Patent Application
20100048891
The invention concerns thiazolidinones, their manufacture and use as polo-like kinase (PLK) inhibitors for treating various diseases.
Tumor cells set themselves apart through their uninhibited cell-cycle process. On the one hand, it is based on the loss of control proteins like RB, p16, p21, p53 etc. as well as the activation of so-called cell-cycle process accelerators, the cyclin-dependant kinases (CDK's). CDK's are a recognized anti-tumor target-protein in pharmacy. In addition to the CDK's, new cell-cycle regulating serine/threonine-kinases, so-called ‘polo-like kinases’ were described that are involved not only in regulating cell-cycles but also in coordinating with other processes during mitosis and cytokinesis (formation of the spindle apparatus, chromosome separation). Consequently, this protein class represents an interesting point of contact for the therapeutic intervention of proliferative diseases like cancer (Descombes and Nigg. Embo j, 17; 1328ff, 1998; Glover et al. Genes Dev 12, 3777ff, 1998).
A high expression rate of PLK-1 was found in ‘non-small cell lung’-cancer (Wolf et al. Oncogene, 14, 543ff, 1997), in melanomas (Strebhardt et al. JAMA, 283, 479ff, 2000), in ‘squamous cell carcinomas’ (Knecht et al. Cancer Res, 59, 2794ff, 1999) and in ‘esophageal carcinomas’ (Tokumitsu et al. Int J Oncol 15, 687ff, 1999).
A correlation of high expression rate was shown in tumor patients with a poor prognosis for sundry tumors (Strebhardt et al. JAMA, 283, 479ff, 2000, Knecht et al. Cancer Res, 59, 2794ff, 1999 and Tokumitsu et al. Int J Oncol 15, 687ff, 1999).
Constitutive expression of PLK-1 in NIH-3t3-cells resulted in malignant transformation (increased proliferation, soft-agar growth, colony formation, and tumor development in naked mice (Smith et al. Biochem Biophys Res Comm, 234, 397ff., 1997).
Microinjections of PLK-1-antibodies into HeLa-cells resulted in defective mitosis (Lane et al.; Journal Cell Biol, 135, 1701 ff, 1996).
Using a ‘20-mer’ antisense oligo the expression of PLK-1 in a549-cells could be inhibited and their ability to survive stopped. A clear anti-tumor-effect could also be demonstrated in naked mice (Mundt et al., Biochem Biophys Res Comm, 269, 377ff., 2000).
Microinjecting anti-PLK-antibodies into nonimmortalized human hs68-cells exhibited, in contrast to HeLa cells, significantly higher fraction of cells, which remained in a growth arrest on G2 and exhibited far fewer indications of defective mitosis (Lane et al.; Journal Cell Biol, 135, 1701ff, 1996).
In contrast to tumor cells, antisense-oligo-molecules did not inhibit the growth and viability of primary human mesangial cells (Mundt et al., Biochem Biophys Res Comm, 269, 377ff., 2000).
Until now, besides PLK-1, three other polo-kinases that are mitogenic response-induced and that perform their function in the G1 phase of the cell cycle, have been documented in mammals. They are the so-called PRK/PLK-3 (the human homologue of the mouse FNK=fibroblast growth factor induced kinase; Wiest et al, Genes, Chromosomes & Cancer, 32: 384ff, 2001), SNK/PLK-2 (serum induced kinase, Liby et al., DNA Sequence, 11, 527-33, 2001) and SAK/PLK4 (Fode et al., Proc. Natl. Acad. Sci. U.S.A., 91, 6388ff; 1994).
The inhibition of PLK-1 and the other kinases of the polo-family, like PLK-2, PLK-3 and PLK-4 therefore represent a promising approach for treating a variety of diseases.
The sequence identity within the PLK-domains of the polo-family lies between 40 and 60%, such that sometimes the inhibitors of one kinase will interact with one or several other kinases of that family. But depending on the structure of the inhibitor, the effect can also occur selectively or preferably on only kinase of the polo family.
International application WO 03/093249 discloses thiazolidinone compounds that inhibit kinases of the polo family.
The task of the present compound is to furnish improved compounds, improved particularly in the inhibition of polo-like kinases as compared to prior art and/or to provide compounds that inhibit kinases, in particular polo-like kinases or that have better physicochemical properties as compared to compounds disclosed in prior art.
In a first embodiment of the present invention it was found in claim 1 that compounds of the general formula I,
Another variation of the first embodiment of the present invention are compounds of the general formula I in claim 2, as described in claim 1, in which the following mean
Another object according to this first embodiment of the present invention are also compounds of the general formula I in claim 3, as described in claim 1 or 2, in which the following mean
Another variation of the first embodiment of the present invention are compounds of the general formula I in claim 4, as described in any of claims 1 through 3, in which the following mean
Another object of the present invention according to this embodiment are also compounds of the general formula I in claim 5, as described in any of claims 1 through 4, in which the following mean
Another object of the invention according to this embodiment are also compounds of the general formula I in claim 6, as described in any of claims 1 through 5, in which
Another object of the first embodiment of this invention are also compounds of the general formula I in claim 7, as described in any of claims 1 through 6, in which the following means
Another object of the first embodiment of this invention are also compounds of the general formula I in claim 8, as described in claim 7, in which the following means
SO2— groups and optionally one or several double bonds can be contained in the ring and the ring itself can be optionally mono- or polysubstituted, identically or differently, with halogen, cyanogen, hydroxyl, aryl or with the group —(CO)—R5, —(CO)—O—R12, —(SO2)—R14, —NR12R13 or with C1-C3-alkyl optionally mono- or polysubstituted, identically or differently, with halogen, hydroxyl, C1-C3-alkylthiol or phenyl, wherein the aryl itself can be optionally mono- or polysubstituted, identically or differently with halogen or C1-C3-alkoxyl,
In a second embodiment of the present invention it was found that compounds of the general formula I in claim 9, as described in claim 1, in which
Another variation of the second embodiment of the present invention are compounds of the general formula I in claim 10, as described in claim 9,
in which
Another variation of the second embodiment of the present invention are compounds of the general formula I in claim 22, as described in claim 9, in which
Another variation of the second embodiment of the present invention are compounds of the general formula I in claim 23, as described in claim 10, in which
Another variation of the second embodiment of the present invention are compounds of the general formula I in claim 25, as described in any of claims 9, 10, 22, 23 or 24, in which R18 and R19 independently represent C1-C5-alkyl, pyrrolidinyl, phenyl or pyridinyl optionally mono- or polysubstituted, identically or differently, with halogen, C1-C3-alkyl or C1-C3-alkoxyl, wherein either R18 and R19 represent pyrrolidinyl or pyridinyl or a pyrrolidinyl or pyridinyl mono- or polysubstituted, identically or differently with halogen, C1-C3-alkyl or C1-C3-alkoxyl.
The task of the present compound in the third embodiment is to furnish improved compounds, improved particularly in the inhibition of polo-like kinases as compared to prior art and/or to provide compounds that have better physicochemical properties as compared to compounds disclosed in prior art.
In a third embodiment of the present invention it was found in claim 11, as described in claim 1 and/or 2, that compounds of the general formula I, in which the following mean
Another variation of the third embodiment of the present invention are compounds of the general formula I in claim 12, as described in claim 11, in which
The task of the present compound in the third embodiment is to furnish improved compounds, improved particularly in the inhibition of polo-like kinases as compared to prior art and/or to provide compounds that have better physicochemical properties as compared to compounds disclosed in prior art.
In a fourth embodiment of the present invention it was found in claim 13, as described in claim 1 and/or 2, that compounds of the general formula I, in which the following mean
Especially well suited to solve the task of the present invention according to this fourth embodiment therefore are compounds of the general formula I for which R3 represents M, M represents the group —NR12—(CO)—R16 and R16 represents methyl, wherein the methyl in turn is substituted at least with C2-C10-heterocycloalkyl, heteroaryl or with the group —NR10R11 and the heterocycloalkyl and the heteroaryl contain at least one nitrogen.
Another variation of the fourth embodiment of the present invention are compounds of the general formula I in claim 14, as described in claim 13, in which
In a fifth embodiment of the present invention it was found that compounds of the general formula I,
in which the following mean
In particular those compounds of the general formula I are preferred in which
The following compounds of the general formula I are also preferred, in which
The following compounds of the general formula I are also preferred, in which
Those compounds of the general formula I are in turn also preferred, in which the following mean
Moreover, preferred among those are those compounds of the general formula I, in which the following mean
Other preferred compounds of the general formula I are those in which
The compounds of the general formula II are likewise objects of the invention
in which
R1 and R2 have the meanings set forth in general formula I, as well as their solvates, hydrates, diastereomers, enantiomers and salts as intermediate products.
Another object of the first four embodiments of the present invention are compounds of the general formula II as per claim 15 in claim 16 with the following formulas:
Another object of the first four embodiments of the present invention are compounds in claim 17 of the general formulas (II) or (IV) as described in claim 15 or compounds as described in claim 16 for use as intermediate products for producing compounds of the general formula (I).
Another object of the first four embodiments of the present invention are the use of the compounds of the general formulas (II) or (IV) in claim 18 as described in claim 15 or compounds as described in claim 16 as intermediate products for producing compounds of the general formula (I).
Another object of the first four embodiments of the present invention is drugs in claim 19 that contain at least one compound described in any of claims 1 through 14.
Another object of the first four embodiments of the present invention is the use of compounds of the general formula I in claim 20, as described in any of claims 1 through 14, for producing a drug.
Another object of the first four embodiments of the present invention are compounds in claim 21 described in any of claims 1 through 14 or the drug described in claim 19 with suitable formulation substances and carrier substances.
Another object of the first four embodiments of the present invention is a method in claim 22 for producing compounds of the general formula I, wherein compounds of the general formula II are heated with compounds of the general formula III,
in which
R3, U, T1, T2 and T3 have the same meaning as R3, U, T1, T2 and T3 described in any of claims 1 through 14, in a formic acid orthoester with three identical or different alkoxy- or aryloxy residues optionally bridged or substituted with halogen and optionally a polar solvent, or
compounds of the general formula IV
in which
R1, R3, U, T1, T2 and T3 have the same meaning as R1, R3, U, T1, T2 and T3 as described in any of claims 1 through 14, are converted with an allyl acceptor and a catalyst in an aprotic solvent and, after completion of a first partial reaction with a coupling reagent, a base and R2—NH2, wherein R2 has the same meaning as R2 as set forth in any of claims 1 through 14, converted in an aprotic solvent into compounds of the general formula I.
Another object of the first four embodiments of the present invention is a method in claim 23, according to claim 22, wherein for producing the compounds of the general formula II, compounds of the general formula V,
in which
R1 has the same meaning as R1 as described in any of claims 1 through 14, are converted with an allyl acceptor and a catalyst in an aprotic solvent and, after completion of a first partial reaction, converted with a coupling reagent, a base and R2—NH2, wherein R2 has the same meaning as R2 as described in any of claims 1 through 14, and with an aprotic solvent into the compounds of the general formula I.
Understood under formic acid orthoester with three identical or different alkoxy residues optionally bridged or substituted with halogen, as described in either of claims 22 or 23, is preferably a triethylorthoformate. Other formic acid orthoesters that fall under this definition are known to people skilled in the field.
Polar solvents suitable for performing the method described in claim 22 are C1 through C5 alcohols or diols like e.g. glycol, preferably C1 through C5 alcohols and especially preferably ethanol or 1-propanol. If there is an excess of formic acid orthoester on hand, no polar solvent is needed to perform the reaction of the compounds of the general formula II with compounds of the general formula III to the compounds of the general formula I.
For reacting the compounds of the general formula II with compounds of the general formula III to the compounds with the general formula I as described in claim 22, they must be heated up. In a preferred variation, the reaction is supposed to occur at, at least, 70° C., more preferably between 70° C. and 150° C. and even more preferably between 100° C. and 150° C. The reaction can also be performed at higher temperatures, but then—as anyone skilled in the field knows—a higher-boiling solvent or pressure vessel should be used. In a preferred variation of the invention the heating reaction is performed for 2 to 24 hours.
