, HER3 and HER4.
  • Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • the second subfamily of RTKs designated the insulin subfamily, is comprised of the INS—R, the IGF-1R and the IR—R.
  • the third RTK subfamily, the “PDGF” family includes the PDGF ⁇ and ⁇ receptors, CSFIR, c-kit and FLK-II.
  • Another subfamily of RTKs, identified as the FLK family is believed to be comprised of the kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (fit-1).
  • RTK receptor for hematopoietic growth factors.
  • FGF receptor family FGFR1, FGFR2, FGFR3 and FGFR4
  • Met subfamily c-met and Ron. Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together.
  • the known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference.
  • the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference.
  • PTKs protein tyrosine kinases
  • RTKs protein tyrosine kinases
  • RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).
  • the present invention is directed to compounds represented by Formula I capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction, and uses of the compounds and compositions incorporating the compounds for disease treatment and prevention.
  • R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
  • Z is selected from the group consisting of
  • R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkyl, cycloalkyl
  • the present invention is directed to a series of compounds with multiple aromatic components useful as protein tyrosine kinase inhibitors.
  • the compounds of the present invention are useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
  • compounds of the present invention are useful for the treatment of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.
  • the present invention is directed to a compound of Formula I:
  • R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
  • Z is selected from the group consisting of
  • Ring B is selected from the group consisting of:
  • R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkyl, cycloalkyl
  • reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solid forms, crystal forms, polymorphic forms, hydrates, solvates, metabolites, mixtures of stereoisomers, mixtures of crystal forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structure or a chemical name.
  • a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
  • a “prodrug” is a compound, which when administered to the body of a subject (such as a mammal), breaks down in the subject's metabolic pathway to provide an active compound of Formula I. More specifically, a prodrug is an active or inactive “masked” compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject or patient.
  • a prodrug is a masked carboxylic acid group.
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (19
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group.
  • Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
  • Tautomers are isomers that are in rapid equilibrium with one another.
  • tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
  • a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.
  • Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
  • alternate solid forms may be amorphous forms, crystal forms, polymorphs, and the mixtures thereof.
  • Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
  • the present invention is also directed to the use of the compounds as protein tyrosine kinase modulators and inhibitors. These compounds can be used to treat diseases related to unregulated tyrosine kinase signal transduction, for example, various cancers, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
  • compounds of the present invention are useful for the treatment and/or prevention of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders in the human being.
  • the present invention is also directed to the preparation of a medicament for the treatment and prevention of diseases and conditions related with abnormal activities of tyrosine kinase receptors.
  • the medicament contains a pharmaceutical acceptable composition, which comprises the therapeutic effective amount of the compounds of present invention, together with a pharmaceutical acceptable carrier.
  • treat refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable conditions.
  • compositions contain therapeutic effective amount of the compounds of the present invention. These compositions can be used as a medicament and administered to a mammal, such as a person, in need thereof.
  • suitable dosage forms and medicaments are well known in the art, and can be readily adapted for delivery of the compounds of the present invention, such as, but not limited to, systematic, parenteral, local and topical delivery.
  • the dosage forms can be tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots, nasal sprays and ointment, various rectal or vaginal preparations.
  • Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (5 g, 0.022 mol) and the 4-amino-3-fluorophenol (3.3 g, 0.026 mol) were added to a round bottom flask containing cesium carbonate (14.8 g, 0.045 mol), ethyl-2-cyclohexanone carboxylate (0.73 g, 0.004 mol), and copper (I) chloride (0.22 g, 0.002 mol).
  • the mixture was diluted with DMSO (250 mL) and stirred at 70 ⁇ C under an atmosphere of nitrogen for 2 hours.
  • Methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.62 g, 5.1 mmol) was taken up in 55 mL of ethyl acetate followed by the dropwise addition of 2-fluoro-5-methylphenyl isocyanate (0.85 g, 5.6 mmol) in 5 mL ethyl acetate. The solution afforded a lavender solid after stirring at room temperature for overnight.
  • Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl.
  • the insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering.
  • the filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-( ⁇ [(2-fluoro-5-methylphenyl)amino]carbonyl ⁇ amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid.
  • Example 13 was prepared using the experiment procedure described in Example 12, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 18 was prepared using the experiment procedure described in Example 25, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 19 was prepared using the experiment procedure described in Example 26, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 24 was prepared using the experiment procedure described in Example 38, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 27 was prepared using the experiment procedure described in Example 26, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 28 was prepared using the experiment procedure described in Example 30, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 31 was prepared using the experiment procedure described in Example 25, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 39 was prepared using the experiment procedure described in Example 42, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 43 was prepared using the experiment procedure described in Example 34, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 49 was prepared using the experiment procedure described in Example 54, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 51 was prepared using the experiment procedure described in Example 42, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • Example 55 was prepared using the experiment procedure described in Example 34, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
  • the above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • the above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • the above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • the above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • Step 1 A mixture of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (500 mg, 2.20 mmol), 3-aminophenol (330 mg, 3.0 mmol), ethyl 2-cyclohexanonecarboxylate (73 mg, 0.43 mmol), copper(I) chloride (22 mg, 0.22 mmol) and cesium carbonate (1.48 g, 4.55 mmol) in 20 ml of anhydrous DMSO was placed in a 50 ml pressure tube, flushed with nitrogen, sealed and heated at 70° C. for 3 hours. The mixture was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate as brown solid. Yield: 330 mg.
  • Step 1 To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38 mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) and DIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657 mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled to room temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl (200 ml).
  • Step 2 A solution of 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide (1.5 g, 4.48 mmol from Step 1) in 20 ml of MeOH containing 10% Pd/C (150 mg) was stirred under a hydrogen balloon at room temperature for 2 hours. The catalyst was removed by filtration. The filtrate solution was evaporated to dryness under reduced pressure to give N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide as light-beige solid. Yield: 1.1 g, 100%.
  • Biological data for the compounds of the present invention was generated by the use of one or more of the following assays.
  • HUVEC human umbilical vein endothelial cells
  • CO.sub.2 5% CO.sub.2
  • Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37.degree. C.
  • Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye.
  • Test compounds were reconstituted in 100% DMSO and added to the cells to give a final DMSO concentration of 0.1%.
  • test agents For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 .mu.M) or at concentrations ranging from 0.01 to 10.0 .mu.M followed by VEGF stimulation (5 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC.sub.50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
  • the cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an His engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30 .mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction.
  • PBS Phosphate Buffered Saline
  • Reactions were carried out in 120 .mu.L reaction volumes containing 3.6 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4).
  • Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%.
  • Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree.
  • mice Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane, sheared, and given a single dose of drug or the respective vehicle. The guinea pigs were dosed orally unless indicated otherwise in Table 3. Ten minutes prior to the end of drug treatment, guinea pigs were anesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS (13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes, triplicate intradermal injections of 100 ng rhVEGF.sub.165 in 100 .mu.l PBS and of 100 .mu.l PBS alone were administered on the flank.
  • EBD Evans blue dye
  • each animal was cuthanized with Pentosol, and the skin containing the intradermal injection sites was removed for image analysis.
  • an analog video camera coupled to a PC an image of each trans-illuminated skin sample was captured, and the integrated optical density of each injection site was measured using ImagePro 4.
  • ImagePro 4 the difference between the mean optical density of the VEGF sites and mean optical density of the PBS sites is the measure of VEGF-induced EBD extravasation in that animal.
  • the percent inhibition data was plotted as a function of oral dose, using the ‘best-fit’ analysis within MicroSoft Excel software.
  • the ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose).
  • CNV was induced and quantified in this model as previously described (Edelman and Castro. Exp. Eye Res. 2000; 71:523-533).
  • male Brown Norway rats 200-300 g were anesthetized with 100 mg/kg Ketamine and 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide.
  • 3 laser bums 90 mW for 0.1 s; 100 .mu.m diameter
  • Rats were dosed with test compounds in their indicated vehicles orally once daily.
  • FITC-dextran MW 2.times. 10.sup.6
  • images were obtained from the flat mounts of the RPE-choroid-sclera from each eye, and the area occupied by hyperfluorescent neovessels within each laser lesion was measured using ImagePro 4 software.
  • the percent inhibition data was plotted as a function of oral dose, using the ‘best-fit’ analysis within MicroSoft Excel software.
  • the ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose).
  • test agents For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 ⁇ M) or at concentrations ranging from 0.001 nM to 10 ⁇ M followed by PDGF stimulation (10 ng/mL). Changes in fluorescence at 515 nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from % inhibition of PDGF stimulated responses in the absence of inhibitor.

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Abstract

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.
Figure US20160355527A1-20161208-C00001

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 14/444,161, filed Jul. 28, 2014, which is a continuation in part of U.S. application Ser. No. 12/875,223, filed Sep. 3, 2010, now U.S. Pat. No. 8,809,534, issued Aug. 19, 2014, which claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/239,603, filed on Sep. 3, 2009, 61/306,616, filed on Feb. 22, 2010, 61/356,699 filed on Jun. 21, 2010 and 61/360,531 filed on Jul. 1, 2010, all of which are expressly incorporated herein by reference in their entireties.
    • FIELD OF THE INVENTION
  • The present invention is directed to novel compounds with multiple aromatic components capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including but not limited to, cell growth disorders, metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases and immune disorders.
    • BACKGROUND OF THE INVENTION
  • Protein tyrosine kinases (“PTKs”) play an important role in the control of cell growth and differentiation. PTKs comprise a large and diverse class of proteins having enzymatic activity. PTKs can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). For example, signal transduction mediated by receptor tyrosine kinases (“RTKs”) is initiated by extracellular interaction with a specific growth factor (i.e., a ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
  • With respect to RTKs, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with RTKs have been identified and are divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack a catalytic domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability, but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
  • The RTKs comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses. At present, at least nineteen distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4. Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. The second subfamily of RTKs, designated the insulin subfamily, is comprised of the INS—R, the IGF-1R and the IR—R. The third RTK subfamily, the “PDGF” family, includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II. Another subfamily of RTKs, identified as the FLK family, is believed to be comprised of the kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (fit-1). Each of these receptors was initially believed to be a receptor for hematopoietic growth factors. Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron). Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together. The known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference.
  • The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference.
  • Many of the protein tyrosine kinases (PTKs), whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades and pathogenic conditions such as cancer, psoriasis and hyper immune responses. In view of the importance of PTKs to the control, regulation and modulation of cell proliferation and the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase “inhibitors” using a variety of approaches, including the use of mutant ligands (U.S. Pat. No. 4,966,849), soluble receptors and antibodies (Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).
  • More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT Application No. WO 92/20642), vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT Application No. WO 94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO 92/21660) and benzylphosphonic acid compounds (PCT Application No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer.
  • In addition, other small molecules were studied as tyrosine kinase inhibitors, such as the compounds disclosed in U.S. Pat. Nos. 6,765,012; 6,541,504; 6,747,025; 5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020, all of which are incorporated by reference in their entireties.
  • The identification and use of compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine is one aspect of the present invention.
    • SUMMARY OF THE INVENTION
  • The present invention is directed to compounds represented by Formula I capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction, and uses of the compounds and compositions incorporating the compounds for disease treatment and prevention.
  • The compounds of the present invention can be found in general Formula I:
  • Figure US20160355527A1-20161208-C00002
  • wherein
      • X is selected from the group consisting of NR1, O, S(O)n;
      • n is 0 or an integer of from 1 to 2;
      • R1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF3, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R2R3), wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • RI is selected from the group consisting of hydrogen, halogen, C1 to C8 alkyl, S(O)fR4, (CR5R6)dC(O)OR4, S(O)f(CR5R6)dC(O)OR4, (CR5R6)dAr, NR4(CR5R6)dAr, O(CR5R6)dAr, S(O)f(CR5R6)dAr, (CR5R6)dS(O)fR4, NR4(CR5R6)dS(O)fR4, O(CR5R6)d S(O)fR4, S(O)f(CRR6)eS(O)fR4, (CR5R6)dC(O)N(R4)2, NR4(CR5R6)dC(O)N(R4)2, O(CR5R6)dC(O)N(R4)2, S(O)f(CR5R6)eC(O)N(R4)2, (CR5R6)dOR4, S(O)f(CR5R6)dOR4, (CR5R6)dOSO2R4, S(O)f(CR5R6)eOSO2R4, (CR5R6)dP(O)(OR4)2, S(O)f(CR5R6)eP(O)(OR4)2, OC(O)(CR5R6)dN(R4)2, C(O)(CR5R6)dN(R4)2, C(O)N═S(O)R5R6, NR2C(O)(CR5R6)dN(R4)2, (CR5R6)dR5, S(O)f(CR5R6)dR5, HNC(O)R4, HN—C(O)OR4, (CR5R6)dN(R4)2, S(O)f (CR5R6)dN(R4)2, OC(O)OR4, (CR5R6)dC(O)(CR5R6)dR4, (CR5R6)dC(O)(CR5R6)dOR4, and (CR5R6)dC(O)(CR5R6)dN(R4)2, wherein each R4 is independently selected from the group consisting of hydrogen, hydroxyl, C1-C8 alkyl, aryl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, (CR5R6)d and N(R4)2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R5; wherein R5 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR5R6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR5R6)d and (CR5R6)e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate;
      • a is 0 or an integer of from 1 to 3;
      • d is 0 or an integer of from 1 to 5;
      • e is an integer of from 1 to 4;
      • f is 0 or an integer of from 1 to 2;
      • RII is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR2R3)alkoxy, (NR2R3)alkenyl, (NR2R3)alkyl, (NR2R3)carbonylalkenyl, and (NR2R3)carbonylalkyl, wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • b is 0 or an integer of from 1 to 2;
      • Y is selected from the group consisting of
        • (1) —(CH2)g-O—(CH2)h-;
        • (2) —(CH2)g-NR—(CH2)h-;
        • (3) —(CH2)g-CO—(CH2)h-;
        • (4) —(CH2)g-C(O)NR2—(CH2)h-;
        • (5) —(CH2)g-NR2C(O)—(CH2)h-;
        • (6) —(CH2)g-(CH2)h-;
        • (7) —(CH2)g-CH(OH)—(CH2)h-;
        • (8) —(CH2)g-C═C—(CH2)h-;
      •  and (9) a single bond;
      • wherein
      • g is 0 or an integer of from 1 to 3;
      • h is 0 or an integer of from 1 to 3;
      • R1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF3, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R2R3), wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • R2 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;
        Ring A is selected from the group consisting of:
  • Figure US20160355527A1-20161208-C00003
    • (i) Phenyl; (ii) Naphthyl;
  • (iii) A 5 or 6 membered monocyclic heteroaryl group which has 1-5 heteroatoms independently selected from the group consisting of O, N and S;
    and (iv) An 8 to 10 membered bicyclic heteroaryl group which has 1-6 heteroatoms independently selected from the group consisting of O, N and S;
    RIII represents optionally 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C5 alkoxy, hydroxy, amino, C1-C5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
    Z is selected from the group consisting of
      • (1′) (CH2)iN(R7)C(O)N(R8)(CH2)j;
      • (2′) (CH2)iN(R7)C(S)N(R8)(CH2)j;
      • (3′) (CH2)iN(R8)C(O);
      • (4′) C(O)N(R8)(CH2)j;
      • (5′) (CH2)iN(R7)S(O)2;
      • and (6′) S(O)2N(R8)(CH2)j;
  • wherein
      • i is 0 or 1;
      • j is 0 or 1;
      • R7 and R8 are independently selected from the group consisting of hydrogen and alkyl.
