WO2008061236A2 - Sulfoximines as kinase inhibitors - Google Patents

Sulfoximines as kinase inhibitors Download PDF

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Publication number
WO2008061236A2
WO2008061236A2 PCT/US2007/084999 US2007084999W WO2008061236A2 WO 2008061236 A2 WO2008061236 A2 WO 2008061236A2 US 2007084999 W US2007084999 W US 2007084999W WO 2008061236 A2 WO2008061236 A2 WO 2008061236A2
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Prior art keywords
phenyl
methyl
sulfanylidene
ethynyl
nicotinamide
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PCT/US2007/084999
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French (fr)
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WO2008061236A3 (en
Inventor
Julie A. Wurster
Eugene C. Hull, Iii
Richard D. Yee
Sougato Boral
Thomas C. Malone
Shimiao Wang
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Allergan, Inc.
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Priority to JP2009537394A priority Critical patent/JP2010510242A/en
Priority to AU2007319151A priority patent/AU2007319151B2/en
Priority to EP07864544.7A priority patent/EP2099757B1/en
Priority to BRPI0718895-1A priority patent/BRPI0718895A2/en
Priority to CA002669704A priority patent/CA2669704A1/en
Publication of WO2008061236A2 publication Critical patent/WO2008061236A2/en
Publication of WO2008061236A3 publication Critical patent/WO2008061236A3/en
Priority to HK10102636.4A priority patent/HK1134674A1/en

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Definitions

  • the present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • the present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or nonreceptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
  • PTKs Protein tyrosine kinases
  • receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (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 receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • RTKs receptor tyrosine kinases
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • 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 (19) 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.
  • a second family of RTKs designated the insulin subfamily, is comprised of the INS-R, the IGF-IR and the IR-R.
  • a third family, the "PDGF" subfamily 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 (flt-1). Each of these receptors was initially believed to be receptors for hematopoietic growth factors.
  • Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl , FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).
  • 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 (11) subfamilies (Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified.
  • the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, BIk, 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.
  • the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
  • the compounds of the present invention have the following general formula I:
  • R 1 is selected from the group consisting of hydrogen, alkyl, halogen, OR 4 , CN, NO 2 , COR 4 ,
  • R 2 is selected from the group consisting of hydrogen, halogen, alkyl, OR 4 , CN, NO 2 ,
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, OR 4 , CN, NO 2 , SO 2 N(R 4 ) 2 , COR 4 , (CH 2 ) a OR 4 , (CH 2 ) a N(R 4 ) 2 , C(O)N(R 4 ) 2 , N(R 4 ) 2 and N(R 6 )(CR 7 R 8 ) a R 10 ;
  • R 4 is hydrogen or Ci to C 4 alkyl;
  • E' is selected from the group consisting of alkyl, CF 3 ,
  • R 7 R 8 a C(O)OR 10 , (CR 7 R 8 ) a C(O)N(R 10 ) 2 , (CR 7 R 8 ) a C(O)N(OR 10 )(R 10 ), (CR 7 R 8 ) a (OR 10 ), (CR 7 R 8 ) a N(R 10 ) 2 , and (CR 7 R 8 ) a R 10 ; wherein R 7 and R 8 are selected from the group consisting of H, halogen, hydroxyl, and alkyl or CR 7 R 8 may represent a carbocyclic ring of from 3 to 6 carbons; and
  • R 10 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl, (CR 7 R 8 ) a C(O)OR 6 , (CR 7 R 8 ) a C(O)R 6 , (CR 7 R 8 ) a C(O)N(R 6 ) 2 , (CR 7 R 8 ) a C(O)N(OR 6 )(R 6 ), (CR 7 R 8 ) a (OR 6 ), (CR 7 R 8 ) a N(R 6 ) 2 and (CR 7 R 8 ) a R 6 , wherein R 6 is selected from the group consisting of hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R 6 is a 5 or 6 membered carbocyclic or heterocyclic group;
  • B is a carbocyclic aryl or heterocyclic aryl represented by formula II below:
  • R 6 is selected from the group consisting of hydrogen, alkyl, dilower alkyl amine or a heterocyclic group represented by the list below or N(R 6 ) 2 may represent a 3 to 7 membered heterocyclic group, wherein R 5 is hydrogen, halogen, simple alkyl, CF 3 , hydroxyl, OR 7 , N(R 7 ) 2 or NO2.
  • E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl represented by formula III below:
  • carbocyclic aryl and heterocyclic aryl is selected from the group consisting of: -r (mR)a_ ⁇
  • Compounds of formula I below are useful as kinase inhibitors. As such compounds of formula I will be 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 treatment of mesangial cell proliferative disorders and metabolic diseases, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetis mellitus, wound healing, inflammation and neurodegenerative diseases.
  • 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 treatment of mesangial cell proliferative disorders and metabolic diseases, diabetic retinopathy, age-related macular de
  • the present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient.
  • a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
  • compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • Me refers to methyl.
  • Et refers to ethyl.
  • tBu refers to t-butyl
  • iPr refers to i-propyl
  • Ph refers to phenyl
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • Alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond.
  • the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond.
  • the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Alkoxyl refers to an "O-alkyl” group.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Alkaryl refers to an alkyl that is covalently joined to an aryl group.
  • the alkyl is a lower alkyl.
  • Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
  • Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
  • Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
  • the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
  • Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
  • Amide refers to -C(O)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • Thioamide refers to -C(S)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • Amide refers to a -N(R")R'" group, wherein R" and R'" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
  • Thioether refers to -S-R", wherein R" is alkyl, aryl, or alkylaryl.
  • the compounds of this invention may be prepared by the general scheme set forth in
  • the compounds of the present invention are selected from the compounds of Table 1, Table 2 and Table 2.1 below.
  • Table 1 the compounds of the present invention are exemplified by any combination of Ar 1 and R 2 attached to the core template illustrated.
  • the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
  • Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (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 effects and responses to the extracellular microenvironment).
  • tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine kinases
  • Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
  • This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced such proteins.
  • the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • Biological data for the compounds of the present invention was generated by use of the following assays.
  • HUVEC human umbilical vein endothelial cells
  • Clonetics were seeded in 96- well fibronectin coated black- walled plates overnight @ 37°C/5%CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37°C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye.
  • test agents For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.01 to 10.0 uM followed by VEGF stimulation (5ng/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 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 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 ⁇ g of poly-Glu-Tyr (4:1) in 1OmM 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 ⁇ L reaction volumes containing 3.6 ⁇ M ATP in kinase buffer (5OmM Hepes buffer pH 7.4, 2OmM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 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° C, the reactions were washed four times with PBS containing 0.05% Tween-20.
  • lOO ⁇ 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, lOO ⁇ 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 lOO ⁇ l of 2.5N H 2 SO 4 to each well and read using a microplate ELISA reader set at 492 nm. IC 5 O values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
  • Step 1 Representative procedure for the preparation of sulfoxides Methyl phenyl sulfoxide To a stirred suspension of iodoxybenzoic acid (3.7 g, 13.2 mmol, 1.1 eq) in 100:1 CHCI3/H 2 O (25 mL) was added tetraethylammonium bromide (TEAB) (126 mg, 5 mol%), followed by the addition of/?-tolyl sulfide (1.66 g, 12 mmol) in one portion. The mixture was stirred at room temperature for approximately 30 minutes until consumption of sulfide was observed (TLC, hexanes/EtOAc 1/1).
  • TEAB tetraethylammonium bromide
  • Step 2 Representative procedure for the preparation of subtitituted sulfoximines
  • the reaction mixture was allowed to warm to room temperature, stirred for 20 h and the solvent then evaporated.
  • the residue was dissolved in EtOAc (50 mL) and filtered through a pad of silica gel. The ethyl acetate solution was evaporated and the residue was triturated with hexanes to provide the title compound as a white solid (3.0 g, recovery 96%, purity >95% by HPLC). If required, the compound can be further purified by silica gel column chromatography (50% hexanes/EtOAc).
  • Step 3 Representative procedure for the deprotection of (trimethylsilyl)ethyl]sulfonyl substituted sulfoximines S-(4-methoxyphenyl)-S-methyl-sulfoximine
  • Step 4 Representative procedure for the Sonagashira reaction of ethyl 5-bromonicotinate with acetylenes
  • reaction mixture was heated at 50 0 C for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil.
  • Silica gel column chromatography (9/1 - 4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%).
  • Step 5 Representative procedure for nicotinic acid ester hydrolysis 5-Phenylethynyl-nicotinic acid
  • Step 6 Representative procedure for coupling of substituted sulfoximine's to substituted nicotinic acids N-[l-(4-Methoxy-phenyl)-methylsulfoximine]-5-phenylethynyl-nicotinamide
  • Examples 2 through 422 were prepared by the methods described in Example 1 by employing appropriate combinations of the aryl sulfides illustrated in table 3 and the acetylenes illustrated in table 4. Table 3.
  • Aryl Sulfide Reagents were employed in Example 1 by employing appropriate combinations of the aryl sulfides illustrated in table 3 and the acetylenes illustrated in table 4. Table 3.
  • the reaction was heated at 70 0 C for 20 hours then partitioned between EtOAc and H 2 O.
  • the EtOAc layer was washed with acetic acid solution, saturated NaHC ⁇ 3, brine, dried with anhydrous Na 2 S ⁇ 4 and concentrated.
  • the dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
  • Example 428 (S)-5-[(4-phenoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide
  • (S)-5-bromo-N- [methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide and 1 -ethynyl-4-phenoxybenzene were reacted to give the title compound as an off-white solid (95 mg, 68%).
  • Example 436 (S)-5-[(4-hydroxy-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-
  • reaction mixture was then heated to 85 0 C and tetrabutylammonium fluoride (1.0 M solution in THF, 0.46 mL, 0.46 mmol) was added dropwise over 10 min.
  • the reaction was allowed to be stirred at 85 0 C for 2 hours.
  • the reaction mixture was partitioned between EtOAc and H 2 O.
  • the organic extracts and associated solid were collected and concentrated.
  • the residue was purified by chromatography (silica gel, gradient elution MeOH-CHCl 3 : 1 : 100-1 :4).
  • the product containing fractions were collected, concentrated, and the brown solid residue was triturated with a combination of MeOH and EtOAc.
  • the resulting mixture was filtered and the filtrate allowed to stand at room temperature.
  • the solid which precipitated from solution was collected and dried to give the title compound as a white solid (11 mg).
  • Example 449 (S)-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]-5-( ⁇ 4-[(2- thienylcarbonyl)amino]phenyl ⁇ ethynyl)nicotinamide.
  • thiophene-2-carboxylic acid (4-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol)
  • (S)-5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide 100 mg, 0.295 mmol
  • N-(4-ethynyl-phenyl)-2,6-difluoro- benzamide (0.114 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (113 mg, 74%)
  • N-(4-ethynyl-phenyl)-4-fluoro- benzamide (0.106 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (106 mg, 72%).
  • N-(4-ethynyl-phenyl)-4-methyl- benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (118 mg, 81%).
  • Example 454 ((SS))--55--(( ⁇ 44--[[((22--methylbenzoyl)amino]phenyl ⁇ ethynyl)-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide.
  • N-(4-ethynyl-phenyl)-2-methyl- benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound (109 mg, 75%).
  • Step 1 tert-butyl 4-ethynylphenylcarbamate.
  • Step 2 ((SS))--NN--[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]-5-( ⁇ 3-[(2- thienylcarbonyl)amino]phenyl ⁇ ethynyl)nicotinamide.
  • N-(3-ethynylphenyl)-3- methylthiophene-2-carboxamide (0.213 g, 0.885 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide (0.200 g, 0.590 mmol) were reacted to give the title compound as a solid (274 mg, 93%).
  • Step 2 ((SS))--55--(( ⁇ 3-[(2-methylbenzoyl)amino]phenyl ⁇ ethynyl)-N-[methyl(oxo)phenyl- ⁇ 6 - sulfanylidene]nicotinamide
  • N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5- bromo-N-[methyl(oxo)phenyl- ⁇ 6 -sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for -20 min after which NEt 3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh 3 ) 2 Cl 2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol).
  • reaction mixture was allowed to stir at 50 0 C for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL). The organic extracts were combined, dried over anhydrous Na 2 S ⁇ 4 and concentrared. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
  • Step 1 methyl 6-amino-5-iodonicotinate To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanol at room temperature was added silver sulfate (4.37 g, 14.0 mmol) and methyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours the reaction was filtered to isolate a tan precipitate. The solid was heated with 20% MeOH/CHCl3 then cooled to room temperature, filtered, and rinsed with MeOH and CHCl 3 . The filtrate was evaporated, dissolved in hot MeOH, filtered to remove brownish impurities, and then crystallized from MeOH to give the title compound as a light tan solid (1.73g,
  • the reaction mixture was degassed (alternating vacuum and argon) and placed under an atmosphere of 1 :3 Argon/hydrogen atmosphere. Copper( I + ) iodide was added and the reaction mixture was heated at 60 0 C for 50 min.
  • the brown reaction mixture was partitioned between saturated aqueous NaHCO 3 and EtOAc.
  • the organic layer was collected and washed further with saturated aqueous NaHCO 3 (IX), brine (IX), and dried over anhydrous Na 2 SO 4 .
  • the residue was purified by chromatography (silica gel, 50: 1 CHCl 3 :MeOH). The product containing fractions were concentrated to give the title compound as a light yellow solid (220 mg, 94 %).
  • step 1 3-methylthiophene-2- carboxylic acid (0.100 g, 0.794 mmol) and 2-ethynyl-phenylamine (0.093 g, 0.794 mmol) were reacted to give the title compound as a tan solid (0.110 g, 56 %).
  • Step 1 N-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-ethynyl-benzamide 3-Ethynylbenzoic acid (0.1 g, 0.685 mmol) was added to a dry 50 mL round bottom flask and dissolved in DMF (6.85 mL). To the resulting solution was added l,3-dimethyl-lH-pyrazol-5- amine (0.076 g, 0.685 mmol), followed by BOP (0.393 g, 0.890 mmol), and 0.238 mL of DIPEA (1.37 mmol). This reaction mixture was heated to 50 0 C for 3 h.
  • step T (S)-5-bromo-N- [methyl(oxido)phenyl- ⁇ 4 -sulfanylidene]nicotinamide (0.141 g, 0.418 mmol) and N-(1, 3-dimethyl- lH-pyrazol-5-yl)-3-ethynylbenzamide (O. lg, 0.418mmol) were reacted to give the title compound
  • N-(3-ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5- carboxamide (0.888 g, 3.71 mmol) and 5-bromo nicotinic acid (0.50 g, 2.47 mmol) were dissolved in DMF (15 mL)
  • DMF 15 mL
  • the mixture was then degassed by bubbling N 2(g) through it for -20 min.
  • the mixture was then treated sequentially with NEt 3 (1.37 mL, 9.90 mmol), Pd(PPh 3 ) 2 Cl 2 (0.173g,
  • methyl 3-(4-(methylthio)phenyl)propanoate (0.50 g, 2.38 mmol) was dissolved in MeOH under a N 2(g) .
  • the resulting solution was cooled to 0 0 C, then 0.5 M NaIO 4 (4.76 mL, 2.38 mmol) was added dropwise to the cooled solution causing the formation of a white precipitate.
  • the reaction was allowed to warm to room temperature. When HPLC indicated complete consumption of starting thioether, the reaction was filtered and the filtrate was concentrated. The resulting residue was taken up in CHCl 3 (25 mL) then extracted with brine.
  • Step 1 tert- Butyl [4-(methylthio)phenyl]carbamate
  • Step 3 tert-butyl ⁇ 4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl ⁇ -carbamate
  • tert-Butyl [4- (methylsulfinyl)phenyl]carbamate (0.300 g, 1.18 mmol) was converted to the title compound
  • Step 5 tert-butyl (4- ⁇ N-[(5-bromopyridin-3-yl)carbonyl]-S- methylsulfonimidoyl ⁇ phenyl)carbamate
  • Step 7 N- [(4- ⁇ amino ⁇ phenyl)(methyl)oxido- ⁇ 4 -sulfanylidene] -5- [(3 - ⁇ [( 1 ,3 -dimethyl- IH- pyrazol-5-yl)carbonyl] amino ⁇ phenyl)ethynyl]nicotinamide
  • the resulting reaction mixture was then treated slowly with CF 3 COOH (1 mL) and allowed to stir while warming to rt.
  • the reaction mixture was stirred at room temperature for 4 hours and then was diluted with CHCI3 (5 mL).
  • the organic mixture was extracted with H 2 O (5 mL), then with a saturated aqueous solution of NaHCO 3 (2 x 5 mL) and then with brine (5 mL).
  • the organic layer was then dried over anhydrous Na 2 S ⁇ 4(S) , filtered and concentrated in vacuo give the title compound (0.086 g, 95%).
  • N-[(4- ⁇ amino ⁇ phenyl)(methyl)oxido- ⁇ 4 -sulfanylidene]-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol- 5-yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinamide (0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treated with (3-Chloro-propyl)-diethyl-amine (0.047g, 0.252mmol) and TEA (0.070 mL, 0.504 mmol). The reaction mixture was then heated to 100 0 C for 48 h then cooled to room temperature.
  • Example 488 N- ⁇ [4-(3- ⁇ 4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl ⁇ -3-oxopropyl)phenyl](methyl)oxido- ⁇ 4 - sulfanylidene ⁇ -5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ ethynyl)nicotinamide
  • Step 1 tert-butyl(dimethyl) ⁇ [4-(methylthio)benzyl]oxy ⁇ silane t-Butyldimethylsilyl chloride (2.45g, 16.2 mmol) was dissolved in DMF (3.25 mL) then treated with imidazole (2.2 Ig, 32.4 mmol). The reaction mixture was allowed to stir for 20 minutes before 4-Methylsulfanyl-phenyl)-methanol (0.5g, 3.25mmol) was added. The reaction was stirred overnight and then dissolved in EtOAc (20 mL). The organic mixture was extracted with H 2 O (3 x 10 mL).
  • Step 2 tert-butyl(dimethyl) ⁇ [4-(methylsulfinyl)benzyl]oxy ⁇ silane
  • Step 4 tert-Butyl(dimethyl) ⁇ [4-(S-methylsulfonimidoyl)benzyl]oxy ⁇ silane
  • Step 5 N- ⁇ [4-( ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ methyl)phenyl](methyl)oxido- ⁇ 4 -sulfanylidene ⁇ -5- ( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ -ethynyl)nicotinamide
  • Step 6 N- ⁇ [4-(hydroxymethyl)phenyl](methyl)oxido- ⁇ 4 -sulfanylidene ⁇ -5-( ⁇ 3-[(3-methyl-2- furoyl)amino]phenyl ⁇ -ethynyl)nicotinamide
  • Step 1 N- ⁇ [4-(Bromomethyl)phenyl](methyl)oxido- ⁇ 4 -sulfanylidene ⁇ -5-( ⁇ 3-[(3-methyl-2- furoyl)amino]phenyl ⁇ ethynyl)nicotinamide N- ⁇ [4-(hydroxymethyl)phenyl](methyl)oxido- ⁇ 4 -sulfanylidene ⁇ -5-( ⁇ 3-[(3-methyl-2- furoyl)amino]phenyl ⁇ ethynyl)nicotmamide (0.1 g, 0.195 mmol) and CBr 4 ( 0.097 g, 0.293 mmol) were dissolved in CH 2 Cl 2 (0.485 mL) and the resulting solution was cooled to 0 0 C.
  • PPh 3 (0.858 g, 0.293 mmol) was dissolved in CH 2 Cl 2 (0.250 mL) and then added dropwise to the 0 0 C reaction mixture. Subsequently the reaction was allowed to warm to room temperature and stir for -1.5 h. The reaction was then diluted with CH 2 Cl 2 (5 mL) and the resulting organic mixture was washed with a saturated aqueous solution OfNaHCO 3 (5 mL), then with brine (5 mL). The organic layer was dried anhydrous Na 2 SO 4(S) , filtered and concentrated in vacuo. The crude product was then taken on without further purification.
  • Step 2 N- ⁇ [4-( ⁇ 4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl ⁇ methyl)phenyl](methyl)-oxido- ⁇ 4 - sulfanylidene ⁇ -5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ ethynyl)nicotinamide
  • Step 1 6-Amino-5- ⁇ 3-[(3-methyl-fi ⁇ ran-2-carbonyl)-amino]-phenylethynyl ⁇ -nicotinic acid methyl ester
  • N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.607g, 2.70 mmol) and methyl 6-amino-5-iodonicotinate (0.5g, 1.80mmol) were dissolved in DMF (6 mL).
  • the solution was degassed by bubbling N 2(g) through it for -30 min.
  • To the degassed solution was added DIPEA (1.25 mL, 7.19mmol), followed by Pd(PPh 3 ) 2 Cl 2 (0.126g, 0.18 mmol) and CuI
  • Step 2 6-Amino-5- ⁇ 3-[(3-methyl-furan-2-carbonyl)-amino]-phenylethynyl ⁇ -nicotinic acid
  • Methyl 6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinate (0.550 g, 1.47 mmol) was dissolved in THF (15 mL) and then treated with 1.0 M NaOH (7.33 mL, 7.33 mmol). The reaction mixture was heated to 50 0 C. Once the reaction was done by TLC, the reaction was cooled to room temperature and then acidified with acetic acid. The reaction mixture was taken up in of EtOAc (-15 mL) then extracted with H 2 O (2 x 15 mL).
  • Step 3 Methyl 3-[4-(N- ⁇ [6-amino-5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ -ethynyl)pyridin-3- yl]carbonyl ⁇ -S-methylsulfonimidoyl)phenyl]propanoate 6-Amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.1 g, 0.277 mmol) was dissolved in DMF (2.8 mL).
  • Step 4 3-[4-(N- ⁇ [6-amino-5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ ethynyl)-pyridin-3-yl]carbonyl ⁇ -S- methylsulfonimidoyl)phenyl]propanoic acid
  • Step 5 Methyl (3- ⁇ N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl ⁇ phenyl)acetate
  • 5-bromonicotinic acid (648 mg, 3.21 mmol)
  • methyl [3-(S- methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol)
  • catalytic DMAP in 15.0 ml DMF at room temperature
  • l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 738 mg, 3.85 mmol.
  • the reaction was stirred 1 hour at room temperature then added to EtOAc.
  • Step 6 methyl ⁇ 3-[N-( ⁇ 5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino ⁇ phenyl)ethynyl]pyridin-3- yl ⁇ carbonyl)-S-methylsulfonimidoyl]phenyl ⁇ acetate
  • the sample was dissolved in EtOAc, washed with brine/dilute HCl, brine, dried with anhydrous Na 2 SO 4 and rotary evaporated.
  • the yellow-orange oil was dissolved in 60ml MeOH, K 2 CO3 (6.76 g, 48.9 mmol) added, and the mixture stirred at room temperature for 12 minutes.
  • the MeOH filtrate was decanted from the solids, which were then rinsed with MeOH and EtOAc.
  • the pH of the combined organic filtrates were adjusted to pH 2 using 4% HCl, then the aqueous layer diluted by adding H 2 O.
  • the aqueous layer was washed with 30% EtOAc in hexane, then the pH adjusted to pH 9 with saturated Na 2 CO 3 .
  • Step 5 methyl 3 - [N-( ⁇ 5- [(3 - ⁇ [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino ⁇ phenyl)ethynyl]pyridin-3 - yl ⁇ carbonyl)-S-methylsulfonimidoyl]benzoate
  • methyl 3- ⁇ N-[(5-bromopyridin-3- yl)carbonyl]-S-methylsulfonimidoyl ⁇ benzoate and N-(3-ethynylphenyl)-l,3-dimethyl-lH- pyrazole-5-carboxamide were reacted to give the title compound.
  • Example 502 N- ⁇ [3-( ⁇ [2-(diethylamino)ethyl]amino ⁇ carbonyl)phenyl](methyl)oxido- ⁇ 4 -sulfanylidene ⁇ -5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinamide
  • Example 504 methyl 3-[N-( ⁇ 6-amino-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- y ⁇ carbonylJaminojpheny ⁇ ethynylJpyridin-S-yljcarbony ⁇ -S-methylsulfonimidoyllbenzoate
  • 6-amino-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinic acid 68 mg, 0.18 mmol
  • methyl 3-(S- methylsulfonimidoyl)benzoate 42 mg, 0.198 mmol
  • N, N-diisopropylethylamine 0.063 ml
  • the brown oil was dissolved in anhydrous THF (40 mL) and the resulting solution was cooled to -78 0 C followed by dropwise addition of nBuLi (17.1 mL, 2.5 M in hexanes). The reaction mixture was stirred 10 min at -78 0 C and then 20 min at 0 0 C. After hexamethylphosphoramide (13.5 mL) was added, the reaction mixture was cooled back to -78 0 C followed by dropwise addition of 2-bromoethoxy-tert- butyl-dimethylsilane over a few minutes. The reaction mixture was stirred at -78 0 C for about an hour and allowed to warm-up to room temperature within 4 hours.
  • reaction system was placed under a N 2 -H 2 (1 : 1) atmosphere and CuI (145 mg) was added in one portion. After the reaction mixture was stirred and heated at 60 0 C for 1.5 hours, it was poured into saturated aqueous NaHC ⁇ 3. The aqueous was extracted with EtOAc (IX), which was subsequently washed with aqueous NaHC ⁇ 3 (IX), brine (IX), and dried (anhydrous Na 2 SO ⁇ . The organic layer was decanted, evaporated and wrapped with silica gel. Two times column chromatography
  • Step 4 (S)-N- [(3 -hydroxypropyl)(oxido)phenyl- ⁇ 4 -sulfanylidene] -5-( ⁇ 3 - [(3 -methyl-2- furoyl)amino]phenyl ⁇ ethynyl)nicotinamide
  • N-[(3-bromopropyl)(oxido)phenyl- ⁇ 4 -sulfanylidene]-5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ ethynyl)nicotinamide and 3- fluoropiperidine were converted to the title compound.
  • step 1 3-methyl-furan-2- carboxylic acid (3-ethynyl-phenyl)-amide and 5-bromo nicotinic acid were reacted to provide the title compound.
  • step T (S)-Ethyl (S)-(S- phenylsulfonimidoyl) acetate and 5 - [(3 - ⁇ [( 1 , 3 -dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino ⁇ phenyl)ethynyl]nicotinic acid were reacted to give the title compound.
  • N-[(3-bromopropyl)(oxido)phenyl- ⁇ 4 -sulfanylidene]-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinamide and 2-amino-3-hydroxypropionic acid methyl ester were reacted to give the title compound.
  • Example 555 rel-(2R,4S)-l- ⁇ 3-[N-( ⁇ 5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino ⁇ phenyl)ethynyl]pyridin-3-yl ⁇ carbonyl)-R-phenylsulfonimidoyl]propyl ⁇ -4- hydroxypyrrolidine-2-carboxylic acid Methyl rel-(2R,4S)-l- ⁇ 3-[N-( ⁇ 5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino ⁇ phenyl)ethynyl]pyridin-3-yl ⁇ carbonyl)-R-phenylsulfonimidoyl]propyl ⁇ -4- hydroxypyrrolidine-2-carboxylate (116 mg, 0.17mmol) was dissolved in THF (3.5 m
  • Example 558 l- ⁇ 3-[N-( ⁇ 5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino ⁇ phenyl)ethynyl]pyridin-3- yljcarbony ⁇ -S-phenylsulfonimidoyllpropyljpiperidine-S-carboxyric acid
  • N-[(3-bromopropyl)(oxido)phenyl- ⁇ 4 -sulfanylidene]-5-( ⁇ 3-[(3-methyl-2-furoyl)amino]phenyl ⁇ ethynyl)nicotinamide and ethyl nipecotate are converted to the title compound.
  • Step 1 methyl 6-amino-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinate
  • 6-amino-5- [(3 - ⁇ [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino ⁇ phenyl)ethynyl]nicotinic acid A solution of methyl 6-amino-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino ⁇ phenyl)ethynyl]nicotinate (51 mg, 0.13 mmol) and KOH (37 mg, 0.65 mmol) in 4.0ml MeOHiH 2 O (3: 1) was heated at 65°C for 1 hour 40 minutes.
  • Step 3 methyl ⁇ 3-[N-( ⁇ 6-amino-5-[(3- ⁇ [(l,3-dimethyl-lH-pyrazol-5- y ⁇ carbonylJaminolpheny ⁇ ethynylJpyridin-S-yljcarbony ⁇ -S-methylsulfonimidoyllphenyl ⁇ acetate
  • step 5 6-amino-5-[(3- ⁇ [(l,3- dimethyl-lH-pyrazol-S-y ⁇ carbonylJaminojpheny ⁇ ethynylJnicotinic acid and methyl ⁇ 3-[S- methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl ⁇ acetate were reacted to give the title compound
  • novel compounds of this invention include any compound which is a substituted aroyl sulfoximine compound which binds to the tyrosine kinase receptor wherein said substituted aryl moiety may be represented by formula IV below:
  • B 1 , R 12 and R 13 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano or said novel sulfoxime may be represented by formula VI below
  • Z is said substituted aroyl group and E 1 and E 2 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano.
  • the compounds of the present invention may be prepared by methods that are analogous to the methods disclosed in such references, with one of skill in the art varying the reactants to achieve the desired compounds. Also, the compounds of the present invention may be tested by the various in- vitro and in- vivo assays disclosed in such references to demonstrate the claimed utilities.