“Catalysts” employable for the methods described in any of claims 22 or 23 are known to people skilled in the field. The use of a palladium catalyst is preferable.
“Aprotic solvents” employable for performing the methods of claims 22 or 23 are known to people skilled in the field. Tetrahydrofurane and dichloromethane are suitable aprotic solvents that are preferably used. In the coupling reaction (2nd partial reaction) of claims 22 or 23, dimethylformamide can preferably also be used as an aprotic solvent. People skilled in the field also know, however, that other aprotic solvents like e.g. dimethylacetamide (DMA) and n-methylpyrrolidone (NMP) can also be used to perform the methods of claims 22 or 23.
Understood to be preferable allyl acceptors according to the present invention and according to claims 22 or 23 are 1,3-dimethylbarbituric acid, barbituric acid and/or a silane. People skilled in the field also are also aware of other allyl acceptors that can be used to perform the production method described.
“Coupling reagents” employable for performing the methods of claim 22 or 23 are known to people skilled in the field. Preferably used coupling reagents are 0-(BENZOTRIAZOL-1-YL)-N,N,N′,N′-TETRAMETHYLURONIUM TETRAFLUOROBORATE (TBTU) and/or O-(7-AZABENZOTRIAZOL-1-YL)-N,N,N′,N′-TETRAMETHYLURONIUM HEXAFLUORO-PHOSPHATES (HATU).
“Bases” employable for performing the methods of claims 22 or 23 are known to people skilled in the field. Preferably used bases are triethylamine, Hunig's base or sodiumhydrogencarbonate.
The reactions of compounds of the general formula IV to the compounds of the general formula I described in claim 22 and of compounds of the general formula V to compounds of the general formula II as described in claim 23, are preferably performed at a temperature of 0° C. to 50° C. and even more preferably at ambient temperature.
Understood under alkyl is any straight-chained or branched alkyl residue, like e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
Understood under alkoxyl is any straight-chained or branched alkoxyl residue, like e.g. methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec. butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy. Preferred in the present invention, however, are C1-C6-alkoxy groups, especially preferred are C1-C3-alkoxyl groups and especially preferred is a methoxyl group.
The alkenyl substituents are respectively straight-chained or branched, wherein e.g. the following residues are intended: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, allyl.
Understood under alkinyl is any straight-chained or branched alkinyl residue that contains 2-6, preferably 2-4 C-atoms. The following residues are given as examples: acetylene, propin-1-yl, propin-3-yl (propargyl), but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.
C2-C10-heterocycloalkyl represents an alkyl ring comprising 2-10 carbon atoms, preferably 3 to 10 carbon atoms and especially preferably 5 to 6 carbon atoms, wherein the heterocycloalkyl contains at least one atom in the ring, identically or differently, from the group oxygen, sulfur or nitrogen and can be optionally interrupted in the ring by one or several —(CO)—, —(CS)— or —SO2— groups and optionally one or several double bonds can be contained in the ring and the ring itself can be optionally mono- or polysubstituted or annealed identically or differently.
Examples mentioned of heterocycloalkyls are: oxiranyl, oxethanyl, dioxolanyl, dithianyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisochinolinyl, octahydroisochinolinyl, tetrahydrochinolinyl, octahydrochinolinyl, tetrahydroimidazolonyl, pyrazolidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, piperazinonyl, n-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, n-methylpiperazinyl, n-acetylpiperazinyl, n-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazolonyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, trithianyl, tetrahydrotriazinthionyl, triazinthionyl, chinuclidinyl, nortropinyl, etc.
or rings of the aforementioned, which are benzocondensed, like e.g. benzopyrrolidinyl, benzomorpholinyl, etc.
Substituents on the heterocycloalkylring can be e.g.:
cyanogen, halogen, hydroxyl, C1-C6-alkyl, C1-C6-alkoxyl, C1-C6-alkoxyalkyl, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, aryl or C1-C6-alkyl optionally mono- or polysubstituted, identically or differently with halogen, hydroxyl or C1-C6-alkylthiol, or with the group —(CO)—C1-C6-alkyl, —(CO)—O—C1-C6— alkyl, —(SO2)—C1-C6— alkyl, —(SO2)-phenyl, —NH2, —N(C1-C6— alkyl)2, —NH(C1-C6— alkyl) etc.
Understood under cycloalkyl are monocyclic alkyl rings like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings like e.g. adamantanyl. The cycloalkyl may also be optionally benzocondensed, like e.g. (tetralin)yl, etc.
Understood under halogen are fluorine, chlorine, bromine or iodine respectively.
The heteroaryl residue comprises 5-16 ring atoms, preferably 5 to 10 ring atoms and especially preferably 5 to 7 ring atoms, and, instead of carbon, contain one or several, identical or different, heteroatoms, like oxygen, nitrogen or sulfur in the ring, and can be mono-, bi- or tricyclic, and can also be benzocondensed.
Examples mentioned are:
Thienyl, furanyl, pyrrolidinylyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzoderivates thereof, like e.g. benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzoderivates thereof, like e.g. chinolyl, isochinolyl, etc.; or oxepinyl,
azocinyl, indolizinyl, indolyl, indolinyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzoderivates thereof; or chinolinyl, isochinolinyl, cinnolinyl, phthalazinyl, chinazolinyl, chinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl etc.
Especially preferred heteroaryl residues are e.g. 5-ring heteroaromates like thiophene, furanyl, oxazolyl, thiazol, imidazolyl and benzoderivates thereof (like e.g. benzimidazolyl) and 6-ring heteroaromates like pyridinyl, pyrimidinyl, triazinyl, chinolinyl, isochinolinyl and benzoderivates thereof.
The aryl residue comprises respectively 3-12 carbon atoms and may be respectively substituted or benzocondensed.
Mentioned as examples: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, tetralinyl, tolyl etc.
As it is used in this application, “C1-C5” means, e.g. in connection with the definition of “C1-C5-alkyl”, an alkyl group with an end number of 1 to 5 carbon atoms, i.e. 1, 2, 3, 4 or 5 carbon atoms. The definition of “C1-C5” is further interpreted to include any possible subgroup, like e.g., C1-C5, C2-C5, C3-C5, C4-C5, C1-C2, C1-C3, C1-C4, C1-C5.
The information of the application regarding the different groups not explicitly listed here is defined in the same way as the “C1-C5” groups mentioned as examples above.
Understood under isomers are chemical compounds of the same sum formula but of a different chemical structure. A differentiation is generally made between isomers and stereoisomers.
Constitutional isomers possess the same sum formula, but are set apart, however, by how their atoms or atom groups link. These include functional isomers, position isomers, tautomers or valence isomers.
Stereoisomers have basically the same structure (constitution)—and therefore the same formula as well—but differ through the spatial configuration of the atoms. A differentiation is generally made between configurational isomers and conformational isomers. Configurational isomers are stereoisomers that can only be converted into each other by bond breakage. They include enantiomers, diastereomers and E/Z (cis/trans) isomers.
Enantiomers are stereoisomers that behave like an image to a mirror image and do not exhibit any plane of symmetry. All stereoisomers that are not enantiomers are called diastereomers. E/Z (cis/trans) isomers at double bonds are the special case. Conformational isomers are stereoisomers that can be converted into each other through single bond rotation.
For delineating isomery types from each other, see also the IUPAC rules, section E (Pure Appl. Chem. 45, 11-30, 1976).
The inventive compounds of the general formula I also include the possible tautomeric forms and include the E or Z isomers or, if there is a chiral center, the racemates and enantiomers as well. These are understood to include double bond isomers as well.
The compounds of the invention may also be in the form of solvates, particularly hydrates, wherein the compounds of the invention accordingly contain polar solvents, particularly of water, as a structural element of the crystal lattice of the compounds of the invention. The portion of polar solvent, in particular water, can be in stoichiometric or unstoichiometric ratio. For stoichiometric solvates or hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are also mentioned.
If there is an acidic function, physiologically compatible salts of organic and inorganic bases are suitable as salts, like e.g. well-soluble alkali- and earth alkali salts as well as n-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak-base, 1-amino-2,3,4-butantriol.
If it contains a basic function, the physiologically compatible salts of organic and inorganic acids are suitable, like hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, maleinic acid, fumaric acid, etc.
The compounds of the invention of the general formula I essentially inhibit polo-like kinases, on which their effect is also based, e.g. against cancer, like solid tumors and leukemia, autoimmune diseases like psoriasis, alopecia, and multiple sclerosis, chemotherapeutically-induced alopecia and mucositis, cardiovascular diseases like stenoses, arterioscleroses and restenoses, infectious diseases, like those brought upon e.g. by unicellular parasites like trypanosoma, toxoplasma or plasmodium, or by fungi, nephrological diseases like e.g. glomerulonephritis, chronic neurodegenerative diseases like Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS-induced dementia and Alzheimer's disease, acute neurodegenerative diseases like cerebral ischemias and neurotraumas, viral infections like e.g. cytomegalus-infections, herpes, hepatitis B and C, and HIV diseases.
An object of the present invention is also the use of the compounds of the general formula II as well as their solvates, hydrates, diastereomers, enantiomers and salts as intermediate products.
To use the inventive compounds of the general formula I as a drug, they are brought into the form of a pharmaceutical preparation that, in addition to the agent for the enteral or parenteral application, contains pharmaceutical, organic or inorganic inert carrier materials, like e.g. water, gelatins, Arabian rubber, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. In addition to that they also contain adjuvants, like preservatives, stabilizers or emulsifiers; salts to change osmotic pressure or buffers.
These pharmaceutical preparations are also an object of the present invention.
Particularly suited for parenteral application are injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated ricinus oil.
Surface-active adjuvants like salts of gallic acids or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or their components can also be used as carrier systems.
Suited particularly for oral application are tablets, dragees or capsules with talcum and/or carbon hydrogen carriers or binders, like e.g. lactose, corn or potato starch. Application can also be done in liquid form, like e.g. as a juice with an optionally added sweetener.
The enteral, parenteral and oral applications are also an object of the present invention. The dosage of these agents can vary depending on the administration path, age and weight of the patient, type and severity of the disease being treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, wherein the dose can be given as a one-time dose or divided into 2 or more daily doses.
Likewise an object of the present invention is the use of the compounds of the general formula I for producing a drug for treating cancer, autoimmune diseases, cardiovascular diseases, chemotherapeutically-induced alopecia and mucositis, infectious diseases, nephrological diseases, chronic and acute neurodegenerative diseases and viral infections, wherein understood under cancer are solid tumors and leukemia, understood under autoimmune diseases are psoriasis, alopecia and multiple sclerosis, understood under cardiovascular diseases are stenoses, arterial scleroses and restenoses, understood under infectious diseases are diseases brought about by unicellular parasites, understood under nephrological diseases are glomerulonephritis, understood under chronic neurodegenerative diseases are Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS-induced dementia and Alzheimer's disease, understood under acute neurodegenerative diseases are cerebral ischemias and neurotraumas, and understood under viral infections are cytomegalus-infections, herpes, hepatitis B or C, and HIV diseases.
Likewise an object of the present invention are drugs for treating the diseases listed above that contain at least one compound of the general formula I as well as drugs with suitable formulation and carrier substances.
The compounds of the invention of general formula I are among other things excellent inhibitors of polo-like kinases, like PLK 1, PLK 2, PLK 3 and PLK 4.
Where the production of the starting compounds is not described, they are known or similar to known compounds or producible according to methods described here. It is also possible to perform all the conversions described here in parallel reactors or by means of combined work methods.
The isomer mixtures can be separated according to standard methods like e.g. crystallization, chromatography or salification into isomers, like e.g. into enantiomers, diastereomers or E/Z isomers as long as the isomers do not stand in equilibrium with each other.
The salts are produced in the standard way by mixing a solution of the compound of formula I with the equivalent amount or an excess of a base or acid that is preferably in solution and separating off the precipitate or preparing the solution in the standard manner.