        Ring B is selected from the group consisting of:
  • Figure US20160355527A1-20161208-C00004
  • (i′) Phenyl;
    (ii′) Naphthyl;
    (iii′) A 5 or 6 membered monocyclic heteroaryl group which has 1-3 heteroatoms independently selected from the group consisting of O, N and S;
    and (iv′) An 8 to 10 membered bicyclic heteroaryl group which has 1-3 heteroatoms independently selected from the group consisting of O, N and S;
    RIV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR9R10; wherein R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
  • Some embodiments of the present invention are included in the following paragraphs:
      • 1) A compound according to Formula I, including any tautomer, stereoisomer, diastereoisomeric form, polymorphic form, crystal form, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or prodrug, mixture of different stereoisomers, mixture of different crystal forms.
      • 2) A compound of Formula I in the form of a prodrug.
      • 3) The compound according to paragraph 1, wherein Y is selected from the group consisting of
        • (a) —(CH2)g-C═C—(CH2)h-;
        • (b) —(CH2)g-NR—(CH2)h-;
        • (c) —(CH2)g-CO—(CH2)h-;
        • (d) —(CH2)g-C(O)NR2—(CH2)h-;
        • (e) —(CH2)g-NR2C(O)—(CH2)h-;
        • (f) —(CH2)g-(CH2)h-;
        • (g) —(CH2)g-CH(OH)—(CH2)h-;
        • (h) —(CH2)g-O—(CH2)h-;
        • and (i) a single bond.
      • 4) The compound according to paragraphs 1-3, wherein Z is selected from the group consisting of (CH2)iN(R7)C(O)N(R8)(CH2)j, (CH2)iN(R7)C(S)N(R8)(CH2)j, (CH2)iN(R7)C(O), and C(O)N(R8)(CH2)j.
      • 5) The compound according to paragraphs 1-4, wherein X is NH.
      • 6) The compound according to paragraphs 1-5, wherein Ring A and Ring B are independently selected from the group consisting of
  • Figure US20160355527A1-20161208-C00005
      • 7) The compound according to paragraph 6, wherein X is S.
      • 8) The compound according to paragraph 1, which can be further represented by Formula II:
  • Figure US20160355527A1-20161208-C00006
        • including any tautomer, stereoisomer, diastereoisomeric form, crystal form, polymorphic form, mixture of stereoisomers, mixture of polymorphic forms, mixture of crystal forms, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug.
      • 9) The compound according to paragraphs 1-8, wherein RI is selected from the group consisting of hydrogen, halogen, C1 to C8 alkyl, (CR5R6)dC(O)OR4, (CR5R6)dAr, NR4(CR5R6)dAr, (CR5R6)dC(O)N(R4)2, NR4(CR5R6)dC(O)N(R4)2, O(CR5R6)dC(O)N(R4)2, (CR5R6)dOR4, OC(O)(CR5R6)dN(R4)2, C(O)(CR5R6)dN(R4)2, NR2C(O)(CR5R6)dN(R4)2, (CR5R6)dR5, HNC(O)R4, HN—C(O)OR4, (CR5R6)dN(R4)2, S(O)f (CR5R6)dN(R4)2, OC(O)OR4, (CR5R6)dC(O)(CR5R6)dR4, (CR5R6)dC(O)(CR5R6)dOR4, and (CR5R6)dC(O)(CR5R6)dN(R4)2, wherein each R4 is independently selected from the group consisting of hydrogen, hydroxyl, C1-C8 alkyl, aryl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, (CR5R6)d and N(R4)2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R5; wherein R5 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR5R6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR5R6)d and (CR5R6)e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate.
      • 10) A compound selected from the group consisting of
  • Figure US20160355527A1-20161208-C00007
    Figure US20160355527A1-20161208-C00008
    Figure US20160355527A1-20161208-C00009
    Figure US20160355527A1-20161208-C00010
      • 11) A method of use of the compounds of paragraphs 1-10, wherein the compounds are
      • 12) Use of the compounds of paragraphs 1-10 in the preparation of a medicament for the treatment or prevention of diseases or conditions related with unregulated tyrosine kinase activities, comprising administering a therapeutically effective amount of the compound of paragraphs 1-10 together with a pharmaceutically acceptable carrier;
      • 13) The use of paragraph 12, wherein the diseases or conditions are selected from the group consisting of cell growth and metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases, and immune disorders.
      • 14) The use of paragraphs 12-13 wherein the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.
      • 15) A pharmaceutical composition comprising a therapeutic effective amount of a compound according to paragraphs 1-10 together with a pharmaceutically acceptable carrier which is suitable for systematic, parenteral, local or topical delivery.
      • 16) The pharmaceutical composition of paragraph 15 which are in the form selected from the group consisting of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots.
      • 17) Use of the compounds of paragraph 10 in the preparation of a medicament for the treatment of diseases and conditions, wherein the medicament contains a pharmaceutical acceptable composition according to paragraphs 15 and 16.
    DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is directed to a series of compounds with multiple aromatic components useful as protein tyrosine kinase inhibitors. The compounds of the present invention are useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases. In particular, compounds of the present invention are useful for the treatment of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.
    • 1. Compounds of the Invention
  • The present invention is directed to a compound of Formula I:
  • Figure US20160355527A1-20161208-C00011
      • wherein
      • X is selected from the group consisting of NR1, O, S(O)1;
      • n is 0 or an integer of from 1 to 2;
      • R1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF3, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R2R3), wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • RI is selected from the group consisting of hydrogen, halogen, C1 to C8 alkyl, S(O)fR4, (CR5R6)dC(O)OR4, S(O)f(CR5R6)dC(O)OR4, (CR5R6)dAr, NR4(CR5R6)dAr, O(CR5R6)dAr, S(O)f(CR5R6)dAr, (CR5R6)dS(O)fR4, NR4(CR5R6)dS(O)fR4, O(CR5R6)d S(O)fR4, S(O)f(CR5R6)eS(O)fR4, (CR5R6)dC(O)N(R4)2, NR4(CR5R6)dC(O)N(R4)2, O(CR5R6)dC(O)N(R4)2, S(O)f(CR5R6)eC(O)N(R4)2, (CR5R6)dOR4, S(O)f(CR5R6)dOR4, (CR5R6)dOSO2R4, S(O)f(CR5R6)eOSO2R4, (CR5R6)dP(O)(OR4)2, S(O)f(CR5R6)eP(O)(OR4)2, OC(O)(CR5R6)dN(R4)2, C(O)(CR5R6)dN(R4)2, C(O)N═S(O)R5R6, NR2C(O)(CR5R6)dN(R4)2, (CR5R6)dR5, S(O)f(CR5R6)dR5, HNC(O)R4, HN—C(O)OR4, (CR5R6)dN(R4)2, S(O)f (CR5R6)dN(R4)2, OC(O)OR4, (CR5R6)dC(O)(CR5R6)dR4, (CR5R6)dC(O)(CR5R6)dOR4, and (CR5R6)dC(O)(CR5R6)dN(R4)2, wherein each R4 is independently selected from the group consisting of hydrogen, hydroxyl, C1-C8 alkyl, aryl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, (CR5R6)d and N(R4)2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R5; wherein R5 and R6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR5R6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR5R6)d and (CR5R6)e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate;
      • a is 0 or an integer of from 1 to 3;
      • d is 0 or an integer of from 1 to 5;
      • e is an integer of from 1 to 4;
      • f is 0 or an integer of from 1 to 2;
      • RII is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR2R3)alkoxy, (NR2R3)alkenyl, (NR2R3)alkyl, (NR2R3)carbonylalkenyl, and (NR2R3)carbonylalkyl, wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • b is 0 or an integer of from 1 to 2;
      • Y is selected from the group consisting of
        • (1′) —(CH2)g-O—(CH2)h-;
        • (2′) —(CH2)g-NR1—(CH2)h-;
        • (3′) —(CH2)g-CO—(CH2)h-;
        • (4′) —(CH2)g-C(O)NR2—(CH2)h-;
        • (5′) —(CH2)g-NR2C(O)—(CH2)h-;
        • (6′) —(CH2)g-(CH2)h-;
        • (7′) —(CH2)g-CH(OH)—(CH2)h-;
        • (8′) —(CH2)g-C═C—(CH2)h-;
      • and (9′) a single bond;
      • wherein
      • g is 0 or an integer of from 1 to 3;
      • h is 0 or an integer of from 1 to 3;
      • R1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF3, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R2R3), wherein R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R2 and R3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
      • R2 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl;
        Ring A is selected from the group consisting of:
  • Figure US20160355527A1-20161208-C00012
    • (i) Phenyl; (ii) Naphthyl;
  • (iii) A 5 or 6 membered monocyclic heteroaryl group which has 1-5 heteroatoms independently selected from the group consisting of O, N and S;
    and (iv) An 8 to 10 membered bicyclic heteroaryl group which has 1-6 heteroatoms independently selected from the group consisting of O, N and S;
    RIII represents optionally 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl, C1-C5 alkoxy, hydroxy, amino, C1-C5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
    Z is selected from the group consisting of
      • (1′) (CH2)iN(R7)C(O)N(R8)(CH2)j;
      • (2′) (CH2)iN(R7)C(S)N(R8)(CH2)j;
      • (3′) (CH2)iN(R7)C(O);
      • (4′) C(O)N(R8)(CH2)j;
      • (5′) (CH2)iN(R7)S(O)2;
      • and (6′) S(O)2N(R8)(CH2)j.
  • wherein
      • i is 0 or 1;
      • j is 0 or 1;
      • R7 and R8 are independently selected from the group consisting of hydrogen and alkyl;
  • Ring B is selected from the group consisting of:
  • Figure US20160355527A1-20161208-C00013
  • (i′) Phenyl;
    (ii′) Naphthyl;
    (iii′) A 5 or 6 membered monocyclic heteroaryl group which has 1-3 heteroatoms independently selected from the group consisting of O, N and S;
    and (iv′) An 8 to 10 membered bicyclic heteroaryl group which has 1-3 heteroatoms independently selected from the group consisting of O, N and S;
    RIV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR9R10; wherein R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
  • Unless otherwise indicated, reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solid forms, crystal forms, polymorphic forms, hydrates, solvates, metabolites, mixtures of stereoisomers, mixtures of crystal forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structure or a chemical name.
  • A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
  • A “prodrug” is a compound, which when administered to the body of a subject (such as a mammal), breaks down in the subject's metabolic pathway to provide an active compound of Formula I. More specifically, a prodrug is an active or inactive “masked” compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject or patient. One common form of a prodrug is a masked carboxylic acid group. Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
  • Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion. Unless stereochemistry is explicitly and unambiguously depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.
  • Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be amorphous forms, crystal forms, polymorphs, and the mixtures thereof.
  • Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
    • 2. Uses, Formulation and Administration
  • The present invention is also directed to the use of the compounds as protein tyrosine kinase modulators and inhibitors. These compounds can be used to treat diseases related to unregulated tyrosine kinase signal transduction, for example, various cancers, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases. In particular, compounds of the present invention are useful for the treatment and/or prevention of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders in the human being.
  • The present invention is also directed to the preparation of a medicament for the treatment and prevention of diseases and conditions related with abnormal activities of tyrosine kinase receptors. The medicament contains a pharmaceutical acceptable composition, which comprises the therapeutic effective amount of the compounds of present invention, together with a pharmaceutical acceptable carrier.
  • For the purposes of this disclosure, “treat,” “treating,” or “treatment” refer to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable conditions.
  • The pharmaceutical acceptable compositions contain therapeutic effective amount of the compounds of the present invention. These compositions can be used as a medicament and administered to a mammal, such as a person, in need thereof. Different types of suitable dosage forms and medicaments are well known in the art, and can be readily adapted for delivery of the compounds of the present invention, such as, but not limited to, systematic, parenteral, local and topical delivery. The dosage forms can be tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots, nasal sprays and ointment, various rectal or vaginal preparations.
    • 3. Examples
  • TABLE 1
    Exemplified Compounds of the Present Invention
    Compound Structure MW Chemical Name
    F1
    Figure US20160355527A1-20161208-C00014
         		451 methyl 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxylate
    F2
    Figure US20160355527A1-20161208-C00015
         		437 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid
    F3
    Figure US20160355527A1-20161208-C00016
         		451 methyl 7-[3-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxylate
    F4
    Figure US20160355527A1-20161208-C00017
         		435 methyl 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenyl]thieno[3,2-b]pyridine-2-carboxylate
    F5
    Figure US20160355527A1-20161208-C00018
         		421 7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenyl]thieno[3,2-b]pyridine-2-carboxylic acid
    F6
    Figure US20160355527A1-20161208-C00019
         		509 3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoic acid
    F7
    Figure US20160355527A1-20161208-C00020
         		527 3-[({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoic acid
    F8
    Figure US20160355527A1-20161208-C00021
         		455 7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid
    F9
    Figure US20160355527A1-20161208-C00022
         		469 methyl 7-(3-fluoro-4-(3-(2-fluoro-5- methylphenyl)ureido)phenoxy)thieno[3,2- b]pyridine-2-carboxylate
    F10
    Figure US20160355527A1-20161208-C00023
         		541 methyl 3-[({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoate
    F11
    Figure US20160355527A1-20161208-C00024
         		523 methyl 3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propanoate

    Additional compounds of the present invention are listed below.