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation. Formula (I)

Description

SULFOXIMINES AS KINASE INHIBITORS
BACKGROUND OF THE INVENTION
Cross Reference To Related Applications
This application is based on, and claims the benefit of, U.S. Provisional Application No. 60/866,080, filed November 16, 2006, and which is incorporated herein by reference.
1. Field Of The Invention
The present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or nonreceptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
2. Description Of The Related Art
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation.
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (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 receptor tyrosine kinases, 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 receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such 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 the 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 receptor tyrosine kinase 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.
Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
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 (19) 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.
A second family of RTKs, designated the insulin subfamily, is comprised of the INS-R, the IGF-IR and the IR-R. A third family, the "PDGF" subfamily 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 (flt-1). Each of these receptors was initially believed to be receptors for hematopoietic growth factors. Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl , 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 (11) subfamilies (Src, Frk, Btk, Csk, AbI, 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, BIk, 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 tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades leading to pathogenic conditions, including cancer, psoriasis and hyper immune response. In view of the surmised importance of PTKs to the control, regulation and modulation of cell proliferation 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. Patent No. 4,966,849), soluble receptors and antibodies (PCT Application No. WO 94/10202; 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, MoI. 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 (PCT Application Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Patent 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 l-cyclopropyl-4-pyridyl-quinolones (U.S. Patent No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al), 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. The identification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation is therefore desirable and one object of this invention.
In addition, certain small compounds are disclosed in U.S. Patents 5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful for the treatment of diseases related to unregulated TKS transduction. See also Patents and PCT Published Patent Application WO 02/29630; 6,599,173; 6,765,012; 6,699,863; 6,541,504 and 6,747,025. These patents are hereby incorporated by reference in its entirety for the purpose of disclosing starting materials and methods for the preparation thereof, screens and assays to determine a claimed compound's ability to modulate, regulate and/or inhibit cell proliferation, indications which are treatable with said compounds, formulations and routes of administration, effective dosages, etc.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
In one illustrative embodiment, the compounds of the present invention have the following general formula I:
Figure imgf000005_0001
wherein:
X is CR4 or N; Y is CR1 or N;
R1 is selected from the group consisting of hydrogen, alkyl, halogen, OR4, CN, NO2 , COR4,
(CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2and N(R4)2;
R2 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2 ,
SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10; R3 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2 , SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10; R4 is hydrogen or Ci to C4 alkyl; A is selected from the group consisting of C≡C ; CH=CH, CH2CH2, CH2O, CF2O, OCH2, OCF2, O, N(R4), C(O), S(O)6, NR7C(O), C(O)NR7 and N(R7)C(O)NR7; B is selected from the group consisting of hydrogen, alkyl and alkyloxyalkyl or B may be a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group; E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group;
E' is selected from the group consisting of alkyl, CF3,
(CR7R8)aC(O)OR10, (CR7R8)aC(O)N(R10)2, (CR7R8)aC(O)N(OR10)(R10), (CR7R8)a(OR10), (CR7R8)aN(R10)2, and (CR7R8)aR10; wherein R7 and R8 are selected from the group consisting of H, halogen, hydroxyl, and alkyl or CR7R8 may represent a carbocyclic ring of from 3 to 6 carbons; and
R10 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl, (CR7R8)aC(O)OR6, (CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), (CR7R8)aN(R6)2 and (CR7R8)aR6, wherein R6 is selected from the group consisting of hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group;
a is O or an integer of from 1 to 5; b is an integer of from 2 to 5; c is O or an integer of from 1 to 4; d is O or an integer of from 1 to 5; e is O or an integer of from 1 to 2 and further including prodrugs, pharmaceutically acceptable salts, racemic mixtures and enantiomers of said compound.
Preferably, B is a carbocyclic aryl or heterocyclic aryl represented by formula II below:
Figure imgf000006_0001
wherein said carbocyclic aryl and heterocyclic aryl groups are selected from the group consisting of:
Figure imgf000007_0001
wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, SR6, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6,
S(O)e(CR7R8)aC(O)R6 ,(CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2 S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and, S(O)e(CR7R8)aR6.
Most preferably R6 is selected from the group consisting of hydrogen, alkyl, dilower alkyl amine or a heterocyclic group represented by the list below or N(R6)2 may represent a 3 to 7 membered heterocyclic group, wherein R5 is hydrogen, halogen, simple alkyl, CF3, hydroxyl, OR7, N(R7)2 or NO2.
Preferably, E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl represented by formula III below:
Figure imgf000008_0002
III wherein said carbocyclic aryl and heterocyclic aryl is selected from the group consisting of: -r (mR)a_ ^
J-(R). I nJ-(R). I V -Sp,(mR).. Y ζ i-j-(R).
^
Figure imgf000009_0001
Compounds of formula I below are useful as kinase inhibitors. As such compounds of formula I will be 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 treatment of mesangial cell proliferative disorders and metabolic diseases, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetis mellitus, wound healing, inflammation and neurodegenerative diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient. Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
More particularly, the compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
The following defined terms are used throughout this specification:
"Me" refers to methyl. "Et" refers to ethyl.
"tBu" refers to t-butyl.
"iPr" refers to i-propyl.
"Ph" refers to phenyl.
"Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
"Alkyl" refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH.
"Alkenyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH. "Alkynyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH.
"Alkoxyl" refers to an "O-alkyl" group. "Aryl" refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, amine, thioether, cyano, alkoxy, alkyl, and amino.
"Alkaryl" refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
"Carbocyclic ring" refers to a substituted or unsubstituted cyclic radical, including cycloalkyl, cycloalkenyl and carbocyclic aryl wherein the ring atoms are carbon and said substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH.
"Carbocyclic aryl" refers to an aryl group wherein the ring atoms are carbon. "Heterocyclic ring" refers to a substituted or unsubstituted cyclic radical including cycloalkyl, cycloalkenyl and heterocyclic aryl wherein 1 to 3 of the ring atoms are heteroatoms and the remainder of the ring atoms are carbon substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH.
"Heterocyclic aryl" refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
"Hydrocarbyl" refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
"Substituted hydrocarbyl" refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
"Amide" refers to -C(O)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Thioamide" refers to -C(S)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Amine" refers to a -N(R")R'" group, wherein R" and R'" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
"Thioether" refers to -S-R", wherein R" is alkyl, aryl, or alkylaryl. "Sulfonyl" refers to -S(O)2-R"", where R"" is aryl, C(CN)=C-aryl, CH2CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl. The compounds of this invention may be prepared by the general scheme set forth in
Scheme 1. Scheme 1 - General Route to Acyl Sulfoximines Si(CH3)
Figure imgf000012_0001
IJi
Figure imgf000012_0002
Figure imgf000012_0003
Scheme 2 - General Route to Acyl Sulfoximines
Figure imgf000013_0001
I
Figure imgf000013_0002
Vl
In particular the compounds of the present invention are selected from the compounds of Table 1, Table 2 and Table 2.1 below. In table 1 the compounds of the present invention are exemplified by any combination of Ar1 and R2 attached to the core template illustrated.
Table 1 -
Figure imgf000013_0003
Figure imgf000013_0004
Figure imgf000014_0001
Figure imgf000015_0011
Table 2
Example Number Structure Example Number Structure
Example 423 Example 450
Figure imgf000015_0001
Figure imgf000015_0002
Example 424 Example 451
Figure imgf000015_0004
Figure imgf000015_0003
Example 425 Example 452
Figure imgf000015_0005
Figure imgf000015_0006
Example 426 Example 453
Figure imgf000015_0007
Figure imgf000015_0008
Example 427 Example 454
Figure imgf000015_0010
Figure imgf000015_0009
Figure imgf000016_0001
Table 2
Example Example Number Structure Number Structure
Example 434
Figure imgf000017_0001
Example 461
Figure imgf000017_0002
Example 435 Example 462
Figure imgf000017_0003
Figure imgf000017_0004
Example 436 Example 463
Figure imgf000017_0005
Figure imgf000017_0006
Example 437 Example 464
Figure imgf000017_0007
Figure imgf000017_0008
Example 438 Example 465
Figure imgf000017_0009
Figure imgf000017_0010
Example 439 Example 466
Figure imgf000017_0011
Figure imgf000017_0012
Table 2
Example Number Structure Example Number Structure
Example 440 Example 467
Figure imgf000018_0002
Figure imgf000018_0001
Example 441 Example 468
Figure imgf000018_0003
Figure imgf000018_0004
Example 442 Example 469
Figure imgf000018_0005
Figure imgf000018_0006
Example 443 Example 470
Figure imgf000018_0007
Figure imgf000018_0008
Example 444 Example 471
Figure imgf000018_0009
Figure imgf000018_0010
Example 445 Example 472
Figure imgf000018_0011
Figure imgf000018_0012
Table 2
Example Example Number Structure Number Structure
Example 446
Figure imgf000019_0001
Example 473
Figure imgf000019_0002
Example 447 Example 474
Figure imgf000019_0003
Figure imgf000019_0004
Example 448 Example 475
Figure imgf000019_0005
Figure imgf000019_0006
Example 449
Figure imgf000019_0007
Table 2-1
Example
Structure
#
476
477
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
The present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (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 effects and responses to the extracellular microenvironment).
It has been shown that tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the 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 receptor tyrosine kinase 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. Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration). This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced such proteins. More particularly, the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers. Biological data for the compounds of the present invention was generated by use of the following assays.
VEGF Stimulated Ca++ 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 @ 37°C/5%CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37°C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.01 to 10.0 uM followed by VEGF stimulation (5ng/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. IC50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
Protocol for KDR 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 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 30μg of poly-Glu-Tyr (4:1) in 1OmM 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 120μL reaction volumes containing 3.6μM ATP in kinase buffer (5OmM Hepes buffer pH 7.4, 2OmM MgCl2, 0.1 mM MnCl2 and 0.2 mM Na3VO4). 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° C, the reactions were washed four times with PBS containing 0.05% Tween-20. lOOμl 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, lOOμl 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 lOOμl of 2.5N H2SO4 to each well and read using a microplate ELISA reader set at 492 nm. IC5O values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
The invention is further illustrated by the following non-limiting examples.
The invention is further illustrated by the following non-limiting examples.
Example 1
N-[(4-methoxyphenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide
Step 1 - Representative procedure for the preparation of sulfoxides Methyl phenyl sulfoxide To a stirred suspension of iodoxybenzoic acid (3.7 g, 13.2 mmol, 1.1 eq) in 100:1 CHCI3/H2O (25 mL) was added tetraethylammonium bromide (TEAB) (126 mg, 5 mol%), followed by the addition of/?-tolyl sulfide (1.66 g, 12 mmol) in one portion. The mixture was stirred at room temperature for approximately 30 minutes until consumption of sulfide was observed (TLC, hexanes/EtOAc 1/1). The residual solids were removed by filtration and washed with CHCI3 (40 mL). The combined filtrate was washed successively with saturated aq. NaHCO3 (30 mL), saturated aq. NaCl (30 mL), dried over sodium sulfate, and concentrated to provide the crude product. Purification by silica gel column chromatography (50% hexanes/EtOAc elution) afforded the title compound (1.68 g, yield 91%). 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 2.71 (s, 3H), 2.42 (s, 3H); ESI-MS m/z 154.7 (M+H)+.
Step 2 - Representative procedure for the preparation of subtitituted sulfoximines
S-methyl-S-(4-methoxyphenyl)-N-[[2-(trimethylsilyl)ethyl]sulfonyl]sulfoximine
To a solution of 1 -methanesulfinyl-4-methoxy -benzene (1.51 g, 8.88 mmol) in dry acetonitrile (35 mL), was added CuPF6(CH3CN)4 (165 mg, 0.44 mmol, 0.05 eq.). The mixture was cooled to 0 0C and [N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyl-iodinate (3.75 g, 9.8 mmol, 1.1 eq.) (prepared by the method described in J. Org. Chem. 1999, 64, 5304-5307) was added. The reaction mixture was allowed to warm to room temperature, stirred for 20 h and the solvent then evaporated. The residue was dissolved in EtOAc (50 mL) and filtered through a pad of silica gel. The ethyl acetate solution was evaporated and the residue was triturated with hexanes to provide the title compound as a white solid (3.0 g, recovery 96%, purity >95% by HPLC). If required, the compound can be further purified by silica gel column chromatography (50% hexanes/EtOAc). 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 9.0 Hz, 2H), 7.05 (d, J= 9.0 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 3H), 3.16-3.10 (m, 2H), 1.18-1.12 (m, 2H), 0.04 (s, 9H); ESI-MS m/z 349.9 (M+H)+.
Step 3 - Representative procedure for the deprotection of (trimethylsilyl)ethyl]sulfonyl substituted sulfoximines S-(4-methoxyphenyl)-S-methyl-sulfoximine
A mixture of S-methyl-S-(4-methoxyphenyl)-N-[[2-(trimethylsilyl)ethyl]sulfonyl]-sulfoximine (2.9 g, 8.3 mmol) and 1.0 M of TBAF (12.5 mL, 12.5 mmol, 1.5eq.) was heated in a microwave at 120 0C for 20 minutes. After cooling to room temperature, the solvent was evaporated and the resulting mixture was purified by silica gel column chromatography (elution with 100% EtOAc) to provide the title compound (1.46 g, yield 96 %). 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J= 9.0 Hz, 2H), 6.99 (d, J= 9 Hz, 2H), 3.87 (s, 3H), 3.08 (s, 3H); ESI-MS m/z 186.1 (M+H)+.
Step 4 - Representative procedure for the Sonagashira reaction of ethyl 5-bromonicotinate with acetylenes
5-Phenylethynyl-nicotinic acid ethyl ester
To a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethyl acetate (20 mL) under an N2 atmosphere, was added triethylamine (1.1 mL, 7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.), dichloro-fe(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05 eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reaction mixture was heated at 50 0C for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil. Silica gel column chromatography (9/1 - 4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%). 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J= 1.8 Hz, IH), 8.87 (d, J= 2.1 Hz, IH), 8.39 (dd, J=1.8, 2.1 Hz, IH), 7.56- 7.53 (m, 2H), 7.40-7.30 (m, 3H), 4.42 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2Hz, 3H); ESI-MS m/z 251.9 (M+H)+.
Step 5 - Representative procedure for nicotinic acid ester hydrolysis 5-Phenylethynyl-nicotinic acid
To a solution of 5-phenylethynyl-nicotinic acid ethyl ester (1.17 g, 4.64 mmol) in methanol (10 mL) was added 5 N aqueous sodium hydroxide (2 mL, 10 mmol). The mixture was stirred at room temperature for approximately 20 h, before the reaction mixture was diluted with water (3 mL) and extracted with hexanes/EtOAc (95/5) (10 mL). The aqueous solution was acidified with 1 N HCl to pH 4. The white precipitate that formed was collected by filtration, washed with water (2 mL), and dried under vacuum to provide the title compound as a white solid (987 mg, yield 95%). 1H NMR (300 MHz, ^6-DMSO) δ 9.02 (d, J= 1.8 Hz, IH), 8.94 (d, J= 2.4 Hz, IH), 8.34 (dd, J= 1.8, 2.4 Hz, IH), 7.63-7.60 (m, 2H), 7.48-7.44 (m, 3H); ESI-MS m/z 223.9 (M+H)+.
Step 6 - Representative procedure for coupling of substituted sulfoximine's to substituted nicotinic acids N-[l-(4-Methoxy-phenyl)-methylsulfoximine]-5-phenylethynyl-nicotinamide
A solution of 5-phenylethynyl-nicotinic acid (0.1 mmol) and S-(4-methoxyphenyl)-S-methyl- sulfoximine (0.1 mmol), 1 -hydroxybenzotriazole (0.15 mmol) in dimethyformamide (1.5 mL) was treated with l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.15 mmol) in dimethyformamide (1.5 mL). The reaction mixture was shaken at room temperature for 20 hours and concentrated. The residue was purified by high pressure liquid chromatography (phenomenex Luna C 18 5 μm column, gradient elution, acetonitrile/10 mM aqueous ammonium carbonate) and concentrated to give the title compound.
Examples 2-422
Examples 2 through 422 (table 5) were prepared by the methods described in Example 1 by employing appropriate combinations of the aryl sulfides illustrated in table 3 and the acetylenes illustrated in table 4. Table 3. Aryl Sulfide Reagents
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Example 423 (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide
To a slurry of 5-(2-phenyleth-l-ynyl)nicotinic acid (339 mg, 1.5mmol) in 6.0 mL THF at room temperature was added 1, l '-carbonyldiimidazole (271 mg, 1.7 mmol). After stirring 1.25 hour, a solution of (S)-(+)-S-methyl-S-phenylsulfoximine (260 mg, 1.7 mmol) in 1.5mL THF was added and the mixture heated at 50 0C for 22 hours. Then an additional 50 mg (0.32 mmol) (S)- (+)-S-methyl-S-phenylsulfoximine was added and heating continued at 60 0C for 3.5 hours. The reaction was quenched with NaHCO3 solution and then extracted into EtOAc. The EtOAc layer was washed with NaHCO3 solution, H2O, brine, dried with anhydrous Na24 and concentrated. The yellow oil obtained was chromatographed eluting with hexane/EtOAc to give N- [methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide as a white foam (303mg, 55%).
Example 424
(R)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide
In a manner similar to that described in Example 423, 5-(2-phenyleth-l-ynyl)nicotinic acid and (R)-(-)-S-methyl-S-phenylsulfoximine were reacted to give the title compound as a white foam (54mg, 25%).
Example 425 5-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
Step 1
(S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a solution of 5-bromonicotinic acid (1.21g, 6.0 mmol), N, N-diisopropylethylamine (2.1 mL, 12.0 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (931 mg, 6.0 mmol) in DMF (11.OmL) cooled to 0 0C was treated with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (3.43 g, 6.6 mmol). The reaction mixture was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na24 and concentrated. The residual brown oil was purified by chromatography (silica gel, hexane/EtOAc). The product containing eluent was concentrated and then triturated with hexane to give the title compound as an off-white solid (1.88 g, 92%).
Step 2
(S)-5-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
A mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31mmol) and 1 -ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mL EtOAc was degassed with argon at 70 0C. Upon cooling to room temperature the reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I)iodide (2 mg, 0.012 mmol). The reaction was heated at 70 0C for 20 hours then partitioned between EtOAc and H2O. The EtOAc layer was washed with acetic acid solution, saturated NaHCθ3, brine, dried with anhydrous Na24 and concentrated. The dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
Example 426
(S)-5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 425 a mixture of (S)-5-bromo-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-chloro-l-ethynylbenzene were reacted to give the title compound as white needles (60 mg, 49%).
Example 427 (S)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 425, a mixture of (S)-5-bromo-N-
[methyl [((ooxxoo))pphheennyyll--λλ66--ssuullffaannyylliiddeennee]]nniiccoottiinnaammiiddee aanndd 3 : -hydroxy-l-ethynylbenzene were to give the title compound as an off- white solid (19 mg,