5 g 3-nitrophenyl ethanol, 9.4 g triphenylphosphine and 3.1 g imidazol are dissolved in 250 ml THF, mixed with 9.1 g iodine in portions and stirred for 15 hours at ambient temperature. The reaction mixture is mixed with ammonium chloride solution and extracted with dichloromethane. The organic phase is washed consecutively with sodiumthiosulfate solution and water and dried over sodium sulfate. After purification by chromatography on silica gel, 7.51 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=3.31 (t, 2H); 3.41 (t, 2H); 7.46-7.60 (m, 2H); 8.09 (s, 1H); 8.16 (d, 1H); ppm.
1.88 g of the compound described under INT1) is dissolved in 10 ml dimethylformamide, slowly mixed with 0.85 ml pyrrolidine and stirred for 15 hours at ambient temperature. The solution is condensed off in the high vacuum, the residue is incorporated into acetic acid ethylester and washed three times with water. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 350 g of title compound is obtained.
1H-nMR (CDCl3): δ=1.81 (m, 4H); 2.57 (m, 4H); 2.74 (t, 2H); 2.93 (t, 2H); 7.45 (t, 1H); 7.56 (d, 1H); 8.03-8.13 (m, 2H) ppm.
650 mg of the compound described under INT2) is dissolved in 250 ml ethanol and mixed (10%) with 130 mg palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 540 mg of the title compound is obtained.
1H-nMR (DMSO-d6): δ=1.78 (m, 4H); 2.65 (t, 2H); 2.70-2.92 (m, 6H); 4.99 (s, 2H); 6.31-6.45 (m, 3H); 6.92 (t, 1H) ppm.
5.0 g of 1,3-diaminobenzol is dissolved in 50 ml dichloromethane and mixed at 0° C. with 24 ml diisopropylethylamine and 10.4 ml pivalic acid anhydride. It is stirred for 2 hours at 0° C. and 18 hours at ambient temperature. The reaction mixture is mixed with semisaturated sodiumhydrogencarbonate solution and extracted with acetic acid ethylester. The organic solution is washed with saturated sodiumchloride solution, dried over sodium sulfate, condensed and after being purified by chromatography on silica gel, 5.7 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.20 (s, 9H); 4.98 (s, 2H); 6.24 (d, 1H); 6.70 (d, 1H); 6.83-6.96 (m, 2H) ppm.
1.5 g of 2-hydroxy-2-methyl-propionic acid is mixed in 50 ml dimethylacetamide at −10° C. with 1.05 ml thionylchloride and stirred for 30 minutes at −10° C. A solution of 2 g 3-nitroaniline is dropped into 10 ml dimethylacetamide at −10° C. and stirred consecutively for one hour at −10° C., one hour at 0° C. and for 15 hours at ambient temperature. The solution is condensed off in the high vacuum, the residue is incorporated into a mixture of acetic acid ethylester and dichloromethane (1:3) and washed twice with semisaturated sodiumhydrogencarbonate solution. The organic phase is dried over sodium sulfate. After being purified by chromatography on silica gel, 2.42 g of title compound is obtained.
1H-nMR (CDCl3): δ=1.49 (s, 6H); 2.35 (s, 1H); 7.50 (t, 1H); 7.98 (d, 2H); 8.49 (s, 1H); 8.98 (s, b, 1H) ppm.
1.92 g of the compound described under INT5) is dissolved in 400 ml ethanol and mixed with 50 mg Raney nickel. It is stirred for 18 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 1.9 g of title compound is obtained.
1H-nMR (CDCl3): δ=1.51 (s, 6H); 2.68 (s, 1H); 3.71 (s, b, 2H); 6.42 (d, 1H); 7.08 (t, 1H); 7.20 (s, 1H); 8.60 (s, b, 1H) ppm.
5 g (2-methoxyethoxy)-acetic acid is dissolved in 500 ml tetrahydrofurane. 9.7 ml triethylamine and 5.6 ml isobutylchloroformate is added at 0° C., and it is stirred for 30 minutes at 0° C. 5.0 g of 3-nitroaniline is added and it is stirred for another for 15 hours. The reaction mixture is mixed with semisaturated sodiumhydrogencarbonate solution and extracted with acetic acid ethylester. The organic solution is washed with saturated sodiumchloride solution, dried over sodium sulfate, condensed, and after being purified by chromatography on silica gel, 7.5 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=3.30 (s, 3H); 3.53 (m, 2H); 3.70 (m, 2H); 4.04 (s, 1H); 7.62 (t, 1H); 7.93 (d, 1H); 8.02 (d, 1H); 8.69 (s, 1H); 10.20 (s, b, 1H) ppm.
7.5 g of the compound described under INT7) is dissolved in 150 ml ethanol and mixed (10%) with 1.3 g palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 6.5 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=3.31 (s, 3H); 3.51 (m, 2H); 3.65 (m, 2H); 4.02 (s, 2H); 6.10 (s, 2H); 6.28 (d, 1H); 6.70 (d, 1H); 6.87-6.98 (m, 2H); 9.27 (s, 1H) ppm.
10 g of 2,6-diaminopyridine is dissolved in 150 ml tetrahydrofurane. 48 ml diisopropylethylamine and 20.8 ml pivalic acid anhydride is added and it is stirred for 15 hours at ambient temperature. The solvent is condensed off on the rotary evaporator. After purification by chromatography on silica gel, 10.6 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.20 (s, 9H); 5.72 (s, 2H); 6.07 (d, 1H); 7.18 (d, 1H); 7.33 (t, 1H); 8.93 (s, 1H) ppm.
4.9 ml of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml tetrahydrofurane. 9.7 ml triethylamine and 5.6 ml isobutylchloroformate is added at 0° C. and it is stirred for 30 minutes at 0° C. 3.96 g of 2,6-diaminopyridine is added and it is stirred for another 4 hours at ambient temperature. The reaction mixture is mixed with semisaturated sodiumhydrogencarbonate solution and extracted with acetic acid ethylester. The organic solution is washed with saturated sodiumchloride solution, dried over sodium sulfate, condensed and after being purified by chromatography on silica gel, 5.04 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=3.31 (s, 3H); 3.50 (m, 2H); 3.67 (m, 2H); 4.07 (s, 2H); 5.88 (s, 2H); 6.19 (d, 1H); 7.21 (d, 1H); 7.36 (t, 1H); 9.13 (s, 1H) ppm.
2.0 g of 2-chloro-4-nitro-pyridine 1-oxide is dissolved in 20 ml ethanol. 11.5 ml triethylamine is added and it is stirred for 4 hours under reflux. The solution is condensed off on the rotary evaporator. After purification by chromatography on silica gel, 1.5 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.19 (t, 3H); 3.39 (pentuplet, 2H); 7.39 (dd, 1H); 7.47 (d, 1H); 7.64 (t, 1H); 8.35 (d, 1H) ppm.
800 mg of the compound described under INT11) is dissolved in 50 ml ethanol and mixed with 50 mg Raney nickel. It is hydrated in a 3.5 bar hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 610 mg of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.09 (t, 3H); 3.11 (m, 2H); 5.48 (s, 2H); 5.52 (d, 1H); 5.71 (t, 1H); 5.78 (dd, 1H); 7.49 (d, 1H) ppm.
13.8 g of 3-nitroaniline is dissolved in 500 ml tetrahydrofurane. 30.5 ml triethylamine and 19.4 g chloroformic acid anhydride is added at 0° C. It is stirred for 12 hours at ambient temperature. The reaction mixture is mixed with semisaturated sodiumhydrogencarbonate solution and extracted with acetic acid ethylester. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, condensed and after being purified by chromatography on silica gel, 20.0 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=4.31 (s, 2H); 7.64 (t, 1H); 7.89-8.00 (m, 2H); 8.61 (s, 1H); 10.79 (b, 1H) ppm.
2.14 g of the compound described under INT13) is dissolved in 100 ml dimethylformamide. 2.0 ml triethylamine, 248 mg potassium iodide and 1.48 ml piperidine is added. It is stirred for 4 hours at ambient temperature. The reaction mixture is mixed with semisaturated sodiumhydrogencarbonate solution and extracted with acetic acid ethylester. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, condensed and after being purified by chromatography on silica gel, 1.97 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.34-1.48 (m, 2H); 1.51-1.63 (m, 4H); 2.5 (m, 4H); 3.12 (s, 2H); 7.60 (t, 1H); 7.91 (d, 1H); 8.02 (d, 1H); 8.70 (s, 1H); 10.18 (s, 1H) ppm.
5.0 g of the compound described under INT13) is dissolved in 200 ml dimethylformamide. 19.1 g sodiumacetate and 350 mg potassium iodide is added. It is stirred for 24 hours at ambient temperature. The reaction mixture is mixed with water and extracted with acetic acid ethylester. The organic solution is washed three times with semisaturated sodiumchloride solution, dried over sodium sulfate, condensed and after being purified by chromatography on silica gel, 4.7 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=2.14 (s, 3H); 4.70 (s, 2H); 7.62 (t, 1H); 7.87-7.98 (m, 2H); 8.60 (s, 1H); 10.57 (b, 1H) ppm.
A suspension of 10 g 2-methyl-5-nitrophenol, 12 g 4-(2-chlorethyl)-morpholine and 27.1 g potassium carbonate is heated under reflux in 200 ml acetone for 15 hours. The batch is made free of solvent with the vacuum and the residue is incorporated into ethylacetate. It is extracted with NaOH aq. (1 n, 3×200 ml) and the united organic phases are dried over sodiumcarbonate, the solvent is distilled off on the rotary evaporator and a yield of 62% is obtained (10.9) of 4-[2-(2-methyl-5-nitro-phenoxy)-ethyl]-morpholine.
1H-nMR (300 MHz, CDCl3): δ=2.30 (s, 3H); 2.61 (m, 4H); 2.86 (m, 2H); 3.71 (m, 4H); 4.20 (m, 2H); 7.22 (d, 1H); 7.68 (d, 1H); 7.75 (dd, 1H) ppm.
15.9 g of the compound described under INT16) and 2 g palladium on carbon is hydrated in 300 ml methanol at low pressure and ambient temperature. After hydrogen incorporation is completed, it is filtered off from the catalyst and the raw product is freed of solvent on the rotary evaporator. A quantitative yield of title compound is obtained. The raw product is used in the next step without further purification.
1H-nMR (300 MHz, CDCl3): δ=2.10 (s, 3H); 2.62 (m, 4H); 2.85 (m, 2H); 3.77 (m, 4H); 4.10 (m, 2H); 6.21 (m, 2H); 6.90 (d, 1H) ppm.
The following compounds are produced according to the method described above.
1H-nMR
2-(3-amino-phenyl)-ethanol
N-(5-amino-2-fluoro- phenyl)-2,2-dimethyl- propionamide
N-(3-amino-phenyl)-2- piperidin-1-yl-acetamide
N-(3-ntro-phenyl)-2- pyrrolidin-1-yl-acetamide
N-(3-amino-phenyl)-2- pyrrolidin-1-yl-acetamide
2-morpholin-4-yl-n-(3-nitro- phenyl)-acetamide
N-(3-amino-phenyl)-2- morpholin-4-yl-acetamide
(3-nitro-phenyl)-carbamic acid tert-butyl ester
(3-amino-phenyl)-carbamic acid tert-butyl ester
Acetic acid (3-amino- phenylcarbamoyl)-methyl ester
Dimethyl-[2-(3-nitro- phenoxy)-ethyl]-amine
1-[2-(3-nitro-phenoxy)- ethyl]-piperidine
1-[2-(3-nitro-phenoxy)- ethyl]-pyrrolidine
3-(2-dimethylamino-ethoxy)- phenylamine
3-(2-piperidin-1-yl-ethoxy)- phenylamine
3-(2-pyrrolidin-1-yl-ethoxy)- phenylamine
N-(3′-nitro-phenyl)- isobutyramide
N-(3′-amino-phenyl)- isobutyramide
N-(3′-amino-phenyl)-n- methyl-acetamide
2-dimethylamino-n-(3′-nitro- phenyl)-acetamide
N-(3′-amino-phenyl)-2- dimethylamino-acetamide
2,2-dimethyl-n-(3′-nitro- phenyl)-propionamide
2,2,n-trimethyl-n-(3-nitro- phenyl)-propionamide
N-(3-amino-phenyl)-2,2,N- trimethyl-propionamide
N-methyl-n-(3′-nitro- phenyl)-isobutyramide
N-(3-amino-phenyl)-n- methyl-isobutyramide
2-(3-amino-phenylamino)- ethanol
N-(2-methoxy-ethyl)- benzen-1,3-diamine
2-(ethyl-methyl-amino)-n- (3′-nitro-phenyl)-acetamide
N-(3-amino-phenyl)-2- (ethyl-methyl-amino)- acetamide
0.43 g of sodiumhydride (60% suspension in mineral oil) is washed in a round-bottomed flask in protective gas with n-hexane (3×) and suspended in a little THF. A solution of 1.3 g 3-nitroacetanilide in 15 ml THF is dripped into that suspension. After the formation of gas has abated, 4.5 ml methyliodide is dripped into the reaction mixture. It is stirred for 2 hours at ambient temperature. The solvent is then distilled off to the greatest extent possible. Any sodium hydride that is left unconverted is broken down by adding a little water. The residue yielded is incorporated into ethylacetate. The organic phase is consecutively washed with water and saturated sodiumchloride solution and dried over magnesium sulfate. The oil yielded after evaporation is purified in silica gel. 1.23 g of title compound was yielded as a light-yellow oil.