  • Example# Chemical Structure MW Chemical Name
    12
    Figure US20160355527A1-20161208-C00025
         		547 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide
    13
    Figure US20160355527A1-20161208-C00026
         		533 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2- b]pyridine-2-carboxamide
    14
    Figure US20160355527A1-20161208-C00027
         		649 ethyl (4-{3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}piperazin- 1-yl)acetate
    15
    Figure US20160355527A1-20161208-C00028
         		592 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-{3-[3-(hydroxymethyl)piperidin- 1-yl]propyl}thieno[3,2-b]pyridine- 2-carboxamide
    16
    Figure US20160355527A1-20161208-C00029
         		594 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-{3-[2-(hydroxymethyl)morpholin- 4-yl]propyl}thieno[3,2-b]pyridine- 2-carboxamide
    17
    Figure US20160355527A1-20161208-C00030
         		622 methyl rel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}-4- hydroxypyrrolidine-2-carboxylate
    18
    Figure US20160355527A1-20161208-C00031
         		556 methyl ({3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}amino) acetate
    19
    Figure US20160355527A1-20161208-C00032
         		566 dimethyl 2,2′-({3-[({7-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}imino) diacetate
    20
    Figure US20160355527A1-20161208-C00033
         		638 N-(3-aminopropyl)-7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2- carboxamide
    21
    Figure US20160355527A1-20161208-C00034
         		494 tert-butyl {3-[({7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}carbamate
    21A
    Figure US20160355527A1-20161208-C00035
         		594 N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2- carboxamide
    22
    Figure US20160355527A1-20161208-C00036
         		493 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-(3-oxopropyl)thieno[3,2-b]pyridine- 2-carboxamide
    23
    Figure US20160355527A1-20161208-C00037
         		639 ethyl 4-{2-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]ethyl}piperazine-1- carboxylate
    24
    Figure US20160355527A1-20161208-C00038
         		653 ethyl 4-{3-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}piperazine- 1-carboxylate
    25
    Figure US20160355527A1-20161208-C00039
         		584 methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}amino)acetate
    26
    Figure US20160355527A1-20161208-C00040
         		656 dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}imino) diacetate
    27
    Figure US20160355527A1-20161208-C00041
         		642 dimethyl 2,2′-({2-[({7-[3-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]ethyl}imino)diacetate
    28
    Figure US20160355527A1-20161208-C00042
         		567 methyl 1-({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)pyrrolidine-3-carboxylate
    29
    Figure US20160355527A1-20161208-C00043
         		736 ethyl (4-{[4-({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)piperazin-1-yl]acetyl}piperazin- 1-yl)acetate
    30
    Figure US20160355527A1-20161208-C00044
         		610 ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)piperazin-1-yl]acetate
    31
    Figure US20160355527A1-20161208-C00045
         		570 methyl ({2-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]ethyl}amino)acetate
    32
    Figure US20160355527A1-20161208-C00046
         		498 N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2- carboxamide
    33
    Figure US20160355527A1-20161208-C00047
         		598 tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]ethyl}carbamate
    34
    Figure US20160355527A1-20161208-C00048
         		595 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-[3- (4-methylpiperazin-1-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide
    35
    Figure US20160355527A1-20161208-C00049
         		571 N-(2,2-diethoxyethyl)-7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy] thieno[3,2-b]pyridine-2-carboxamide
    36
    Figure US20160355527A1-20161208-C00050
         		610 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- {3-[3-(hydroxymethyl)piperidin-1- yl]propyl}thieno[3,2-b]pyridine-2- carboxamide
    37
    Figure US20160355527A1-20161208-C00051
         		612 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-{3- [2-(hydroxymethyl)morpholin-4- yl]propyl}thieno[3,2-b]pyridine-2- carboxamide
    38
    Figure US20160355527A1-20161208-C00052
         		596 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N-[3-(4- hydroxypiperidin-1-yl)propyl]thieno[3,2- b]pyridine-2-carboxamide
    39
    Figure US20160355527A1-20161208-C00053
         		640 methyl (2S,4R)-1-{3-[({7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]propyl}- 4-hydroxypyrrolidine-2-carboxylate
    40
    Figure US20160355527A1-20161208-C00054
         		585 N-(3,3-diethoxypropyl)-7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2- b]pyridine-2-carboxamide
    41
    Figure US20160355527A1-20161208-C00055
         		496 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (2-oxoethyl)thieno[3,2-b]pyridine-2- carboxamide
    42
    Figure US20160355527A1-20161208-C00056
         		624 methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}pyrrolidine- 2-carboxylate
    43
    Figure US20160355527A1-20161208-C00057
         		566 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (3-pyrrolidin-1-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide
    44
    Figure US20160355527A1-20161208-C00058
         		612 tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}carbamate
    45
    Figure US20160355527A1-20161208-C00059
         		512 N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide
    46
    Figure US20160355527A1-20161208-C00060
         		612 (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]-5- oxopentanoic acid
    47
    Figure US20160355527A1-20161208-C00061
         		668 tert-butyl (4S)-5-(ethylamino)-4-[({7-[3- fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy] thieno[3,2-b]pyridin-2-yl}carbonyl) amino]-5-oxopentanoate
    48
    Figure US20160355527A1-20161208-C00062
         		641 (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]-5- oxopentanoic acid
    49
    Figure US20160355527A1-20161208-C00063
         		655 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro- 4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl) amino]pentanedioate
    50
    Figure US20160355527A1-20161208-C00064
         		610 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}pyrrolidine- 3-carboxylic acid
    51
    Figure US20160355527A1-20161208-C00065
         		666 tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]propyl}pyrrolidine- 3-carboxylate
    52
    Figure US20160355527A1-20161208-C00066
         		511 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (3-oxopropyl)thieno[3,2-b]pyridine- 2-carboxamide
    53
    Figure US20160355527A1-20161208-C00067
         		513 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (3-hydroxypropyl)thieno[3,2- b]pyridine-2-carboxamide
    54
    Figure US20160355527A1-20161208-C00068
         		613 dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]pentanedioate
    55
    Figure US20160355527A1-20161208-C00069
         		582 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (3-morpholin-4-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide
    56
    Figure US20160355527A1-20161208-C00070
         		551 ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]butanoate
    57
    Figure US20160355527A1-20161208-C00071
         		569 ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]butanoate
    58
    Figure US20160355527A1-20161208-C00072
         		531 N-[dimethyl(oxido)-λ-4-sulfanylidene]-7- [3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridine-2-carboxamide
    59
    Figure US20160355527A1-20161208-C00073
         		603 4-[N-({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)- S-methylsulfonimidoyl]butanoic acid
    60
    Figure US20160355527A1-20161208-C00074
         		585 4-[N-({7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)-S- methylsulfonimidoyl]butanoic acid
    61
    Figure US20160355527A1-20161208-C00075
         		513 N-[dimethyl(oxido)-lambda~4~- sulfanylidene]-7-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2- carboxamide
    62
    Figure US20160355527A1-20161208-C00076
         		512 [({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]acetic acid
    63
    Figure US20160355527A1-20161208-C00077
         		495 [({7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]acetic acid
    64
    Figure US20160355527A1-20161208-C00078
         		541 4-[({7-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2- yl}carbonyl)amino]butanoic acid
    65
    Figure US20160355527A1-20161208-C00079
         		523 4-[({7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]thieno[3,2- b]pyridin-2-yl}carbonyl)amino]butanoic acid
    66
    Figure US20160355527A1-20161208-C00080
         		561 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]-N- (3-piperidin-1-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide
    67
    Figure US20160355527A1-20161208-C00081
         		577 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-[3-(4-methylpiperazin-1- yl)propyl]thieno[3,2-b]pyridine-2- carboxamide
    68
    Figure US20160355527A1-20161208-C00082
         		547 7-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]- N-(3-pyrrolidin-1-ylpropyl)thieno[3,2- b]pyridine-2-carboxamide
    69
    Figure US20160355527A1-20161208-C00083
         		535 N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide
    70
    Figure US20160355527A1-20161208-C00084
         		549 N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro- 5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridine-2-carboxamide
    71
    Figure US20160355527A1-20161208-C00085
         		408 Methyl 7-{3-[(3-methyl-2-furoyl) amino]phenoxy}thieno[3,2-b]pyridine- 2-carboxylate
    72
    Figure US20160355527A1-20161208-C00086
         		394 7-{3-[(3-methyl-2-furoyl) amino]phenoxy}thieno[3,2- b]pyridine-2-carboxylic acid
    73
    Figure US20160355527A1-20161208-C00087
         		421 N-ethyl-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide
    74
    Figure US20160355527A1-20161208-C00088
         		449 N,N-diethyl-7-{3-[(3-methyl-2-furoyl) amino]phenoxy}thieno[3,2-b]pyridine- 2-carboxamide
    75
    Figure US20160355527A1-20161208-C00089
         		409 N-hydroxy-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide
    76
    Figure US20160355527A1-20161208-C00090
         		451 N-(3-hydroxypropyl)-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide
    77
    Figure US20160355527A1-20161208-C00091
         		437 N-(2-hydroxyethyl)-7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxamide
    78
    Figure US20160355527A1-20161208-C00092
         		489 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}- N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2- b]pyridine-2-carboxamide
    79
    Figure US20160355527A1-20161208-C00093
         		452 3-hydroxypropyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxylate
    80
    Figure US20160355527A1-20161208-C00094
         		438 2-hydroxyethyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxylate
    81
    Figure US20160355527A1-20161208-C00095
         		452 2-methoxyethyl 7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridine-2-carboxylate
    82
    Figure US20160355527A1-20161208-C00096
         		522 Methyl [(3-{[(7-{3-[(3-methyl-2- furoyl)amino]phenoxy}thieno[3,2- b]pyridin-2-yl)carbonyl]amino}propyl) amino]acetate
    83
    Figure US20160355527A1-20161208-C00097
         		436 Methyl 7-(3-((2-fluoro-5-methylphenyl) carbamoyl)phenoxy)thieno[3,2- b]pyridine-2-carboxylate
    84
    Figure US20160355527A1-20161208-C00098
         		422 7-(3-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)thieno[3,2- b]pyridine-2-carboxylic acid
    85
    Figure US20160355527A1-20161208-C00099
         		449 N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)thieno[3,2- b]pyridine-2-carboxamide
    86
    Figure US20160355527A1-20161208-C00100
         		477 N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)thieno[3,2- b]pyridine-2-carboxamide
    87
    Figure US20160355527A1-20161208-C00101
         		550 Methyl {[3-({[7-(3-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy) thieno[3,2-b]pyridin-2-yl]carbonyl}amino) propyl]amino}acetate
    • 3.1 Compound Synthesis and Characterization Compound F1 Methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00102
  • To a stirred solution of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (200 mg, 0.74 mmol) in 8 ml of DMSO, were added CuBr (10 mg, 0.074 mmol), ethyl 2-cyclohexanonecarboxylate (26 mg, 0.15 mmol), cesium carbonate (500 mg, 1.54 mmol) and 4-aminophenol (96 mg, 0.88 mmol). The mixture was purged with nitrogen for 10 minutes, and then heated at 70° C. under N2 for 3 hours. The reaction was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude aniline intermediate as a pale green solid (˜140 mg). This crude material was dissolved in 10 ml of THF, and 2-fluoro-5-methylphenyl isocyanate (70 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 5 hours, and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate as light brown solid. Yield: 90 mg, 27%.
  • 1H NMR (d6-DMSO) d: 9.25 (s, 1H), 8.61 (d, J=5.3 Hz, 1H), 8.50 (br. s., 1H), 8.21 (s, 1H), 7.96 (d, J=6.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.09 (dd, J=11.4, 8.2 Hz, 1H), 6.71-6.85 (m, 2H), 3.91 (s, 3H), 2.26 (s, 3H)
  • LR MS (ES+): 452 (MH), 474 (M+Na+)
  • LR MS (ES−): 450 (M−H)
    • Compound F2 7-[4-({[(2-Fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid
  • Figure US20160355527A1-20161208-C00103
  • To a stirred suspension of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate (50 mg, 0.11 mmol) in MeOH (3 ml), was added 0.4M LiOH/MeOH solution (10 ml, 4.0 mmol). The mixture was heated at 50° C. for 7 hours, and poured into 100 ml of water. 1M HCl was added until pH=4. The resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as light grey solid. Yield: 40 mg, 83%.
  • 1H NMR (DMSO-d6) δ: 13.88 (br. s., 1H), 9.19 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.10 (s, 1H), 7.96 (dd, J=7.9, 1.8 Hz, 1H), 7.53-7.59 (m, 2H), 7.22-7.27 (m, 2H), 7.08 (dd, 1H), 6.77-6.80 (m, 1H), 6.73 (d, J=5.6 Hz, 1H), 2.25 (s, 3H)
  • LR MS (ES−): 436 (M−H)
    • Compound F3 Methyl 7-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00104
  • prepared using procedures similar to Compound F1.
  • 1H NMR (DMSO-d6) δ: 9.51 (s, 1H), 8.64 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.58 (t, J=2.1 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.23 (dd, J=8.2, 1.2 Hz, 1H), 7.06 (dd, J=11.3, 8.4 Hz, 1H), 6.91 (dd, J=7.9, 1.8 Hz, 1H), 6.85 (d, J=5.3 Hz, 1H), 6.77 (td, J=5.2, 2.2 Hz, 1H), 3.91 (s, 3H), 2.21 (s, 3H)
  • LR MS (ES+): 452 (MH), 474 (M+Na+)
  • LR MS (ES−): 450 (M−H)
    • Compound F4 Methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00105
  • To a mixture of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (68 mg, 0.25 mmol) and 1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (102 mg, 0.28 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.25 ml, 0.5 mmol). The mixture was heated at 70° C. under N2 for 1 hour, cooled to room temperature and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate as light yellow solid. Yield: 30 mg, 28%.
  • 1H NMR (d6-DMSO) d: 9.38 (s, 1H), 8.84 (d, J=4.7 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.28 (s, 1H), 7.60-8.06 (m, 6H), 7.06-7.19 (m, 1H), 6.82 (br. s., 1H), 3.93 (s, 3H), 2.28 (s, 3H)
  • LR MS (ES−): 434 (M−H)
    • Compound F5 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid
  • Figure US20160355527A1-20161208-C00106
  • To a stirred solution of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate (20 mg, 0.046 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 70° C. for 30 minutes, cooled to room temperature and poured into 50 ml of water. 1M HCl was added until pH=4 and the resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid.
  • Yield: 20 mg, 100%.
  • LR MS (ES−): 420 (M−H)
    • Preparation of 7-chlorothieno[3,2-b]pyridine
  • Figure US20160355527A1-20161208-C00107
  • Thieno[3,2-b]pyridin-7-ol (20 g, 0.132 mol) was suspended in phosphorous oxy chloride (80.9 g, 0.528 mol) and stirred at 100 □C for 2 hours. The solution was cooled to room temperature and was poured over ice. The aqueous solution was neutralized with sodium hydroxide and the resulting precipitate was collected by filtration and washed with water. The filter cake was taken up in dichloromethane and dried over magnesium sulfate. The solution was filtered and the filtrate was concentrated to dryness to give 7-chlorothieno[3,2-b]pyridine as a brown liquid which solidified to a beige solid under high vacuum. Yield: 20.4 g (91%); MS [M+H]+ 169.9; 1HNMR (CDCl3) δ: □8.7 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.3 (d, 1H) ppm.