Example 428 (S)-5-[(4-phenoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide In a manner similar to that describe in Example 425 a mixture of (S)-5-bromo-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 1 -ethynyl-4-phenoxybenzene were reacted to give the title compound as an off-white solid (95 mg, 68%).
Example 429
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide
To a degassed solution of 10.0 mL DMF at room temperature was added (S)-5-bromo-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (1.02 g, 3.0 mmol), triethylamine (1.3 mL, 9.0 mmol), trimethylsilylacetylene (0.83 mL, ό.Ommol), and dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.3 mmol). After 15 minutes added copper(I)iodide (29 mg, 0.15 mmol) and continued reaction for 4 hours. The reaction was then partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na24 and rotary evaporated to 20ml volume. The solution was placed overnight in the refrigerator and the resulting solid filtered and rinsed with 40%
EtOAc/hexane to give The title compound (674 mg) as a tan solid. The filtrate was evaporated and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give an additional 301 mg of the title compound. The product lots were combined and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give the title compound as a tan solid (959 mg, 90%).
Example 430 (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
A solution of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5- [(trimethylsilyl)ethynyl]nicotinamide (806 mg, 2.3 mmol) in 70 mL THF/methanol (1 : 1 ratio) at room temperature was degassed with argon. The solution was cooled to 0 0C and K2CO3 (937 mg, 6.8 mmol) added. After 5 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na24 and concentrated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to the title compound as a thick pale orange oil (630 mg, 98 %).
Example 431 (S)-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a degassed solution of 1.3 mL DMF at room temperature containing (S)-5-ethynyl-N-
[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (63 mg, 0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09 mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.022 mmol) and copper(I)iodide (4 mg, 0.022 mmol). After proceeding for 1 hour the reaction was partitioned between EtOAc and H2O. The mixture was filtered to remove an insoluble brown precipitate and the EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown film was chromatographed eluting with CHCVEtO Ac to give a yellow solid which was recrystallized from CHCl3/hexane to give the title compound as an off-white solid (38 mg, 45%).
Example 432 (S)-5-[(2-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 1 -ethynyl-2-hydroxybenzene were reacted to give the title compound as a white solid (6 mg, 7%).
Example 433
Step 1 (R)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a solution of 5-bromonicotinic acid (303 mg, 1.5mmol), N, N-diisopropylethylamine (0.523 mL, 3.0mmol), and (R)-(-)-S-methyl-S-phenylsulfoximine (233 mg, 1.5 mmol) in DMF (3.0 mL) cooled to 0 0C was added 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (859 mg, 1.65 mmol). The solution was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2.5 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was chromatographed eluting with hexane/EtOAc to give the title compound as a yellow solid (478 mg, 94%).
Step 2 (R)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a degassed solution of 2.0 mL DMF at room temperature containing (R)-5-bromo-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31mmol), 3- hydroxyphenylacetylene (73 mg, 0.62 mmol) and triethylamine (0.13 mL, 0.93mmol) was added dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I)iodide (3 mg, 0.016 mmol). The reaction was stirred at room temperature for 1.5 hours. Additional 3- hydroxyphenylacetylene was added (30 mg, 0.25 mmol) and the reaction was stirred at room temperature for an additional 3.5 hours. After proceeding for 5 hours the reaction was partitioned between EtOAc and H2O and the EtOAc layer washed with H2O, brine, dried with anhydrous Na24 and concentrated. The residual dark oil was purified by chromatography (silica gel, CHCl3/EtOAc) and the product containing fractions were concentrated. The resulting solid was triturated with EtOAc/hexane to give the title compound as an off-white solid (37 mg, 32 %).
Example 434
(S)-3-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoic acid
A mixture of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5- [(trimethylsilyl)ethynyl]nicotinamide (54 mg, 0.15 mmol), 3-iodobenzoic acid (56 mg, 0.23 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.02 mmol), triphenylphosphine (1.0 mg, .004 mmol) and triethylamine (0.073 mL, 0.53mmol) in 1.5 mL DMF at room temperature was degassed using vacuum and a H2/N2 (1 :1) mixture and then copper(I)iodide (2 mg, 0.01 mmol) added. The reaction was heated to 60 0C then tetrabutylammonium fluoride (1.0 M in THF, 0.15 ml) added over 3.5 minutes. After 25 minutes the reaction was partitioned between EtOAc and dilute AcOH. The EtOAc layer was collected and washed with H2O, brine, dried with anhydrous Na24 and concentrated to a yellow solid. The solid was triturated with EtOAc at room temperature to give the title compound as a yellow solid (45 mg, 74%).
Example 435
(S)-5-[(4-acetylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 434 a mixture of (S)-5-ethynyl-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodoacetophenone were reacted to give the title compound as a light yellow foam (52 mg, 86%).
Example 436 (S)-5-[(4-hydroxy-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-
[methyl [((ooxxoo))pphheennyyll--λλ66--ssuullffaannyylliiddeennee]]nniiccoottiinnaammiiddee aanndd 44--iiooddo-2-methylphenol were reacted to give the title compound as a light yellow solid (43 mg, 73%).
Example 437
((SS))--22--hhyyddrrooxxy; -5- { [5-( { [methyl(oxo)phenyl-λ6-sulfanylidene] amino } carbonyl)pyridin-3 - yl]ethynyl}benzoic acid
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N- [methyl [((ooxxoo))pphheennyyll--λλ66--ssuullffaannyylliiddeennee]]nniiccoottiinnaammiiddee a and 5-iodosalicyclic acid were reacted to give the title compound as a light tan solid (28 mg, 45%).
Example 438
((SS))--4-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoic acid
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-
[methyl [((ooxxoo))pphheennyyll--λλ66--ssuullffaannyylliiddeennee]]nniiccoottiinnaammiiddee aanndd L 4-iodobenzoic acid were reacted to give the title compound as a light yellow solid (30 mg, 49%).
Example 439 (S)-5-(lH-imidazol-5-ylethynyl)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo- lH-imidazole were reacted to give the title compound as a white foam (24 mg, 46%).
Example 440
(S)-5-(lH-imidazol-2-ylethynyl)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 2-iodo-lH-imidazole were reacted to give the title compound as a white solid (15 mg, 29%).
Example 441
(S)-5-[(2 -methyl- lH-imidazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo-2-methyl-lH-imidazole were reacted to give the title compound as an off-white foam (28 mg, 51%).
Example 442 (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(lH-pyrazol-4-ylethynyl)nicotinamide
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N- [methyl i((ooxxoo))pphheennyyll--λλ66--ssuullffaannyylliiddeennee]]nniicotinamide and 4-iodopyrazole were reacted to give the title compound as a white film (15 mg,
Example 443 (S)-5-[(6-hydroxypyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
A solution of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]- nicotinamide (150 mg, 0.42 mmol) and 2-hydroxy-5-iodopyridine (105.4 mg, 0.46 mmol) in DMF (2.1 mL) was degassed (vacuum and argon). The resulting solution was treated tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol), triethylamine (0.08 mL, 0.55 mmol), and CuI (8 mg, 0.042 mmol). The reaction mixture was then heated to 85 0C and tetrabutylammonium fluoride (1.0 M solution in THF, 0.46 mL, 0.46 mmol) was added dropwise over 10 min. The reaction was allowed to be stirred at 85 0C for 2 hours. The reaction mixture was partitioned between EtOAc and H2O. The organic extracts and associated solid were collected and concentrated. The residue was purified by chromatography (silica gel, gradient elution MeOH-CHCl3: 1 : 100-1 :4). The product containing fractions were collected, concentrated, and the brown solid residue was triturated with a combination of MeOH and EtOAc. The resulting mixture was filtered and the filtrate allowed to stand at room temperature. The solid which precipitated from solution was collected and dried to give the title compound as a white solid (11 mg).
Example 444
(S)-5-(lH-indol-6-ylethynyl)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that described in Example 443, (S)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 6-bromoindole (90.7 mg, 0.46 mmol) were reacted to give the title compound (30 mg). Example 445
((SS))--55--[[((22,,33--ddii(oxo-2,3-dihydro-lH-indol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
In a manner similar to that described in Example 443, (S)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromoisatin (116 mg, 0.46 mmol) were reacted to give the title compound as a reddish oil (40 mg).
Example 446 (S)-5-[(6-chloropyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that described in Example 443, (S)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (250 mg, 0.70 mmol) and 2-chloro-5- iodopyridine (173 mg, 0.70 mmol) were reacted to give the title compound as white solid (250 mg).
Example 447 (S)-5-[(6-aminopyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
In a manner similar to that described in Example 443, (S)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (100 mg, 0.28 mmol) and 2-amino-5- iodopyridine (69.3 mg, 0.31 mmol) were reacted to give the title compound as light yellow solid (89 mg).
Example 448 ((SS))--NN-- [[mmeetthhvyl(oxo)phenyl-λ6-sulfanylidene]-5-[(2-oxo-2,3-dihydro-l,3-benzoxazol-5- yl)ethynyl]nicotinamide
In a manner similar to that described in Example 443, (S)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromo-2- benzoxazolinone (102 mg, 0.46 mmol) were reacted to give the title compound as light yellow solid (71 mg).
Example 449 (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({4-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide. In a 4 mL vial, thiophene-2-carboxylic acid (4-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were added and dissolved into EtOAc (2 mL). The mixture was then degassed for -20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (20.7 mg, 0.0295 mmol) and CuI (2.8 mg, 0.148 mmol). The reaction mixture was allowed to stir at 50 0C for 3 hours after which the reaction mixture was extracted twice with EtOAc (~5 mL) and of water (~5 mL). The organic extracts were combined and dried over anhydrous Na2SOzt(s) and then concentrated in vacuo. The crude residue was then purified by chromatography (silica gel, gradient elution, 25% EtO Ac/hexanes to 100% EtOAc/hexanes). The product containing fractions were concentrated to give the title compound as a tan solid (87 mg, 0.18 mmol, 61%).
Example 450
(S)-5- {[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide.
In a manner similar to that described in Example 449, N-(3-ethynyl-phenyl)-acetamide (0.0469 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (83 mg, 0.20 mmol,
Example 451
(S)-5-( {4- [(2,6-difluorobenzoyl)amino]phenyl} ethynyl)-N- [methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2,6-difluoro- benzamide (0.114 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- λ6- sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (113 mg, 74%)
Example 452
(S)-5-({4-[(4-fluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide.
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-fluoro- benzamide (0.106 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (106 mg, 72%).
Example 453 (S)-5-({4-[(4-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-methyl- benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (118 mg, 81%).
Example 454 ((SS))--55--(({{44--[[((22--methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide.
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2-methyl- benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound (109 mg, 75%).
Example 455
tert-butyl (4-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yl]ethynyl}phenyl)carbamate
Step 1 tert-butyl 4-ethynylphenylcarbamate.
A dry 25mL flask was charged with 3-ethynyl-phenylamine (0.100 g, 0.855 mmol) and then THF (5 mL) was added. Di-tert-butyl dicarbonate (0.242 g, 1.11 mmol) was added to the THF solution followed by NEt3 (0.23 ImL, 1.71 mL). The mixture was allowed to stir at 55 0C after which it was cooled to room temperature and extracted twice with EtOAc (-10 mL), water (-10 mL) and saturated aqueous NaHCO3. The combined organic extracts were dried over anhydrous Na2SOzt(s) and then concentrated to give the title compound (0.15 g, 0.67 mmol,
Step 2 (S)-tert-butyl (4-{[5-({[methyl(oxo)phenyl-λ6-sulfanyh'dene]amino}carbonyl)pyridin-3- yl] ethynyl} phenyl)carbamate
In a manner similar to that described in Example 449, tert-butyl 4-ethynylphenylcarbamate (0.096 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (63 mg, 0.13 mmol, 45%).
Example 456
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide.
Step 1 N-(3-ethynylphenyl)thiophene-2-carboxamide
A dry 25mL flask was charged with thiophene-2-carbonyl chloride and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55 0C. The reaction mixture was then allowed to cool to room temperature and extracted with EtOAc (-10 mL), IM HCl (-10 mL), followed by brine (-10 mL). The combined organic extracts were combined and dried over anhydrous Na2SO4(s) and the concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 50%). The product containing fractions were concentrated to give the title compound as a tan solid (0.33 mg, 1.45 mmol, 85%).
Step 2 ((SS))--NN--[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide.
In a manner similar to that described in Example 449, thiophene-2-carboxylic acid (3- ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (44 mg, .092 mmol, 31%).
Example 457 (S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide Step 1
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide
A dry 25mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55 0C. The reaction mixture was then allowed to cool to room temperature. The reaction was extracted twice with EtOAc (~5mL) and water (-10 mL) followed by saturated aqueous NaHCC>3(~10 mL). The combined organic layers were dried over anhydrous Na2SC^ (s) and then concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 60%). The product containing fractions were concentrated to give the title compound as a tan solid (147 mg.
Step 2
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide.
In a manner similar to that described in Example 449, 2,5-Dimethyl-2H-pyrazole-3- carboxylic acid (3-ethynyl-phenyl)-amide (0.0354 g, 0.222 mmol) and (S)-5-bromo-N-
[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) were reacted to give the title compound as a white solid (47 mg, 64%).
Example 458
NN--[[mmeetthhyyll((ooχxιo)phenyl-λ6-sulfanylidene] -5-( {3 - [(3 -methylthienyl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide
Step 1 N-(3-ethynylphenyl)-3-methylthiophene-2-carboxamide
A dry 25mL flask was charged with 3-methylthiophene-2-carboxylic acid (0.201 g, 1.41 mmol) followed by thionyl chloride (10 mL). The reaction was heated to 50 0C for 2 h after which the reaction was cooled to room temperature and concentrated to afford the crude acid chloride. The crude acid chloride was dissolved into 10 mL of THF and 3-ethynyl-phenylamine (0.165 g, 1.41 mmol) was added to the solution followed by NEt3, and the mixture was allowed to stir at 55 0C for 4 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and water. The organic layer was then washed once with of IM HCl (-10 mL) and then twice with of saturated aqueousNaHCO3 (-10 mL). The organic extracts were combined, dried over anhydrous Na2SO4(s) and then concentrated to give the title compound as a tan solid (265 mg, 1.10 mmol, 78%).
Step 2
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(3-methylthienyl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described in Example 449, N-(3-ethynylphenyl)-3- methylthiophene-2-carboxamide (0.213 g, 0.885 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl- λ6-sulfanylidene]nicotinamide (0.200 g, 0.590 mmol) were reacted to give the title compound as a solid (274 mg, 93%).
Example 459
(S)-tert-butyl (3-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yl] ethynyl} phenyl)carbamate.
Step 1 tert-butyl 3-ethynylphenylcarbamate
A dry 25mL flask was charged with 3-ethynyl-phenylamine (0.100 g, 0.855 mmol) and THF (5 mL) was added. Di-tert-butyl dicarbonate (0.242 g, 1.11 mmol) was added to the THF solution followed by NEt3 (0.23mL, 1.71 mmol). The mixture was allowed to stir at 55 0C after which it was cooled to room temperature and extracted twice with EtOAc (-10 mL), water (-10 mL) and saturated aqueous NaHCO3. The combined organic extracts were dried over anhydrous Na2SO4(S) and then concentrated to give the title compound (0.13 g, 0.67 mmol, 72%).
Step 2
(S)-tert-butyl (3-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yl] ethynyl} phenyl)carbamate. In a manner similar to that described in Example 449, tert-butyl 3-ethynylphenylcarbamate (0.098 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) reacted to give the title compounds as a white solid (32 mg, 23%).
Example 460
(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
Step 1
N-(3-ethynylphenyl)-2-methylbenzamide.
A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g, 1.00 mmol) was cooled to room temperature, and THF (10 mL) was added. 3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solution of the acid chloride followed by NEt3 (0.272 mL, 2.00 mmol), and the mixture was allowed to stir at 55 0C. The reaction mixture was then allowed to cool to room temperature and partitioned between EtOAc (10 mL) and H2O (15 mL). The organic layer was washed with then washed once with IM HCl (-20 mL) followed by of saturated aqueous NaHCO3 (-20 mL) and of brine (-20 mL). The organic extracts were concentrated and the crude residue was purified by chromatography (silica gel, gradient elution EtOAc/hexanes 10 to 70%). The product containing fractions were concentrated to give the title compound as a tan solid (434 mg, 0.88 mmol, 88%).
Step 2 ((SS))--55--(({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5- bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for -20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50 0C for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL). The organic extracts were combined, dried over anhydrous Na24 and concentrared. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
Example 461
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(3-methylruryl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide
Step 1
N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide.
A dry 25 mL flask was charged with 3-methylfuran-2-carboxylic acid (0.500 g, 3.46mmol) and thionyl chloride (10 mL). The reaction was heated to 50 0C and allowed to react for 2 h. The reaction was then cooled to room temperature and concentrated affording the crude acid chloride.
The acid chloride was then dissolved in THF (5 mL) and 3-ethynyl-phenylamine (0.41 g, 3.47 mmol) was added followed by NEt3 (0.95 mL, 7 mmol). The mixture was allowed to stir at 55 0C for 3 hours and the cooled to room temperature. The reaction was then partitioned between EtOAc and water. The organic layer was then washed once with IM HCl (5 mL) and then once with saturated aqueous NaHCO3 (5 mL). The organic extracts were then concentrated to give the title compound as a light brown solid (631 mg, 2.80 mmol, 81%).
Step 2
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(3-methylfuryl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described in Example 460, N-(3-ethynylphenyl)-3-methylfuran-
2-carboxamide (0.199 g, 0.885 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (0.200 g, 0.590 mmol) were reacted to give the title compound as a solid (243 mg, 87%).
Example 462
(S)-tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yljethynyl} - 1 ,3-thiazol-2-yl)carbamate Step 1 tert-buiyl (5-bromo-l,3-thiazol-2-yl)carbamate The title compound was prepared by a modification of the procedure described in J. Med. Chem. 2005, 48, 1886-1900. A mixture of 2-amino-6-bromothiazole monohydrobromide (390 mg, 1.5 mmol) and NaHCO3 (441 mg, 5.3 mmol) in 6.0 mL tert-butyl alcohol was heated for 1 minute at near reflux, then cooled to room temperature. To this mixture was added DMAP (18 mg, 0.15 mmol) and di-tert-butyl dicarbonate (1.0 M in THF, 1.65 mL) and the reaction stirred at room temperature for 16 hours. In order to drive reaction to completion, additional di-tert-butyl dicarbonate (1.0 M in THF, 0.5 mL) was added, the reaction heated at 50 0C for 2 hours, then di- tert-butyl dicarbonate (1.0 M in THF, 1.0 mL) and 100 mg NaHCO3 added and continued heating at 50 0C an additional 2 hours. The mixture was filtered and rinsed with EtOAc, then the EtOAc filtrate washed with H2O, dilute aqueous HCl, saturated NaHCO3 solution, brine, dried with anhydrous anhydrous Na2SO4 and rotary evaporated. The brown solid was chromatographed eluting with hexane/EtOAc and the product triturated with hexane to give the title compound as a cream solid (204 mg, 49%).
Step 2
(S)-tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yljethynyl} - 1 ,3-thiazol-2-yl)carbamate