1H-nMR (CDCl3): δ=1.93 (s, 3H); 3.31 (s, 3H); 7.56-7.64 (m, 2H); 8.09 (s, 1H); 8.18-8.20 (m, 1H) ppm. MS (ESI) [M+1]+: 195.
195 mg glycoaldehyde, 195 mg sodium cyanoborohydride and 0.08 ml glacial acetate is added to a solution of 200 mg 3-nitroaniline in 10 ml methanol cooled to 0° C. It is stirred for 5 hours at ambient temperature. For conversion it is mixed with 150 ml sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic phase is washed with saturated sodiumchloride solution and dried over magnesium sulfate. The oil yielded after evaporation is purified on silica gel. 224 mg of title compound was yielded as orange crystals.
1H-nMR (DMSO-d6): δ=3.15 (q, 2H); 3.56 (q, 2H); 4.76 (t, 1H); 6.39 (t, 1H); 6.97-6.99 (m, 1H); 7.28-7.34 (m, 3H) ppm. MS (ESI) [M+1]+: 183.
A mixture comprising 5 g 1,3-phenylenediamine, 4.2 ml 2-methoxyethylchloride, 4.9 g sodiumcarbonate (anhydride) and 30 ml water is boiled for 12 hours under reflux. It is then diluted with water (600 ml) and filtered. The filtrate is extracted with ethylacetate. The organic phase is washed consecutively with water and saturated sodiumchloride solution and dried over magnesiumsulfate. The oil yielded after evaporation is purified on silica gel. 1.85 g of title compound was yielded as oil.
1H-nMR (DMSO-d6): δ=3.09 (q, 2H); 3.25 (s, 3H); 3.43 (t, 2H); 4.68 (s, 2H); 5.10 (t, 1H); 5.78-5.81 (m, 3H); 6.69 (t, 1H) ppm. MS (ESI) [M+1]+: 167.
10 g of 2-bromo-1-(3-nitro-phenyl)-ethanone is dissolved in 200 ml ethanol, mixed with 1.55 g sodiumborohydride and stirred for 1 hour at ambient temperature. 2.1 g potassium hydroxide is added and it is stirred for another for 15 hours at ambient temperature. 1000 ml acetic acid ethylester is added and washed twice with 300 ml semisaturated ammonium chloride solution and once with 100 ml water. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 7.48 g of title compound is obtained. 1H NMR (CDCl3): δ=2.79 (dd, 1H); 3.19 (dd, 1H); 3.93 (dd, 1H); 7.50 (t, 1H); 7.60 (d, 1H); 8.08-8.16 (m, 2H) ppm.
1.68 g of the compound described under INT52 was dissolved in 10 ml tetrahydrofurane and mixed with 1.5 ml piperidine and stirred under reflux for 15 hours. The solvent is distilled off on the rotary evaporator, and after being purified by chromatography on silica gel, 1.4 g of title compound is obtained. P 1H NMR (CDCl3): δ=1.40-1.80 (m, 6H); 2.23-2.49 (m, 3H); 2.59 (dd, 1H); 2.71 (b, 2H); 4.35 (b, 1H); 4.80 (dd, 1H); 7.51 (t, 1H); 7.73 (d, 1H); 8.13 (d, 1H); 8.28 (s, 1H) ppm.
2.0 g of the compound described under INT53 is dissolved in 250 ml ethanol and mixed (10%) with 200 mg palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 1.76 g of title compound is obtained.
1H NMR (CDCl3): δ=1.40-1.70 (m, 6H); 2.28-2.55 (m, 4H); 2.58-2.77 (m, 2H); 3.65 (b, 2H); 4.63 (dd, 1H); 6.52-6.62 (m, 1H); 6.72 (d, 1H); 6.75 (s, 1H); 7.11 (t, 1H) ppm.
5.0 g of the compound described under INT52 is dissolved in 50 ml tetrahydrofurane and mixed with 7.3 g trans-decahydroisochinolin and stirred for 20 hours under reflux. The solvent is distilled off on the rotary evaporator, and after being purified by chromatography on silica gel, 5.75 g of title compound is obtained.
1H NMR (CDCl3): δ=0.72-1.45 (m, 7H); 1.45-1.85 (m, 6H); 1.95-3.20 (m, 5H); 4.43 (b, 1H); 4.75-4.86 (m, 1H); 7.51 (t, 1H); 7.72 (d, 1H); 8.13 (d, 1H); 8.25 (s, 1H) ppm.
5.75 g of the compound described under INT55 is dissolved in 100 ml tetrahydrofurane and mixed at 0° C. with 5.4 ml triethylamine and 3.6 ml acetanehydride and then stirred for 48 hours at ambient temperature. Half the solvent is distilled off on the rotary evaporator, 100 ml semisaturated sodiumhydrogencarbonate solution is added and it is extracted three times with 150 ml dichlormethane each time. The united organic phases are dried over sodium sulfate. After purification by chromatography on silica gel and then recrystallization, 4.07 g of title compound is obtained.
1H NMR (CDCl3; main isomer): δ=0.72-1.05 (m, 3H); 1.06-1.35 (m, 4H); 1.40-1.89 (m, 6H); 2.00-2.22 (m, 4H); 2.55 (dd, 1H); 2.64-2.96 (m, 3H); 5.97 (dd, 1H); 7.51 (t, 1H); 7.68 (d, 1H); 8.14 (d, 1H); 8.22 (s, 1H) ppm.
4.07 g of the compound described under INT56) is dissolved in 400 ml acetic acid ethylester and 100 ml glacial acetate and mixed (10%) with 400 mg palladium on carbon. It is hydrated for 15 hours under 100 bar hydrogen at ambient temperature. Another 1000 mg palladium on carbon is added (10%) and hydrated for another 15 hours under 100 bar hydrogen at ambient temperature. Half the solvent is distilled off on the rotary evaporator, approx. 1 L of 2 normal sodium hydroxide solution is added until the solution has a pH von 9.5. The solution is consecutively extracted with 300 ml acetic acid ethylester and with 500 ml of a mixture of chloroform and methanol (10:1). The united organic phases are washed with water (100 ml) and saturated table salt solution (100 ml) and dried over sodium sulfate. After filtering and condensing off the solvent on the rotary evaporator, 2.57 g of title compound is obtained.
1H NMR (CDCl3): δ=0.69-1.03 (m, 3H); 1.03-1.33 (m, 4H); 1.39-1.73 (m, 6H); 1.86. 2.00 (m, 1H); 2.41-2.53 (m, 2H); 2.61-2.71 (m, 2H); 2.75-2.83 (m, 1H); 2.88-3.00 (m, 1H); 3.37-3.70 (b, 2H); 6.40-6.50 (m, 2H); 6.54 (d, 1H); 7.00 (t, 1H) ppm.
10 g 2-fluoro-5-nitro-phenylamine is dissolved in 330 ml tetrahydrofurane mixed at 0° C. with 19.5 ml triethylamine, 0.5 ml pyridine and 5.6 ml chloracetylchloride and then stirred for 24 hours at ambient temperature. The solvent is distilled off on the rotary evaporator, 1 L of acetic acid ethylester is added and washed with 200 ml semisaturated sodiumhydrogencarbonate solution. The organic phases are dried over sodium sulfate. After purification by chromatography on silica gel, 5.4 g of title compound is obtained.
1H NMR (CDCl3): δ=4.27 (s, 2H); 7.21-7.38 (m, 1H); 7.97-8.31 (m, 1H); 8.66 (s, b, 1H); 9.19-9.32 (m, 1H) ppm.
3.0 g of the compound described under INT58 is dissolved in 50 ml dimethylformamide, mixed with 2.68 ml triethylamine, 330 mg potassium iodide and 1.18 ml 4,4-morpholine and stirred for 15 hours at ambient temperature. The solvent is distilled off on the rotary evaporator, 500 ml acetic acid ethylester is added and then it is washed with 50 ml water and twice with 50 ml semisaturated sodiumhydrogencarbonate solution. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 2.7 g of title compound is obtained.
1H NMR (CDCl3): δ=2.66 (t, 4H); 3.23 (s, 2H); 3.79 (t, 4H); 7.18-7.33 (m, 1H); 7.92-8.05 (m, 1H); 9.27-9.39 (m, 1H); 9.73 (s, b, 1H) ppm.
2.7 g of the compound described under INT59 is dissolved in 500 ml ethanol and mixed (10%) with 270 mg palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 2.4 g of title compound is obtained.
1H NMR (CDCl3): δ=2.62 (t, 4H); 3.15 (s, 2H); 3.35-3.70 (b, 2H); 3.77 (t, 4H); 6.25-6.39 (m, 1H); 6.81-6.95 (m, 1H); 7.70-7.84 (m, 1H); 9.44 (s, b, 1H) ppm.
1.41 g of the compound described under INT58 is dissolved in 25 ml dimethylformamide, mixed with 1.26 ml triethylamine, 155 mg potassium iodide and 1.0 g 4,4-difluoropiperidine and stirred for 15 hours at ambient temperature. The solvent is distilled off on the rotary evaporator, 500 ml of a mixture of dichloromethane and methanol (100:1) is added and then it is washed twice each time with 50 ml semisaturated sodiumhydrogencarbonate solution. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 1.1 g of title compound is obtained.
1H NMR (CDCl3): δ=2.00-2.21 (m, 4H); 2.78 (t, 4H); 3.28 (s, 2H); 7.18-7.34 (m, 1H); 7.91-8.52 (m, 1H); 9.25-9.38 (m, 1H); 9.62 (s, b, 1H) ppm.
1.1 g of the compound described under INT61 is dissolved in 200 ml ethanol and mixed (10%) with 110 mg palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 0.99 g of title compound is obtained.
1H NMR (CDCl3): δ=1.93-2.20 (m, 4H); 2.73 (t, 4H); 3.20 (s, 2H); 3.60 (b, 2H); 6.24-6.44 (m, 1H); 6.87 (t, 1H); 7.65-7.85 (m, 1H); 9.36 (s, b, 1H) ppm.
5.0 g 5-bromo-2,4-dichloropyrimidine is dissolved in 100 ml acetonitrile, mixed with 5.2 ml triethylamine and 1.85 ml 2-methoxyethylamine and stirred for 15 hours at ambient temperature. 100 ml acetic acid ethylester is added and then it is washed twice with 50 ml water and twice with 50 ml saturated sodiumchloride solution. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 4.97 g of title compound is obtained.
1H NMR (CDCl3): δ=3.46 (s, 3H); 3.62 (t, 2H); 3.77 (m, 2H); 5.98 (s, b, 1H); 8.18 (s, 1H) ppm.