    • Preparation of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00108
  • 7-chlorothieno[3,2-b]pyridine (19.7 g, 0.116 mol) was taken up in THF (400 mL) and cooled to approximately −70 □C. The n-butyllithium (1.6M, 80 mL, 0.128 mol) was added dropwise with stirring under an atmosphere of nitrogen. The solution was stirred at −70 □C for 1 hour at which time neat methyl chloroformate was added via dropwise addition. The reaction mixture gradually warmed to room temperature and was stirred for over the weekend. The reaction mixture was treated with 25 mL of methanol and then concentrated to dryness leaving a maroon residue. The crude solid was taken up in dichloromethane and passed through a silica gel column eluting with 1:1 hexane/ethyl acetate. Fractions containing the product were combined and concentrated to give a red solid. Trituration with 9:1 hexane/diethyl ether afforded methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate as a pink solid after filtration. Yield: 14.5 g (55%); MS [M+H]+ 227.9; 1HNMR (CDCl3) δ: □8.7 (d, 1H), 8.3 (s, 1H), 7.4 (d, 1H) ppm.
    • Preparation of methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00109
  • Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (5 g, 0.022 mol) and the 4-amino-3-fluorophenol (3.3 g, 0.026 mol) were added to a round bottom flask containing cesium carbonate (14.8 g, 0.045 mol), ethyl-2-cyclohexanone carboxylate (0.73 g, 0.004 mol), and copper (I) chloride (0.22 g, 0.002 mol). The mixture was diluted with DMSO (250 mL) and stirred at 70 □C under an atmosphere of nitrogen for 2 hours. The dark reaction mixture was cooled to room temperature and poured into ethyl acetate (500 mL)/water (1 L) with vigorous stirring. The mixture was filtered through celite and the organic portion of the filtrate was separated and dried over magnesium sulfate. The solution was filtered and the filtrate was concentrated to give a purple viscous liquid. The crude product was taken up in dichloromethane and passed through a silica gel column eluting with 1:1 hexane/ethyl acetate. Fractions containing the product were combined and concentrated to afford methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate as red solid. Yield: 1.62 g (23%); MS [M+H]+ 319.1
    • Compound F9 methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate
  • Figure US20160355527A1-20161208-C00110
  • Methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.62 g, 5.1 mmol) was taken up in 55 mL of ethyl acetate followed by the dropwise addition of 2-fluoro-5-methylphenyl isocyanate (0.85 g, 5.6 mmol) in 5 mL ethyl acetate. The solution afforded a lavender solid after stirring at room temperature for overnight. The solid was collected by filtration and washed with diethyl ether to give methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as an off white solid.
  • Yield: 1.75 g (73%); MS [M+H]+ 470.1; 1HNMR (DMSO-d6) δ: □9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H, 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 3.9 (s, 3H), 2.1 (s, 3H) ppm.
    • Compound F10 methyl 3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate
  • Figure US20160355527A1-20161208-C00111
  • 1H NMR (DMSO-d6) δ: 9.10 (br. s., 1H), 9.03 (t, J=5.4 Hz, 1H), 8.96 (br. s., 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.40 (dd, J=11.6, 2.5 Hz, 1H), 7.06-7.16 (m, 2H), 6.74-6.84 (m, 2H), 3.60 (s, 3H), 3.48-3.55 (m, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.25 (s, 3H)
  • LR MS (ES+): 563 (M+Na+)
  • LR MS (ES−): 539 (M−H)
    • Compound F11 methyl 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate
  • Figure US20160355527A1-20161208-C00112
  • A mixture of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl)}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol), HATU (122 mg, 0.32 mmol) and N,N-diisopropylethylamine (105 mg, 0.81 mmol) in anhydrous THF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (56 mg, 0.40 mmol). The mixture was heated and stirred at 60° C. for 30 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate as white solid. Yield: 128 mg, 90%.
  • 1H NMR (DMSO-d6) δ: 9.18 (s, 1H), 9.01 (t, 1H), 8.54 (br. s., 1H), 8.47 (br. s., 1H), 8.20 (br. s., 1H), 7.95 (d, J=6.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.08 (dd, J=11.0, 8.7 Hz, 1H), 6.78 (br. s., 1H), 6.69 (d, J=5.0 Hz, 1H), 3.60 (s, 3H), 3.46-3.55 (m, 2H), 2.62 (t, J=6.7 Hz, 2H), 2.25 (s, 3H)
  • LR MS (ES+): 545 (M+Na+)
  • LR MS (ES−): 521 (M−H)
    • Compound F6 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid
  • Figure US20160355527A1-20161208-C00113
  • To a stirred solution of methyl 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate (98 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 2M HCl was added until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid as off-white solid. Yield: 90 mg, 95%.
  • 1H NMR (DMSO-d6) δ: 12.25 (br. s., 1H), 9.18 (s, 1H), 8.99 (t, J=5.1 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.47 (br. s., 1H), 8.21 (s, 1H), 7.95 (d, J=6.5 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.08 (dd, J=11.0, 8.4 Hz, 1H), 6.78 (br. s., 1H), 6.68 (d, J=5.3 Hz, 1H), 3.42-3.53 (m, 2H), 2.53 (t, J=6.9 Hz, 2H), 2.25 (s, 3H)
  • LR MS (ES−): 507 (M−H)
    • Compound F7 3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid
  • Figure US20160355527A1-20161208-C00114
  • 1H NMR (DMSO-d6) δ: 12.26 (br. s., 1H), 9.09 (br. s., 1H), 9.00 (t, J=4.7 Hz, 1H), 8.96 (br. s., 1H), 8.56 (d, J=5.3 Hz, 1H), 8.25 (t, J=9.0 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.35-7.44 (m, 1H), 7.05-7.16 (m, 2H), 6.71-6.85 (m, 2H), 3.42-3.54 (m, 2H), 2.53 (t, J=6.7 Hz, 2H), 2.25 (s, 3H)
  • LR MS (ES−): 525 (M−H)
    • Compound F8 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid
  • Figure US20160355527A1-20161208-C00115
  • Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl. The insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering. The filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid. Yield: 1.6 g (90%); MS [M+H]+ 456.1; 1HNMR (DMSO-d6) δ: □13.9 (bs, 1H), □9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 2.1 (s, 3H) ppm.
  • Other compounds which may be made according to the teachings of the present application include:
  • Figure US20160355527A1-20161208-C00116
    Figure US20160355527A1-20161208-C00117
  • Synthesis and Characterization of the additional compounds is listed below.
    • Example 12
  • Figure US20160355527A1-20161208-C00118
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (Compound F1) (100 mg, 0.23 mmol) in 10 ml of anhydrous acetonitrile were added HATU (95 mg, 0.25 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred at room temperature for 20 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (57 mg, 0.35 mmol). The mixture was stirred at room temperature for another 40 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 8˜12% methanol in chloroform containing 0.5% of triethylamine to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 50 mg, 40%.
  • 1H NMR (DMSO-d6): 9.28 (s, 1H), 9.18 (t, J=5.6 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.26 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.82 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 3.37-3.40 (m, 2H), 2.87-2.91 (m, 2H), 2.27 (s, 3H), 1.98 (quin, J=7.3 Hz, 2H)
  • LR MS (ES−): 545 (M−H)
  • The following Example 13 was prepared using the experiment procedure described in Example 12, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 13
  • Figure US20160355527A1-20161208-C00119
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (DMSO-d6): 9.22 (s, 1H), 9.12 (t, J=5.9 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 8.51 (d, J=2.9 Hz, 1H), 8.18 (s, 1H), 7.98 (dd, J=8.4, 1.9 Hz, 1H), 7.57-7.60 (m, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.24-7.27 (m, 1H), 7.25 (d, J=9.1 Hz, 1H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H), 6.72 (d, J=5.6 Hz, 1H), 3.66-3.69 (m, 2H), 3.20 (t, J=7.0 Hz, 2H), 2.28 (s, 3H)
  • LR MS (ES−): 531 (M−H)
    • Example 14
  • Figure US20160355527A1-20161208-C00120
    • ethyl (4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate
  • To a stirred solution of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (180 mg, 0.36 mmol) and 1-(ethoxycarbonylmethyl)piperazine (124 mg, 0.72 mmol) in anhydrous DMF was added 2 drops of acetic acid. The solution was stirred at room temperature for 30 minutes, followed by addition of 1M NaCNBH3 solution in THF (0.72 ml, 0.72 mmol). Stirring was continued for another hour, and the mixture was poured into 100 ml of water. The precipitates were filtered to give the crude, which was purified by silica gel chromatography eluting with 8-12% of methanol in chloroform to give ethyl (4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate as light yellow solid. Yield: 70 mg, 30%.
  • 1H NMR (DMSO-d6): 9.20 (s, 1H), 8.90 (t, J=5.7 Hz, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.48 (dd, J=2.3, 0.6 Hz, 1H), 8.19 (s, 1H), 7.93-7.98 (m, 1H), 7.53-7.58 (m, 2H), 7.20-7.24 (m, 2H), 7.08 (dd, J=11.4, 8.5 Hz, 1H), 6.75-6.81 (m, 1H), 6.68 (d, J=5.6 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.25-3.33 (m, 2H), 3.15 (s, 2H), 2.27-2.43 (m, 10H), 2.25 (s, 3H), 1.68 (quin, J=7.1 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H)
  • LR MS (ES+): 671 (M+Na+)
  • LR MS (ES−): 647 (M−H)
  • The following Examples 15 through 17 were prepared using the experiment procedure described in Example 14, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 15
  • Figure US20160355527A1-20161208-C00121
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide
  • LR MS (ES+): 592 (MH+)
    • Example 16
  • Figure US20160355527A1-20161208-C00122
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide
  • LR MS (ES+): 616 (M+Na+)
  • LR MS (ES−): 592 (M−H)
    • Example 17
  • Figure US20160355527A1-20161208-C00123
    • methyl rel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate
  • 1H NMR (DMSO-d6): 9.22 (s, 1H), 8.92 (t, J=5.6 Hz, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.6, 2.1 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 4.89 (d, J=4.4 Hz, 1H), 4.20-4.26 (m, 1H), 3.61 (s, 3H), 3.40 (t, J=7.8 Hz, 1H), 3.32-3.36 (m, 2H), 3.25-3.28 (m, 1H), 2.70 (dt, J=12.0, 7.5 Hz, 1H), 2.49-2.52 (m, 1H), 2.28 (s, 3H), 2.26-2.29 (m, 1H), 1.96-2.01 (m, 1H), 1.89 (td, J=8.4, 4.0 Hz, 1H), 1.63-1.71 (m, 2H)
  • LR MS (ES+): 622 (MH+)
  • LR MS (ES−): 620 (M−H)
  • The following Example 18 was prepared using the experiment procedure described in Example 25, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 18
  • Figure US20160355527A1-20161208-C00124
    • methyl ({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate
  • 1H NMR (DMSO-d6): 9.22 (s, 1H), 8.95 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.8, 2.2 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H), 6.72 (s, 1H), 3.63 (s, 3H), 3.38 (s, 2H), 3.32-3.36 (m, 2H), 2.61 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.69 (quin, J=7.0 Hz, 2H)
  • LR MS (ES−): 564 (M−H)
  • The following Example 19 was prepared using the experiment procedure described in Example 26, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 19
  • Figure US20160355527A1-20161208-C00125
    • dimethyl 2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate
  • 1H NMR (DMSO-d6): 9.21 (s, 1H), 8.88 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.21 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.27 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.6 Hz, 1H), 3.60 (s, 6H), 3.54 (s, 4H), 3.32-3.35 (m, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.67 (quin, J=6.9 Hz, 2H)
  • LR MS (ES+): 660 (M+Na+)
  • LR MS (ES−): 636 (M−H)
    • Example 20
  • Figure US20160355527A1-20161208-C00126
    • N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (380 mg, 0.64 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 270 mg, 85%.
  • LR MS (ES+): 516 (M+Na+)
  • LR MS (ES−): 492 (M−H)
    • Example 21
  • Figure US20160355527A1-20161208-C00127
    • tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate
  • A mixture of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.69 mmol), HATU (288 mg, 0.76 mmol) and N,N-diisopropylethylamine (196 mg, 1.52 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (180 mg, 1.03 mmol). The mixture was stirred for another 30 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=6. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as brown solid. Yield: 380 mg, 93%.
  • 1H NMR (DMSO-d6): 9.25 (s, 1H), 8.89 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.53 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.6, 2.1 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.26 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.81 (ddd, J=10.9, 5.4, 2.8 Hz, 1H), 6.71 (d, J=5.6 Hz, 1H), 6.70-6.72 (m, 1H), 3.27-3.30 (m, 2H), 3.00 (q, J=6.7 Hz, 2H), 2.28 (s, 3H), 1.67 (quin, J=7.1 Hz, 2H), 1.38 (s, 9H)
  • LR MS (ES+): 616 (M+Na+)
  • LR MS (ES−): 592 (M−H)
    • Example 21A Preparation of N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • Figure US20160355527A1-20161208-C00128
  • To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (600 mg, 1.37 mmol) in 10 ml of anhydrous acetonitrile were added HATU (608 mg, 1.6 mmol) and N,N-diisopropylethylamine (388 mg, 3.0 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 680 mg, 88%.
  • 1H NMR (DMSO-d6) δ: 9.21 (s, 1H), 8.90 (t, J=5.7 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.57-7.60 (m, 2H), 7.24-7.28 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.80-6.83 (m, 1H), 6.71 (d, J=5.3 Hz, 1H), 4.59 (t, J=5.6 Hz, 1H), 3.60 (dq, J=9.4, 7.0 Hz, 2H), 3.46 (dq, J=9.4, 7.0 Hz, 2H), 3.32-3.36 (m, 2H), 2.28 (s, 3H), 1.81-1.85 (m, 2H), 1.12 (t, J=7.0 Hz, 6H)
  • LR MS (ES+): 589 (M+Na+)
  • LR MS (ES−): 565 (M−H)
    • Example 22
  • Figure US20160355527A1-20161208-C00129
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred solution of N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (680 mg, 1.20 mmol) in 10 ml of THF was added 1 ml of 2M HCl. The mixture was stirred at room temperature for 3 hours, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 550 mg, 93%.