A mixture of N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (73 mg, 0.21 mmol), tert-butyl (5-bromo-l,3-thiazol-2-yl)carbamate (74 mg, 0.27 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol), triphenylphosphine (2.7 mg, .004 mmol) and triethylamine (0.071 mL, 0.51 mmol) in 1.8 mL DMF at room temperature was degassed using vacuum and a H2/N2 (1: 1) mixture and then copper(I)iodide (2 mg, 0.01 mmol) added. While stirring the mixture at room temperature, tetrabutylammonium fluoride (1.0 M in THF, 0.21 mL) was added over 2.5 minutes. After 5 minutes the reaction was heated at 60 0C for 2 hours. The reaction was partitioned between EtOAc and H2O and the EtOAc layer washed with H2O, aqueous HCl, saturated NaHCO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The brown oil was chromatographed eluting with hexane/acetone and the product containing fractions were concentrated to give the title compound as a light yellow solid (17 mg, 18%).
Example 463
(S)-5-[(2-amino-l,3-thiazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide To a solution containing tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6- sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-l,3-thiazol-2-yl)carbamate (16 mg, 0.032 mmol) in 2.0 mL dichloromethane at room temperature was added trifluoroacetic acid (0.099 mL, 1.3mmol). The reaction was stirred at room temperature for 17 hours, then partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, dried with anhydrous Na24 and rotary evaporated. The resulting solid film was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a tan solid (9 mg, 74%).
Example 464 (S)-5- {[2-(benzoylamino)-l,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-lambda~4 — sulfanylidene]nicotinamide
Step 1
N-(5-bromo- 1 ,3-thiazol-2-yl)benzamide
A mixture of 2-amino-6-bromothiazole monohydrobromide (156 mg, 0.6 mmol) in 2.0 mL pyridine (degassed) at room temperature was added benzoyl chloride (0.058 mL, 0.5mmol) over 1 minute. After stirring at room temperature for 20 minutes the reaction was quenched with H2O, and then extracted into EtOAc. The EtOAc layer was washed with H2O, saturated NaHCO3 solution, brine, dried with anhydrous Na24 and rotary evaporated. The solid was triturated with hot 10% EtOAc/hexane to give a quantitative yield (142mg) of the title compound as a light tan solid.
Step 2 5-{[2-(benzoylamino)-l,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide
In a manner similar to that described in Example 462, 5-ethynyl-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (74 mg, 0.26 mmol), N-(5-bromo-l,3-thiazol-2-yl)benzamide (74 mg, 0.26 mmol) were reacted to give the title compound as a cream solid (33 mg, 26%).
Example 465 (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide
Step 1 methyl 6-amino-5-iodonicotinate To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanol at room temperature was added silver sulfate (4.37 g, 14.0 mmol) and methyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours the reaction was filtered to isolate a tan precipitate. The solid was heated with 20% MeOH/CHCl3 then cooled to room temperature, filtered, and rinsed with MeOH and CHCl3. The filtrate was evaporated, dissolved in hot MeOH, filtered to remove brownish impurities, and then crystallized from MeOH to give the title compound as a light tan solid (1.73g,
Step 2
6-amino-5-iodonicotinic acid
A solution of methyl 6-amino-5-iodonicotinate (723 mg, 2.6 mmol) and potassium hydroxide (729 mg, 13.0 mmol) in 40 mL methanol/H2O (3: 1 ratio) was heated at 50 0C. After 4 hours 10 mL THF was added and the reaction continued until 22 hours. The reaction was cooled to room temperature and concentrated HCl added until the solution was pH 4. The solution was concentrated to a volume of 15mL and the resulting precipitate filtered, rinsed with H2O and 40% EtOAc/hexane to give the title compound as a white solid (443mg, 65%).
Step 3 (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a solution of 6-amino-5-iodonicotinic acid (330 mg, 1.3 mmol), N, N- diisopropylethylamine (0.44 mL, 2.5 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (291 mg, 1.9 mmol) in 7.0 mL DMF at room temperature was added BOP (608 mg, 1.4 mmol). The solution was stirred 10 minutes and then heated at 60 0C for 5 hours. The mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, hexane/acetone). The product containing fractions were purified by chromatography one additional time (silica gel, EtOAc/MeOH). To give the title compound as a white foam (354 mg, 71%). Step 4 (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide
To a degassed solution containing (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was added triethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol), and copper(I)iodide (16 mg, 0.09 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. Then added 30 mL ethyl ether to the dark oil, filtered to remove the dark precipitate. The organic extracts were concentrated and the residue was purifed by chromatography (silica gel, ethyl ether/EtOAc) to the title compound as a tan foam (317 mg,
Example 466 (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a solution of (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5- [(trimethylsilyl)ethynyl]nicotinamide (308 mg, 0.83 mmol) in 20 mL THF/methanol (1 : 1 ratio) at 0 0C was added K2CO3 (344 mg, 2.5 mmol) added. After 7 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (193 mg, 78 %).
Example 467 6-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
A mixture of (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (60 mg, 0.2 mmol), 3-iodophenol (66 mg, 0.3 mmol), triethylamine (0.07 mL, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol), triphenylphosphine (1.3 mg, .005 mmol) in 1.8 mL DMF at room temperature was degassed using a H2/N2 (1 : 1) mixture and then copper(I)iodide (2 mg, 0.01 mmol) added. The reaction was heated at 60 0C for 15 minutes and then partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to a brown oil. Before chromatography a different lot of product (23 mg) was added and the combined lots were purified by chromatography (silica gel, EtOAc/EtOH) to the title compound as an off-white solid (91 mg,
Example 468
(S)-6-amino-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide In a manner similar to that describe in Example 467, (S)-6-amino-5-ethynyl-N-
[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodophenol are converted to the title compound (41 mg, 62%).
Example 469 (S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
Step 1
(S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide To a solution of 2-amino-5-bromonicotinic acid (189 mg, 0.87 mmol), N, N- diisopropylethylamine (0.30 mL, 1.7 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (162 mg, 1.0 mmol) in 4.0 mL DMF at room temperature was added BOP (423 mg, 0.96 mmol). The solution was stirred 30 minutes, then heated at 60 0C for 30 minutes, and then cooled back to room temperature. After 19 hours, the mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na24 and rotary evaporated. The yellow foam was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a light yellow solid (260 mg, 84%).
Step 2
(S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide
To a degassed solution containing (S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide (106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in 2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol), and copper(I)iodide (6 mg, 0.03 mmol). The reaction was stirred at 70 0C for 3.3 hours. Additional 3- hydroxyphenylacetylene was added (50 mg, 0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reaction was cooled to room temperature, and after 23 hours additional dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) was added. The reaction was heated to 60 0C and 3-hydroxyphenylacetylene (120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7 minutes. The heat was removed after 1 hour and the reaction stirred an additional 22 hours at room temperature. The reaction was dissolved in EtOAc and washed with H2O. The EtOAc layer was extracted with 2% aqueous HCl. The combined acidic aqueous layers were washed with 30% EtOAc/hexane and then made basic with Na2CO3. The basic aqueous layer was extracted with EtOAc. Then the combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (5 mg, 4%).
Example 470
Step 1 (S)-trimethyl { [methyl(oxo)phenyl-λ6-sulfanylidene] amino } silane
To a stirred pre-warmed solution of (S)-(+)-S-methyl-S-phenylsulphoximine (3 g, 18.7 mmol) in acetonitrile (2 mL) at 65 0C was added (trimethylsilyl)diethylamine (4.12 g, 21.1 mmol) dropwise via a syringe. The reaction was maintained at 65 °C and stirred for 3 hours. Additional amount of (trimethylsilyl)diethylamine (2 mL, 10.2 mmol) was added and the reaction mixture was stirred at 65 0C overnight. The reaction was then concentrated under reduced pressure and dried under vacuum to give the title compound. This material was used directly in next step of the synthesis without further purification.
Step 2
(S)-Ethyl [S-phenyl-N-(trimethylsilyl)sulfonimidoyl]acetate
To a 100 mL round bottom flask equipped with a magnetic stir-bar and a rubber septum was added a solution of 2,2,6,6-tetra-methylpiperidine (8.91 mL, 52.5 mmol) in anhydrous THF (22 mL). The solution was cooled to 0 0C and was treated with n-BuLi (18 mL, 45 mmol) (2.5 M in hexanes) via a syringe. The resulting solution was stirred for 10 min at 0 0C, cooled to -78 0C, and treated dropwise with a solution of (S)-trimethyl{[methyl(oxo)phenyl-λ6- sulfanylidene] amino} silane (18.7 mmol) in THF (10 mL). The reaction mixture was stirred at -78 0C for 30 min and then was treated with ethyl chloroformate (5.16 mL, 52.5 mmol) dropwise. The reaction mixture was stirred for an hour and warmed to room temperature. The reaction mixture was treated with saturated aqueous NH4Cl (2.5 mL). The white solid which formed was collected by filtration and discarded. The filtrate was treated with additional saturated aqueous NH4Cl solution and the resulting mixture was stored in a -20 0C fridge for 15 hours. The organic layer was collected and concentrated to give the title compound. This material was used directly in the next step of the synthesis
Step 3
(S)-Ethyl (S-phenylsulfonimidoyl)acetate
A solution of Ethyl [S-phenyl-N-(trimethylsilyl)sulfonimidoyl] acetate (18.7 mmol, obtained as crude oil from step 2) in MeOH-H2O (10: 1, 7.5 mL) was treated with cesium fluoride (0.25 g, 1.65 mmol) in one portion. The reaction mixture was heated to 50 0C and stirred for 2 hours. The reaction mixture was concentrated, the residue absorbed to silica gel and purified by chromatography (silica gel, EtOAc-Hexane, Et3N 0.1 %). The product containing fractions were concentrated to give the title compound as a pale yellow oil (1.65g, 39 % for steps 1 - 3).
Step 4 (S)-Ethyl {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl} acetate
To a solution of 5-bromonicotinic acid (343 mg, 1.66 mmol) in anhydrous DMF (5.5 mL) was added N,N-diisopropylethylamine (0.58 mL, 3.32 mmol) and ethyl (S- phenylsulfonimidoyl)acetate (415 mg, 1.83 mmol) followed by the final addition of (benzotriazol- l-yloxy)-tris(dimethylamino)-phophonium hexafluorophophate (0.81 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 20 min, and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated and washed once with brine and dried over anhydrous Na2SOzI. The organic layer was concentrated and the residue purified by chromatography (silica gel, gradient elution (5: 1 Hexane/EtOAc to 3: 1 Hexane/EtOAc). The product containing fractions were concentrated to give the title compound as a white solid (230 mg, 34 %).
Step 5
(S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S- phenylsulfonimidoyl] acetate
A solution ethyl {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl} acetate (216 mg, 0.52 mmol) and 3-hydroxyphenylacetylene (0.052 mL, 0.79 mmol) in anhydrous DMF (3 mL) was treated with triethylamine (0.22 mL, 1.58 mmol). The reaction mixture was degassed (alternating vacuum and argon) and PdCl2(Ph3P)2 (36.9 mg, 0.052 mmol) and triphenylphosphine (3.4 mg, 0.013 mmol) were added. The reaction mixture was degassed (alternating vacuum and argon) and placed under an atmosphere of 1 :3 Argon/hydrogen atmosphere. Copper( I+) iodide was added and the reaction mixture was heated at 60 0C for 50 min. The brown reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was collected and washed further with saturated aqueous NaHCO3 (IX), brine (IX), and dried over anhydrous Na2SO4. The residue was purified by chromatography (silica gel, 50: 1 CHCl3 :MeOH). The product containing fractions were concentrated to give the title compound as a light yellow solid (220 mg, 94 %).
Example 471 (S)-N-[(2-{[2-(diethylamino)ethyl]amino}-2-oxoethyl)(oxo)phenyl-λ6-sulfanylidene]-5-[(3- hydroxyphenyl)ethynyl]nicotinamide
(S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S- phenylsulfonimidoyl] acetate (73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was added N,N- diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reaction mixture was heated at 30 0C for 4 hours. The reaction mixture was evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed once with brine, dried (anhydrous Na2SO4), concentrated. The residue was purified by chromatography (silica gel, 50:1 CHCl3: MeOH to 10:1 CHCl3MeOH) . The product containing fractions were concentrated to give the title compound as a foamy solid (50 mg, 59 %).
Example 472
(S)-N-[{2-[(2-hydroxyethyl)(methyl)amino]-2-oxoethyl}(oxo)phenyl-λ6-sulfanylidene]-5-[(3- hydroxyphenyl)ethynyl]nicotinamide
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3- hydroxypheny^ethynyljpyridin-S-yljcarbony^-S-phenylsulfonimidoyllacetate (65 mg, 0.14 mmol) and 2-(methylamino)ethanol (0.1 mL, 1.2 mmol) were reacted to give the title as clear oil (42 mg, 61 %).
Example 473
5-[(3-hydroxyphenyl)ethynyl]-N- {[2-(methylamino)-2-oxoethyl](oxo)phenyl-λ6- sulfanylidene} nicotinamide
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3- hydroxypheny^ethynyljpyridin-S-yljcarbony^-S-phenylsulfonimidoyllacetate (50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0 mmol) were reacted to give the title compound as colorless oil (43 mg, 90 %).
Example 474
N-[{2-[(2-hydroxyethyl)amino]-2-oxoethyl}(oxo)phenyl-λ6-sulfanylidene]-5-[(3- hydroxyphenyl)ethynyl]nicotinamide In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3- hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81 %).
Example 475
N-[{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}(oxo)phenyl-λ6-sulfanylidene]-5-[(3- hydroxyphenyl)ethynyl]nicotinamide
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3- hydroxypheny^ethynyljpyridin-S-yljcarbony^-S-phenylsulfonimidoyllacetate (75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) were reacted to give the title compound as colorless oil (40 mg, 50 %).
Example 476
(S)-5-[(2-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
Step 1
N-(3-ethynylphenyl)- 1 ,3-dimethyl- lH-pyrazole-5-carboxamide
In a manner similar to that described in Example 457, 2,5-dimethyl-2H-pyrazole-3- carbonyl chloride (0.135 g, 0.854 mmol) was and 2-ethynyl-phenylamine (0.100 g, 0.854 mmol) were reacted to give the title compound as a tan solid (0.101 mg, 53 %).
Step 2
(S)-5-[(2-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 460 (step 2) N-(3-ethynylphenyl)-l,3- dimethyl-lH-pyrazole-5-carboxamide (0.0354 g, 0.222) and (S)-5-bromo-N-
[methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) reacted to give the title compound as a white solid (0.025 g, 34 %).
Example 477
(S)-5-({2-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[methyl(oxido)phenyl-λ4- sulfanylidene]nicotinamide
Step 1 3-Methyl-furan-2-carboxylic acid (2-ethynyl-phenyl)-amide
In a manner similar to that described in Example 458 (step 1), 3-methylthiophene-2- carboxylic acid (0.100 g, 0.794 mmol) and 2-ethynyl-phenylamine (0.093 g, 0.794 mmol) were reacted to give the title compound as a tan solid (0.110 g, 56 %).
Step 2 (S)-5-({2-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[methyl(oxido)phenyl-λ4- sulfanylidene]nicotinamide
In a manner similar to that described for Example 460(step T), (S)-5-bromo-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) and 3-methyl-furan-2- carboxylic acid (2-ethynyl-phenyl)-amide (0.050 g, 0.222 mmol) were reacted to give the title compound (0.031 g, 43%).
Example 478
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)amino]carbonyl}phenyl)ethynyl]-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
Step 1 N-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-ethynyl-benzamide 3-Ethynylbenzoic acid (0.1 g, 0.685 mmol) was added to a dry 50 mL round bottom flask and dissolved in DMF (6.85 mL). To the resulting solution was added l,3-dimethyl-lH-pyrazol-5- amine (0.076 g, 0.685 mmol), followed by BOP (0.393 g, 0.890 mmol), and 0.238 mL of DIPEA (1.37 mmol). This reaction mixture was heated to 50 0C for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (15 mL) and extracted with brine (3 x 15 mL). The EtOAc layer was then washed with saturated aqueous NaHCθ3 (2 x 15 mL). The organics were dried over anhydrous Na2SO^8), filtered and concentrated in vacuo. The crude residue was purified via column chromatography (silica gel, gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) affording N-(l,3-dimethyl-lH-pyrazol-5-yl)-3-ethynylbenzamide (0.128 g,
Step 2
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)amino]carbonyl}phenyl)ethynyl]-N-
[methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 460 (step T), (S)-5-bromo-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide (0.141 g, 0.418 mmol) and N-(1, 3-dimethyl- lH-pyrazol-5-yl)-3-ethynylbenzamide (O. lg, 0.418mmol) were reacted to give the title compound
(0.126 g, 61%)
Example 479 (S)-5-({3-[(methoxyamino)carbonyl]phenyl}ethynyl)-N-[methyl(oxido)phenyl-λ4- sulfanylidene]nicotinamide Step 1
3 -Ethynyl-N-methoxy-benzamide
In a manner similar to that described for Example 478 (step 1), 3-ethynylbenzoic acid (0.1 g, 0.685 mmol) and O-methylhydroxylamine hydrogen chloride (0.057 g, 0.685 mmol) were reacted to give the title compound (0.128 g, 61 %).
Step 2
(S)-5-({3-[(methoxyamino)carbonyl]phenyl}ethynyl)-N-[methyl(oxido)phenyl-λ4- sulfanylidene]nicotinamide
In a manner similar to that described in Example 460 (step 2), (S)-5-bromo-N-
[methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) and 3-Ethynyl-N- methoxy-benzamide (0.106 g, 0.442 mmol) were reacted to give the title compound yield (0.126 g, 86 %)
Example 480
Methyl 3-{4-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]- amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}-propanoate
Step 1
5- [(3 - { [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino } phenyl)-ethynyl]nicotinic acid
In a 50 mL round bottom flask, N-(3-ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5- carboxamide (0.888 g, 3.71 mmol) and 5-bromo nicotinic acid (0.50 g, 2.47 mmol) were dissolved in DMF (15 mL) The mixture was then degassed by bubbling N2(g) through it for -20 min. The mixture was then treated sequentially with NEt3 (1.37 mL, 9.90 mmol), Pd(PPh3)2Cl2 (0.173g,
0.247 mmol) and CuI (0.094g, 4.95 mmol). The reaction mixture was allowed to stir at 50 0C for 4 h. The reaction mixture was diluted with EtOAc (25 mL) causing a pale yellow precipitate to form. The white precipitate was filtered off giving the title compound (0.105 g, 12 %).
Step 2
Methyl 3-[4-(methylthio)phenyl]propanoate
In a 100 mL round bottom flask, 3-(4-(methylthio)phenyl)propanoic acid (1.00 g, 5.10 mmol) was dissolved in DMF (17 mL) under N2(g). CDI (1.24g, 7.65 mmol) was then added to the reaction mixture and the resulting mixture was allowed to stir at room temperature for -45 min. MeOH (6 mL) was then added in dropwise fashion to the reaction. The reaction was allowed to stir for an additional 1 h, after which time it was extracted with EtOAc (3 x 50 mL) and brine(3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4(S), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution mixture: 10% EtOAc in Hexanes to 100% EtOAc) to give the title compound (0.771 g,
Step 3
Methyl 3-[4-(methylsulfinyl)phenyl]propanoate
In a 250 mL round bottom flask, methyl 3-(4-(methylthio)phenyl)propanoate (0.50 g, 2.38 mmol) was dissolved in MeOH under a N2(g). The resulting solution was cooled to 0 0C, then 0.5 M NaIO4 (4.76 mL, 2.38 mmol) was added dropwise to the cooled solution causing the formation of a white precipitate. The reaction was allowed to warm to room temperature. When HPLC indicated complete consumption of starting thioether, the reaction was filtered and the filtrate was concentrated. The resulting residue was taken up in CHCl3 (25 mL) then extracted with brine. The brine layer was subsequently extracted with CHCI3 (2 x 25 mL). The combined organic extracts were then dried over anhydrous Na2SO4(S), filtered and concentrated. The resulting sulfoxide was then purified by passing through a plug of silica using EtOAc/Hexanes as eluant affording methyl 3-(4-(methylsulfinyl)phenyl)propanoate (0.436 g, 81%).
Step 4 Methyl 3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}-propanoate
In a 100 mL round bottom flask, methyl 3-(4-(methylsulfmyl)phenyl)propanoate (0.4 g, 1.77 mmol) was added to CH2Cl2 (18 mL). Subsequently the reaction was treated with MgO (0.285 g, 7.08 mmol), trifluoroacetamide (0.400 g, 3.54 mmol), PhI(OAc)4 (0.884 g, 2.66 mmol), and Rh2(OAc)4 (19.55 mg, 0.0443mmol). The suspension was stirred overnight then filtered through celite. The filtrate was the concentrated. The resulting residue was purified via column chromatography (silica gel, gradient eluant mixture: 20% EtOAc in hexanes to 100% EtOAc) to give the title compound (0.294 g, 69%).
Step 5: Methyl 3-[4-(S-methylsulfonimidoyl)phenyl]propanoate
Methyl 3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}propanoate (0.200 g, 0.653 mmol) was dissolved in MeOH (3 mL). K2CO3 (0.450 g, 3.27 mmol) was added to the solution, and the resulting suspension was allowed to stir for 5 minutes. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and dried over anhydrous anhydrous Na2SO4(s) to give the title compound (0.147 g, 93%). Step 6
Methyl 3-{4-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]- amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}-propanoate