2.97 g of the compound described under INT63 is dissolved in 80 ml methanol. The solution is saturated at 8 bar with ammoniac and the closed autoclave is stirred for 20 hours at 80° C. The solvent is distilled off on the rotary evaporator. The residue is mixed with 10 ml methanol, incorporated into 100 ml chloroform and washed twice with 20 ml water. After purification by chromatography on silica gel, 1.4 g of title compound is obtained.
1H NMR (CDCl3): δ=3.39 (s, 3H); 3.54 (t, 2H); 3.61 (m, 2H); 4.82 (s, b, 2H); 5.54 (s, b, 1H); 7.86 (s, 1H) ppm.
1.1 g of the compound described under INT64 is dissolved in 250 ml ethanol and mixed (10%) with 110 mg palladium on carbon. It is stirred for 15 hours in a hydrogen atmosphere at ambient temperature. After filtration over kieselguhr and condensing off the solvent on the rotary evaporator, 0.99 g of title compound is obtained as HBr salt.
1H NMR (DMSO-d6, stored over K2CO3): δ=3.27 (s, 3H); 3.43-3.58 (m, 4H); 6.12 (d, 1H); 7.64 (d, 1H); 7.73 (s, b, 2H); 8.81 (s, b, 1H); 11.57 (s, b, 1H) ppm.
Analogous to the production of intermediate INT63, the title compound is obtained starting from 5-bromo-2,4-dichloropyrimidine and (R)-2-amino-3-methyl-butan-1-ol.
Mol. weight/MS (ESI) [M+1]+: 294.58/294; 296 (100%); 298.
1.0 g of the compound described under INT66 is dissolved in 100 ml methanol. The solvent is saturated at 8 bar with ammoniac and the closed autoclave is stirred for 20 hours at 80° C. The solvent is distilled off on the rotary evaporator. The residue is mixed with 5 ml methanol, incorporated into 50 ml chloroform and washed twice with 20 ml water. After purification by chromatography on silica gel, 640 mg of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=0.90-1.04 (m, 6H); 1.91-2.08 (m, 1H); 3.00 (s, b, 1H); 3.70 (dd, 1H); 3.80 (dd, 1H); 3.95 (m, 1H); 4.89 (s, 2H); 5.33 (d, 1H); 7.89 (s, 1H) ppm.
6.75 g 2,6-dibromopyridine is dissolved in 40 ml dimethylsulfoxide. 4.1 g of copper powder and 7.51 g ethylbromodifluoroacetate is added and stirred for 4 hours at 50° C. The reaction mixture is mixed with 200 ml acetic acid ethylester and 200 ml 1.3 molar potassium hydrogenphosphate solution and stirred for 30 minutes at ambient temperature. The solid substance is filtered off, the organic phase is separated off, it is washed three times consecutively with 50 ml semisaturated table salt solution and dried over sodium sulfate. After purification by chromatography on silica gel, 4.1 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=1.24 (t, 3H); 4.38 (q, 2H); 7.88-7.97 (m, 2H); 8.03 (t, 1H) ppm.
7.75 g of the compound described under INT68 is dissolved in 130 ml ethanol, mixed at 0° C. with 785 mg sodium borohydride and stirred for 4 hours at ambient temperature. 15 ml of 2 molar salt acid is added subject to the cooling of an ice bath. It is stirred for 10 minutes at ambient temperature and brought up to pH 10 with caustic soda. The reaction mixture is mixed with 500 ml dichloromethane and 100 ml semisaturated table salt solution, the organic phase is separated off and dried over sodium sulfate. After purification by filtration through silica gel, 6.3 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=3.93 (t, 2H); 5.59 (s, 1H); 7.70 (d, 1H); 7.79 (d, 1H); 7.90 (t, 1H) ppm.
6.9 g of the compound described under INT69 is dissolved in 60 ml dimethylformamide, mixed with 3.77 g imidazol and 5.27 g tert.-butyldimethylsilylchloride and stirred for 15 hours at ambient temperature. 300 ml semisaturated sodiumhydrogencarbonate solution is added and extracted three times with 150 ml acetic acid ethylester. The united organic phases are dried over sodium sulfate. After purification by filtration through silica gel, 9.2 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=−0.07 (s, 6H); 0.70 (s, 9H); 4.16 (t, 2H); 7.72 (d, 1H); 7.80 (d, 1H); 7.91 (t, 1H) ppm.
2.5 g of the compound described under INT70 is dissolved in 25 ml dioxane, mixed with 2.7 ml of 2,4-dimethylbenzylamine, 168 mg palladium acetate, 218 mg BINAP and 950 mg sodium-tert-butylate and stirred for 3 hours at 80° C. 100 ml water is added and extracted three times with 50 ml acetic acid ethylester. The united organic phases are dried over sodium sulfate. After purification by chromatography on silica gel, 2.3 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=−0.07 (s, 6H); 0.75 (s, 9H); 3.69 (s, 3H); 3.77 (s, 3H); 4.06 (t, 2H); 4.30 (d, 2H); 6.39 (d, 2H); 6.48-6.58 (m, 2H); 6.69 (d, 1H); 6.97 (t, 1H); 7.20 (d, 1H); 7.41 (t, 1H) ppm.
2.3 g of the compound described under INT71 is dissolved in 100 ml tetrahydrofurane and mixed with 13 ml of a 1 molar solution of tetrabutylammoniumfluoride in tetrahydrofurane and stirred for 1 hour at ambient temperature. 100 ml semisaturated sodiumhydrogencarbonate solution is added and extracted three times with 100 ml acetic acid ethylester. The united organic phases are dried over sodium sulfate. After purification by chromatography on silica gel, 1.42 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=3.70 (s, 3H); 3.77 (s, 3H); 3.87 (t, 2H); 4.30 (d, 2H); 5.37 (s, b, 1H); 6.41 (d, 1H); 6.50-6.59 (m, 2H); 6.70 (d, 1H); 6.95 (t, 1H); 7.13 (d, 1H); 7.41 (t, 1H) ppm.
1.37 g of the compound described under INT72 is dissolved in 100 ml tetrahydrofurane and mixed at 0° C. with 1.47 ml triethylamine and 0.49 ml methanesulfonic acid chloride and then stirred for 2 hours at ambient temperature. 100 ml water is added and extraction with 50 ml acetic acid ethylester occurs. The united organic phases are dried over sodium sulfate. After purification by chromatography on silica gel, 1.56 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=3.19 (s, 3H); 3.70 (s, 3H); 3.77 (s, 3H); 4.31 (d, 2H); 4.79 (t, 2H); 6.41 (d, 1H); 6.52 (s, 1H); 6.62 (d, 1H); 6.79 (d, 1H); 7.08-7.19 (m, 2H); 7.49 (t, 1H) ppm.
2.0 g of the compound described under INT73 is dissolved in 40 ml dimethylformamide, mixed with 1.38 g potassium carbonate, 120 mg potassium iodide and 2.1 ml pyrrolidine and then stirred for 24 hours at 120° C. 200 ml acetic acid ethylester is added and then washed three times with water (50 ml) and three times with 50 ml semisaturated sodiumchloride solution. The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 1.35 g of title compound is obtained.
1H NMR (DMSO-d6, stored over K2CO3): δ=1.54 (b, 4H); 2.40 (b, 4H); 3.14 (t, 2H); 3.70 (s, 3H); 3.77 (s, 3H); 4.30 (d, 2H); 6.39 (d, 1H); 6.48-6.57 (m, 2H); 6.68 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.42 (t, 1H) ppm.
1.34 g of the compound described under INT74 is dissolved in 70 ml dichlormethane, mixed with 14 ml trifluoroacetic acid and stirred for 1 hour at ambient temperature. 50 ml sodiumhydrogencarbonate solution is added and extracted three times with 50 ml dichloromethane. The united organic phases are dried over sodium sulfate. 520 mg of title compound as raw product is yielded and used without purification.
1H NMR (DMSO-d6, stored over K2CO3): δ=1.58 (b, 4H); 2.49 (b, 4H); 3.14 (t, 3H); 6.15 (s, 2H); 6.46 (d, 1H); 6.69 (d, 1H); 7.42 (t, 1H) ppm.
3-nitrophenoxyacetic acid (9.3 g, 50 mmol) is dissolved in dimethylacetamide (200 ml) and dripped in at ambient temperature among argon SOCl2 (7.4 ml, 102 mmol) within 5 minutes. It is stirred for 30 minutes at ambient temperature and then the boc-piperazine (19.1 g, 102 mmol) is added in portions subject to ice cooling. It was stirred for 50 minutes at ambient temperature among argon and then the reaction mixture was poured onto water (500 ml), neutralized with sodiumcarbonate and extracted with ethyl acetate (3×100 ml). The united organic phases were washed with water (3×100 ml), dried over sodium sulfate and the solvent was distilled off in the vacuum. The title compound is obtained in a quantitative yield as black oil, which slowly completely crystallizes. The raw product was used in the next step without further repurification.
1H-nMR (CDCl3): δ=1.49 (s, 9H); 3.42 (m, 4H); 3.50 (m, 4H); 4.82 (s, 2H); 7.32 (dd, 1H); 7.48 (t, 1H); 7.77 (m, 1H); 0.88 (dd, 1H) ppm.
22 g (50 mmol) of the compound described under INT76 is dissolved in methanol (600 ml). Pd/C (4 g) is added among argon and hydrated until the hydrogen incorporation is complete. The catalyst is filtered off and the solvent distilled off in the vacuum. The title compound is obtained in the form of a viscous brown oil in a quantitative yield. The raw product is used in the next step without any further purification.
1H-nMR (CDCl3): δ=1.48 (s, 9H); 3.41 (m, 4H); 3.59 (m, 4H); 4.68 (s, 2H); 6.31 (m, 3H); 7.07 (t, 1H) ppm.
2.81 g Dess-martin periodinanes are added to a solution of 0.80 g 3-(3-nitrophenyl)-1-propanol (ref. J. Med. Chem., 1989, 32, 2104) in 100 ml dichlormethane. It is stirred for 2 hours at ambient temperature. 50 ml 10% sodiumthiosulfate solution and 50 ml saturated sodiumhydrogen carbonate solution is added, it is stirred for 10 minutes at ambient temperature and the dichloromethane is distilled off on the rotary evaporator. The residue is extracted twice with 100 ml acetic acid ethylester, the united organic phases are washed consecutively with 100 ml water and with 100 ml saturated table salt solution and dried over sodium sulfate. After condensing off the solvent on the rotary evaporator, 780 mg of title compound as raw product is yielded, which is further used without further purification.
1H-nMR (CDCl3): δ=2.86 (t, 2H); 3.06 (t, 2H); 7.44-7.49 (m, 1H); 7.55 (d, 1H); 8.08 (m, 2H); 9.83 (s, 1H) ppm.
1.27 ml piperidine and 0.16 g sodium cyanoborohydride is added to a solution of 0.46 g of the compound produced under INT78 in 10 ml methanol. It is stirred for 3 hours at ambient temperature and 50 ml water and 40 ml acetic acid ethylester is added. The phases are separated and the aqueous phase is extracted twice with 40 ml acetic acid ethylester. The united organic phases are washed with 40 ml saturated table salt solution and dried over sodium sulfate. After purification by chromatography on silica gel, 635 mg of title compound is obtained.
1H-nMR (CDCl3): δ=1.41-1.48 (m, 2H); 1.57-1.65 (m, 4H); 1.87 (q, 2H); 2.32-2.44 (m, 6H); 2.75 (t, 2H); 7.43 (t, 1H); 7.52 (d, 1H); 8.06 (m, 2H) ppm.
13 g 2,6-difluoropyridine and 15 ml of a 25% aqueous ammoniumhydroxide solution is stirred for 24 hours at 125° C. in a [sic: elbow pipe]. The reaction mixture is cooled to 0° C. and stirred for 2 hours at that temperature. The resulting solid substance is filtered off and dried at 40° C. in the vacuum. 5.0 g of title compound is obtained.
Mol. weight/MS (ESI) [M+1]+: 112.107/113. 1H NMR (CDCl3): δ=4.52, (bs, 2H), 6.24 (dd, 1H); 6.35 (dd, 1H); 7.50 (q, 1H) ppm.