  • LR MS (ES+): 515 (M+Na+)
  • LR MS (ES−): 491 (M−H)
    • Example 23
  • Figure US20160355527A1-20161208-C00130
    • ethyl 4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1-carboxylate
  • 1H NMR (DMSO-d6) δ: 9.13 (d, J=2.6 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.92 (t, J=5.9 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.29 (t, J=9.1 Hz, 1H), 8.24 (s, 1H), 8.01 (dd, J=7.8, 2.2 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H), 7.12-7.16 (m, 1H), 7.12 (dd, J=11.4, 8.5 Hz, 1H), 6.80-6.85 (m, 1H), 6.80 (d, J=5.6 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H), 3.43 (q, J=6.5 Hz, 2H), 3.36 (t, J=5.0 Hz, 4H), 2.51-2.56 (m, 2H), 2.39-2.44 (m, 4H), 2.28 (s, 3H), 1.17 (t, J=7.0 Hz, 3H)
  • LR MS (ES+): 639 (MH+)
  • LR MS (ES−): 637 (M−H)
  • The following Example 24 was prepared using the experiment procedure described in Example 38, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 24
  • Figure US20160355527A1-20161208-C00131
    • ethyl 4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate
  • 1H NMR (DMSO-d6) δ: 9.13 (d, J=2.6 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.94 (t, J=5.6 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.29 (t, J=9.2 Hz, 1H), 8.24 (s, 1H), 8.01 (dd, J=7.9, 2.3 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H), 7.09-7.16 (m, 2H), 6.79-6.85 (m, 1H), 6.80 (d, J=5.3 Hz, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.32-3.38 (m, 6H), 2.31-2.40 (m, 6H), 2.28 (s, 3H), 1.73 (quin, J=6.9 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H)
  • LR MS (ES+): 653 (MH+)
  • LR MS (ES−): 651 (M−H)
    • Example 25
  • Figure US20160355527A1-20161208-C00132
    • methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate
  • To a stirred solution of N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (125 mg, 0.24 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (36 mg, 0.24 mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5˜8% of MeOH in CHCl3 to afford methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate as light beige solid. Yield: 54 mg, 38%.
  • 1H NMR (DMSO-d6): 9.10 (d, J=1.8 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.93 (t, J=5.6 Hz, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H), 7.11 (dd, J=9.0, 2.5 Hz, 1H), 7.09 (dd, J=11.4, 8.2 Hz, 1H), 6.78-6.81 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.59 (s, 3H), 3.32 (s, 2H), 3.29-3.34 (m, 2H), 2.56 (t, J=6.7 Hz, 2H), 2.25 (s, 3H), 1.65 (quin, J=7.0 Hz, 2H)
  • LR MS (ES+): 584 (MH+)
  • LR MS (ES−): 582 (M−H)
    • Example 26
  • Figure US20160355527A1-20161208-C00133
    • dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate
  • To a stirred solution of N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (125 mg, 0.24 mmol) and N,N-diisopropylethylamine (77 mg, 0.60 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (92 mg, 0.60 mmol). The mixture was heated at 60° C. for 1 hour and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜4% of MeOH in CHCl3 to afford dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate as white solid. Yield: 140 mg, 88%.
  • 1H NMR (DMSO-d6): 9.10 (d, J=2.1 Hz, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.86 (t, J=5.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.8, 2.5 Hz, 1H), 7.39 (dd, J=11.6, 2.8 Hz, 1H), 7.11 (dd, J=9.2, 2.8 Hz, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.6 Hz, 1H), 3.58 (s, 6H), 3.51 (s, 4H), 3.29-3.33 (m, 2H), 2.69 (t, J=6.9 Hz, 2H), 2.25 (s, 3H), 1.64 (quin, J=7.0 Hz, 2H)
  • LR MS (ES+): 677 (MNa+)
  • LR MS (ES−): 654 (M−H)
  • The following Example 27 was prepared using the experiment procedure described in Example 26, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 27
  • Figure US20160355527A1-20161208-C00134
    • dimethyl 2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate
  • 1H NMR (acetone) d: 8.59 (d, J=5.3 Hz, 1H), 8.56 (br. s., 1H), 8.46 (t, J=9.1 Hz, 1H), 8.42 (d, J=2.9 Hz, 1H), 8.40 (t, J=5.0 Hz, 1H), 8.15-8.18 (m, 1H), 8.15 (s, 1H), 7.25 (dd, J=11.6, 2.8 Hz, 1H), 7.13-7.17 (m, 1H), 7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.86 (m, 1H), 6.78 (d, J=5.3 Hz, 1H), 3.69 (s, 6H), 3.68 (s, 4H), 3.42-3.48 (m, 2H), 3.00 (t, J=5.9 Hz, 2H), 2.32 (s, 3H)
  • LR MS (ES+): 642 (MH+)
  • LR MS (ES−): 640 (M−H)
  • The following Example 28 was prepared using the experiment procedure described in Example 30, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 28
  • Figure US20160355527A1-20161208-C00135
    • methyl 1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate
  • LR MS (ES+): 567 (MH+)
  • LR MS (ES−): 565 (M−H)
    • Example 29
  • Figure US20160355527A1-20161208-C00136
    • ethyl (4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin-1-yl)acetate
  • The title compound was isolated as a side product in the preparation of ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate.
  • LR MS (ES+): 736 (MH+)
  • LR MS (ES−): 734 (M−H)
    • Example 30
  • Figure US20160355527A1-20161208-C00137
    • ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate
  • A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydrous tetrahydrofuran (10 ml) was heated at 60° C. for 10 minutes, followed by addition of ethyl piperazinoacetate (57 mg, 0.33 mmol). Heating was continued at 60° C. for 30 minutes and the mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate as white solid. Yield: 73 mg, 54%.
  • 1H NMR (DMSO-d6) δ: 9.11 (br. s., 1H), 8.97 (br. s., 1H), 8.56 (d, J=5.6 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 7.39 (dd, J=11.7, 2.3 Hz, 1H), 7.06-7.13 (m, 2H), 6.78-6.81 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.66 (br. s., 4H), 3.27 (s, 2H), 2.58 (br. s., 4H), 2.25 (s, 3H), 1.16 (t, J=7.2 Hz, 3H)
  • LR MS (ES+): 610 (MH+)
  • LR MS (ES−): 608 (M−H)
  • The following Example 31 was prepared using the experiment procedure described in Example 25, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 31
  • Figure US20160355527A1-20161208-C00138
    • methyl ({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate
  • 1H NMR (DMSO-d6): 9.10 (s, 1H), 8.96 (s, 1H), 8.89 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.39 (dd, J=11.7, 2.3 Hz, 1H), 7.10-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.59 (s, 3H), 3.36 (s, 2H), 3.31-3.35 (m, 2H), 2.70 (t, J=6.5 Hz, 2H), 2.25 (s, 3H)
  • LR MS (ES+): 570 (MH+)
    • Example 32
  • Figure US20160355527A1-20161208-C00139
    • N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate (488 mg, 0.82 mmol) in 10 ml of dichloromethane was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for one hour and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 400 mg, 99%.
  • LR MS (ES+): 498 (MH+)
  • LR MS (ES−): 496 (M−H)
    • Example 33
  • Figure US20160355527A1-20161208-C00140
    • tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate
  • A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (400 mg, 0.88 mmol), HATU (400 mg, 1.05 mmol) and N,N-diisopropylethylamine (250 mg, 1.94 mmol) in anhydrous THF (10 ml) was heated at 60° C. for 15 minutes, followed by addition of N-Boc-ethylenediamine (210 mg, 1.32 mmol). The mixture was stirred at 60° C. for another 5 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate as off-white solid. Yield: 518 mg, 99%.
  • 1H NMR (DMSO-d6) δ: 9.12 (d, J=1.8 Hz, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.95 (t, J=5.9 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.28 (t, J=9.1 Hz, 1H), 8.22 (s, 1H), 8.01 (dd, J=7.8, 2.2 Hz, 1H), 7.42 (dd, J=11.7, 2.6 Hz, 1H), 7.10-7.15 (m, 2H), 6.95 (t, J=6.0 Hz, 1H), 6.81-6.84 (m, 1H), 6.80 (d, J=5.6 Hz, 1H), 3.31-3.34 (m, 2H), 3.14 (q, J=6.6 Hz, 2H), 2.28 (s, 3H), 1.37 (s, 9H)
  • LR MS (ES+): 598 (MH+)
  • LR MS (ES−): 596 (M−H)
    • Example 34
  • Figure US20160355527A1-20161208-C00141
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide
  • A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (90 mg, 0.24 mmol) and N,N-diisopropylethylamine (55 mg, 0.43 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of 3-(4-methylpiperazin-1-yl)propan-1-amine (40 mg, 0.25 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 110 mg, 84%.
  • 1H NMR (acetone): 8.56-8.60 (m, 2H), 8.42-8.49 (m, 3H), 8.14-8.18 (m, 1H), 8.06 (s, 1H), 7.24 (dd, J=11.6, 2.8 Hz, 1H), 7.14 (dt, J=8.9, 2.0 Hz, 1H), 7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.86 (m, 1H), 6.78 (d, J=5.3 Hz, 1H), 3.49 (q, J=6.5 Hz, 2H), 2.48 (t, J=6.5 Hz, 2H), 2.39 (br. s., 8H), 2.32 (s, 3H), 2.18 (s, 3H), 1.80 (quin, J=6.6 Hz, 2H)
  • LR MS (ES+): 595 (MH+)
  • LR MS (ES−): 593 (M−H)
    • Example 35
  • Figure US20160355527A1-20161208-C00142
    • N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • The following Examples 36 and 37 were prepared using the experiment procedure described in Example 38, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 36
  • Figure US20160355527A1-20161208-C00143
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide
  • LR MS (ES+): 610 (MH+)
  • LR MS (ES−): 608 (M−H)
    • Example 37
  • Figure US20160355527A1-20161208-C00144
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide
  • LR MS (ES+): 612 (MH+)
  • LR MS (ES−): 610 (M−H)
    • Example 38
  • Figure US20160355527A1-20161208-C00145
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl)propyl]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred solution of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF were added 4-hydroxypiperidine (59 mg, 0.58 mmol) and acetic acid (10 mg, 0.17 mmol). The mixture was stirred at room temperature for 40 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60 ml, 0.60 mmol) and stirring was continued for another 30 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 10-20% of MeOH in CHCl3 to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 70 mg, 40%.
  • 1H NMR (DMSO-d6): 9.11 (s, 1H), 8.97 (s, 1H), 8.94 (br. s., 1H), 8.56 (d, J=5.3 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.06-7.14 (m, 2H), 6.79 (td, J=5.3, 2.3 Hz, 1H), 6.77 (d, J=5.3 Hz, 1H), 4.56 (br. s., 1H), 3.44 (br. s., 1H), 3.36 (br. s., 2H), 2.76 (br. s., 2H), 2.28-2.45 (m, 2H), 2.25 (s, 3H), 2.05 (br. s., 2H), 1.71 (br. s., 4H), 1.39 (br. s., 2H)
  • LR MS (ES+): 596 (MH+)
  • LR MS (ES−): 594 (M−H)
  • The following Example 39 was prepared using the experiment procedure described in Example 42, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 39
  • Figure US20160355527A1-20161208-C00146
    • methyl (2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate
  • 1H NMR (acetone): 8.66 (t, J=6.2 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.56 (d, J=2.1 Hz, 1H), 8.45 (t, J=9.1 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.14-8.17 (m, 1H), 8.08 (s, 1H), 7.24 (dd, J=11.6, 2.8 Hz, 1H), 7.14 (dt, J=9.1, 1.6 Hz, 1H), 7.02 (dd, J=11.3, 8.4 Hz, 1H), 6.81-6.85 (m, 1H), 6.78 (d, J=5.3 Hz, 1H), 4.35-4.44 (m, 1H), 4.05 (d, J=4.1 Hz, 1H), 3.72 (s, 3H), 3.59-3.67 (m, 1H), 3.56 (t, J=8.2 Hz, 1H), 3.39-3.52 (m, 2H), 2.87-2.94 (m, 1H), 2.66 (dt, J=12.5, 4.7 Hz, 1H), 2.38 (dd, J=10.0, 4.1 Hz, 1H), 2.32 (s, 3H), 2.07-2.14 (m, 2H), 1.74-1.83 (m, 1H), 1.65-1.74 (m, 1H)
  • LR MS (ES+): 640 (MH+)
  • LR MS (ES−): 638 (M−H)
    • Example 40
  • Figure US20160355527A1-20161208-C00147
    • N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (1.0 g, 2.2 mmol) in 20 ml of anhydrous tetrahydrofuran were added HATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (620 mg, 4.8 mmol). The mixture was heated at 60° C. for 20 minutes, followed by addition of 1-amino-3,3-diethoxypropane (388 mg, 2.6 mmol). The mixture was heated at 60° C. for another 30 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as off-white solid. Yield: 1.23 g, 95%.
  • 1H NMR (DMSO-d6): 9.10 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.89 (t, J=5.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.10-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.6 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 3.57 (dq, J=9.4, 7.0 Hz, 2H), 3.43 (dq, J=9.7, 7.0 Hz, 2H), 3.29-3.34 (m, 2H), 2.25 (s, 3H), 1.75-1.85 (m, 2H), 1.09 (t, J=7.0 Hz, 6H)
  • LR MS (ES+): 607 (MNa+)
  • LR MS (ES−): 583 (M−H)
    • Example 41
  • Figure US20160355527A1-20161208-C00148
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred solution of N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (300 mg, 0.53 mmol) in 10 ml of THF was added 2 ml of 2M HCl. The mixture was heated under nitrogen at 60° C. for 4 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 250 mg, 96%.
  • LR MS (ES+): 497 (MH+)
  • LR MS (ES−): 495 (M−H)
    • Example 42
  • Figure US20160355527A1-20161208-C00149
    • methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate
  • To a stirred solution of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF was added L-proline methyl ester hydrochloride (96 mg, 0.58 mmol) and triethylamine (58 mg, 0.58 mmol). The mixture was stirred at room temperature under nitrogen for one hour, and 1M solution of sodium cyanoborohydride in THF (0.60 ml, 0.60 mmol) was added. The mixture was stirred for another hour, and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to afford methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate as white solid. Yield: 90 mg, 50%.
  • 1H NMR (DMSO-d6): 9.10 (s, 1H), 8.96 (s, 1H), 8.92 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.18 (s, 1H), 7.95-8.01 (m, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.06-7.13 (m, 2H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.9 Hz, 1H), 3.58 (s, 3H), 3.29-3.34 (m, 2H), 3.15-3.21 (m, 1H), 2.97-3.05 (m, 1H), 2.67 (dt, J=11.9, 7.6 Hz, 1H), 2.40-2.45 (m, 1H), 2.29-2.38 (m, 1H), 2.25 (s, 3H), 2.02 (dq, J=12.0, 8.2 Hz, 1H), 1.76-1.81 (m, 1H), 1.70-1.76 (m, 2H), 1.60-1.70 (m, 2H)
  • LR MS (ES+): 624 (MH+)
  • LR MS (ES−): 622 (M−H)
  • The following Example 43 was prepared using the experiment procedure described in Example 34, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 43
  • Figure US20160355527A1-20161208-C00150
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl)}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (DMSO-d6): 9.10 (dd, J=2.1, 0.6 Hz, 1H), 8.93-8.98 (m, 2H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.39 (dd, J=11.6, 2.8 Hz, 1H), 7.10-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.29-3.34 (m, 2H), 2.37-2.45 (m, 6H), 2.25 (s, 3H), 1.70 (quin, J=7.0 Hz, 2H), 1.63-1.67 (m, 4H)
  • LR MS (ES+): 566 (MH+)
  • LR MS (ES−): 564 (M−H)
    • Example 44
  • Figure US20160355527A1-20161208-C00151
    • tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate
  • A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.66 mmol), HATU (277 mg, 0.73 mmol) and N,N-diisopropylethylamine (187 mg, 1.45 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (172 mg, 0.99 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as light yellow solid. Yield: 345 mg, 85%.