A solution of 5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)- ethynyl]nicotinic acid (0.149 g, 0.414 mmol) in DMF (4 mL) was treated with methyl 3-(4-(S- methylsulfonimidoyl)phenyl)propanoate (0.100 g, 0.414 mmol), followed by BOP (0.238 g, 0.539 mmol) and DIPEA (0.144 mL, 0.830 mmol). The reaction mixture was heated to 50 0C for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (10 mL) and extracted with brine (3 x 10 mL). The EtOAc layer was then washed with saturated aqueous Na2COs (2 x 10 mL). The organic layer was dried over anhydrous Na24(S), filtered and concentrated. The crude residue was purified via column chromatography (silica gel, gradient elution, EtOAc in Hexanes: 0% to 100% EtOAc) affording the title compound (0.108 g, 45%).
Example 481
3-{4-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3- yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoic acid
A solution of Methyl 3-{4-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}- phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoate (0.075 g, 0.129 mmol) in THF (3 mL) was cooled to 00C and slowly treated with 0.5M NaOH (1.29 mL,
0.643mmol). The reaction mixture was allowed to slowly come to room temperature. Once the reaction was done by TLC, the reaction was acidified with acetic acid and then extracted with
EtOAc (20 mL) and H2O (20 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered, and concentrated to give the title compound (0.052 g, 71%).
Example 482
N-[(4-{[3-(dimethylamino)propyl]amino}phenyl)(methyl)oxido-λ4-sulfanylidene]-5-[(3-{[(l,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
Step 1 : tert- Butyl [4-(methylthio)phenyl]carbamate
4-Methylsulfanyl-phenylamine (0.5 g, 3.59 mmol) was dissolved in THF (12 mL) The resulting solution was treated with di-tert butyl dicarbonate (1.02 g, 4.67 mmol) and then with
TEA (1.5 mL, 10.78 mmol). The reaction was heated at 50 0C for 3 h and then allowed to cool to room temperature. The cool reaction mixture was taken up in EtOAc (20 mL) and extracted with
H2O (20 mL). The organic layer was further washed with a saturated aqueous solution of NaHCθ3 (20 mL). The organic layer was dried over anhydrous Na2SO4(S), filtered and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) to the tilte compound (0.652 g, 76%).
Step 2: tert-Butyl [4-(methylsulfinyl)phenyl]carbamate
In a manner similar to that described in Example 480 (step 3), tert-Butyl [4- (methylthio)phenyl]carbamate (0.650 g, 2.72 mmol) was converted to the title compound (0.347 g,
Step 3: tert-butyl {4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}-carbamate In a manner similar to that described in Example 480 (step 4), tert-Butyl [4- (methylsulfinyl)phenyl]carbamate (0.300 g, 1.18 mmol) was converted to the title compound
(0.224 g, 52%).
Step 4: tert-Butyl [4-(S-methylsulfonimidoyl)phenyl]carbamate
In a manner similar to that described in Example 480 (step 5), tert-butyl {4-[S-methyl-N- (trifluoroacetyl)sulfonimidoyl]phenyl} -carbamate (0.224 g, 0.612 mmol) was converted to the title compound (0.15O g, 91%).
Step 5: tert-butyl (4- {N-[(5-bromopyridin-3-yl)carbonyl]-S- methylsulfonimidoyl}phenyl)carbamate
In a manner similar to that described in Example 480 (step 6), tert-Butyl [4-(S- methylsulfonimidoyl)phenyl]carbamate (0.141 g, 0.522 mmol) and 5-bromonicotinic acid (0.104 g, 0.522 mmol), were converted to the title compound (0.177 g, 75%).
Step 6:
N- [(4- { [tertbutyloxycarbonyljamino } phenyl)(methyl)oxido-λ4-sulfanylidene] -5- [(3 -{[(1,3- dimethyl-lH-pyrazol-5yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described in Example 460, tert-butyl (4- {N-[(5-bromopyridin- 3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)carbamate (0.158 g, 0.349 mmol) and 2,5- dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide (0.125 g, 0.0524 mmol) were reacted to give the title compound (0.108 g, 51%).
Step 7 : N- [(4- {amino } phenyl)(methyl)oxido-λ4-sulfanylidene] -5- [(3 - { [( 1 ,3 -dimethyl- IH- pyrazol-5-yl)carbonyl] amino } phenyl)ethynyl]nicotinamide The BOC protected N- [(4- {amino } phenyl)(methyl)oxido-λ4-sulfanylidene] -5- [(3 - {[(1,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (0.108 g, 0.177 mmol) was dissolved in CHCI3 (3.5 mL) and the resulting solution was cooled to 00C. The resulting reaction mixture was then treated slowly with CF3COOH (1 mL) and allowed to stir while warming to rt. The reaction mixture was stirred at room temperature for 4 hours and then was diluted with CHCI3 (5 mL). The organic mixture was extracted with H2O (5 mL), then with a saturated aqueous solution of NaHCO3 (2 x 5 mL) and then with brine (5 mL). The organic layer was then dried over anhydrous Na24(S), filtered and concentrated in vacuo give the title compound (0.086 g, 95%).
Step 8:
N-[(4-{[3-(dimethylamino)propyl]amino}phenyl)(methyl)oxido-λ4-sulfanylidene]-5-[(3-{[(l,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
N-[(4-{amino}phenyl)(methyl)oxido-λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol- 5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treated with (3-Chloro-propyl)-diethyl-amine (0.047g, 0.252mmol) and TEA (0.070 mL, 0.504 mmol). The reaction mixture was then heated to 1000C for 48 h then cooled to room temperature. The cooled mixture was dissolved in EtOAc (5 mL) and then extracted with water (3 x 5 mL) and with brine (5 mL). The organic layer was dried over anhydrous Na2SO^8), filtered and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to give the title compound (4 mg, 3.5%).
Example 483 Methyl 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3- yl]carbonyl}sulfonimidoyl)phenyl]propanoate
In a manner similar to that described in Example 480 (step 6), Methyl 3-(4-(S- methylsulfonimidoyl)phenyl)propanoate (0.25 g, 1.037 mmol) and 5-((3-(3-methylfuran-2- carboxamido)phenyl)ethynyl)nicotinic acid (0.326 g, 0.943 mmol) reacted to give the title compound (0.508 g,
Example 484:
3-[4-(S-methyl-N- {[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3- yljcarbonyl} sulfonimidoyl)phenyl]propanoic acid In a manner similar to that described in Example 481, Methyl 3-(4-(S-methyl-N-(5-((3-(3- methylfuran-2-carboxamido)phenyl)ethynyl)-nicotinoyl)-sulfonimidoyl)phenyl)propanoate (0.4 g, 0.703mmol) was converted to the title compound (0.350 g, 89%).
Example 485
5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-{methyl[4-(3-morpholin-4-yl-3- oxopropyl)phenyl]oxido-λ4-4-sulfanylidene}nicotinamide
3-[4-(S-methyl-N- {[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3- yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.050 g, 0.090 mmol) was dissolved in DMF (1 mL) then treated with BOP (0.051 g, 0.117 mmol) and TEA (0.050 mL, 0.360 mmol) and allowed to stir for 20 min. Morpholine (0.015 mL, 0.180 mmol) was then added and the reaction was allowed to stir for an additional 4 h. The resulting reaction mixture was dissolved in EtOAc (5mL) and then extracted with brine (2 x 5 mL). The organic layer was then dried over anhydrous Na2SOzI(S), filtered and concentrated in vacuo. The crude mixture was then purified via column chromatography (silica gel, gradient eluant mixture of MeOH in EtOAc: 0% to 0% MeOH) give the title compound (0.023 g, 41%).
Example 486
N-[(4-{3-[(2,3-dihydroxypropyl)(methyl)amino]-3-oxopropyl}phenyl)-(methyl)oxido-λ4- sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3- methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 3-methylamino-propane-l,2-diol (0.050 mL, 0.520mmol) were reacted to give the title compound (0.020 g, 35%).
Example 487:
N-[{4-[3-(3-hydroxypyrrolidin-l-yl)-3-oxopropyl]phenyl}(methyl)oxido-λ4-sulfanylidene]-5-({3-
[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3- methyl-2-furoyl)amino]phenyl} -ethynyl)pyridin-3-yl]carbonyl} sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and pyrrolidin-3-ol (0.016 g, 0.180mmol) were reacted to give the title compound (0.015 g, 27%).
Example 488: N-{[4-(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl}-3-oxopropyl)phenyl](methyl)oxido-λ4- sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3- methyl-2-ruroyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 2-(2-piperazin-l-yl-ethoxy)-ethanol (0.030 mL, 0.180mmol) were reacted to give the title compound (0.030 g, 47%).
Example 489:
2-hydroxyethyl 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3- yl]carbonyl}sulfonimidoyl)phenyl]propanoate
3-[4-(S-methyl-N- {[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3- yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.150 g, 0.270 mmol) was dissolved in DMF (2.7 mL) then treated with EDCI (0.062 g, 0.324 mmol) and DMAP (0.003 g, 0.027 mmol) and allowed to stir at 60 0C for 30 min. Ethylene glycol (3 mL) was then added and the reaction was allowed to stir for 4 hours. The reaction mixture was then cooled to room temperature and dissolved in EtOAc (10 mL) and extracted with brine (3 x 10 mL). The organic layer was dried over anhydrous Na2SO4(S), filtered and concentrated in vacuo. The crude mixture was then redisolved in EtOAc (1 mL) and triturated with Hexanes (20 mL) causing the product to precipitate out. The resulting white solid to give the title compound (0.125 g, 77%).
Example 490 N-{[4-(hydroxymethyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}-ethynyl)nicotmamide
Step 1 : tert-butyl(dimethyl){[4-(methylthio)benzyl]oxy}silane t-Butyldimethylsilyl chloride (2.45g, 16.2 mmol) was dissolved in DMF (3.25 mL) then treated with imidazole (2.2 Ig, 32.4 mmol). The reaction mixture was allowed to stir for 20 minutes before 4-Methylsulfanyl-phenyl)-methanol (0.5g, 3.25mmol) was added. The reaction was stirred overnight and then dissolved in EtOAc (20 mL). The organic mixture was extracted with H2O (3 x 10 mL). The organic organic layer was dried over anhydrous Na2SO4(S), filtered and concentrated in vacuo. The crude residue was then purified purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOActo give the title compound (0.828g, 95%).
Step 2: tert-butyl(dimethyl){[4-(methylsulfinyl)benzyl]oxy}silane
In a manner similar to that described in Example 480 (step 3), tert-Butyl-dimethyl-(4- methylsulfanyl-benzyloxy)-silane (0.828 g, 3.08 mmol), was converted to the title compound in 82% yield (0.716 g, Step 3: tert-Butyl(dimethyl) {[4-(S- methyl-N-(trifluoroacetyl)-sulfonimidoyl)benzyl]oxy}silane
In a manner similar to that described in Example 480 (step 4), tert-butyl(dimethyl) {[4- (methylsulfinyl)benzyl]oxy}silane (0.716 g, 2.52 mmol) was converted to the title compound (0.524 g, 52%).
Step 4: tert-Butyl(dimethyl){[4-(S-methylsulfonimidoyl)benzyl]oxy}silane
In a manner similar to that described in Example 480 (step 5), tert-Butyl(dimethyl){[4-(S- methyl-N-(trifluoroacetyl)-sulfonimidoyl)benzyl]oxy}silane (0.524 g, 1.32 mmol) was converted to the title compound (0.385 g, 97%).
Step 5: N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5- ({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide
In a manner similar to that described in Example 480 (step 6), tert-Butyl(dimethyl){[4-(S- methylsulfonimidoyl)benzyl]oxy}silane (0.485 g, 1.62 mmol) and 5-((3-(3-methylfuran-2- carboxamido)phenyl)ethynyl)nicotinic acid (0.561 g, 1.62 mmol) were reacted to give the title compound (0.722 g, 71%)
Step 6 N-{[4-(hydroxymethyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}-ethynyl)nicotinamide
N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5- ({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide (0.722 g, 1.15 mmol) was dissolved in THF (2.3 mL). The resulting solution was treated with IM solution of TBAF in THF (2.3 mL, 2.30 mmol) causing the mixture to turn black in color. The mixture was allowed to stir for 1 h, subsequently dissolved in EtOAc (10 mL) and extracted with H2O (3 x 15 mL). The organic layer was dried over anhydrous Na2SO^8), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) to afford the tilte compound in 94% yield (0.350 g, 0.682 mmol).
Example 491
N-{[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl}methyl)phenyl](methyl)oxido-λ4- sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
Step 1 : N- {[4-(Bromomethyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide N-{[4-(hydroxymethyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotmamide (0.1 g, 0.195 mmol) and CBr4 ( 0.097 g, 0.293 mmol) were dissolved in CH2Cl2 (0.485 mL) and the resulting solution was cooled to 0 0C. PPh3 (0.858 g, 0.293 mmol) was dissolved in CH2Cl2 (0.250 mL) and then added dropwise to the 0 0C reaction mixture. Subsequently the reaction was allowed to warm to room temperature and stir for -1.5 h. The reaction was then diluted with CH2Cl2 (5 mL) and the resulting organic mixture was washed with a saturated aqueous solution OfNaHCO3 (5 mL), then with brine (5 mL). The organic layer was dried anhydrous Na2SO4(S), filtered and concentrated in vacuo. The crude product was then taken on without further purification.
Step 2: N- {[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl}methyl)phenyl](methyl)-oxido-λ4- sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
Crude N- {[4-(Bromomethyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide was dissolved in THF (2 mL). 2-(2-Piperazin- 1 -yl- ethoxy)-ethanol (0.064 g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to the solution and the resulting reaction mixture was allowed to stir for Ih at rt. The reaction mixture, subsequently, was dissolved in EtOAc and then extracted with H2O (2 x mL). The organic layer was dried over anhydrous Na2SO4(S), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g, 49% overall for step 1 and 2).
Example 492
Methyl 3-{4-[N-({6-amino-5-[(3- {[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino } phenyl)ethynyl]pyridin-3 -yl} carbonyl)- S- methylsulfonimidoyl]phenyl} propanoate
In a manner similar to that described in Example 480 (step 6), 6-Amino-5- {3-[(2,5- dimethyl-2H-pyrazole-3-carbonyl)-amino]-phenylethynyl} -nicotinic acid (0.250 g, 0.666 mmol) and methyl 3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.160 g, 0.666 mmol) were reacted to give the title compound (0.167 g, 42%)
Example 493 3-{4-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]- aminojpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllphenyllpropanoic acid
In a manner similar to that described for Example 481, methyl 3- {4-[N-({6-amino-5-[(3-
{[(l^-dimethyl-lH-pyrazol-S-y^carbonylJaminol-pheny^ethynylJpyridin-S-yllcarbony^-S- methylsulfonimidoyl]-phenyl}propanoate (0.167 g, 0.280 mmol) was converted to the title compound (0.150 g, 89%) Example 494:
3-[4-(N-{[6-amino-5-({3-[(3-methyl-2-fiαroyl)amino]phenyl}ethynyl)-pyridin-3-yl]carbonyl}-S- methylsulfonimidoyl)phenyl]propanoic acid
Step 1 : 6-Amino-5-{3-[(3-methyl-fiαran-2-carbonyl)-amino]-phenylethynyl} -nicotinic acid methyl ester
In a 4 mL vial, N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.607g, 2.70 mmol) and methyl 6-amino-5-iodonicotinate (0.5g, 1.80mmol) were dissolved in DMF (6 mL). The solution was degassed by bubbling N2(g) through it for -30 min. To the degassed solution was added DIPEA (1.25 mL, 7.19mmol), followed by Pd(PPh3)2Cl2 (0.126g, 0.18 mmol) and CuI
(0.068 g, 0.360 mmol). The reaction mixture was allowed to stir at 50 0C for 3 h. The reaction mixture then was taken up in EtOAc (10 mL) and was extracted with brine (3 x 10 mL). The organic layers were combined and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 25% to 100% EtOAc) to give the title compound as a white solid (0.554g,
Step 2: 6-Amino-5-{3-[(3-methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinic acid
Methyl 6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinate (0.550 g, 1.47 mmol) was dissolved in THF (15 mL) and then treated with 1.0 M NaOH (7.33 mL, 7.33 mmol). The reaction mixture was heated to 50 0C. Once the reaction was done by TLC, the reaction was cooled to room temperature and then acidified with acetic acid. The reaction mixture was taken up in of EtOAc (-15 mL) then extracted with H2O (2 x 15 mL). The water layer then was re-washed with EtOAc (-15 mL) and the combined organic layers were dried over anhydrous Na2SOzt(s). The mixture was then filtered and concentrated in vacuo to give the title compound (0.495 g, 1.37 mmol).
Step 3: Methyl 3-[4-(N- {[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3- yl]carbonyl}-S-methylsulfonimidoyl)phenyl]propanoate 6-Amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.1 g, 0.277 mmol) was dissolved in DMF (2.8 mL). EDCI (0.64 g, 0.332 mmol) and DMAP (3.42 mg, 0.028 mmol) were then added and the reaction mixture was stirred at 60 0C for 20 minutes. Methyl 3-(4- (S-methylsulfonimidoyl)-phenyl)propanoate (0.068 g, 0.277mmol) was then added, and the reaction was allowed to stir for 3 hours at 60 0C. The mixture was cooled to room temperature then taken up in EtOAc (10 mL) and extracted with brine (3 x 10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 10% MeOH) to give the title compound (0.060 g, 37%).
Step 4 3-[4-(N-{[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-pyridin-3-yl]carbonyl}-S- methylsulfonimidoyl)phenyl]propanoic acid
In a manner similar to that described in Example 481, methyl 3-(4-(N-(6-amino-5-((3-(3- methylfuran-2-carboxamido)phenyl)ethynyl)-nicotinoyl)-S- methylsulfonimidoyl)phenyl)propanoate (0.060 g, 0.103 mmol) was converted to the title compound in (0.040 g, 68%). Example 495
6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
Step 1
N-(3-iodophenyl)- 1 ,3-dimethyl- lH-pyrazole-5-carboxamide
To a solution of 3-iodoaniline (131 mg, 0.60 mmol) in 1.5 ml pyridine at room temperature was added over 2 minutes a solution of l,3-dimethylpyrazole-5-carbonyl chloride (79 mg, 0.50 mmol) in 0.3 ml 1 ,2-dichloroethane. The reaction was stirred at room temperature for 30 minutes, quenched into a NaHCθ3 solution, and extracted into EtOAc. The EtOAc solution was washed with NaHCθ3 solution, brine, dried with anhydrous Na24 and rotary evaporated. The resultant gummy solid was recrystallized from hexane/EtOAc to give the title compound as solid white needles (135 mg,
Step 2
6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- [methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide
A mixture of 6-amino-5-ethynyl-N-[methyl(oxido)phenyl-λ4-sulfanylidene]nicotinamide (42 mg, 0.14 mmol), N-(3-iodophenyl)-l,3-dimethyl-lH-pyrazole-5-carboxamide (57 mg, 0.17 mmol), triethylamine (0.049 ml, 0.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (8 mg, 0.011 mmol), and triphenylphosphine (1.8 mg, 0.007 mmol) in 1.2 ml DMF at room temperature was degassed using a H2/N2 (1 : 1) mixture and then copper(I)iodide (1.3 mg, 0.007 mmol) added. The reaction was stirred at room temperature for 15 minutes and then partitioned between EtOAc and saturated NaHCOs/brine mixture. The EtOAc layer was washed with NaHCOs/brine mixture, brine, dried with anhydrous Na2SO4 and rotary evaporated. The orange oil was chromatographed eluting with hexane/acetone to give the title compound as a light tan solid (64 mg, 90%).
Example 496
Step 1 [3-(methylsulfinyl)phenyl]acetic acid
In a manner similar to that described in Example 480 (step 3), 3-(methylthio)phenylacetic acid (2.55 g, 14.0 mmol) was converted to give the title compound as a light tan solid (2.36 g, 85%).
Step 2
Methyl [3 - (methylsulfmyl)phenyl] acetate
A solution of [3-(methylsulfmyl)phenyl]acetic acid (1.31 g, 6.60 mmol) and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirred at room temperature for 15 minutes, then methanol (2.ImL, 52.8 mmol) was added. After 10 minutes the reaction was briefly warmed to near reflux temperature, then allowed to cool to room temperature. After 20 minutes, the reaction was partitioned between EtOAc and NaHCOs/brine mixture. The EtOAc layer was washed with dilute brine, dilute HCl solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a yellow-orange oil (1.14 g, 82%).
Step 3
Methyl {3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl} acetate
In a manner similar to that decribed in Example 480 (step 4), methyl [3- (methylsulfinyl)phenyl] acetate (1.18 g, 5.54 mmol), was converted to the title compound as a white solid (1.23 g, 68%).
Step 4
Methyl [3-(S-methylsulfonimidoyl)phenyl]acetate In a manner similar that described in Example 480 (step 5), methyl {3-[S-methyl-N-
(trifluoroacetyl)sulfonimidoyl]phenyl}acetate (1.29 g, 3.98 mmol) was converted to the title compound as a cloudy white oil (849 mg, 94%).
Step 5 Methyl (3- {N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol), methyl [3-(S- methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), and catalytic DMAP in 15.0 ml DMF at room temperature was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg, 3.85 mmol). The reaction was stirred 1 hour at room temperature then added to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO3 solution, brine, dilute HCl/brine mixture, brine/NaHCO3 solution, dried with anhydrous Na24 and rotary evaporated. The oil was chromatographed eluting with CHCl3/EtOAc to give viscous clear oil (994 mg, 75%).
Step 6 methyl {3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl} carbonyl)-S-methylsulfonimidoyl]phenyl} acetate
In a manner similar to that described in Example 460, methyl (3-{N-[(5-bromopyridin-3- yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate (202 mg, 0.492 mmol) and N-(3- ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5-carboxamide (153 mg, 0.64 mmol), were converted to the title compound as a light yellow solid foam (275 mg, 98%).
Example 497
{3-[N-({5-[(3- {[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl} carbonyl)-S-methylsulfonimidoyl]phenyl} acetic acid A 50 ml THF solution of methyl {3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminolpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllphenyl} acetate (216 mg, 0.38 mmol) and 0.5M NaOH (6.1 ml, 3.04 mmol) was stirred at room temperature for 2 hours. The reaction was quenched with acetic acid (0.174 ml, 3.04 mmol) and rotary evaporated to remove the THF solvent. Additional impure lots of product (22 mg) were combined and the aqueous mixture partitioned between EtOAc and NaHCO3 solution. The EtOAc layer was extracted with another portion OfNaHCO3 solution. The combined basic aqueous layers were adjusted to pH 4 using 10% HCl and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried with anhydrous Na24 and rotary evaporated. The off-white solid foam was chromatographed eluting with CHCl3/MeOH and then recrystallized from a mixture of CHCl3/EtOAc/MeCN to give white solid (144 mg, 62%).