0.5 g of the compound described under INT80 is dissolved in 10 ml tetrahydrofurane, mixed with 10 mg dimethylaminopyridine, 1.57 ml diisopropylethylamine and 0.97 g di-tert-butyldicarbonate and then stirred for 4 hours at ambient temperature. 100 ml acetic acid ethylester is added and it is washed with water (50 ml). The organic phase is dried over sodium sulfate. After purification by chromatography on silica gel, 100 mg of title compound is obtained.
Mol. weight/MS (ESI) [M+1]+: 212.226/213. 1H NMR (CDCl3): δ=1.54, (s, 9H), 6.56 (dd, 1H); 7.08 (bs, 1H); 7.74 (m, 2H) ppm.
1.0 g of the compound described under INT81 and 5.0 ml 2-methoxy-ethylamine is stirred for 48 hours at 80° C. The reaction mixture is vacuum-condensed. The residue is incorporated with 100 ml acetic acid ethylester, and washed consecutively with 50 ml water and with 50 ml saturated table salt solution and dried over sodium sulfate. After purification by chromatography on silica gel, 500 mg of title compound is obtained.
Mol. weight/MS (ESI) [M+1]+: 267.331/268. 1H NMR (CDCl3): 1.50, (s, 9H); 3.32 (s, 3H); 3.42 (m, 2H); 3.52 (m, 2H); 4.64 (t, 1H); 6.08 (d, 1H); 6.90 (s, 1H); 7.18 (d, 1H); 7.34 (t, 1H) ppm.
0.51 g of the compound described under INT82 is dissolved in 5 ml dichloromethane and mixed with 4.0 ml of 4 molar HCl in dioxane. It is stirred for 48 hours at ambient temperature. The solvent is distilled off in the vacuum, the residue is incorporated with 100 ml acetic acid ethylester and washed consecutively with 50 ml of 1 normal sodiumhydrogen carbonate solution, 50 ml water and 50 ml saturated table salt solution and dried over sodium sulfate. After the solvent is distilled off, 300 mg of title compound is obtained.
Mol. weight/MS (ESI) [M+1]+: 167.212/168. 1H NMR (DMSO-d6, supported via K2CO3): δ=3.36 (s, 3H); 3.42 (m, 2H); 3.54 (m, 2H); 4.16 (s, 2H); 4.60 (s, 1H); 5.80 (m, 2H); 7.18 (t, 1H) ppm.
5.0 g 2,3,5,6-tetrafluoropyridine, 140 ml tetrahydrofurane and 25 ml of 25% aqueous ammonium hydroxide solution is stirred for 48 hours at 60° C. in an [sic: elbow pipe]. The reaction mixture is mixed with 100 ml water and extracted three times with 150 ml diethylether. After drying over sodium sulfate and distilling off the solvent, 3.5 g of title compound as raw product is yielded, which is used without further purification.
Mol. weight/MS (ESI) [M+1]+: 148.088/149.
The following compounds are produced according to the method described above.
1H-nMR
3-[2-(4-methyl-piperazin-1- yl)-ethoxy]-phenylamine
3-[2-(4-methyl-piperazin-1- yl)-ethoxy]-nitrobenzene
3-[2-(4-methyl-piperidin-1- yl)-ethoxy]-phenylamine
3-[2-(4-methyl-piperidin-1- yl)-ethoxy]-nitrobenzene
3-(2-azepan-1-yl-ethoxy)- phenylamine
3-(2-azepan-1-yl-ethoxy)- nitrobenzene
3-(3-pyrrolidin-1-yl-propyl)- phenylamine
3-(3-morpholin-4-yl-propyl)- phenylamine
3-(3-piperidin-1-yl-propyl)- phenylamine
3-(3-thiomorpholin-4-yl- propyl)-phenylamine
3-[3-(4,4-difluoro-piperidin- 1-yl)-propyl]-phenylamine
2-diethylamino-n-(3-nitro- phenyl)-acetamide
N-(3-amino-phenyl)-2- diethylamino-acetamide
2-(methyl-propyl-amino)-n- (3-nitro-phenyl)-acetamide
N-(3-amino-phenyl)-2- (methyl-propyl-amino)- acetamide
2-(isopropyl-methyl-amino)- n-(3-nitro-phenyl)-aetamide
N-(3-amino-phenyl)-2-(iso- ropyl-methyl-amino)- acetamide
2-[(2-methoxy-ethyl)- methyl-amino]-n-(3-nitro- phenyl)-acetamide
N-(3-amino-phenyl)-2-[(2- methoxy-ethyl)-methyl- amino]-acetamide
2-[ethyl-(2-methoxy-ethyl)- amino]-n-(3-nitro-phenyl)- acetamide
N-(3-amino-phenyl)-2- [ethyl-(2-methoxy-ethyl)- amino]-acetamide
2-(benzyl-methyl-amino)-n- (3-nitro-phenyl)-acetamide
N-(3-amino-phenyl)-2- (benzyl-methyl-amino)- acetamide
2-(tert-butyl-methyl-amino)- n-(3-nitro-phenyl)- acetamide
N-(3-amino-phenyl)-2-(tert- butyl-methyl-amino)- acetamide
2-(methyl-phenethyl- amino)-n-(3-nitro-phenyl)- acetamide
N-(3-amino-phenyl)-2- (methyl-phenethyl-amino)- acetamide
(3,5,6-trifluoro-pyridin-2-yl)- carbamic acid tert-butyl ester
[3,5-difluoro-6-(2-methoxy- ethylamino)-pyridin-2-yl]- carbamic acid tert-butyl ester
3,5-difluoro-n-(2-methoxy- ethyl)-pyridine-2,6-diamine
(6-morpholin-4-yl-pyridin-2- yl)-carbamic acid tert-butyl ester
6-morpholin-4-yl-pyridin-2- ylamine
[6-(4-methyl-piperazin-1-yl)- pyridin-2-yl]-carbamic acid tert-butyl ester
6-(4-methyl-piperazin-1-yl)- pyridin-2-ylamine
[6-(2-dimethylamino- ethylamino)-pyridin-2-yl]- carbamic acid tert-butyl ester
N-(2-dimethylamino-ethyl)- pyridine-2,6-diamine
2-morpholin-4-yl-pyridin-4- ylamine
2-(4-methyl-piperazin-1-yl)- pyridin-4-ylamine
N*2*-(2-methoxy-ethyl)- pyridine-2,4-diamine
4.25 ml ethylisothiocyanate is added to a mixture of 5 g cyanoacetic acid ethylester and 5 ml triethylamine 25° C. Then it is left to stir for 6 hours at 50° C. After that, the reaction mixture is vacuum-condensed. The residue is incorporated into ethanol and poured onto 150 ml of ice cold 1 normal hydrochloric acid. It is left to stir for 3 hours at 25° C. and then the residue is filtered off. The solid substance yielded is washed with water. 7 g of product is yielded.
Mol mass=200.261; MS (ESI): [M+1]+=201.
7.82 g of the compound described under INTT1) is dissolved in 100 ml tetrahydrofurane. A solution of 3.9 ml bromoacetyl chloride is added and left to stir for 8 hours at 25° C. The reaction mixture is then poured onto saturated aqueous sodium hydrogencarbonate. It is left to stir for 1 hour and then extracted with ethylacetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and vacuum-condensed. The raw product yielded is recrystallized from a mixture of ethylacetate/diisopropylester. 7.7 g of product is obtained.
1H-nMR (CDCl3): δ=1.36 (6H); 3.70 (2H); 4.32 (4H) ppm.
A mixture of 1.54 g of the substance described under INTT2), 2.5 ml triethylorthoformate and 3.5 ml acetic acid anhydride is boiled for 8 hours under reflux. The reaction mixture is then poured onto ice water. It is left to stir for 3 hours and then the residue is filtered off. The solid substance yielded is washed with water. 1.28 g of product is obtained.
1H-nMR (CDCl3): δ=1.38 (9H); 4.20-4.40 (6H); 7.72 (1H) ppm.
A solution of 37.6 ml cyanoacetic acid allylester in 60 ml dimethylformamide is added to a suspension of 12.8 g sodium hydride (60%) at 0° C. It is stirred for 10 minutes at 0° C. and then a solution of 28.0 ml ethylisothiocyanate in 60 ml dimethylformamide is added. It is then stirred for 2 hours at 25° C. A solution of 32 ml bromoacetylchloride in 60 ml dimethylformamide is then added at 0° C. and stirred for 15 hours at 25° C. The reaction mixture is then poured onto saturated sodiumhydrogencarbonate solution. Acetic acid ethylester is used to extract, the organic phase is washed with saturated sodiumchloride solution, dried over sodium sulfate and vacuum-condensed. The raw product is purified by column chromatography on silica gel with a mixture made from hexane/ethylacetate. 33.9 g of product is yielded.
1H-nMR (CDCl3): δ=1.23 (3H); 4.11 (2H); 4.71 (2H); 5.25 (1H); 5.37 (1H); 5.90-6.04 (1H) ppm.
Analogous to intermediate INTT3), 14.8 g of product is yielded from 12.8 g of the compound described under INTT4), 20.9 ml triethylorthoformiate and 29.4 ml acetic acidanhydride.
1H-nMR (CDCl3): δ=1.32-1.45 (6H); 4.23 (2H); 4.38 (2H); 4.73 (2H); 5.29 (1H); 5.41 (1H), 5.92-6.05 (1H); 7.72 (1H) ppm.
5.04 g of the compound described under INTT4) is dissolved in 300 ml tetrahydrofurane. 3.42 g of 1,3-dimethylbarbituric acid and 1.17 g Tetrakis-(triphenylphosphin)-palladium is added. It is stirred for 30 minutes at ambient temperature and the reaction mixture is condensed on the rotary evaporator until dry. The raw product yielded is used without any further purification.
1H-nMR (DMSO-d6, selected signals) δ=1.21 (t, 3H); 3.89 (s, 2H); 4.10 (q, 2H); 13.24 (s, b, 1H) ppm.
Approx. 4.15 g of the compound described under INTT6) (raw product that was yielded from 2.5 g of the compound described under INTT4) is dissolved in 100 ml dimethylformamide. 3.34 g sodiumhydrogencarbonate, 6.0 ml of a solution of ethylamine in tetrahydrofurane (c=2.0 M) and 3.88 g TBTU is added. It is stirred for 3 hours at ambient temperature. The reaction mixture is mixed with water and extracted with acetic acid ethylester. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate and condensed. After purification by means of recrystallization from ethanol, 1.47 g of title compound is obtained.
1H-nMR (DMSO-d6): δ=1.05 (t, 3H); 1.21 (t, 3H); 3.18 (pentuplet, 2H); 3.70 (s, 2H); 4.10 (q, 2H); 7.81 (t, 1H) ppm.
The following compounds are produced according to the method described above.
1H-nMR
2-cyano-2-[3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- n-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- n-prop-2-ynyl-acetamide
2-cyano-n-cyanomethyl-2-[3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-n-(2,2-difluoro-ethyl)-2- [3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- n-(2-hydroxy-1,1-dimethyl-ethyl)- acetamide
2-cyano-2-[3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- n-(2-fluoro-ethyl)-acetamide
740 mg of the compound described under INT3) is dissolved in 50 ml Ethanol. 1.1 g of the compound described under INTT3) is added stirred for 5 hours under reflux. The solvent is condensed off on the rotary evaporator. After purification by chromatography on silica gel, 540 mg of title compound as pH-dependent 5-(E/Z)-isomer mixture is obtained.
1H-nMR (CDCl3, main isomer): δ=1.38 (t, 3H); 1.42 (t, 3H); 1.83 (m, 4H); 2.60 (m, 4H); 2.72 (m, 2H); 2.86 (m, 2H); 4.31 (q, 2H); 4.43 (q, 2H); 6.87-6.97 (m, 2H); 7.00 (d, 1H); 7.29 (t, 1H); 7.62 (d, 1H); 10.56 (d, 1H) ppm.