  • 1H NMR (DMSO-d6): 9.10 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.87 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.21 (s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H), 7.11 (ddd, J=9.0, 2.9, 1.0 Hz, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.78-6.83 (m, 2H), 6.77 (d, J=5.3 Hz, 1H), 3.24-3.28 (m, 2H), 2.97 (q, J=6.7 Hz, 2H), 2.25 (s, 3H), 1.64 (quin, J=7.0 Hz, 2H), 1.35 (s, 9H)
  • LR MS (ES+): 634 (MNa+)
  • LR MS (ES−): 610 (M−H)
    • Example 45
  • Figure US20160355527A1-20161208-C00152
    • N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 10 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 250 mg, 100%.
  • LR MS (ES+): 512 (MNa+)
  • LR MS (ES−): 510 (M−H)
    • Example 46
  • Figure US20160355527A1-20161208-C00153
    • (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid
  • To a stirred suspension of tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate (70 mg, 0.10 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as light yellow solid. Yield: 53 mg, 83%.
  • 1H NMR (DMSO-d6): 12.12 (br. s., 1H), 9.10 (d, J=2.3 Hz, 1H), 8.94-8.98 (m, 2H), 8.59 (d, J=5.6 Hz, 1H), 8.42 (s, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.04 (t, J=5.6 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.40 (dd, J=11.7, 2.6 Hz, 1H), 7.07-7.13 (m, 2H), 6.79-6.81 (m, 1H), 6.77-6.81 (m, 1H), 4.34-4.42 (m, 1H), 3.02-3.13 (m, 2H), 2.29 (td, J=9.4, 6.2 Hz, 2H), 2.25 (s, 3H), 1.97-2.09 (m, 1H), 1.84-1.95 (m, 1H), 1.00 (t, J=7.2 Hz, 3H)
  • LR MS (ES−): 610 (M−H)
    • Example 47
  • Figure US20160355527A1-20161208-C00154
    • tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate
  • To a stirred suspension of (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid (100 mg, 0.16 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of 2M ethylamine solution in THF (0.25 ml, 0.50 mmol). The mixture was heated at 60° C. for another 5 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 73 mg, 70%.
  • 1H NMR (DMSO-d6): 9.10 (d, J=2.3 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H), 8.93 (d, J=7.9 Hz, 1H), 8.58 (d, J=5.6 Hz, 1H), 8.42 (s, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.02 (t, J=5.6 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.11 (ddd, J=9.0, 2.7, 1.2 Hz, 1H), 7.09 (dd, 1H), 6.79 (d, J=5.6 Hz, 1H), 6.78-6.81 (m, 1H), 4.32-4.43 (m, 1H), 3.02-3.14 (m, 2H), 2.26-2.30 (m, 2H), 2.25 (s, 3H), 1.97-2.05 (m, 1H), 1.83-1.92 (m, 1H), 1.36 (s, 9H), 1.00 (t, J=7.2 Hz, 3H)
  • LR MS (ES+): 690 (MNa+)
  • LR MS (ES−): 666 (M−H)
    • Example 48
  • Figure US20160355527A1-20161208-C00155
    • (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid
  • To a stirred solution of 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate (260 mg, 0.40 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 1M HCl was added with stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as off-white solid. Yield: 230 mg, 91%.
  • 1H NMR (DMSO-d6): 12.81 (br. s., 1H), 9.11 (d, J=2.3 Hz, 1H), 9.07 (d, J=7.9 Hz, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.58 (d, J=5.3 Hz, 1H), 8.38 (s, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H), 7.11-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.79 (d, J=5.3 Hz, 1H), 6.78-6.82 (m, 1H), 4.40 (ddd, J=9.8, 7.7, 4.8 Hz, 1H), 2.33-2.37 (m, 2H), 2.25 (s, 3H), 2.04-2.13 (m, 1H), 1.89-2.00 (m, 1H), 1.36 (s, 9H)
  • LR MS (ES−): 639 (M−H)
  • The following Example 49 was prepared using the experiment procedure described in Example 54, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 49
  • Figure US20160355527A1-20161208-C00156
    • 5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate
  • 1H NMR (DMSO-d6): 9.18 (d, J=7.6 Hz, 1H), 9.10 (d, J=2.3 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (dd, J=7.9, 1.8 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H), 7.10-7.13 (m, 1H), 7.09 (dd, J=11.2, 8.2 Hz, 1H), 6.80 (d, J=5.6 Hz, 1H), 6.78-6.81 (m, 1H), 4.48 (ddd, J=9.4, 7.3, 5.3 Hz, 1H), 3.65 (s, 3H), 2.36 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 2.03-2.12 (m, 1H), 1.92-2.01 (m, 1H), 1.37 (s, 9H)
  • LR MS (ES+): 677 (MNa+)
  • LR MS (ES−): 653 (M−H)
    • Example 50
  • Figure US20160355527A1-20161208-C00157
    • 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid
  • To a stirred solution of tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate (40 mg, 0.060 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours, and evaporated to dryness under reduced pressure. 5 ml of water was added to the residue, and the mixture was neutralized to pH=7 with saturated NaHCO3 solution with vigorous stirring. The precipitates were filtered, washed with 5 ml of water, and dried in vacuo to give 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid as light brown solid. Yield: 37 mg, 100%.
  • LR MS (ES+): 610 (MH+)
  • LR MS (ES−): 608 (M−H)
  • The following Example 51 was prepared using the experiment procedure described in Example 42, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 51
  • Figure US20160355527A1-20161208-C00158
    • tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate
  • LR MS (ES+): 688 (MNa+)
  • LR MS (ES−): 664 (M−H)
    • Example 52
  • Figure US20160355527A1-20161208-C00159
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred solution of N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (1.23 g, 2.11 mmol) in 20 ml of tetrahydrofuran was added 2 ml of 2M HCl (4.0 mmol). The mixture was stirred at room temperature for 5 hours and poured into 100 ml of water. 1M NaOH solution was added slowly until pH=7˜8. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 1.07 g, 100%.
  • 1H NMR (DMSO-d6): 9.69 (t, J=1.6 Hz, 1H), 9.10 (d, J=2.3 Hz, 1H), 9.00-9.04 (m, 1H), 8.97 (d, J=2.6 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.20 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.39 (dd, J=11.6, 2.8 Hz, 1H), 7.07-7.13 (m, 2H), 6.78-6.81 (m, 1H), 6.77 (d, J=5.6 Hz, 1H), 3.52-3.60 (m, 2H), 2.73 (td, J=6.7, 1.6 Hz, 2H), 2.25 (s, 3H).
  • LR MS (ES+): 533 (MNa+)
  • LR MS (ES−): 509 (M−H)
    • Example 53
  • Figure US20160355527A1-20161208-C00160
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (1.00 g, 2.20 mmol) in 20 ml of anhydrous THF were added HATU (1.04 g, 2.74 mmol) and N,N-diisopropylethylamine (636 mg, 4.93 mmol). The mixture was heated at 60° C. for 15 minutes, followed by addition of 3-aminopropanol (248 mg, 3.3 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 1.12 g, 100%.
  • 1H NMR (DMSO-d6): 9.10 (s, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.91 (t, J=5.4 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 8.26 (t, J=9.0 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.40 (dd, J=11.4, 2.6 Hz, 1H), 7.06-7.14 (m, 2H), 6.79-6.82 (m, 1H), 6.78 (d, J=5.6 Hz, 1H), 3.46 (t, J=6.2 Hz, 2H), 3.33 (q, J=6.6 Hz, 2H), 2.25 (s, 3H), 1.69 (quin, J=6.7 Hz, 2H)
  • LR MS (ES+): 535 (MNa+)
  • LR MS (ES−): 511 (M−H)
    • Example 54
  • Figure US20160355527A1-20161208-C00161
    • dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate
  • To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (55 mg, 0.26 mmol). The mixture was heated at 60° C. for another 20 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate as white solid. Yield: 126 mg, 94%.
  • 1H NMR (DMSO-d6): 9.21 (d, J=7.3 Hz, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.37 (s, 1H), 8.26 (t, J=9.1 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H), 7.06-7.15 (m, 2H), 6.77-6.82 (m, 2H), 4.48 (ddd, J=9.4, 7.3, 5.3 Hz, 1H), 3.65 (s, 3H), 3.57 (s, 3H), 2.45-2.49 (m, 2H), 2.25 (s, 3H), 2.09-2.18 (m, 1H), 1.97-2.07 (m, 1H)
  • LR MS (ES+): 635 (MNa+)
  • LR MS (ES−): 611 (M−H)
  • The following Example 55 was prepared using the experiment procedure described in Example 34, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation.
    • Example 55
  • Figure US20160355527A1-20161208-C00162
    • 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-morpholin-4-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (DMSO-d6): 9.12 (d, J=1.8 Hz, 1H), 8.98 (d, J=2.3 Hz, 1H), 8.93 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.25 (t, J=9.1 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=7.9, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.6 Hz, 1H), 7.06-7.13 (m, 2H), 6.78-6.82 (m, 1H), 6.77 (d, J=5.3 Hz, 1H), 3.54 (t, J=4.5 Hz, 4H), 3.31 (q, J=6.75 Hz, 2H), 2.29-2.37 (m, 6H), 2.25 (s, 3H), 1.69 (quin, J=7.0 Hz, 2H)
  • LR MS (ES+): 582 (MH+)
  • LR MS (ES−): 580 (M−H)
    • Example 56
  • Figure US20160355527A1-20161208-C00163
    • ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate
  • To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in 10 ml of anhydrous THF were added HATU (122 mg, 0.32 mmol) and N,N-diisopropylethylamine (104 mg, 0.81 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 99%.
  • 1H NMR (DMSO-d6): 9.19 (s, 1H), 8.92 (t, J=5.7 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.21 (s, 1H), 7.94-7.98 (m, 1H), 7.53-7.58 (m, 2H), 7.20-7.25 (m, 2H), 7.08 (dd, J=11.3, 8.4 Hz, 1H), 6.76-6.81 (m, 1H), 6.69 (d, J=5.6 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H), 3.28-3.32 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 1.79 (quin, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H)
  • LR MS (ES+): 573 (MNa+)
  • LR MS (ES−): 549 (M−H)
    • Example 57
  • Figure US20160355527A1-20161208-C00164
    • ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate
  • To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.26 mmol) in 10 ml of anhydrous THF were added HATU (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl)}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 100%.
  • 1H NMR (DMSO-d6): 9.10 (d, 1H), 8.96 (d, J=2.6 Hz, 1H), 8.93 (t, J=5.7 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.22 (s, 1H), 7.98 (dd, J=8.2, 2.1 Hz, 1H), 7.39 (dd, J=11.7, 2.9 Hz, 1H), 7.10-7.13 (m, 1H), 7.09 (dd, J=11.2, 8.2 Hz, 1H), 6.78-6.81 (m, 1H), 6.78 (d, J=5.6 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.27-3.32 (m, 2H), 2.36 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.79 (quin, J=7.2 Hz, 2H), 1.15 (t, J=7.2 Hz, 3H)
  • LR MS (ES+): 591 (MNa+)
  • LR MS (ES−): 567 (M−H)
    • Example 58
  • Figure US20160355527A1-20161208-C00165
    • N-[dimethyl(oxido)-lambda˜4˜sulfanylidene]-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-carboxamide Example 59
  • Figure US20160355527A1-20161208-C00166
    • 4-[N-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoic acid Example 60
  • Figure US20160355527A1-20161208-C00167
    • 4-[N-({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)-S-methylsulfonimidoyl]butanoic acid Example 61
  • Figure US20160355527A1-20161208-C00168
    • N-[dimethyl(oxido)-lambda˜4˜-sulfanylidene]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide Example 62
  • Figure US20160355527A1-20161208-C00169
    • [({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]acetic acid Example 63
  • Figure US20160355527A1-20161208-C00170
    • [({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]acetic acid Example 64
  • Figure US20160355527A1-20161208-C00171
    • 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid
  • To a stirred solution of ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.19 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 2 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 95 mg, 90%.
  • 1H NMR (DMSO-d6): 12.07 (br. s., 1H), 9.11 (d, J=2.3 Hz, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.94 (t, J=5.6 Hz, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.26 (t, J=9.1 Hz, 1H), 8.23 (s, 1H), 7.98 (dd, J=7.9, 2.3 Hz, 1H), 7.40 (dd, J=11.6, 2.8 Hz, 1H), 7.11-7.13 (m, 1H), 7.09 (dd, J=11.3, 8.4 Hz, 1H), 6.79-6.81 (m, 1H), 6.78 (d, J=5.3 Hz, 1H), 3.26-3.33 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.77 (quin, J=7.1 Hz, 2H)
  • LR MS (ES+): 541 (MH+)
  • LR MS (ES−): 539 (M−H)
    • Example 65
  • Figure US20160355527A1-20161208-C00172
    • 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid
  • To a stirred solution of ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.20 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 100 mg, 96%.
  • 1H NMR (DMSO-d6): 12.06 (s, 1H), 9.19 (s, 1H), 8.91 (t, J=5.7 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.47 (d, J=2.9 Hz, 1H), 8.21 (s, 1H), 7.96 (dd, J=7.9, 2.3 Hz, 1H), 7.54-7.58 (m, 2H), 7.20-7.24 (m, 2H), 7.08 (dd, J=11.3, 8.4 Hz, 1H), 6.76-6.81 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 3.27-3.31 (m, 2H), 2.29 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.76 (quin, J=7.2 Hz, 2H)
  • LR MS (ES+): 545 (MNa+)
  • LR MS (ES−): 521 (M−H)
    • Example 66
  • Figure US20160355527A1-20161208-C00173
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred, cooled (0° C.) solution of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in anhydrous DMF (10 ml) were added PyBOP (156 mg, 0.30 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of N-(3-aminopropyl)piperidine (58 mg, 0.41 mmol). Stirring was continued at 0° C. for another 30 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide as beige solid. Yield: 151 mg, 98%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 9.21 (s, 1H) 8.94 (t, J=5.58 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.22 (s, 1H) 7.98 (dd, J=7.63, 2.05 Hz, 1H) 7.57-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.80-6.83 (m, 1H) 6.71 (d, J=5.28 Hz, 1H) 3.30-3.35 (m, 2H) 2.31 (br. s., 6H) 2.28 (s, 3H) 1.69-1.75 (m, 2H) 1.47-1.52 (m, 4H) 1.38 (br. s., 2H)
  • LR MS (ES+): 584 (M+Na+)
  • LR MS (ES−): 560 (M−H)
    • Example 67
  • Figure US20160355527A1-20161208-C00174
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide
  • The above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 9.47 (s, 1H) 8.97 (t, J=5.58 Hz, 1H) 8.62 (d, J=2.35 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.24 (s, 1H) 7.97 (dd, J=7.78, 1.91 Hz, 1H) 7.58-7.61 (m, 2H) 7.23-7.26 (m, 2H) 7.10 (dd, J=11.30, 8.36 Hz, 1H) 6.79-6.82 (m, 1H) 6.71 (d, J=5.28 Hz, 1H) 3.32-3.34 (m, 2H) 2.34-2.47 (m, 10H) 2.27 (s, 3H) 2.21 (s, 3H) 1.72 (quin, J=6.97 Hz, 2H).