Example 498
Step 1
3-(methylsulfinyl)benzoic acid In a manner similar to that described in Example 480 (step 3), 3-(methylthio)benzoic acid (3.03 g, 18.0 mmol) to give the title compound as a white solid (3.11 g, 94%).
Step 2
Methyl 3-(methylsulfmyl)benzoate
In a manner similar to that described in Example 496 (step T), 3-(methylsulfmyl)benzoic acid was converted to the title compound.
Step 3
Methyl 3 -(S-methylsulfonimidoyl)benzoate
A solution of methyl 3-(methylsulfmyl)benzoate (3.23 g, 16.3 mmol), 2,2,2- trifluoroacetamide (3.69 g, 32.6 mmol), magnesium oxide (1.97 g, 48.9 mmol), rhodium(II)acetate dimer (0.18 g, 0.408 mmol), and iodobenzene diacetate (7.88 g, 24.5 mmol) in 150ml dichloromethane was stirred at room temperature. After 16 hours, the mixture was filtered past filter agent (Celite), rinsed with chloroform, and rotary evaporated. The sample was dissolved in EtOAc, washed with brine/dilute HCl, brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow-orange oil was dissolved in 60ml MeOH, K2CO3 (6.76 g, 48.9 mmol) added, and the mixture stirred at room temperature for 12 minutes. The MeOH filtrate was decanted from the solids, which were then rinsed with MeOH and EtOAc. The pH of the combined organic filtrates were adjusted to pH 2 using 4% HCl, then the aqueous layer diluted by adding H2O. The aqueous layer was washed with 30% EtOAc in hexane, then the pH adjusted to pH 9 with saturated Na2CO3. The aqueous layer was extracted with CHCl3, the combined CHCl3 layers washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a light tan solid (2.58 g, 74%).
Step 4
Methyl 3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}benzoate In a manner similar to that described in Example 480 (step 6), 5-bromonicotinic acid and methyl 3-(S-methylsulfonimidoyl)benzoate were reacted to give the title compound.
Step 5 methyl 3 - [N-( {5- [(3 - { [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino } phenyl)ethynyl]pyridin-3 - yl}carbonyl)-S-methylsulfonimidoyl]benzoate In a manner similar to that described in Example 460, methyl 3-{N-[(5-bromopyridin-3- yl)carbonyl]-S-methylsulfonimidoyl}benzoate and N-(3-ethynylphenyl)-l,3-dimethyl-lH- pyrazole-5-carboxamide were reacted to give the title compound.
Example 499
3-[N-({5-[(3- {[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl} carbonyl)-S-methylsulfonimidoyl]benzoic acid
A 50 ml THF solution of methyl 3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllbenzoate (228 mg, 0.41 mmol) and 0.5M NaOH (6.6 ml, 3.28 mmol) was stirred at room temperature for 3 hours. The reaction was quenched with acetic acid (0.188 ml, 3.28 mmol) and rotary evaporated to remove the THF solvent. The aqueous solution was partitioned between EtOAc and dilute HCl/brine mixture, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to white solid foam. The solid was combined with impure product from another lot (14 mg) and recrystallized from EtOAc/hexane to give the title compound as a white solid (147 mg,
Example 500
5- [(3 - { [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl]amino } phenyl)ethynyl] -N- [methyl(3 - {[(2-morpholin-4-ylethyl)amino]carbonyl}phenyl)oxido-λ4-sulfanylidene]nicotinamide
A solution of 3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllbenzoic acid (20 mg, 0.036 mmol) and 1, l '-carbonyldiimidazole (12 mg, 0.072 mmol) in 0.8ml THF was stirred at room temperature for 35 minutes. Then 4-(2-aminoethyl)morpholine (0.009 ml, 0.072 mmol) was added, stirred 30 minutes at room temperature, and the mixture added to EtOAc. The EtOAc solution was washed with NaHCθ3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The clear film was chromatographed eluting with CHCl3/MeOH and then chromatographed again using a preparative TLC plate (eluted with 8:2/CHCl3:MeOH) to afford an off-white solid foam (19 mg, 81%).
Example 501
5- [(3 - { [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl]amino } phenyl)ethynyl] -N- [methyl(3 - {2- [(2- morpholin-4-ylethyl)amino]-2-oxoethyl}phenyl)oxido-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 500, {3-[N-({5-[(3-{[(l,3-dimethyl-lH- pyrazol-S-y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbonyrj-S- methylsulfonimidoyl]phenyl} acetic acid and 4-(2-aminoethyl)morpholine were reacted to give the title compound (54%).
Example 502 N-{[3-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl](methyl)oxido-λ4-sulfanylidene}-5-[(3- {[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
To a solution of 3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllbenzoic acid (52 mg, 0.096 mmol), 2-diethylaminoethylamine (0.016 ml, 0.115 mmol), and N, N- diisopropylethylamine (0.034 ml, 0.192 mmol) in 3.0 ml DMF at room temperature was added benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (47 mg, 0.106 mmol). The reaction was stirred at room temperature for 1.5 hours, and then partitioned between EtOAc and dilute brine. The EtOAc layer was washed with saturated NaHCθ3 solution, dilute brine, dried with anhydrous Na24 and rotary evaporated. The yellow oil (combined 7 mg impure product from another lot) was chromatographed eluting with EtOAc/MeOH, then rechromatographed using a preparative TLC plate (eluted with (1 : 1 :2.5) CHClsiEtOAciMeOH plus NH4OH) to give the title compound as a white solid foam (28 mg).
Example 503 {3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-
3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl} acetic acid
A solution of methyl {3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino } phenyl)ethynyl]pyridin-3 -yl} carbonyl)- S-methylsulfonimidoyl]phenyl} acetate
(13 mg, 0.021 mmol) and 1. OM NaOH (0.171 ml, 0.171 mmol) in 2.0ml MeOH and 0.1ml H2O was stirred at room temperature for 1 hour 10 minutes. The pH of the mixture was adjusted to pH
4 using 10% HCl, brine added, and the aqueous extracted with EtOAc. The combined EtOAc layers were washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The white solid was triturated with hot EtOAc to give white solid (1 lmg, 92%).
Example 504 methyl 3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllbenzoate To a solution of 6-amino-5-[(3- {[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid (68 mg, 0.18 mmol), methyl 3-(S- methylsulfonimidoyl)benzoate (42 mg, 0.198 mmol), and N, N-diisopropylethylamine (0.063 ml,
0.36 mmol) in 1.5ml DMF at room temperature was added benzotriazole- 1 -yl-oxy-tris- (dimethylamino)-phosphoniumhexafluorophosphate (88 mg, 0.198 mmol). The reaction was heated at 600C for 3.5 hours, then at 48°C for 16.5 hours. The mixture was partitioned between EtOAc and dilute brine. The EtOAc layer was washed with NaHCθ3 solution, dilute HCl, NaHCθ3 solution, brine, dried with anhydrous Na24 and rotary evaporated. The dark foam was chromatographed eluting with hexane/acetone yielding light pink solid (38 mg, 37%).
Example 505
3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin- 3-yl}carbonyl)-S-methylsulfonimidoyl]benzoic acid In a manner similar to that described in Example 503, methyl 3-[N-({6-amino-5-[(3-
{[(l^-dimethyl-lH-pyrazol-S-y^carbonylJaminolpheny^ethynylJpyridin-S-yljcarbony^-S- methylsulfonimidoyl]benzoate was converted to the title compound.
Example 506 N-[(3-hydroxypropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
Step 1 (S)-tert-butyl(dimethyl)[3-(S-phenylsulfonimidoyl)propoxy]silane To the sulfoximine (6.46 g, 41.62 mmol) solution in anhydrous CH3CN (5 mL) at 70 0C was added dropwise N,N-diethyl-trimethylsilylamine (1.2 eq ~ 1.5 eq). The reaction mixture was heated and stirred at this temperature for one hour. It was then concentrated under reduced pressure to yield slightly brown oil (9.26 g) which was dried in-vacuo. The brown oil was dissolved in anhydrous THF (40 mL) and the resulting solution was cooled to -78 0C followed by dropwise addition of nBuLi (17.1 mL, 2.5 M in hexanes). The reaction mixture was stirred 10 min at -78 0C and then 20 min at 0 0C. After hexamethylphosphoramide (13.5 mL) was added, the reaction mixture was cooled back to -78 0C followed by dropwise addition of 2-bromoethoxy-tert- butyl-dimethylsilane over a few minutes. The reaction mixture was stirred at -78 0C for about an hour and allowed to warm-up to room temperature within 4 hours. The reaction mixture was then concentrated at room temperature under reduced pressure. The oily residue was taken up in ether (500 mL), which was subsequently washed with ice-water (2X300 mL), brine (IX), and dried with anhydrous Na2SO4 overnight. The ether layer was decanted and concentrated. The crude oily residue was dissolved in MeOH-H2O (16 mL, 10: 1) followed by addition of CsF (1.24 g). The resulting reaction mixture was heated to 50 0C for one hour. It was then concentrated under reduced pressure and the yellow oily residue was partitioned between EtOAc (500 mL) and H2O (300 mL). The organic layer was separated and washed subsequently with H2O (2X), brine (IX), and dried (Anhydrous Na2SO4). The EtOAc layer was decanted and concentrated. The title compound was isolated as clear oil (6.65 g) upon gradient column chromatography (EtO Ac-Hex: from 1 :25 to 1 :2). The overall yield is 51 % for total of three steps.
Step 2
(S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-λ4- sulfanylidene]nicotinamide
To the solution of (S)-tert-butyl(dimethyl)[3-(S-phenylsulfonimidoyl)propoxy]silane (1.55 g, 4.95 mmol) in DMF (15 mL) at room temperature was added N,N-diisopropylethylamine (1.72 mL), 3-bromonicotinic acid (1.07 g), and finally the coupling reagent, (benzotriazol- 1 -yloxy)- tris(dimethylamino)-phosphonium hexafluorophosphate (2.48 g). The reaction was stirred for 15 min and then poured into saturated aqueous NaHCθ3. The aqueous phase was extracted with EtOAC (IX), which was subsequently washed with aqueous NaHCθ3, brine (IX), and dried with anhydrous Na2SOzI. The organic layer was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtO Ac-Hex: from 1 :20 to 1 :6) yielding the title compound as an amber oil (2.39 g, 97%).
Step 3
(S)-N- [(3 - { [tert-buty l(dimethyl)silyl] oxy } propyl)(oxido)phenyl-λ4-sulfanylidene] -5-( {3 - [(3 - methyl-2-furoyl)amino]phenyl} ethynyl)nicotinamide To the solution of (S)-5-bromo-N-[(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-λ4-sulfanylidene]nicotinamide (1.9 g, 3.82 mmol) in anhydrous DMF (19 mL) under nitrogen atmosphere was added sequentially 3-methyl-furan-2- carboxylic acid (3-ethynyl-phenyl)-amide (1.72 g), triethylamine (2.13 mL), bis(triphenylphosphine)palladium(II) dichloride (268 mg), and triphenylphosphine (25 mg). The reaction system was placed under a N2-H2 (1 : 1) atmosphere and CuI (145 mg) was added in one portion. After the reaction mixture was stirred and heated at 60 0C for 1.5 hours, it was poured into saturated aqueous NaHCθ3. The aqueous was extracted with EtOAc (IX), which was subsequently washed with aqueous NaHCθ3 (IX), brine (IX), and dried (anhydrous Na2SO^. The organic layer was decanted, evaporated and wrapped with silica gel. Two times column chromatography
(EtO Ac-Hex: from 1:4 to 1 :2; and MeOH-CH2Cl2: 1 : 100) gave the title compound as yellow foam (2-2 g,
Step 4 (S)-N- [(3 -hydroxypropyl)(oxido)phenyl-λ4-sulfanylidene] -5-( {3 - [(3 -methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide To the solution of (S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-λ4- sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (2.2 g, 3.43 mmol) in anhydrous THF (60 mL) at 0 0C was added dropwise tert-butylammonium fluoride (7.2 mL, 1 M in THF) and the reaction was stirred at 0 0C for 1 hour. The yellow reaction solution was then concentrated at room temperature to give a red oil. The oily residue was diluted with EtOAc, which was washed with saturated aqueous NaHCθ3 (2X), brine (IX), and then dried (anhydrous Na2SOzI). The organic layer was decanted, concentrated, and the resulting oily residue was chromatographed (MeOH-CH2Cl2: from 1 : 100 to 1 :50) yielding the title compound as a clear oil which turned into white foam in-vacuo (1.72 g, 95%).
Example 507
(S)-N-[(3-bromopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
N-[(3-hydroxypropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide (1.71 g, 3.24 mmol) was dissolved in anhydrous
CH2Cl2 (5 mL) and the resulting solution was cooled to 0 0C. A solution of carbon tetrabromide (1.565 g ) in CH2Cl2 (3 mL) was added dropwise followed by a dropwise addition of a solution of triphenylphosphine (1.24 g) in CH2Cl2 (3 mL). The reaction was stirred at room temperature for 1.5 hours and then partitioned between saturated aqueous NaHCθ3 and dichloromethane. The organic layer was separated, washed with brine (IX), dried with anhydrous Na2SOzI, and concentrated with silica gel under reduced pressure. A gradient column chromatography (acetone- hex: from 1 : 10 to 1 :4) rendered title compound as white solid in amount of 1.56 g (82%).
Example 508 (S)-N-[(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-l-yl}propyl)(oxido)phenyl-λ4-sulfanylidene]-5- ({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
To the solution of N-[(3-bromopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-
2-furoyl)amino]phenyl}ethynyl)nicotinamide (450 mg, 0.76 mmol) in anhydrous DMF (5 mL) was added dropwise l-[2-(2-hydroxyethoxy)ethyl]piperazine. The resulting reaction solution was stirred and heated at 80 0C for 30 min. It was then partitioned between saturated aqueous NaHCθ3 and EtOAc. The EtOAc layer was separated and washed with brine (IX). The aqueous NaHCθ3 layer was extracted with CHCI3 (IX) and the extract was washed with brine (IX). The organic layers were combined and dried over anhydrous sodium sulfate. The organic solution was decanted, concentrated, and wrapped with silica gel. Column chromatography (MeOH-EtOAc from 1 : 10 to 1 :6) rendered the title compound as white foam in amount of 500 mg (96 %).
Example 509 (S)-N- {[3-(diethylamino)propyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and diethylamine were converted to the title compound.
Example 510
(S)-N-[{3-[(2-hydroxyethyl)amino]propyl}(oxido)phenyl— λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2- hydroxyethylamine were converted to the title compound.
Example 511 N-{[3-(3-hydroxypyrrolidin-l-yl)propyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3- hydroxypyrrolidine were converted to the title compound.
Example 512
N-[{3-[(2,3-dihydroxypropyl)(methyl)amino]propyl}(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3- methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3- methylamino- 1 ,2-propanediol were converted to the title compound.
Example 513
(S)-N- {[3-(l,l -dioxidothiomorpholin-4-yl)propyl](oxido)phenylv-λ4-sulfanylidene}-5-({3-[(3- methyl-2-furoyl)amino]phenyl} ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and thiomorpholine- 1 , 1 -dioxide were converted to the title compound.
Example 514
(S)-N-[{3-[4-(2-hydroxyethyl)piperazin-l-yl]propyl}(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3- methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 1- piperazineethanol were converted to the title compound. Example 515
N- {[3-(3-fluoropiperidin- 1 -yl)propyl](oxido)phenyl-λ4-sulfanylidene} -5-( {3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3- fluoropiperidine were converted to the title compound.
Example 516 (S)-N- {[3-(3,3-difluoropiperidin-l-yl)propyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3,3- difluoropiperidine were converted to the title compound.
Example 517
(S)-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[(3-morpholin-4-ylpropyl)(oxido)phenyl- λ4-sulfanylidene]nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and morpholine were converted to the title compound.
Example 518
5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[oxido(phenyl) {3-[3- (trifluoromethyl)piperidin- 1 -yljpropyl} -λ4-sulfanylidene]nicotinamide
In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfan nyylliiddeennee]]--55--(({{33--[[((33--mmeetthhyyll--22--ffuurrooyyll))aammiinnoo]]pphheennyyll}}eetthhyynn>yl)nicotinamide and 3- (trifluoromethyl)piperidine were converted to the title compound.
Example 519
(S)-N- {[3-(4-hydroxypiperidin-l-yl)propyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and A- hydroxypiperidine were converted to the title compound.
Example 520
(S)-N-[{3-[(2-hydroxyethyl)(methyl)amino]propyl}(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3- methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2- methylaminoethanol were converted to the title compound.
Example 521
5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[(3-{methyl[(2S,3R,4S,5R)-2,3,4,5,6- pentahydroxyhexyl]amino}propyl)(oxido)phenyl-λ4-sulfanylidene]nicotinamide
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl} ethynyl)nicotinamide and 1 -deoxy- 1 - (methylamino)-D-galactitol were converted to the title compound.
Example 522
(S)-N-[(3-azidopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and sodium azide were converted to the title compound.
Example 523 (S)-N-[(3-aminopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described for example 508, (S)-N-[(3- bromopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide and ammonia were converted to the title compound.
Example 524
(S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-λ4-sulfanylidene]-5-[(3-{[(l,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described in Example 506 (step 3), (S)-5-bromo-N-[(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-λ4-sulfanylidene]nicotinamide and N-(3- ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5-carboxamide are converted to the title compound.
Example 525
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3- hydroxypropyl)(oxido)phenyl-lambda-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 506 (step 4), (S)-N- [(3 -{[tert- butyl(dimethyl)silyl] oxy } propyl)(oxido)phenyl-λ4-sulfanylidene] -5- [(3 - { [( 1 ,3 -dimethyl- 1 H- pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide is converted to the title compound. Example 526
(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino } phenyl)ethynyl]nicotinamide In a manner similar to that described in Example 507, (S)-5-[(3-{[(l,3-dimethyl-lH- pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3-hydroxypropyl)(oxido)phenyl-lambda-λ4- sulfanylidene]nicotinamide is converted to the title compound.
Example 527
(S)-N- {[3-(diethylamino)propyl](oxido)phenyl-λ4-sulfanylidene}-5-[(3-{[(l,3-dimethyl-lH- pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described for example 508, (S)- N-[(3- bromopropy 1) (oxido)phenyl-4- sulfanylidene] -5 - [(3 - { [( 1 , 3 - dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and diethylamine were converted to the title compound.
Example 528
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{3-[(2- hydroxyethyl)amino]propyl}(oxido)phenyl-λ4-sulfanylidene]nicotinamide In a manner similar to that described for example 508, (S)-N-[(3- bromopropy 1) (oxido)phenyl-4- sulfanylidene] -5 - [(3 - { [( 1 , 3 - dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and hydroxyethylamine were converted to the title compound.
Example 529
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{3-[(2- hydroxyethyl)(methyl)amino]propyl}(oxido)phenyl-λ4-sulfanylidene]nicotinamide In a manner similar to that described for example 508, (S)- N-[(3- bromopropy 1) (oxido)phenyl-4- sulfanylidene] -5 - [(3 - { [( 1 , 3 - dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and 2-methylaminoethanol were converted to the title compound.
Example 530 (S)-N- {[3-(dimethylamino)propyl](oxido)phenyl-λ4-sulfanylidene}-5-[(3- {[(l,3-dimethyl- IH- pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described for example 508, (S)-N-[(3- bromopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and dimethylamine were converted to the title compound.
Example 531
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3-{4-[2-(2- hydroxyethoxy)ethyl]piperazin-l-yl}propyl)(oxido)phenyl-λ4-sulfanylidene]nicotinamide In a manner similar to that described for example 508, (S)- N-[(3- bromopropy 1) (oxido)phenyl-4- sulfanylidene] -5 - [(3 - { [( 1 , 3 - dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and l-[2-(2-hydroxyethoxy)ethyl]piperazine were converted to the title compound.
Example 532
(S)-Ethyl (N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl) acetate
Step 1
5- {3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl} -nicotinic acid
In a manner similar to that described for Example 480 (step 1), 3-methyl-furan-2- carboxylic acid (3-ethynyl-phenyl)-amide and 5-bromo nicotinic acid were reacted to provide the title compound.
Step 2
(S)-Ethyl (N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl) acetate
To a solution of ethyl (S)-(S-phenylsulfonimidoyl)acetate (139 mg, 0.61 mmol) in anhydrous DMF (3 mL) at room temperature was added 5- {3-[(3-Methyl-furan-2-carbonyl)- amino]-phenylethynyl} -nicotinic acid (233 mg), catalytic amount of 4-(dimethylamino)pyridine, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (141 mg). The reaction mixture was stirred at room temperature for 30 min. The reaction was then poured into aqueous HCl (0.5 %) and extracted with EtOAc. After the aqueous layer was separated, solid sodium chloride was added and the resulting aqueous mixture was extracted again with EtOAc. The organic layers were combined, washed with brine (IX), saturated aqueous NaHCθ3 (IX), then brine (IX), and finally dried with sodium sulfate. The upper solution was decanted, concentrated, and the yellow oily residue was subject to a column chromatography (silica gel, gradient elution EtO Ac-Hex from 1 :5 to 1 : 1.5) to give the title compound as a white foam (147 mg, 43 %). Example 533
N- {[2-(3-hydroxypyrrolidin- 1 -yl)-2-oxoethyl](oxido)phenyl-λ4-sulfanylidene} -5-( {3-[(3-methyl-
2-fiαroyl)amino]phenyl}ethyny1ΛiΛ^"+^owi^α
Figure imgf000109_0001
reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed sequentially with brine (IX), saturated aqueous NaHCθ3 (IX), brine (IX), and finally dried with anhydrous sodium sulfate overnight. The clear solution was decanted and concentrated. The oily residue was subject to multiple times of column chromatography (eg. from CH2Cl2 to MeOH-CH2Cl2 1 :25 or from EtO Ac-Hex 3: 1 to MeOH- EtOAc 1 :100) the title compound as white foam (2.35 g, 54 %).
Example 534
N-[{2-[(2,3-dihydroxypropyl)(methyl)amino]-2-oxoethyl}(oxido)phenyl-λ4-sulfanylidene]-5-({3- [(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
To the solution of of (S)-ethyl (N- {[5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate (3.5 g, 6.3 mmol) in anhydrous THF (50 mL) was added dropwise 3-methylamino-l,2-propanediol (6.77 g) and the resulting reaction solution was heated at 75 0C for 8.5 hours. The reaction was then concentrated under reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCθ3 (IX), brine (IX), and dried with sodium sulfate. The upper clear solution was decanted and evaporated, the resulting yellowish foamy residue was subjected to a gradient column chromatography (from EtO Ac-Hex 6:1 to MeOH-EtOAc 1 :50) yielding the title compound as white foam in amount of 2.56 g (66 %).
Example 535 (S)-N- {[2-(methylamino)-2-oxoethyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2- furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S-phenylsulfonimidoyl)acetate and methylamine were reacted to give the title compound
Example 536 (S)-N- {[2-(4-hydroxypiperidin- 1 -yl)-2-oxoethyl](oxido)phenyl-λ4-sulfanylidene} -5-( {3-[(3- methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2- furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S-phenylsulfonimidoyl)acetate and 4- hydroxypiperidine were reacted to give the title compound
Example 537
(S)-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[oxido(2-oxo-2-pyrrolidin-l- ylethyl)phenyl-λ4-sulfanylidene]nicotinamide In a manner similar to that described in Example 534, (S)-Ethyl (N- {[5-({3-[(3-methyl-2- furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S-phenylsulfonimidoyl)acetate and pyrrolidine were reacted to give the title compound
Example 538 N-{[2-(3-hydroxypiperidin-l-yl)-2-oxoethyl](oxido)phenyl-λ4-sulfanylidene}-5-({3-[(3-methyl-2- furoyl)amino]phenyl}ethynyl)nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2- furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S-phenylsulfonimidoyl)acetate and 3- hydroxypiperidine were reacted to give the title compound
Example 539
(S)-Ethyl l-[(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)acetyl]piperidine-3-carboxylate
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2- furoy^ammolphenyljethyny^pyridm-S-yllcarbonylj-S-phenylsulfonimidoy^acetate and ethyl nipecotate were reacted to give the title compound
Example 540
(S)-Ethyl [N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl}carbonyl)-S-phenylsulfonimidoyl]acetate
In a manner similar to that described in Example 532 (step T), (S)-Ethyl (S)-(S- phenylsulfonimidoyl) acetate and 5 - [(3 - { [( 1 , 3 -dimethyl- 1 H-pyrazol-5 - yl)carbonyl] amino }phenyl)ethynyl]nicotinic acid were reacted to give the title compound.
Example 541
(S)-N-[{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}(oxido)phenyl-λ4-sulfanylidene]-5-[(3- {[(l,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl [N-({5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl] acetate and glycineamide were reacted to give the title compound Example 542
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- {[2- (methylamino)-2-oxoethyl](oxido)phenyl-λ4-sulfanylidene}nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl [N-({5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl] acetate and methylamine were reacted to give the title compound
Example 543 (S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{2-[(2- hydroxy ethyl)amino]-2-oxoethyl}(oxido)phenyl-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl [N-({5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl] acetate and 2-hydroxyethylamine were reacted to give the title compound
Example 544
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{2-[(2- hydroxyethyl)(methyl)amino]-2-oxoethyl}(oxido)phenyl-λ4-sulfanylidene]nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl [N-({5-[(3-{[(l,3- dimethyl- lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl] acetate and 2-methylaminoethanol were reacted to give the title compound
Example 545
N-[{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}(oxido)phenyl-λ4-sulfanylidene]-5-[(3-{[(l,3- dimethyl- lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
In a manner similar to that described in Example 534, (S)-Ethyl [N-({5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl] acetate and 3-amino-l,2-propanediol were reacted to give the title compound
Example 546
(S)-Methyl 5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-phenylsulfonimidoyllpentanoate
Step 1 (S)-Trimethyl { [methyl(oxido)phenyl-λ4-sulfanylidene] amino } silane
To a stirred solution of (S)-(+)-S-methyl-S-phenylsulphoximine (621 mg, 4.0 mmol) in anhydrous acetonitrile (1 mL) at 70 0C was added (trimethylsilyl)diethylamine (1.37 mL, 7.0 mmol) dropwise. The reaction was maintained at this temperature and stirred for 2 hours, at which time the TLC showed complete conversion of the starting material into a higher Rf component. The reaction solution was concentrated under reduced pressure and dried in vacuo yielding brown oil, which was used directly in the next step without further purification. Step 2
(S)-9,9-dimethoxy-2,2-dimethyl-4-phenyl-10-oxa-λ4-thia-3-aza-2-silaundec-3-ene 4-oxide The brown oil, obtained from last step, was dissolved in 4 mL anhydrous THF. After the solution was cooled to -78 0C, n-butyllithium (1.64 mL, 2.5 M solution in hexanes) was added dropwise. The resulting reaction mixture was stirred at -78 0C for 10 min, then at 0 0C for 20 min, followed by an addition of hexamethyl phosphoramide (1.32 mL). After the reaction was cooled back to -78 0C, trimethyl 4-bromo-orthobutyrate (1.1 mL) was added dropwise. The reaction was stirred and its temperature was allowed to rise to room temperature during 16 hours. The reaction mixture was then diluted with ethyl ether (250 mL) and washed with ice cold water (2X), brine (IX), and dried with anhydrous sodium sulfate. The solution was decanted and concentrated giving a brown oily residue which was used directly for next step.
Step 3
(S)-[S-(5,5,5-trimethoxypentyl)sulfonimidoyl]benzene
To the solution of the oily residue, obtained in last step, in MeOH-H2O (10:1, 2 mL) was added cesium fluoride (91.2 mg) and the resulting reaction mixture was heated at 50 0C for 2 hours. The reaction was then concentrated and the oily residue was partitioned between cold water and EtOAc. The organic layer was separated and washed with brine (IX). After it was dried with anhydrous sodium sulfate, it was concentrated for a direct use in next step.
Step 4
(S)-Methyl 5-(S-phenylsulfonimidoyl)pentanoate The crude oil, obtained in last step, was dissolved in MeOH-H2O (4:0.1, 20 mL) and the resulting solution was cooled in an ice-bath. A catalytic amount of pyridinium toluene-4-sulfonate was added to the reaction and it was stirred at this temperature for 1 hour. The reaction was then concentrated at room temperature to remove most part of MeOH and the residue was diluted with EtOAc. The EtOAc was washed with saturated aqueous NaHCO3 (2X), brine (IX), and dried with anhydrous sodium sulfate. The organic was decanted, concentrated under reduced pressure, and wrapped with silica gel. A gradient chromatography (Et2O-HeX from 1 : 1 to Et2O) rendered the title compound as clear oil in amount of 477 mg (47 % for total of 4 steps).
Step 5 (S)-Methyl 5- {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate To the solution of (S)-Methyl 5-(S-phenylsulfonimidoyl)pentanoate (475 mg, 1.86 mmol) in anhydrous DMF (6 mL) at room temperature under nitrogen atmosphere was added diisopropylethylamine (0.65 mL), 5-bromonicotinic acid (0.38 g), and (benzotriazol- 1 -yloxy)- tris(dimethylamino)-phosphonium hexafluorophosphate (0.81 g). The resulting reaction mixture was stirred for about 15 min at room temperature and then poured into saturated aqueous NaHCO3. The aqueous was extracted with EtOAc (IX), which was then washed with saturated aqueous NaHCO3 and brine (v:v 1 : 1, 2X), brine (IX), and dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. A column chromatography (EtO Ac-Hex 1 :2) rendered the title compound as slightly yellow colored solid in amount of (616 mg, 75 %).
Step 6
(S)-Methyl 5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-phenylsulfonimidoyllpentanoate To the flame-dried 100 mL round bottom flask containing (S)-Methyl 5- {N-[(5- bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate (609 mg, 1.39 mmol), N-(3- ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5-carboxamide (0.50 g), triethylamine (0.77 mL), bis(triphenylphosphine)palladium(II) dichloride (97.3 mg), and triphenylphosphine (9.1 mg) under nitrogen/hydrogen (1 : 1) atmosphere at room temperature was added copper(I) iodide (52.8 mg). The resulting reaction mixture was heated and stirred at 60 0C for 1 hour. It was then diluted with EtOAc, washed sequentially with saturated aqueous NaHCO3 (2X), brine (IX), and finally dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. Chromatography (EtO Ac-Hex from 1 :2 to 3:2) yielded the title compound as white foam in amount of (712 mg, 86 %).
Example 547
N-[{5-[(2,3-dihydroxypropyl)(methyl)amino]-5-oxopentyl}(oxido)phenyl-λ4-sulfanylidene]-5-[(3- {[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide
To the solution of 3-methylamino-l,2-propanediol (180 mg) in anhydrous THF was added (S)-Methyl 5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-phenylsulfonimidoyllpentanoate (100 mg, 0.17 mmol). The reaction solution was heated to 50 0C for 2 hours and then the temperature was raised to 70 0C for 17 hours. Further 3-methylamino-l,2-propanediol (100 mg) was added, and the reaction was stirred and heated at 85 0C for an additional 24 hours. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was isolated and washed with brine (IX), dried (anhydrous Na2SO4) and concentrated. Upon a gradient column chromatography (MeOH-EtOAc from 1 :50 to 1 : 15) the title compound was obtained as a clear oil (74 mg, 66 %) which gave a white foamy solid upon standing in vacuo.
Example 548 (S)-5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl} carbonyl)-S-phenylsulfonimidoyl]pentanoic acid
To the solution of (S)-Methyl 5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-phenylsulfonimidoyllpentanoate (120 mg, 0.2 mmol) in THF (4 mL) at 0 0C was added dropwise a solution of aqueous NaOH (0.5 N, 2.0 mL). After the reaction mixture was stirred at 0 0C for 2 hours, 2 N HCl was carefully added to adjust the pH ~5 followed by a partition between aqueous NH4Cl and EtOAc. The EtOAc layer was further washed with brine once and dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated and subject to a gradient column chromatography (from EtOAc to MeOH-EtOAc 1 :5) yielding the title compound as white foam in amount of (85 mg ,73 %).
Example 549
(S)-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N- {[5-
(hydroxyamino)-5-oxopentyl](oxido)phenyl-λ4-sulfanylidene}nicotinamide
At 0 0C to the solution of 5-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminojpheny^ethynylJpyridin-S-yljcarbony^-S-phenylsulfonimidoyllpentanoic acid (50 mg, 0.086mmol) in DMF (1 mL) was added hydroxylamine hydrochloride (30 mg), 1- hydroxybenzotriazole hydrate (20 mg), (benzotriazol-l-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (57 mg), and triethylamine (84 μL). The reaction mixture was stirred at this temperature for 30 min. The reaction was then poured into aqueous NH4Cl and extracted with EtOAc. The organic layer was isolated, washed further with brine once, and dried (anhydrous Na2SO4). A gradient column chromatography (MeOH-CH2Cl2 from 1 : 100 to 1 :5) gave the title compound as white foam (37 mg, 71 %).
Example 550 Methyl rel-(2R,4S)-l-{3-[N-({5-[(3- {[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4- hydroxypyrrolidine-2-carboxylate
The mixture ofN-[(3-bromopropyl)(oxido)phenyl-λ4-sulfanylidene]-5-[(3-{[(l,3- dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (200 mg, 0.33 mmol), L- 4-hydroxyproline methyl ester hydrochloride (126 mg), and sodium bicarbonate (167 mg) in anhydrous acetonitrile (2 mL) in a seal tube was stirred and heated at 90 0C for 5 hours. After it was cooled to room temperature, the reaction was diluted with EtOAc. The organic was washed with saturated aqueous NaHCO3 (2X), brine (IX), and then dried with anhydrous sodium sulfate. The solution layer was decanted, concentrated, and the oily residual was chromatographed (EtO Ac-Hex 1 :1 to neat EtOAc) yielding the title compound as colorless oil in amount of 128 mg (58%).
Example 551
(S)-Methyl ({3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino } phenyl)ethynyl]pyridin-3 -yl} carbonyl)- S- phenylsulfonimidoyl]propyl}amino)acetate In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and glycine methyl ester were reacted to give the title compound.
Example 552
Methyl 2-({3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminolpheny^ethynylJpyridin-S-yllcarbony^-S-phenylsulfonimidoyllpropyljamino)-
3 -hydroxypropanoate
In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]nicotinamide and 2-amino-3-hydroxypropionic acid methyl ester were reacted to give the title compound.
Example 553 Ethyl l-{3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-
3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}piperidine-3-carboxylate
In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and ethyl nipecotate were reacted to give the title compound.
Example 554
Methyl 2-({3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminolpheny^ethynylJpyridin-S-yllcarbony^-S-phenylsulfonimidoyllpropyljamino)- 3-(lH-imidazol-4-yl)propanoate In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl] amino }phenyl)ethynyl]nicotinamide and histidine methyl ester were reacted to give the title compound.
Example 555 rel-(2R,4S)-l-{3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4- hydroxypyrrolidine-2-carboxylic acid Methyl rel-(2R,4S)-l-{3-[N-({5-[(3- {[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4- hydroxypyrrolidine-2-carboxylate (116 mg, 0.17mmol) was dissolved in THF (3.5 mL) and the resulting solution was cooled in an ice-bath. After aqueous NaOH (0.5 N, 1.75 mL) was dropwise added, the reaction was stirred at 0 0C for 30 min. The reaction was then diluted with ice water followed by a pH adjustment to 3-4 with 2 N HCl. The reaction was further diluted with saturated brine, and then extracted with CHCl3-iPrOH (5:1) (2X). The organic layers were combined, dried
(anhydrous Na2SO4), and then filtered through a plug of cotton. The filtrate was concentrated and the residue was chromatographed (MeOH-CHCi3 1 : 10 to 1:4) yielding the title compound as white solid in amount of 108 mg (95%).
Example 556
({3-[N-({5-[(3- {[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl} carbonyl)-S-phenylsulfonimidoyl]propyl} amino)acetic acid
In a manner similar to that described in Example 555, methyl ({3-[N-({5-[(3- {[(1,3- dimethyl- lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl]propyl}amino)acetate was converted to the title compound
Example 557 2-({3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)-3-hydroxypropanoic acid
In a manner similar to that described in Example 555, methyl 2-({3-[N-({5-[(3- {[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl]propyl}amino)-3-hydroxypropanoate was converted to the title compound
Example 558 l-{3-[N-({5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3- yljcarbony^-S-phenylsulfonimidoyllpropyljpiperidine-S-carboxyric acid
In a manner similar to that described in Example 555, ethyl l- {3-[N-({5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonyljaminolpheny^ethynylJpyridin-S-yljcarbony^-S- phenylsulfonimidoyl]propyl}piperidine-3-carboxylate was converted to the title compound
Example 559
(S)-Methyl {[3-(N- {[5-({3-[(3-methyl-2-ruroyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoy l)propyl] amino } acetate In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and glycine methyl ester are converted to the title compound.
Example 560 methyl l-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylate
In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 2- carboxymethyl pyrollidine are converted to the title compound.
Example 561 methyl l-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylate
In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3- carboxymethyl pyrollidine are converted to the title compound.
Example 562 ethyl l-[3-(N- {[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)propyl]piperidine-3-carboxylate
In a manner similar to that described in Example 550, N-[(3-bromopropyl)(oxido)phenyl- λ4-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and ethyl nipecotate are converted to the title compound.
Example 563
(S)-{[3-(N-{[5-({3-[(3-methyl-2-ruroyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)propyl] amino} acetic acid In a manner similar to that described in Example 555, methyl {[3-(N-{[5-({3-[(3-methyl- 2-furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S- phenylsulfonimidoy l)propyl] amino } acetate is converted to the title compound.
Example 564
1 -[3-(N- {[5-( {3-[(3-methyl-2-furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S- phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylic acid
In a manner similar to that described in Example 555, methyl 1-[3-(N- {[5-({3-[(3-methyl- 2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S- phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylate is converted to the title compound.
Example 565
1 -[3-(N- {[5-( {3-[(3-methyl-2-furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S- phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylic acid
In a manner similar to that described in Example 555, methyl 1-[3-(N- {[5-({3-[(3-methyl- 2-furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S- phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylate is converted to the title compound.
Example 566
1 -[3-(N- {[5-( {3-[(3-methyl-2-furoyl)amino]phenyl} ethynyl)pyridin-3-yl]carbonyl} -S- phenylsulfonimidoyl)propyl]piperidine-3-carboxylic acid
In a manner similar to that described in Example 555, ethyl l-[3-(N-{[5-({3-[(3-methyl-2- furoy^aminolphenyllethyny^pyridin-S-yllcarbonyll-S-phenylsulfonimidoy^propyllpiperidine-S- carboxylate is converted to the title compound
Example 567 methyl {3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminolpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllphenyl} acetate
Step 1 methyl 6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinate A mixture of methyl 6-amino-5-iodonicotinate (111 mg, 0.40 mmol), N-(3- ethynylphenyl)-l,3-dimethyl-lH-pyrazole-5-carboxamide (144 mg, 0.60mmol), triethylamine (0.167 ml, 1.2mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.032 mmol) and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.2 ml DMF at room temperature was degassed using vacuum and a balloon of H2, then copper(I)iodide (3.8 mg, 0.020 mmol) added. The reaction was heated at 600C for 1 hour 40 minutes, then partitioned between EtOAc and dilute brine. The EtOAc layer was dried with anhydrous Na24 and rotary evaporated. The solid was recrystallized from EtOAc/hexane to give the title compound as a yellow-tan solid (122 mg,
Step 2
6-amino-5- [(3 - { [( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino } phenyl)ethynyl]nicotinic acid A solution of methyl 6-amino-5-[(3- {[(l,3-dimethyl-lH-pyrazol-5- yl)carbonyl]amino}phenyl)ethynyl]nicotinate (51 mg, 0.13 mmol) and KOH (37 mg, 0.65 mmol) in 4.0ml MeOHiH2O (3: 1) was heated at 65°C for 1 hour 40 minutes. The pH of the mixture was adjusted to pH 4 using 10% HCl, brine added, and the aqueous extracted with EtOAc. The combined EtOAc layers were dried with anhydrous Na2SO4 and rotary evaporated. The light yellow solid was triturated with hot EtOAc to give the title compound as an off- white solid (41 mg, 84%).
Step 3 methyl {3-[N-({6-amino-5-[(3-{[(l,3-dimethyl-lH-pyrazol-5- y^carbonylJaminolpheny^ethynylJpyridin-S-yljcarbony^-S-methylsulfonimidoyllphenyl} acetate
In a manner similar to that described in Example 496 (step 5), 6-amino-5-[(3-{[(l,3- dimethyl-lH-pyrazol-S-y^carbonylJaminojpheny^ethynylJnicotinic acid and methyl {3-[S- methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl} acetate were reacted to give the title compound
The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention only. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
For example, the novel compounds of this invention include any compound which is a substituted aroyl sulfoximine compound which binds to the tyrosine kinase receptor wherein said substituted aryl moiety may be represented by formula IV below:
Figure imgf000119_0001
or said substituted aryl moiety may be represented by formula V below
Figure imgf000120_0001
wherein B1, R12 and R13 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano or said novel sulfoxime may be represented by formula VI below
Figure imgf000120_0002
wherein Z is said substituted aroyl group and E1 and E2 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano.
Such modifications are intended to fall within the scope of the appended claims. All references cited herein are hereby incorporated by reference in their entirety.
In particular, the compounds of the present invention may be prepared by methods that are analogous to the methods disclosed in such references, with one of skill in the art varying the reactants to achieve the desired compounds. Also, the compounds of the present invention may be tested by the various in- vitro and in- vivo assays disclosed in such references to demonstrate the claimed utilities.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.