1.35 g of the compound described under INT3) is dissolved in 400 ml ethanol. 2.19 g of the compound described under INTT5) is added and stirred for 4 hours under reflux. The solvent is condensed off on the rotary evaporator. After purification by chromatography on silica gel, 2.2 g of title compound as pH-dependent 5-(E/Z)-isomer mixture is obtained.
1H-nMR (DMSO-d6, stored over K2CO3, main isomer): δ=1.24 (t, 3H); 1.69 (m, 4H); 2.50 (m, 4H); 2.66 (m, 2H); 2.76 (m, 2H); 4.25 (q, 2H); 4.71 (d, 2H); 5.26 (d, 1H); 5.38 (d, 1H); 5.90-6.08 (m, 1H); 6.96 (d, 1H); 7.12 (d, 1H); 7.22 (s, 1H); 7.26 (t, 1H); 8.22 (s, 1H); 10.53 (s, b, 1H) ppm.
1.26 g of the compound described under INT6) is dissolved in 400 ml ethanol. 2.0 g of the compound described under INTT5) is added and stirred for 6 hours under reflux. After cooling, the reaction mixture is filtered and the solid substance yielded is recrystallized from ethanol. 1.4 g of title compound as pH-dependent 5-(E/Z)-isomer mixture is obtained. The solution obtained at filtration is condensed on the rotary evaporator. After purification by chromatography on silica gel, the residue yields another 1.1 g of title compound as pH-dependent 5-(E/Z)-isomer mixture.
1H-nMR (DMSO-d6, stored over K2CO3, main isomer): δ=1.28 (t, 3H); 1.38 (s, 6H); 4.26 (q, 2H); 4.72 (d, 2H); 5.27 (d, 1H); 5.39 (d, 1H); 5.76 (s, 1H); 5.90-6.08 (m, 1H); 6.99 (d, 1H); 7.27 (t, 1H); 7.46 (d, 1H); 7.89 (s, 1H); 8.16 (s, 1H); 9.67 (s, 1H); 10.63 (s, 1H) ppm.
0.94 g of the compound described under INT12) is dissolved in 50 ml 1-propanol. 1.85 g of the compound described under INTT5) is added and it is stirred for 4 hours under reflux. After cooling, the reaction mixture is filtered. After purification by chromatography on silica gel, the solid substance yields 1.48 g of title compound as pH-dependent 5-(E/Z)-isomer mixture.
1H-nMR (DMSO-d6, stored over K2CO3, main isomer): δ=1.13 (t, 3H); 1.26 (t, 3H); 3.24 (pentuplet, 2H); 4.25 (q, 2H); 4.72 (d, 1H); 5.28 (d, 1H); 5.39 (d, 1H); 5.90-6.07 (m, 1H); 6.25 (d, 1H); 6.44 (dd, 1H); 6.49 (t, 1H); 7.85 (d, 1H); 8.13 (s, 1H); 10.47 (s, 1H) ppm.
1.35 g of the compound described under INT9) is dissolved in 50 ml 1-propanol. 2.0 g of the compound described under INTT5) is added and it is stirred for 3 hours under reflux. After cooling, the reaction mixture is filtered and the solid substance yielded is recrystallized from ethanol. 2.47 g of title compound is yielded as pH-dependent 5-(E/Z)-isomer mixture.
1H-nMR (DMSO-d6, stored over K2CO3, main isomer): δ=1.20-1.31 (m, 12H); 4.27 (q, 2H); 4.72 (d, 2H); 5.28 (d, 2H); 5.39 (d, 2H); 5.91-6.06 (m, 1H); 6.29 (d, 2H); 7.68-7.80 (m, 2H); 8.86 (s, 1H); 9.71 (s, 1H); 10.94 (s, 1H) ppm.
The following compounds are produced according to the method described above.
1H-nMR
Cyano-[5-[1-[3-(2,2-dimethyl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2-(2- methoxy-ethoxy)-acetylamino]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[5-[1-[6-(2,2-dimethyl- propionylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-(2- ethylamino-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-(3- hydroxymethyl-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid allyl ester
[5-[1-(2-chloro-pyridin-4- ylamino)-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid ethyl ester
[5-[1-(6-amino-pyridin-2- ylamino)-meth-( E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid ethyl ester
Cyano-[5-[1-{3-[3-(1,1-dioxo- 1lambda*6*-thiomorpholin-4-yl)- propionylamino]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-[3-(2- hydroxy-ethyl)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid allyl ester
[5-[1-(3-tert- Butoxycarbonylamino- phenylamino)-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
Cyano-[3-ethyl-4-oxo-5-[1-(3- pyrrolidin-1-ylmethyl- phenylamino)-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
1H-nMR (CDCl3, 300 MHz) (selected peaks) δ = 1.38 (m, 3H); 1.75 (m, 4H); 2.48 (m, 4H); 3.59 (s, 2H); 4.41 (m, 2H); 4.72 (m, 2H); 5.23 (dd, 1H); 5.39 (dd, 1H); 5.97 (m, 1H); 6.97 (dd, 1H); 7.11 (m, 2H); 7.30 (m, 1H); 7.68 (s, 1H); 10.52 (s, 1H).
Cyano-[3-ethyl-4-oxo-5-[1-(3- pyrrolidin-1-ylmethyl- phenylamino)-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid ethyl ester
1H-nMR (CDCl3, 300 MHz) (selected peaks) δ = 1.38 (m, 6H); 1.80 (m, 4H); 2.51 (m, 4H); 3.62 3H); 4.46 (m, 2H); 6.98 (dd, 1H); 7.10 (m, 2H); 7.30 (m, 1H); 7.68 (d, 1H); 10.58 (d, 1H).
Cyano-[5-[1-[3-(2-dimethylamino- ethoxy)-phenylamino]-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid allyl ester
1H-nMR (DMSO-d6, 300 MHz) (selected peaks) δ = 1.29 (m, 3H); 2.22 (s, 6H); 2.63 (m, 2H); 4.08 (m, 2H); 4.27 (m, 2H); 4.71 (d, 2H); 5.28 (dd, 1H); 5.39 (dd, 1H); 6.00 (m, 1H); 6.67 (dd, 1H); 6.91 (m, 1H); 7.24 (m, 1H); 8.22 (s, 1H); 10.48 (s, 1H).
Cyano-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
1H-nMR (CDCl3, 300 MHz) (selected peaks) δ = 1.21 (m, 3H); 2.67 (m, 2H); 3.58 (m, 4H); 4.09 (m, 2H); 4.21 (m, 2H); 4.70 (d, 2H); 5.28 (dd, 1H); 5.40 (dd, 1H); 6.00 (m, 1H); 6.65 (dd, 1H); 6.86 (m, 2H); 7.21 (m, 1H); 8.16 (s, 1H); 10.39 (s, 1H).
Cyano-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid ethyl ester
1H-nMR (CDCl3, 300 MHz) (selected peaks) δ = 1.36 (m, 6H); 2.59 (m, 4H); 2.81 (m, 2H); 3.73 (m, 4H); 4.11 (m, 2H); 4.30 (m, 2H); 4.42 (m, 2H); 6.65 (m, 3H); 7.23 (m, 1H); 7.58 (d, 1H); 10.50 (d, 1H).
Cyano-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-2-oxo-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
1H-nMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.29 (m, 3H); 3.36 (s, 2H); 3.62 (m, 4H); 4.28 (m, 2H); 4.71 (d, 2H); 4.87 (m, 2H); 5.29 (dd, 1H); 5.40 (dd, 1H); 6.01 (m, 1H); 6.68 (dd, 1H); 6.92 (m, 2H); 7.28 (m, 1H); 8.20 (d, 1H); 10.49 (d, 1H).
Cyano-[3-ethyl-4-oxo-5-[1-[3-(2- pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.23 (m, 3H); 1.69 (m, 4H); 2.80 (m, 2H); 4.08 (m, 2H); 4.26 (m, 2H); 4.71 (d, 2H); 5.28 (dd, 1H); 5.40 (dd, 1H); 6.00 (m, 1H); 6.68 (dd, 1H); 6.90 (m, 2H); 7.27 (m, 1H); 8.27 (s, 1H); 10.48 (s, 1H).
Cyano-[3-ethyl-4-oxo-5-[1-[3-(2- piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 1.39 (m, 2H); 1.49 (m, 4H); 2.63 (m, 2H); 4.10 (m, 2H); 4.25 (m, 2H); 4.72 (d, 2H); 5.28 (dd, 1H); 5.39 (dd, 1H); 5.98 (m, 1H); 6.65 (dd, 1H); 6.90 (m, 2H); 7.25 (m, 1H); 8.27 (s, 1H); 10.43 (s, 1H).
Cyano-[3-ethyl-5-[1-[4-methyl-3- (2-morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
1H-NMR (CDCl3, 300 MHz) (selected peaks) δ = 1.40 (m, 3H); 2.19 (s, 3H); 2.68 (m, 4H); 2.89 (m, 2H); 3.75 (m, 4H); 4.13 (m, 2H); 4.42 (m, 2H); 4.73 (m, 2H); 5.28 (dd, 1H); 5.41 (dd, 1H); 5.99 (m, 1H); 6.55 (m, 2H); 7.11 (m, 2H); 8.10 (d, 1H).
Cyano-{3-ethyl-5-[1-(3-isobutyryl- amino-phenylamino)-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid ethyl ester
Cyano-{3-ethyl-5-[1-(3-isobutyryl- amino-phenylamino)-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid allyl ester
{5-[1-[3-(Acetyl-methyl-amino)- phenyl-amino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene}-cyanoacetic acid ethyl ester
{5-[1-[3-(Acetyl-methyl-amino)- phenyl-amino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene}-cyano-acetic acid allyl ester
Cyano-{5-[1-[3-(2- dimethylamino-acetyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene}-acetic acid ethyl ester
Cyano-{5-[1-[3-(2- dimethylamino-acetyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene}-acetic acid allyl ester
Cyano-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]- phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]- phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-{3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid ethyl ester
Cyano-{3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid allyl ester
Cyano-{3-ethyl-5-[1-[3-(2- hydroxy-ethyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid ethyl ester
Cyano-{3-ethyl-5-[1-[3-(2- methoxy-ethylamino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid ethyl ester
Cyano-{3-ethyl-5-[1-[3-(2- methoxy-ethylamino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2-(ethyl- methyl-amino)-acetylamino]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-{3-[2-(ethyl- methyl-amino)-acetylamino]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[3-(1- hydroxy-2-piperidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3- [(4aR,8aS)-2-(octahydro- isoquinolin-2-yl)-ethyl]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
[5-[1-[3-(2-Acetoxy-acetylamino)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
[5-[1-[5-Bromo-4-(2-methoxy- ethylamino)-pyrimidin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
[5-[1-[5-Bromo-4-((R)-1- hydroxymethyl-2-methyl- propylamino)-pyrimidin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[4-(2- methoxy-ethylamino)-pyrimidin- 2-ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[5-[1-[6-(1,1-difluoro-2- pyrrolidin-1-yl-ethyl)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2-(4- ethyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[5-[1-[3-(2-diethylamino- acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid ethyl ester
Cyano-[5-[1-[3-(2-diethylamino- acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E orZ))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (isopropyl-methyl-amino)-acetyl- amino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (isopropyl-methyl-amino)-acetyl- amino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid allyl ester
Cyano-[3-ethyl-5-[1-(3-{2-[ethyl- (2-methoxy-ethyl)-amino]-acetyl- amino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-(3-{2-[ethyl- (2-methoxy-ethyl)-amino]-acetyl- amino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid allyl ester
[5-[1-{3-[2-(Benzyl-methyl- amino)-acetylamino]-phenyl- amino}-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z)-ylidene]-cyano-acetic acid ethyl ester
[5-[1-{3-[2-(Benzyl-methyl- amino)-acetylamino]-phenyl- amino}-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
[5-[1-{3-[2-(tert-Butyl-methyl- amino)-acetylamino]-phenyl- amino}-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2 (E or Z)-ylidene]-cyano-acetic acid ethyl ester
[5-[1-{3-[2-(tert-Butyl-methyl- amino)-acetylamino]-phenyl- amino}-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-cyano-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (methyl-phenethyl-amino)- acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid ethyl ester
Cyano-[3-ethyl-5-[1-{3-[2- (methyl-phenethyl-amino)- acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid allyl ester
Cyano-[3-ethyl-5-[1-(6-fluoro- pyridin-2-ylamino)-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-(2- morpholin-4-yl-pyridin-4- ylamino)-meth-( E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[2-(2- methoxy-ethylamino)-pyridin-4- ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-4-oxo-5-[1-[3-(3- pyrrolidin-1 -yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-4-oxo-5-[1-[3-(3- piperidin-1-yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[3-(3- morpholin-4-yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid allyl ester
Cyano-[3-ethyl-5-[1-[2-(4-methyl- piperazin-1-yl)-pyridin-4- ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E oder Z))- ylidene]-acetic acid allyl ester
[5-[1-(6-tert- Butoxycarbonylamino-pyridin-2- ylamino)-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E oder Z))-ylidene]-cyano-acetic acid allyl ester
[5-[1-[3-(tert-Butoxycarbonyl- methyl-amino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E oder Z))- ylidene]-cyano-acetic acid allyl ester
Dissolve 4.8 g of the compound described under INT77 and 4.4 g of the compound described under INTT5 in ethanol (140 ml) and stir under argon for three hours at 95° C. bath temperature. The condensation, thus arisen, is siphoned off and washed with ethanol. The compound in the title (5.7 g) is obtained in a 67% yield. The raw product is used at the next level without further purification.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer) δ=1.26 (t, 3H); 1.40 (s, 2H); 3.32 (m, 4H); 3.45 (m, 4H); 4.28 (m, 2H); 4.72 (d, 2H); 4.89 (s, 2H); 5.29 (dd, 1H); 5.40 (dd, 1H); 5.99 (m, 1H); 6.68 (dd, 1H); 6.90 (s, 1H); 6.93 (d, 1H); 7.28 (t, 1H); 8.21 (d, 1H); 10.47 (d, 1H) ppm.