  • LR MS (ES+): 577 (MH+)
    • Example 68
  • Figure US20160355527A1-20161208-C00175
    • 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide
  • The above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 9.23 (s, 1H) 8.99 (t, J=5.27 Hz, 1H) 8.57 (d, J=5.27 Hz, 1H) 8.51 (d, J=2.05 Hz, 1H) 8.21 (s, 1H) 7.98 (dd, J=7.77, 1.90 Hz, 1H) 7.55-7.61 (m, 2H) 7.22-7.28 (m, 2H) 7.11 (dd, J=11.43, 8.20 Hz, 1H) 6.78-6.85 (m, 1H) 6.72 (d, J=5.27 Hz, 1H) 3.32-3.39 (m, 2H) 2.56 (br. s., 6H) 2.28 (s, 3H) 1.76 (m, J=8.79 Hz, 6H)
  • LR MS (ES+): 548 (MH+)
  • LR MS (ES−): 546 (M−H)
    • Example 69
  • Figure US20160355527A1-20161208-C00176
    • N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • The above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 9.21 (s, 1H) 8.88 (t, J=5.13 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.21 (s, 1H) 7.98 (dd, J=7.92, 2.05 Hz, 1H) 7.56-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.79-6.82 (m, 1H) 6.71 (d, J=5.28 Hz, 1H) 3.33-3.37 (m, 2H) 2.58 (t, J=7.04 Hz, 2H) 2.50-2.54 (m, 4H) 2.27 (s, 3H) 0.97 (t, J=7.04 Hz, 6H)
  • LR MS (ES+): 536 (MH+)
  • LR MS (ES−): 534 (M−H)
    • Example 70
  • Figure US20160355527A1-20161208-C00177
    • N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide
  • The above compound was prepared using procedures similar to that used to prepare the compound of Example 66 above.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 9.25 (s, 1H) 8.96 (br. s., 1H) 8.57 (d, J=5.28 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H) 8.21 (s, 1H) 7.98 (dd, J=7.48, 1.91 Hz, 1H) 7.57-7.61 (m, 2H) 7.23-7.26 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.80-6.83 (m, 1H) 6.72 (d, J=5.28 Hz, 1H) 3.32-3.35 (m, 2H) 2.38-2.49 (m, 6H) 2.28 (s, 3H) 1.70 (br. s., 2H) 0.97 (br. s., 6H)
  • LR MS (ES+): 550 (MH+)
  • LR MS (ES−): 548 (M−H)
    • Example 71
  • Figure US20160355527A1-20161208-C00178
    • Methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate
  • Step 1: A mixture of methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (500 mg, 2.20 mmol), 3-aminophenol (330 mg, 3.0 mmol), ethyl 2-cyclohexanonecarboxylate (73 mg, 0.43 mmol), copper(I) chloride (22 mg, 0.22 mmol) and cesium carbonate (1.48 g, 4.55 mmol) in 20 ml of anhydrous DMSO was placed in a 50 ml pressure tube, flushed with nitrogen, sealed and heated at 70° C. for 3 hours. The mixture was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate as brown solid. Yield: 330 mg.
  • Step 2: To a stirred solution of 3-methyl-2-furoic acid (166 mg, 1.32 mmol) in anhydrous DMF (10 ml) were added HATU (552 mg, 1.45 mmol) and DIPEA (341 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes, and 330 mg of crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate from step 1 was added. The mixture was then heated at 65° C. for 2 hours, cooled to room temperature, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of MeOH in chloroform to afford methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as off-white solid. Yield: 230 mg, 26% for 2 steps.
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1H) 8.67 (d, J=5.27 Hz, 1H) 8.25 (s, 1H) 7.82 (t, J=2.05 Hz, 1H) 7.80 (dd, J=1.76, 0.59 Hz, 1H) 7.76 (ddd, J=8.21, 2.05, 0.88 Hz, 1H) 7.48 (t, J=8.06 Hz, 1H) 7.05 (ddd, J=8.06, 2.49, 0.88 Hz, 1H) 6.90 (d, J=5.27 Hz, 1H) 6.60 (d, J=2.05 Hz, 1H) 3.93 (s, 3H) 2.32 (s, 3H)
  • LR MS (ES+): 431 (M+Na+)
  • LR MS (ES−): 407 (M−H)
    • Example 72
  • Figure US20160355527A1-20161208-C00179
    • 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid
  • To a stirred solution of methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate (180 mg, 0.44 mmol) in MeOH (10 ml) was added 1M NaOH (1.5 ml, 1.5 mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates was filtered, washed with water and dried to give 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid as off-white solid. Yield: 160 mg, ˜92%.
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 10.26 (s, 1H) 8.65 (d, J=5.27 Hz, 1H) 8.14 (s, 1H) 7.81 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.47 Hz, 1H) 7.76 (ddd, J=8.21, 2.05, 0.88 Hz, 1H) 7.47 (t, J=8.20 Hz, 1H) 7.04 (ddd, J=8.21, 2.34, 0.88 Hz, 1H) 6.87 (d, J=5.57 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 2.32 (s, 3H).
    • Example 73
  • Figure US20160355527A1-20161208-C00180
    • N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred, cooled (0° C.) solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added PyBOP (171 mg, 0.33 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of 2M ethylamine solution in THF (0.18 ml, 0.36 mmol). Stirring was continued at 0° C. for another 40 minutes. The mixture was poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried to give N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide as light yellow solid. Yield: 115 mg, 90%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.25 (s, 1H) 8.94 (t, J=5.43 Hz, 1H) 8.60 (d, J=5.28 Hz, 1H) 8.24 (s, 1H) 7.79-7.80 (m, 2H) 7.75 (ddd, J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14, 2.42, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (dd, J=1.76, 0.59 Hz, 1H) 3.32-3.36 (m, 2H) 2.32 (s, 3H) 1.17 (t, J=7.34 Hz, 3H)
  • LR MS (ES+): 444 (M+Na+)
  • LR MS (ES−): 420 (M−H)
  • The compounds of Examples 74-78 below were prepared using procedures similar to those of Example 73.
    • Example 74
  • Figure US20160355527A1-20161208-C00181
    • N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.26 (s, 1H) 8.61 (d, J=5.58 Hz, 1H) 7.81 (t, J=2.20 Hz, 1H) 7.79-7.80 (m, 2H) 7.75 (ddd, J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.03 (ddd, J=8.07, 2.49, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 3.51 (br. s., 4H) 2.32 (s, 3H) 1.20 (br. s., 6H)
  • LR MS (ES+): 472 (M+Na+)
  • LR MS (ES−): 448 (M−H)
    • Example 75
  • Figure US20160355527A1-20161208-C00182
    • N-hydroxy-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 11.70 (s, 1H) 10.26 (s, 1H) 9.45 (s, 1H) 8.60 (d, J=5.28 Hz, 1H) 8.09 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd, J=8.29, 1.98, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.07, 2.49, 0.88 Hz, 1H) 6.82 (d, J=5.58 Hz, 1H) 6.59 (dd, J=1.76, 0.59 Hz, 1H) 2.32 (s, 3H)
  • LR MS (ES+): 431 (M+Na+)
  • LR MS (ES−): 408 (M−H)
    • Example 76
  • Figure US20160355527A1-20161208-C00183
    • N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.25 (s, 1H) 8.92 (t, J=5.58 Hz, 1H) 8.60 (d, J=5.28 Hz, 1H) 8.25 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd, J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14, 2.42, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.76 Hz, 1H) 4.50 (t, J=5.28 Hz, 1H) 3.46-3.51 (m, 2H) 3.33-3.38 (m, 2H) 2.32 (s, 3H) 1.68-1.76 (m, 2H)
  • LR MS (ES+): 474 (M+Na+)
  • LR MS (ES−): 450 (M−H)
    • Example 77
  • Figure US20160355527A1-20161208-C00184
    • N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.25 (s, 1H) 8.97 (t, J=5.72 Hz, 1H) 8.60 (d, J=5.28 Hz, 1H) 8.28 (s, 1H) 7.79-7.81 (m, 2H) 7.75 (ddd, J=8.22, 2.05, 0.88 Hz, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.22, 2.35, 0.88 Hz, 1H) 6.82 (d, J=5.28 Hz, 1H) 6.59 (d, J=1.47 Hz, 1H) 4.81 (t, J=5.58 Hz, 1H) 3.55 (q, J=5.97 Hz, 2H) 3.37 (q, J=6.06 Hz, 2H) 2.32 (s, 3H)
  • LR MS (ES+): 460 (M+Na+)
  • LR MS (ES−): 436 (M−H)
    • Example 78
  • Figure US20160355527A1-20161208-C00185
    • 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 10.25 (s, 1H) 9.13 (t, J=5.57 Hz, 1H) 8.61 (d, J=5.57 Hz, 1H) 8.20 (s, 1H) 7.78-7.81 (m, 2H) 7.75 (d, J=8.20 Hz, 1H) 7.46 (t, J=8.06 Hz, 1H) 7.02 (ddd, J=8.13, 2.42, 0.88 Hz, 1H) 6.83 (d, J=5.27 Hz, 1H) 6.59 (d, J=1.47 Hz, 1H) 3.63-3.70 (m, 2H) 3.17 (t, J=7.03 Hz, 2H) 2.32 (s, 3H)
  • LR MS (ES+): 490 (MH+)
  • LR MS (ES−): 488 (M−H)
    • Example 79
  • Figure US20160355527A1-20161208-C00186
    • 3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate
  • To a stirred solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added 3-bromo-1-propanol (63 mg, 0.45 mmol) and potassium carbonate (83 mg, 0.60 mmol). The mixture was heated at 50° C. for 5 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give 3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as white solid. Yield: 25 mg, 18%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.27 (s, 1H) 8.67 (d, J=5.28 Hz, 1H) 8.24 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.47 Hz, 1H) 7.76 (dt, J=9.24, 0.95 Hz, 1H) 7.48 (t, J=8.22 Hz, 1H) 7.04 (ddd, J=8.07, 2.49, 0.88 Hz, 1H) 6.89 (d, J=5.28 Hz, 1H) 6.60 (d, J=1.47 Hz, 1H) 4.61 (t, J=5.14 Hz, 1H) 4.42 (t, J=6.60 Hz, 2H) 3.55-3.59 (m, 2H) 2.32 (s, 3H) 1.88 (quin, J=6.31 Hz, 2H)
  • LR MS (ES+): 475 (M+Na+)
  • LR MS (ES−): 451 (M−H)
  • The compounds of Examples 80-81 below were prepared using procedures similar to those of Example 79.
    • Example 80
  • Figure US20160355527A1-20161208-C00187
    • 2-hydroxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.27 (s, 1H) 8.68 (d, J=5.58 Hz, 1H) 8.29 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.17 Hz, 1H) 7.76 (ddd, J=8.36, 1.91, 0.88 Hz, 1H) 7.48 (t, J=8.22 Hz, 1H) 7.05 (ddd, J=8.22, 2.35, 0.88 Hz, 1H) 6.89 (d, J=5.58 Hz, 1H) 6.59-6.60 (m, 1H) 4.99 (t, J=5.72 Hz, 1H) 4.36 (dd, J=5.43, 4.55 Hz, 2H) 3.71-3.75 (m, 2H) 2.32 (s, 3H)
  • LR MS (ES+): 461 (M+Na+)
  • LR MS (ES−): 437 (M−H)
    • Example 81
  • Figure US20160355527A1-20161208-C00188
    • 2-methoxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1H) 8.68 (d, J=5.27 Hz, 1H) 8.24 (s, 1H) 7.82 (t, J=2.20 Hz, 1H) 7.80 (d, J=1.17 Hz, 1H) 7.76 (ddd, J=8.20, 2.05, 0.88 Hz, 1H) 7.47 (t, J=8.20 Hz, 1H) 7.05 (ddd, J=8.13, 2.42, 0.88 Hz, 1H) 6.90 (d, J=5.27 Hz, 1H) 6.60 (d, J=1.47 Hz, 1H) 4.46-4.50 (m, 2H) 3.66-3.71 (m, 2H) 3.33 (s, 3H) 2.32 (s, 3H)
  • LR MS (ES+): 453 (MH+)
  • LR MS (ES−): 451 (M−H)
    • Example 82
  • Figure US20160355527A1-20161208-C00189
    • Methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate
  • To a stirred, cooled (0° C.) solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (150 mg, 0.38 mmol) in anhydrous DMF (10 ml) were added PyBOP (218 mg, 0.42 mmol) and N,N-diisopropylethylamine (245 mg, 1.9 mmol). The mixture was stirred at 0° C. for 10 minutes, followed by addition of methyl [(3-aminopropyl)amino]acetate dihydrochloride (100 mg, 0.46 mmol). Stirring was continued at 0° C. for another 40 minutes. The mixture was diluted with ethyl acetate (100 ml), washed with brine (4×100 ml), dried over Na2SO4, and concentrated to give the crude, which was purified by silica gel chromatography eluting with 5-8% methanol in chloroform to give methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate as light beige solid. Yield: 98 mg, 49%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.25 (s, 1H) 8.95 (t, J=5.58 Hz, 1H) 8.60 (d, J=5.58 Hz, 1H) 8.23 (s, 1H) 7.79-7.80 (m, 2H) 7.73-7.76 (m, 1H) 7.46 (t, J=8.22 Hz, 1H) 7.02 (ddd, J=8.14, 2.42, 0.88 Hz, 1H) 6.82 (d, J=5.58 Hz, 1H) 6.59 (d, J=1.17 Hz, 1H) 3.62 (s, 3H) 3.32-3.36 (m, 4H) 2.58 (t, J=6.75 Hz, 2H) 2.32 (s, 3H) 2.05 (br. s., 1H) 1.68 (quin, J=6.90 Hz, 2H)
  • LR MS (ES+): 545 (M+Na+)
  • LR MS (ES−): 521 (M−H)
    • Example 82A
  • Figure US20160355527A1-20161208-C00190
    • N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide
  • Step 1: To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38 mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) and DIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657 mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled to room temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl (200 ml). The organic phase was washed with 0.5M HCl (2×50 ml), saturated NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4, and evaporated to dryness to afford 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide as light brown solid. Yield: 1.5 g, 100%.