Claims

1. A compound represented by the general formula I
Figure imgf000121_0001
Wherein: X is CR4 or N;
Y is CR1 or N;
R1 is selected from the group consisting of hydrogen, alkyl, halogen, OR4, CN, NO2 , COR4,
(CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2and N(R4)2;
R2 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2 , SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10;
R3 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2 ,
SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10;
R4 is hydrogen or Ci to C4 alkyl;
A is selected from the group consisting of C = C ; CH=CH, CH2CH2, CH2O, CF2O, OCH2, OCF2, O, N(R4), C(O), S(O)6, NR7C(O), C(O)NR7 and N(R7)C(O)NR7;
B is selected from the group consisting of hydrogen, alkyl and alkyloxyalkyl or B may be a
5 or 6 membered carbocyclic aryl or heterocyclic aryl group;
E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group;
E' is selected from the group consisting of alkyl, CF3,
(CR7R8)aC(O)OR10, (CR7R8)aC(O)N(R10)2, (CR7R8)aC(O)N(OR10)(R10), (CR7R8)a(OR10),
(CR7R8)aN(R10)2, and (CR7R8)aR10; wherein R7 and R8 are selected from the group consisting of H, halogen, hydroxyl, and alkyl or CR7R8 may represent a carbocyclic ring of from 3 to 6 carbons; and R10 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl, (CR7R8)aC(O)OR6, (CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), (CR7R8)aN(R6)2 and (CR7R8)aR6, wherein R6 is selected from the group consisting of hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group; wherein R6 is selected from the group consisting of hydrogen, alkyl, carboalkyl, alkylamine, alkylhydroxy and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group;
a is 0 or an integer of from 1 to 5; b is an integer of from 2 to 5; c is 0 or an integer of from 1 to 4; d is 0 or an integer of from 1 to 5; e is 0 or an integer of from 1 to 2 and further including prodrugs, pharmaceutically acceptable salts, racemic mixtures and enantiomers of said compound.
Claim 2. The compound of claim 1 wherein B is a carbocyclic aryl or heterocyclic aryl represented by formula II below:
Figure imgf000122_0001
wherein said carbocyclic aryl and heterocyclic aryl groups are selected from the group consisting of:
Figure imgf000122_0002
wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, SR6, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S,
(CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6 ,(CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2 S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and, S(O)e(CR7R8)aR6
wherein R6 is selected from the group consisting of hydrogen, alkyl, carboalkyl, alkylamine, alkylhydroxy and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group.
3. The compound of claim 2 wherein R6 is selected from the group consisting of hydrogen, alkyl, dilower alkyl amine or a heterocyclic group represented by the list below or N(R6)2 may represent a 3 to 7 membered heterocyclic group,
Figure imgf000124_0001
N J rK. ^ -» Mr(R5
Figure imgf000124_0002
Figure imgf000124_0003
Figure imgf000124_0004
wherein R5 is hydrogen, halogen, simple alkyl, CF3, hydroxyl, OR7, N(R7)2 or NO2.
4. The compound of claim 2 wherein R6 is selected from the group consisting of hydrogen, alkyl, dilower alkyl amine, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl , 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N- (2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1- piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(lH)- l,4-diazepinyl-5(4H)-one, N- methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1 -acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3- (diethylamino)pyrrolidinyl, l,4-dioxa-8-azaspiro[4.5]decaninyl, 1 -(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3- picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1 -(2-pyrimidyl)-piperazinyl, 1 -(2- pyrazinyl)-piperazinyl, 2-methylaminomethyl-l,3-dioxolane,2-(N-methyl-2-aminoethyl)-l,3- dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-l-methoxybutane, 2- methoxyisopropylaminyl, l-(3-aminopropyl)imidazole, histamyl , N ,N- diisopropylethylenediaminyl, 1 -benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl- 1 ,3-dioxolane-4-methanaminyl, (R)-3-amino- 1 -N-BOC-pyrrolidinyl, 4-amino- 1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran and ethanolamine.
5. The compound of claim 2 wherein E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl represented by formula III below:
Figure imgf000125_0001
III wherein said carbocyclic aryl and heterocyclic aryl is selected from the group consisting of:
Figure imgf000125_0002
'V XSχ,( m R)a V Xv>m a l
Figure imgf000125_0003
XN>(R)a
Figure imgf000125_0004
S-(R>-
Figure imgf000125_0005
R, )a V OT<R>-
Figure imgf000125_0006
6. A compound of Claim 3 wherein A is = .
7. A compound of Claim 6 wherein
Figure imgf000126_0001
A compound of Claim 6 wherein B is
Figure imgf000126_0002
9. A compound of Claim 6 wherein R2 is NH2
10. A compound of Claim 6 wherein R3 is NH2.
11. A compound of Claim 8 wherein
Figure imgf000126_0003
12. A compound of Claim 6 wherein B is
1X)- (R)a
13. A compound of Claim 6 wherein B is
Figure imgf000126_0004
14. A compound of Claim 12 wherein R2 is NH2.
15. A compound of Claim 12 wherein R3 is NH2.
16. A compound of Claim 13 wherein R2 is NH2
17. A compound of Claim 13 wherein R3 is NH2.
18. A compound of Claim 12 wherein
Figure imgf000127_0001
19. A compound of Claim 13 wherein
Figure imgf000127_0002
20. A compound of Claim 14 wherein
Figure imgf000127_0003
21. A compound of Claim 15 wherein
Figure imgf000127_0004
22. A compound of Claim 16 wherein
Figure imgf000127_0005
23. A compound of Claim 17 wherein
Figure imgf000128_0001
24. A compound of Claim 18 wherein R selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH,
N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8WOR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2,
S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
25. A compound of Claim 19 wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH,
N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2,
S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
26. A compound of Claim 20 wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2, S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
27. A compound of Claim 21 wherein wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8WOR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2, S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
28. A compound of Claim 22 wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2, S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
29. A compound of Claim 23 wherein wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, S(O)6R6, SO2N(R6)2, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S, N=N-NH, (CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6, (CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2,
S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2, S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6.
30. A compound of Claim 24 wherein R is selected from the group consisting of
N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
31. A compound of Claim 25 wherein R is selected from the group consisting of N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
32. A compound of Claim 26 wherein R is selected from the group consisting of N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
33. A compound of Claim 27 wherein R is selected from the group consisting of N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
34. A compound of Claim 28 wherein R is selected from the group consisting of N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
35. A compound of Claim 29 wherein R is selected from the group consisting of N(R6)(CR7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, , (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), C(O)(CR7R8)aN(R6)2 and N(R6)(CR7R8)aC(O)OR6
36. A compound of Claim 24 selected from the group consisting of 5-[(3-hydroxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ6-sulfanylidene]nicotinamide, N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide,
N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide, 5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(3-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(4-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(4-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(2-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide, 5-[(2-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(2,4-difluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(3-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide, 5-[(3-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(3-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(3,5-dimethoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
5-[(4-methoxy-2-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(4-fluoro-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, 5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ6-sulfanylidene]nicotinamide, 5-[(3-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ6-sulfanylidene]nicotinamide, 5-[(4-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ6-sulfanylidene]nicotinamide, N-[(4-chlorophenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide, N-[(4-chlorophenyl)(methyl)oxo-λ6-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,
N-{[3-(acetylamino)phenyl](methyl)oxo-λ6-sulfanylidene}-5-[(3- hydroxyphenyl)ethynyl]nicotinamide,
N-[(3-chlorophenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide, N- [(3 -chlorophenyl)(methyl)oxo-λ6-sulfanylidene] -5- [(3 -hydroxyphenyl)ethynyl]nicotinamide,
N-[(3,5-dichlorophenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide,
N-[(3,5-dichlorophenyl)(methyl)oxo-λ6-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,
5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ6-sulfanylidene]nicotinamide,
N-[(3-methoxyphenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide, 5-[(3-hydroxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ6-sulfanylidene]nicotinamide,
N-[(3,4-dimethylphenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide,
N- [(3 ,4-dimethylphenyl)(methyl)oxo-λ6-sulfanylidene] -5- [(3 - hydroxyphenyl)ethynyl]nicotinamide,
N-[(3,5-dimethylphenyl)(methyl)oxo-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide, N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ6-sulfanylidene]-5-[(3- hydroxyphenyl)ethynyl]nicotinamide,
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide,
(S)-5-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(S)-5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, (S)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(S)-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(R)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(S)-5-[(4-hydroxy-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(S)-5-(lH-indol-6-ylethynyl)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({4-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide.,
(S)-5- {[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide,
(S)-5-({4-[(2,6-difluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide, (S)-5-({4-[(4-fluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide,
(S)-5-({4-[(4-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide,
(S)-5-({4-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide,
(S)-5- [(3 -{[( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino } phenyl) ethynyl] -N- [methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(3-methylthienyl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide,
(S)-tert-butyl (3-{[5-({[methyl(oxo)phenyl-λ6-sulfanyh'dene]amino}carbonyl)pyridm-3- yl]ethynyl}phenyl)carbamate and
(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide.
37. A compound of Claim 30 selected from
(S)-5-({4-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide.
(S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(2- thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide.
(S)-5- [(3 -{[( 1 ,3 -dimethyl- 1 H-pyrazol-5-yl)carbonyl] amino } phenyl) ethynyl] -N-
[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-({3-[(3-methylthienyl-2- carbonyl)amino]phenyl}ethynyl)nicotinamide
(S)-tert-butyl (3-{[5-({[methyl(oxo)phenyl-λ6-sulfanyh'dene]amino}carbonyl)pyridm-3- yl] ethynyl} phenyl)carbamate.
(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ6- sulfanylidene]nicotinamide and
(S)-5- {[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide.
38. A compound of claim 25 selected from the group consisting of (S)-tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3- yljethynyl} - 1 ,3-thiazol-2-yl)carbamate,
(S)-5-[(2-amino-l,3-thiazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and
(S)-5- {[2-(benzoylamino)-l,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl- λ6- sulfanylidene]nicotinamide.
39. A compound according to claim 31 that is (S)-5- {[2-(benzoylamino)-l,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl- λ6- sulfanylidene]nicotinamide
40. A compound according to claim 26 selected from the group consisting of (S)-6-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and (S)-6-amino-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide.
41. A compound according to Claim 27 that is S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide.
42. A compound which is a substituted aroyl sulfoximine compound which binds to the tyrosine kinase receptor.
43. The compound of claim 42 wherein the substituted aryl moiety is represented by formula IV below:
Figure imgf000134_0001
44. A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula I:
Figure imgf000134_0002
wherein: X is CR4 or N;
Y is CR1 or N;
R1 is selected from the group consisting of hydrogen, alkyl, halogen, OR4, CN, NO2 , COR4,
(CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2and N(R4)2; R2 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2 , SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10; R3 is selected from the group consisting of hydrogen, halogen, alkyl, OR4, CN, NO2, SO2N(R4)2, COR4, (CH2)aOR4, (CH2)aN(R4)2, C(O)N(R4)2 , N(R4)2 and N(R6)(CR7R8)aR10; R4 is hydrogen or Ci to C4 alkyl;
A is selected from the group consisting of C≡C ; CH=CH, CH2CH2, CH2O, CF2O, OCH2, OCF2, O, N(R4), C(O), S(O)6, NR7C(O), C(O)NR7 and N(R7)C(O)NR7;
B is selected from the group consisting of hydrogen, alkyl and alkyloxyalkyl or B may be a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group; E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group; E' is selected from the group consisting of alkyl, CF3,
(CR7R8)aC(O)OR10, (CR7R8)aC(O)N(R10)2, (CR7R8)aC(O)N(OR10)(R10), (CR7R8)a(OR10), (CR7R8)aN(R10)2, and (CR7R8)aR10; wherein R7 and R8 are selected from the group consisting of H, halogen, hydroxyl, and alkyl or CR7R8 may represent a carbocyclic ring of from 3 to 6 carbons; and
R10 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl, (CR7R8)aC(O)OR6, C(R7R8)aC(O)R6, (CR7R8)aC(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), (CR7R8)aN(R6)2 and (CR7R8)aR6, wherein R6 is selected from the group consisting of hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group; wherein R6 is selected from the group consisting of hydrogen, alkyl, carboalkyl, alkylamine, alkylhydroxy and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group;
a is O or an integer of from 1 to 5; b is an integer of from 2 to 5; c is O or an integer of from 1 to 4; d is O or an integer of from 1 to 5; e is O or an integer of from 1 to 2 and further including prodrugs, pharmaceutically acceptable salts, racemic mixtures and enantiomers of said compound.
45. The method of claim 44 wherein B is a carbocyclic aryl or heterocyclic aryl represented by formula II below:
Figure imgf000135_0001
wherein said carbocyclic aryl and heterocyclic aryl groups are selected from the group consisting of:
Figure imgf000136_0001
wherein R is selected from the group consisting of halogen, alkyl, CF3, OCF3, OCF2H, CH2CN, CN, SR6, OP(O)(OR6)2, OCH2O, HC=N-NH, N=CH-S,
(CR7R8)aC(O)R6, O(CR7R8)aC(O)R6, N(R6)(CR7R8)aC(O)R6, C(O)(CR7R8)aC(O)R6, S(O)e(CR7R8)aC(O)R6 ,(CR7R8)aC(O)OR6, O(CR7R8)aC(O)OR6, N(R6)(CR7R8)aC(O)OR6, C(O)(CR7R8)aC(O)OR6, S(O)e(CR7R8)aC(O)OR6, (CR7R8)aC(O)N(R6)2, O(CR7R8)aC(O)N(R6)2, N(R6)(CR7R8)aC(O)N(R6)2, C(O)(CR7R8)aC(O)N(R6)2, S(O)e(CR7R8)aC(O)N(R6)2, (CR7R8)aN(R6)C(O)N(R6)2, O(CR7R8)bN(R6)C(O)N(R6)2, N(R6)(CR7R8)bN(R6)C(O)N(R6)2, C(O)(CR7R8)aN(R6)C(O)N(R6)2, S(O)e(CR7R8)aN(R6)C(O)N(R6)2, (CR7R8)aC(O)N(OR6)(R6), O(CR7R8)aC(O)N(OR6)(R6), N(R6)(CR7R8)aC(O)N(OR6)(R6), C(O)(CR7R8)aC(O)N(OR6)(R6), S(O)e(CR7R8)aC(O)N(OR6)(R6), (CR7R8)a(OR6), O(CR7R8)a(OR6), N(R6)(CR7R8)a(OR6), C(O) (CR7R8)a(OR6), S(O)e(CR7R8)a(OR6), (CR7R8)aN(R6)2, O(CR7R8)bN(R6)2, N(R6)(CR7R8)bN(R6)2, C(O)(CR7R8)aN(R6)2
S(O)e(CR7R8)aN(R6)2, (CR7R8)aR6, 0(CR7R8) aR6, N(R6)(CR7R8)aR6, C(O)(CR7R8)aR6 and S(O)e(CR7R8)aR6 wherein R6 is selected from the group consisting of hydrogen, alkyl, carboalkyl, alkylamine, alkylhydroxy and alkyloxyalkyl or R6 is a 5 or 6 membered carbocyclic or heterocyclic group.
46. The method of claim 44 wherein R6 is selected from the group consisting of hydrogen, alkyl, dilower alkyl amine, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl , 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N- (2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1 - piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(lH)-l,4-diazepinyl-5(4H)-one, N- methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1 -acetylpiperazinyl, 3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3- (diethylamino)pyrrolidinyl, 1 ,4-dioxa-8-azaspiro[4.5]decaninyl, 1 -(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3- picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1 -(2-pyrimidyl)-piperazinyl, 1 -(2- pyrazinyl)-piperazinyl, 2-methylaminomethyl-l,3-dioxolane,2-(N-methyl-2-aminoethyl)-l,3- dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-l-methoxybutane, 2- methoxyisopropylaminyl, l-(3-aminopropyl)imidazole, histamyl , N ,N- diisopropylethylenediaminyl, 1 -benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl- 1 ,3-dioxolane-4-methanaminyl, (R)-3-amino- 1 -N-BOC-pyrrolidinyl, 4-amino- 1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran and ethanolamine.
47. The method of claim 44 wherein E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl represented by formula III below:
Figure imgf000137_0001
III wherein said carbocyclic aryl and heterocyclic aryl is selected from the group consisting of:
Figure imgf000138_0001
Figure imgf000138_0003
Figure imgf000138_0002
48. The method of claim 44 wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.
49. The method of claim 44 wherein the blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis and restenosis.
50. The method of claim 44 wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.
51. The method of claim 44 wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.
52. The method of claim 44 wherein the metabolic diseases is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.
53. A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a substituted aroylsulfoximine compound which binds to the tyrosine kinase receptor.
54. The method of claim 53 wherein the substituted aryl moiety is represented by formula IV below:
Figure imgf000139_0001
55. The compound of claim 41 wherein said substituted aryl moiety is represented by formula V below
Figure imgf000139_0002
wherein B1, R12 and R13 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano.
56. The compound of claim 54 wherein said sulfoximine is represented by formula VI below
Figure imgf000140_0001
wherein Z is said substituted aroyl group and E1 and E2 are selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008121665A1 (en) * 2007-04-02 2008-10-09 Allergan, Inc. Methods and compositions for intraocular administration to treat ocular conditions
WO2010078393A1 (en) * 2009-01-05 2010-07-08 Allergan, Inc. Kinase inhibitors
WO2010127206A3 (en) * 2009-05-01 2011-02-17 Allergan, Inc. Intraocular bioactive agent delivery compositon including a molecular partitioning system
WO2013062843A1 (en) * 2011-10-20 2013-05-02 Allergan, Inc. Pyridine- sulfoximines as tyrosine kinase inhibitors
WO2015089220A1 (en) 2013-12-12 2015-06-18 Allergan, Inc. Substituted nicotinamide derivatives as kinase inhibitors
WO2015089210A1 (en) 2013-12-12 2015-06-18 Allergan, Inc. Substituted dialkyl(oxido)-λ4-sulfanylidene nicotinamide derivatives as kinase inhibitors
US9090564B2 (en) 2009-04-21 2015-07-28 Boehringer Ingelheim International Gmbh 5-alkynyl-pyridines
WO2020177603A1 (en) * 2019-03-06 2020-09-10 中国科学院上海药物研究所 O-aminopyridylalkyne compound and preparation method therefor and use thereof

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7456476B2 (en) 2003-06-27 2008-11-25 Intel Corporation Nonplanar semiconductor device with partially or fully wrapped around gate electrode and methods of fabrication
US8512738B2 (en) 2004-04-30 2013-08-20 Allergan, Inc. Biodegradable intravitreal tyrosine kinase implants
US7771742B2 (en) 2004-04-30 2010-08-10 Allergan, Inc. Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods
US8455656B2 (en) 2004-04-30 2013-06-04 Allergan, Inc. Kinase inhibitors
US7042009B2 (en) 2004-06-30 2006-05-09 Intel Corporation High mobility tri-gate devices and methods of fabrication
US20060086977A1 (en) 2004-10-25 2006-04-27 Uday Shah Nonplanar device with thinned lower body portion and method of fabrication
US7518196B2 (en) 2005-02-23 2009-04-14 Intel Corporation Field effect transistor with narrow bandgap source and drain regions and method of fabrication
US7858481B2 (en) 2005-06-15 2010-12-28 Intel Corporation Method for fabricating transistor with thinned channel
US7547637B2 (en) 2005-06-21 2009-06-16 Intel Corporation Methods for patterning a semiconductor film
US7279375B2 (en) * 2005-06-30 2007-10-09 Intel Corporation Block contact architectures for nanoscale channel transistors
US20070090416A1 (en) 2005-09-28 2007-04-26 Doyle Brian S CMOS devices with a single work function gate electrode and method of fabrication
US7485503B2 (en) 2005-11-30 2009-02-03 Intel Corporation Dielectric interface for group III-V semiconductor device
US8367664B2 (en) 2006-01-24 2013-02-05 Allergan, Inc. Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors
US8143646B2 (en) 2006-08-02 2012-03-27 Intel Corporation Stacking fault and twin blocking barrier for integrating III-V on Si
US8362566B2 (en) * 2008-06-23 2013-01-29 Intel Corporation Stress in trigate devices using complimentary gate fill materials

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4966849A (en) 1985-09-20 1990-10-30 President And Fellows Of Harvard College CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression
WO1991015495A1 (en) 1990-04-02 1991-10-17 Pfizer Inc. Benzylphosphonic acid tyrosine kinase inhibitors
WO1992020642A1 (en) 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
WO1992021660A1 (en) 1991-05-29 1992-12-10 Pfizer, Inc. Tricyclic polyhydroxylic tyrosine kinase inhibitors
US5217999A (en) 1987-12-24 1993-06-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Styryl compounds which inhibit EGF receptor protein tyrosine kinase
WO1994003427A1 (en) 1992-08-06 1994-02-17 Warner-Lambert Company 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties
US5302606A (en) 1990-04-16 1994-04-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Styryl-substituted pyridyl compounds which inhibit EGF receptor tyrosine kinase
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1994014808A1 (en) 1992-12-23 1994-07-07 Farmitalia Carlo Erba Srl Vinylene-azaindole derivatives and process for their preparation
US5330992A (en) 1992-10-23 1994-07-19 Sterling Winthrop Inc. 1-cyclopropyl-4-pyridyl-quinolinones
US5792783A (en) 1995-06-07 1998-08-11 Sugen, Inc. 3-heteroaryl-2-indolinone compounds for the treatment of disease
WO2002029630A2 (en) 2000-10-04 2002-04-11 Gonzalez Emmanuel C Ergonomic graphic interface for webpages, internet browsers and computers

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2383874A (en) * 1941-04-24 1945-08-28 Swiss Firm Of J R Geigy A G p-aminobenzenesulphonamides and a process for their manufacture
GB602558A (en) * 1945-10-24 1948-05-28 Geigy Ag J R Manufacture of aromatic acyl-sulphonamides
DE821977C (en) * 1949-10-02 1951-11-22 Basf Ag Process for the production of azo dyes
DE3068101D1 (en) * 1979-07-18 1984-07-12 Ici Plc Diphenyl ether compounds, and herbicidal compositions and processes utilising them
ZA804076B (en) * 1979-07-18 1981-06-24 Ici Ltd Herbicides
GB2061914A (en) * 1979-11-01 1981-05-20 American Cyanamid Co Substituted anilines and their use as anti-atherosclerotic agents
JPS5998056A (en) * 1982-11-04 1984-06-06 エフ・ホフマン−ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト Herbocidal benzoic acid derivatives
EP0109575A3 (en) 1982-11-04 1984-09-05 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Benzoic-acid derivatives, process and means for its production
JPS5890555A (en) * 1982-11-22 1983-05-30 Ishihara Sangyo Kaisha Ltd Benzamide derivative and herbicide containing the same
JPS6216465A (en) * 1985-03-14 1987-01-24 Nissan Chem Ind Ltd Benzamide derivative, production thereof and soil blight controlling agent
JPH01502755A (en) * 1987-03-18 1989-09-21 アメリカン・ホーム・プロダクツ・コーポレイション Sulfonylcarboxamide
US4826990A (en) * 1987-09-30 1989-05-02 American Home Products Corporation 2-aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents
CA2068355A1 (en) * 1991-05-14 1992-11-15 Mark S. Chambers Benzodiazephine derivatives, compositions containing them and their use in therapy
JP2600644B2 (en) * 1991-08-16 1997-04-16 藤沢薬品工業株式会社 Thiazolyl benzofuran derivative
JPH05294930A (en) * 1992-04-21 1993-11-09 Yoshitomi Pharmaceut Ind Ltd Stylyl compound
DE4410453A1 (en) * 1994-03-25 1995-09-28 Hoechst Ag Substituted heterocyclic carboxylic acid amide esters, their preparation and their use as medicaments
AU705883B2 (en) * 1994-10-27 1999-06-03 Fujisawa Pharmaceutical Co., Ltd. Pyridopyrimidones, quinolines and fused N-heretocycles as bradykinin antagonists
EA002357B1 (en) * 1995-12-28 2002-04-25 Фудзисава Фармасьютикал Ко., Лтд. Benzimidazole derivatives
AU7552198A (en) * 1997-06-11 1998-12-30 Sankyo Company Limited Benzylamine derivatives
BR9915194A (en) * 1998-11-09 2001-08-07 Black James Foundation Compound, method for making the same, pharmaceutical composition, and method for making the same
WO2001070692A2 (en) * 2000-03-22 2001-09-27 Bayer Cropscience Gmbh Heterocyclic acylsulfimides, a method for their production, agents containing the same and their use as pesticides
DE10021246A1 (en) * 2000-04-25 2001-10-31 Schering Ag New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis
JP2002205464A (en) * 2000-11-10 2002-07-23 Oji Paper Co Ltd Heat-sensitive recording medium
HUP0303538A2 (en) 2000-12-21 2005-02-28 Bristol-Myers Squibb Co. Thiazolyl inhibitors of tec family tyrosine kinases and pharmaceutical compositions containing them
JP4335136B2 (en) * 2002-08-09 2009-09-30 メルク エンド カムパニー インコーポレーテッド Tyrosine kinase inhibitor
DE10349423A1 (en) * 2003-10-16 2005-06-16 Schering Ag Sulfoximine-substituted parimidines as CDK and / or VEGF inhibitors, their preparation and use as medicaments
JPWO2005108370A1 (en) * 2004-04-16 2008-03-21 味の素株式会社 Benzene compounds
DE102004031323A1 (en) * 2004-06-29 2006-01-19 Bayer Cropscience Ag Substituted Pyridazincarboxamide and derivatives thereof
WO2006013449A1 (en) 2004-07-30 2006-02-09 Adriaan Francois Roberts A swimming pool installation and accessory
US7776869B2 (en) 2004-10-18 2010-08-17 Amgen Inc. Heteroaryl-substituted alkyne compounds and method of use
WO2006082373A1 (en) 2005-02-01 2006-08-10 Astrazeneca Ab Pyrimidine compounds having ties (tek) inhibitory activity
GB0502418D0 (en) 2005-02-05 2005-03-16 Astrazeneca Ab Compounds
EP1863785B1 (en) * 2005-03-16 2009-12-02 Janssen Pharmaceutica N.V. Novel thiophene sulfoximines for treating complement-mediated diseases and conditions
EP1705177A1 (en) * 2005-03-23 2006-09-27 Schering Aktiengesellschaft N-aryl-sulfoximine-substituted pyrimidines as CDK- and/or VEGF inhibitors, their production and use as pharmaceutical agents
US20080194552A1 (en) * 2005-03-31 2008-08-14 Astrazeneca Ab Aminopyrimidine Derivatives With Tie2 Inhibiting Activity
PT1973545E (en) 2005-12-23 2013-02-11 Ariad Pharma Inc Bicyclic heteroaryl compounds
DE102006041382A1 (en) * 2006-08-29 2008-03-20 Bayer Schering Pharma Ag Carbamoyl sulfoximides as protein kinase inhibitors
TW200930369A (en) * 2007-11-15 2009-07-16 Astrazeneca Ab Bis-(sulfonylamino) derivatives in therapy

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4966849A (en) 1985-09-20 1990-10-30 President And Fellows Of Harvard College CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression
US5217999A (en) 1987-12-24 1993-06-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Styryl compounds which inhibit EGF receptor protein tyrosine kinase
WO1991015495A1 (en) 1990-04-02 1991-10-17 Pfizer Inc. Benzylphosphonic acid tyrosine kinase inhibitors
US5302606A (en) 1990-04-16 1994-04-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Styryl-substituted pyridyl compounds which inhibit EGF receptor tyrosine kinase
WO1992020642A1 (en) 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
WO1992021660A1 (en) 1991-05-29 1992-12-10 Pfizer, Inc. Tricyclic polyhydroxylic tyrosine kinase inhibitors
WO1994003427A1 (en) 1992-08-06 1994-02-17 Warner-Lambert Company 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties
US5330992A (en) 1992-10-23 1994-07-19 Sterling Winthrop Inc. 1-cyclopropyl-4-pyridyl-quinolinones
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1994014808A1 (en) 1992-12-23 1994-07-07 Farmitalia Carlo Erba Srl Vinylene-azaindole derivatives and process for their preparation
US5792783A (en) 1995-06-07 1998-08-11 Sugen, Inc. 3-heteroaryl-2-indolinone compounds for the treatment of disease
US5834504A (en) 1995-06-07 1998-11-10 Sugen, Inc. 3-(2'-halobenzylidenyl)-2-indolinone compounds for the treatment of disease
US5883116A (en) 1995-06-07 1999-03-16 Sugen, Inc. 3-(2'-alkoxybenzylidenyl)-2-indolinone and analogues thereof for the treatment of disease
US5883113A (en) 1995-06-07 1999-03-16 Sugen, Inc. 3-(4'-Bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease
US5886020A (en) 1995-06-07 1999-03-23 Sugen, Inc. 3-(4'-dimethylaminobenzylidenyl)-2-indolinone and analogues thereof for the treatment of disease
WO2002029630A2 (en) 2000-10-04 2002-04-11 Gonzalez Emmanuel C Ergonomic graphic interface for webpages, internet browsers and computers

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
JELLINEK ET AL., BIOCHEMISTRY, vol. 33, pages 10450 - 56
KENDALL; THOMAS, PROC. NAT'L ACAD. SCI, vol. 90, 1994, pages 10705 - 09
KIM ET AL., NATURE, vol. 362, 1993, pages 841 - 844
KINSELLA ET AL., EXP. CELL RES., vol. 199, 1992, pages 56 - 62
MARIANI ET AL., PROC. AM. ASSOC. CANCER RES., vol. 35, 1994, pages 2268
TAKANO ET AL., MOL. BIO. CELL, vol. 4, 1993, pages 358A
WRIGHT ET AL., J. CELLULAR PHYS., vol. 152, 1992, pages 448 - 57

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US8143410B2 (en) 2006-11-16 2012-03-27 Allergan, Inc. Kinase inhibitors
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US8558002B2 (en) 2006-11-16 2013-10-15 Allergan, Inc. Sulfoximines as kinase inhibitors
WO2008121665A1 (en) * 2007-04-02 2008-10-09 Allergan, Inc. Methods and compositions for intraocular administration to treat ocular conditions
WO2010078393A1 (en) * 2009-01-05 2010-07-08 Allergan, Inc. Kinase inhibitors
US9090564B2 (en) 2009-04-21 2015-07-28 Boehringer Ingelheim International Gmbh 5-alkynyl-pyridines
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WO2013062843A1 (en) * 2011-10-20 2013-05-02 Allergan, Inc. Pyridine- sulfoximines as tyrosine kinase inhibitors
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US9567324B2 (en) 2013-12-12 2017-02-14 Allergan, Inc. Substituted nicotinamide derivatives as kinase inhibitors
WO2015089210A1 (en) 2013-12-12 2015-06-18 Allergan, Inc. Substituted dialkyl(oxido)-λ4-sulfanylidene nicotinamide derivatives as kinase inhibitors
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