  • Step 2: A solution of 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide (1.5 g, 4.48 mmol from Step 1) in 20 ml of MeOH containing 10% Pd/C (150 mg) was stirred under a hydrogen balloon at room temperature for 2 hours. The catalyst was removed by filtration. The filtrate solution was evaporated to dryness under reduced pressure to give N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide as light-beige solid. Yield: 1.1 g, 100%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 9.92 (s, 1H) 9.75 (br. s., 1H) 7.37-7.40 (m, 2H) 7.33 (t, J=2.05 Hz, 1H) 7.31 (t, J=7.78 Hz, 1H) 7.15 (dd, J=10.56, 8.51 Hz, 1H) 7.03-7.07 (m, 1H) 6.96-6.99 (m, 1H) 2.30 (s, 3H)
  • LR MS (ES+): 268 (M+Na+)
  • LR MS (ES−): 244 (M−H)
    • Example 83
  • Figure US20160355527A1-20161208-C00191
    • Methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate
  • A mixture of N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide (270 mg, 1.1 mmol), methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (300 mg, 1.3 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in 10 ml of anhydrous DMSO was heated at 68° C. for 16 hours, cooled to room temperature and partitioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with more EtOAc (2×50 ml). All the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to dryness to give the crude, which was purified by silica gel chromatography eluted with 1˜2% of MeOH in CHCl3 to give methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as light brown oil. Yield: 170 mg, 37%.
    • Example 84
  • Figure US20160355527A1-20161208-C00192
    • 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid
  • To a stirred solution of methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (170 mg, 0.39 mmol) in 15 ml of MeOH was added 1 ml of 1M NaOH. Reaction was complete within 2.5 hours. The mixture was poured into 100 ml of water and acidified with 2M HCl to pH=5 with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid as white solid. Yield: 150 mg, 91%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 13.96 (br. s., 1H) 10.15 (s, 1H) 8.66 (d, J=4.40 Hz, 1H) 8.15 (s, 1H) 7.97 (d, J=7.92 Hz, 1H) 7.90 (s, 1H) 7.70 (t, J=7.92 Hz, 1H) 7.60 (dd, J=8.07, 1.61 Hz, 1H) 7.38 (dd, J=7.34, 1.76 Hz, 1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H) 7.04-7.09 (m, 1H) 6.87 (d, J=5.28 Hz, 1H) 2.29 (s, 3H)
  • LR MS (ES+): 423 (MH+)
  • LR MS (ES−): 421 (M−H)
    • Example 85
  • Figure US20160355527A1-20161208-C00193
    • N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide
  • To a stirred, cooled (0° C.) solution of 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.28 mmol) in anhydrous DMF (10 ml) were added PyBOP (161 mg, 0.31 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of 2M ethylamine solution in THF (0.2 ml, 0.4 mmol). Stirring was continued at 0° C. for another 30 minutes. The mixture was poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried to give N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 112 mg, 88%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.15 (s, 1H) 8.96 (t, J=5.58 Hz, 1H) 8.62 (d, J=5.58 Hz, 1H) 8.26 (s, 1H) 7.96 (dd, J=7.78, 1.03 Hz, 1H) 7.87-7.89 (m, 1H) 7.69 (t, J=7.92 Hz, 1H) 7.58 (ddd, J=8.14, 2.57, 1.03 Hz, 1H) 7.38 (dd, J=7.34, 1.76 Hz, 1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H) 7.05-7.09 (m, 1H) 6.83 (d, J=5.58 Hz, 1H) 3.34 (qd, J=7.24, 5.58 Hz, 2H) 2.29 (s, 3H) 1.17 (t, J=7.34 Hz, 3H)
  • LR MS (ES+): 472 (M+Na+)
  • LR MS (ES−): 448 (M−H)
  • The compound of Examples 86 below was prepared using procedures similar to those used to prepare the compound of Example 85.
    • Example 86
  • Figure US20160355527A1-20161208-C00194
    • N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.15 (s, 1H) 8.62 (d, J=5.28 Hz, 1H) 7.97 (d, J=7.92 Hz, 1H) 7.89-7.90 (m, 1H) 7.82 (s, 1H) 7.69 (t, J=7.92 Hz, 1H) 7.58 (ddd, J=8.07, 2.49, 1.17 Hz, 1H) 7.38 (dd, J=7.19, 1.91 Hz, 1H) 7.16 (dd, J=10.42, 8.36 Hz, 1H) 7.07 (td, J=5.21, 2.49 Hz, 1H) 6.83 (d, J=5.58 Hz, 1H) 3.52 (br. s., 4H) 2.29 (s, 3H) 1.21 (br. s., 6H)
  • LR MS (ES+): 500 (M+Na+)
  • LR MS (ES−): 476 (M−H)
    • Example 87
  • Figure US20160355527A1-20161208-C00195
    • Methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate
  • To a stirred, cooled (0° C.) solution of 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid (80 mg, 0.19 mmol) in anhydrous DMF (10 ml) were added PyBOP (109 mg, 0.21 mmol) and N,N-diisopropylethylamine (123 mg, 0.95 mmol). The mixture was stirred at 0° C. for 10 minutes, followed by addition of methyl [(3-aminopropyl)amino]acetate dihydrochloride (50 mg, 0.23 mmol). Stirring was continued at 0° C. for 10 minutes then room temperature for 2 hours. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 5-8% methanol in chloroform to give methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate as light beige solid. Yield: 40 mg, 38%.
  • 1H NMR (600 MHz, DMSO-d6) δ ppm 10.15 (s, 1H) 8.97 (t, J=5.58 Hz, 1H) 8.62 (d, J=5.28 Hz, 1H) 8.25 (s, 1H) 7.96 (dt, J=7.70, 1.28 Hz, 1H) 7.87-7.89 (m, 1H) 7.69 (t, J=7.92 Hz, 1H) 7.58 (ddd, J=8.14, 2.42, 0.88 Hz, 1H) 7.38 (dd, J=7.19, 1.91 Hz, 1H) 7.16 (dd, J=10.56, 8.51 Hz, 1H) 7.05-7.08 (m, 1H) 6.83 (d, J=5.28 Hz, 1H) 3.62 (s, 3H) 3.34-3.37 (m, 4H) 2.59 (t, J=6.90 Hz, 2H) 2.29 (s, 3H) 1.68 (quin, J=6.97 Hz, 2H)
  • LR MS (ES+): 551 (MH+)
    • 4. Biological Testing
  • Biological data for the compounds of the present invention was generated by the use of one or more of the following assays.
    • VEGF Stimulated Ca.Sup.++ Signal In Vitro
  • Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of VEGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. HUVEC (human umbilical vein endothelial cells) (Clonetics) were seeded in 96-well fibronectin coated black-walled plates overnight at 37.degree. C./5% CO.sub.2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37.degree. C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye. Test compounds were reconstituted in 100% DMSO and added to the cells to give a final DMSO concentration of 0.1%. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 .mu.M) or at concentrations ranging from 0.01 to 10.0 .mu.M followed by VEGF stimulation (5 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC.sub.50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
    • VEGFR2 Kinase Assay
  • The cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an His engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30 .mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120 .mu.L reaction volumes containing 3.6 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20.100 .mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes. Following four washes with PBS-Tween-20, 100 .mu.l of O-phenylenediamine Dihydrochloride in Phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100 .mu.l of 2.5N H.sub.2 SO.sub.4 to each well and read using a microplate ELISA reader set at 492 nm. IC.sub.50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
    • VEGF-Induced Dermal Extravasation in Guinea Pig (Miles Assay)
  • Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane, sheared, and given a single dose of drug or the respective vehicle. The guinea pigs were dosed orally unless indicated otherwise in Table 3. Ten minutes prior to the end of drug treatment, guinea pigs were anesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS (13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes, triplicate intradermal injections of 100 ng rhVEGF.sub.165 in 100 .mu.l PBS and of 100 .mu.l PBS alone were administered on the flank. After 20 minutes, each animal was cuthanized with Pentosol, and the skin containing the intradermal injection sites was removed for image analysis. Using an analog video camera coupled to a PC, an image of each trans-illuminated skin sample was captured, and the integrated optical density of each injection site was measured using ImagePro 4. For each skin sample, the difference between the mean optical density of the VEGF sites and mean optical density of the PBS sites is the measure of VEGF-induced EBD extravasation in that animal. These measured values were averaged per study group to determine the mean VEGF-induced EBD extravasation for each experimental condition, and the group means were then compared to assess inhibition of VEGF-induced EBD extravasation in the drug-treated groups relative to the vehicle-treated controls. To determine the dose required for 50% inhibition (ID.sub.50), the percent inhibition data was plotted as a function of oral dose, using the ‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose).
    • Laser-Induced Choroidal Neovascularization (CNV) in Rat (CNV Assay)
  • CNV was induced and quantified in this model as previously described (Edelman and Castro. Exp. Eye Res. 2000; 71:523-533). On day 0, male Brown Norway rats (200-300 g) were anesthetized with 100 mg/kg Ketamine and 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide. Using the blue-green setting of a Coherent Novus Argon Laser, 3 laser bums (90 mW for 0.1 s; 100 .mu.m diameter) were given to each eye between the retinal vessels around the optic nerve head. Rats were dosed with test compounds in their indicated vehicles orally once daily.
  • On day 10, rats were sacrificed with 100% CO.sub.2, and blood vessels were labeled by vascular perfusion with 10 mg/ml FITC-dextran (MW 2.times. 10.sup.6). Using an epifluorescence microscope (20.times.) coupled to a spot digital camera and a PC, images were obtained from the flat mounts of the RPE-choroid-sclera from each eye, and the area occupied by hyperfluorescent neovessels within each laser lesion was measured using ImagePro 4 software.
  • To determine the dose required for 50% inhibition (ID.sub.50), the percent inhibition data was plotted as a function of oral dose, using the ‘best-fit’ analysis within MicroSoft Excel software. The ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose).
    • Rabbit Eye VEGF Permeability Model
  • Assay used was detailed by Jeffrey Edelman, etc in Exp. Eye. Res. 80(2005), Pg 249-258.
    • PDGF Stimulated Ca2+ Signal in Vitro
  • Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of PDGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad (Normal human dermal fibroblasts) (Lonza) were seeded in 384-well fibronectin coated black-walled plates overnight at 37° C./5% CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cells were washed 4 times (ELx405-CW, Bio-Tek) to remove extracellular dye. Test compounds were reconstituted in 100% DMSO and added to the cells to give a final DMSO concentration of 0.1%. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 μM) or at concentrations ranging from 0.001 nM to 10 μM followed by PDGF stimulation (10 ng/mL). Changes in fluorescence at 515 nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC50 values for test compounds were calculated from % inhibition of PDGF stimulated responses in the absence of inhibitor.
  • TABLE II
    Biological Activities of Compounds of the Present Invention
    In Vivo
    Cellular Enzymic Enzymic Rabbit Eye
    VEGFR2 VEGFR2 VEGFR1 VEGF
    Compound IC50 (nM) IC50 (nM) IC50 (nM) Permeability
    F1  2 18
    F2 29 20 16 efficacious
    F3 35 21
    F4  104  104
    F5  104  104
    F6 11
    F7 10
    F8 11
    In Vivo
    Cellular Enzymic Enzymic Enzymic Rabbit Eye
    VEGFR2 VEGFR2 VEGFR1 PDGFRβ VEGF
    Example IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) Permeability
    12 126 3 4 20
    13 97 6 10 19
    14 34 4 5 13
    15 39 3 3 10
    16 7 10 15
    17 4 10 15
    18 0.8 3 6 11 Efficacious
    19 0.3 4 9 14
    23 9 7 13 14
    24 14 10 9 14
    25 5 8 11
    26 5 10 12
    27 16 11 17
    28 5 8 17
    29 5 10 13
    30 7 112 17
    31 9 9 13
    32 4 11 15
    33 24 60 69
    34 3 6 11
    36 7 8
    37 1 7 9
    38 14 7 8
    39 2 5 8
    42 4 6
    43 6 3
    44 16 11
    45 10 7
    46 328 19 Efficacious
    48 7
    50 80 16 18
    53 12
    54 4 34
    55 7 11 7 Efficacious
    56 20 16
    57 1 14 15
    58 3
    61 2
    64 13 7
    65 2 12 7
    66 16 4 16
    67 2 2 9
    68 20 6 16
    69 11 4 5 13
    70 9 3 3 12
    71 24 169
    72 162 39 920
    73 9 191
    74 27 424
    75 16 11 277
    76 11 146
    77 17 392
    78 14 323
    79 9 146
    80 17 212
    81 19 273
    82 11 238
    84 87 20 223
    85 16 10 74
    86 64 7 206
    87 9 16 59

Claims (7)

1.-10. (canceled)
11. A compound of Formula I:
Figure US20160355527A1-20161208-C00196
or a pharmaceutically acceptable salt thereof, wherein:
Y is O;
the A ring is selected from the group consisting of phenyl and fluorophenyl;
Z is selected from the group consisting of
Figure US20160355527A1-20161208-C00197
the B ring is selected from the group consisting of
Figure US20160355527A1-20161208-C00198
and
R is selected from the group consisting of
Figure US20160355527A1-20161208-C00199
Figure US20160355527A1-20161208-C00200
Figure US20160355527A1-20161208-C00201
Figure US20160355527A1-20161208-C00202
12. The compound of claim 1, wherein the compound is selected from the group consisting of:
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;
ethyl (4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;
methyl rel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;
dimethyl 2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;
N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;
N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;
ethyl 4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1-carboxylate;
ethyl 4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate;
methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate;
dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;
dimethyl 2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate;
methyl 1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate;
ethyl (4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin-1-yl)acetate;
ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate;
methyl ({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate;
N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;
N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;
methyl (2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;
N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide;
methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;
tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;
N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate;
(2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid;
5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;
1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid;
tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;
7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide;
dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;
ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;
ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;
7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;
N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;
Methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;
7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid;
N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;
N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;
N-hydroxy-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;
N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;
N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;
7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;
3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;
2-hydroxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;
2-methoxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;
Methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate;
Methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate;
7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid;
N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide;
N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide; and
Methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a therapeutic effective amount of at least one compound of claim 11, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
14. The composition of claim 13, wherein the composition is in the form of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic bioerodible implant, and non-bioerodible ophthalmic inserts and depots.
15. A pharmaceutical composition comprising a therapeutic effective amount of at least one compound of claim 12, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
16. The composition of claim 15, wherein the composition is in the form of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic bioerodible implant, and non-bioerodible ophthalmic inserts and depots.
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