Dissolve 2.99 g of the compound described under INTE77 in dichloro-methane (100 ml) and slowly add trifluoro-acetic acid (10 ml) to it. Stir for 2.5 hours under argon at room temperature and then end the reaction through the addition of a 10% watery sodium carbonate solution (approx. 170 ml). Then extract the reaction mixture with dichloro-methane (3×100 ml), wash the unified organic phases with a sodium chloride solution (1×100 ml) and dry following this over sodium sulfate. After distilling off the solvent on the rotation vaporizer, the compound in the title (2 g) is obtained in an 80% yield. The raw product was used at the next level without further purification.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer) δ=1.23 (m, 3H); 2.68 (m, 2H); 2.71 (m, 2H); 4.25 (m, 2H); 4.73 (m, 2H); 4.82 (s, 2H); 5.29 (dd, 1H); 5.39 (dd, 1H); 5.99 (m, 1H); 6.64 (dd, 1H); 6.88 (s, 1H); 6.91 (d, 1H); 7.27 (t, 1H); 8.22 (s, 1H) ppm.
Suspend 2.9 g of the compound described under INTE78 and 0.92 ml benzaldehyde in methanol (240 ml) and add acetic acid (24 ml) and sodium cyanoborohydride (0.7 g) to it at room temperature. Stir the residue at room temperature for 5 hours under argon, neutralize the reaction mixture through the addition of sodium carbonate and siphon off the condensation thus arisen. The compound in the title (2.54 g) is obtained in a 71% yield. The product is used at the next level without further purification.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer) 1H-NMR δ=1.29 (m, 3H); 2.32 (m, 2H); 2.41 (m, 2H); 3.43 (m, 4H); 4.26 (m, 2H); 4.72 (d, 2H); 4.86 (s, 2H); 5.29 (d, 1H); 5.40 (d, 1H); 6.00 (m, 1H); 6.68 (dd, 1H); 6.89 (s, 1H); 6.92 (d, 1H); 7.30 (m, 6H); 8.21 (d, 1H); 10.50 (d, 1H) ppm.
Pre-place 1.1 g potassium-(tert)-butylate in 50 ml tetrahydrofurane at 0° C. and add 45 μl water. Add 540 mg of the compound described under Intermediate INTEL) and stir for 30 minutes at 0° C., and for 20 hours at room temperature. At 0° C., add 0.25 ml triethylamine and 10.5 ml two molar salt acid (hydrochloric acid) in diethylether and stir at room temperature for an hour. Allow the solvent to condense under high vacuum and use the residue without any further purification.
MW: 412.51; MS (ESI) [M+1]+: 413
Dissolve 300 mg of the compound described under INTE2), 80 mg Pd (PPh3)4 and 0.6 ml morpholine in 18 ml tetrahydrofurane and stir for 15 hours. After an addition of 40 ml diethylether, filter the solid thus obtained, dry in vacuum and dissolve in 10 ml dimethylformamide. Add the solution to a suspension of 770 mg PL-MIA Resin of the firm Polymer Laboratories GmbH in 5 ml dimethylformamide and stir for 15 hours at room temperature. Filter the reaction mixture and allow the solvent to condense under high vacuum. 280 mg of the compound in the title is obtained as a raw product.
1H-NMR (DMSO-d6, stored over K2CO3): δ=1.20 (t, 3H); 1.88 (m, 4H); 2.50 (m, 4H); 3.09 (m, 2H); 3.20 (m, 2H); 4.20 (q, 2H); 6.93 (d, 1H); 7.04-7.12 (m, 2H); 7.23 (t, 1H); 7.88 (s, 1H); 9.97 (s, 1H) ppm.
Dissolve 1.2 g of the compound described under INTE4), 350 mg Pd (PPh3)4 and 2.6 ml morpholine in 60 ml tetrahydrofurane and stir for an hour at room temperature. After the addition of 40 ml of hexane, filter the solid obtained, dry in vacuum and dissolve in 20 ml dimethylformamide. Add the solution to a suspension of 6.0 g PL-MIA Resin of the firm Polymer Laboratories GmbH in 30 ml dimethylformamide and stir for 15 hours at room temperature. Filter the reaction mixture and allow the solvent to condense under high vacuum. 970 mg of the compound in the title is obtained as a raw product.
MW: 359.41; MS (ESI) [M+1]+: 360 1H-NMR (DMSO-d6, stored over K2CO3): δ=1.11 (t, 3H); 1.22 (t, 3H); 3.23 (m, 2H); 4.22 (q, 2H); 6.25 (s, 1H); 6.42 (d, 1H); 6.54 (s, b, 1H); 7.81 (d, 1H); 7.95 (s, 1H); 10.20 (s, 1H) ppm.
Dissolve 2.2 g of the compound described under INTE5), 560 mg Pd (PPh3)4 and 4.2 ml morpholine in 110 ml tetrahydrofurane and stir for an hour at room temperature. After the addition of 50 ml of hexane, filter the excluded solid, dry in vacuum and dissolve in 25 ml dimethylformamide. Add the solution to a suspension of 9.6 g PL-MIA Resin of the firm Polymer Laboratories GmbH in 50 ml dimethylformamide and stir for 15 hours at room temperature. Filter the reaction mixture and allow the solvent to condense under high vacuum. 2.1 g of the compound in the title is obtained as a raw product.
MW: 415.47; MS (ESI) [M+1]+: 416 1H-NMR (DMSO-d6, stored over K2CO3): δ=1.15-1.30 (m, 12H); 4.23 (q, 2H); 6.80 (m, 1H); 7.64-7.74 (m, 2H); 8.73 (d, 1H); 9.68 (s, 1H); 10.68 (d, 1H) ppm.
The following compounds are manufactured in addition to the process described above.
1H-NMR
Cyano-[5-[1-[3-(2,2-dimethyl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-{3-[2-(2- methoxy-ethoxy)-acetylamino]- phenylamino}-methyl(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(e or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-[3-(2- hydroxy-ethyl)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
[5-[1-(3-tert- Butoxycarbonylamino- phenylamino)-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- cyano-acetic acid
Cyano-[3-ethyl-5-[1-[3-(2- hydroxy-2-methyl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[3-ethyl-5-[1-[4-methyl-3- (2- Morpholin-4-yl-ethoxy)- phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
1H-NMR (DMSO-d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 2.09 (s, 3H); 2.58 (m, 4H); 2.81 (m, 2H); 3.61 (m, 4H); 4.15 (m, 2H); 4.26 (m, 2H); 6.81 (dd, 1H); 6.92 (s, 1H); 7.01 (d, 1H); 8.20 (d, 1H); 10.35 (d, 1H); 11.08 (s, 1H).
Cyano-[3-ethyl-4-oxo-5-[1-[3-(2- piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid
1H-NMR (DMSO-d6, 300 MHz) (selected peaks) δ = 1.19 (m, 3H); 1.47 (m, 2H); 1.66 (m, 4H); 2.88 (m, 4H); 3.10 (m, 2H); 4.12 (m, 2H); 4.21 (m, 2H); 6.62 (dd, 1H); 6.82 (m, 2H); 7.21 (m, 1H); 8.00 (d, 1H); 10.00 (d, 1H).
Cyano-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
1H-NMR (CDCl3, 300 MHz) (selected peaks) δ = 1.23 (m, 3H); 2.88 (s, 6H); 4.23 (m, 2H); 4.37 (m, 2H); 6.73 (dd, 1H); 6.97 (m, 2H); 7.30 (m, 1H); 8.20 (s, 1H).
Cyano-[3-ethyl-4-oxo-5-[1-[3-(2- pyrrolidin-1-yl-ethoxy)- phenylamino]-mEth-(E/Z)- ylidene]-thiazolidin-(2-(Z or E))- ylidene]-acetic acid
[5-[1-(3-Carboxymethoxy- phenylamino)-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- cuano-acetic acid
Cyano-[3-ethyl-5-[1-(3- isobutyryl-amino-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
[5-[1-[3-(Acetyl-methyl-amino)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- cyano-acetic acid
Cyano-[5-[1-[3-(2- dimethylamino-acetylamino)- phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]- phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[3-ethyl-5-[1-[3- (isobutyryl- methyl-amino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[3-ethyl-5-[1-[3-(2- methoxy- ethylamino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[3-ethyl-5-[1-{3-[2-(ethyl- methyl-amino)-acetylamino]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z)- ylidene]-acetic acid
Suspend 2.5 g of the compound described under INTE79 in THF (320 ml) and add to barbituric acid (0.6 g) and Pd(PPh3)4 (0.49 g). Stir the reaction mixture overnight, press on the rotary evaporator until a precipitation occurs and extract the resulting condensation. The compound in the title (522 mg) is obtained in a 23% yield. The product is used at the next level without further purification.
EI-MS=548.
The following compounds are manufactured in addition to the process described above.
1H-NMR
Cyano-[5-[1-[6-(1,1-difluoro-2- pyrrolidin-1-yl-ethyl)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-({3- [(4aR,8aS)-2- (octahydro-isoquinolin-2-yl)- ethyl]-phenylamino}-meth-(E/Z)- ylidene-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-{3-[2-(4- ethyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetic acid
Cyano-[5-[1-[3-(2-diethylamino-0 acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2--(E or Z))- ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazol- idin-(2-(E or Z))-ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)- meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-(3-{2-[ethyl- (2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
[5-[1-{3-[2-(Benzyl-methyl- amino)-acetylamino]-phenyl- amino}-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazol-idin-(2-(E or Z))-ylidene]-cyano acetic acid
Cyano-[3-ethyl-5-[1-(3- hydroxymethyl-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetic acid
Cyano-[3-ethyl-4-oxo-5-[1-[3-(3- pyrrolidin-1-yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid
Cyano-[3-ethyl-4-oxo-5-[1-[3-(3- piperidin-1-yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetic acid
Cyano-[3-ethyl-5-[1-[3-(3- morpholin-4-yl-propyl)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetic acid
[5-[1-[3-(tert-Butoxycarbonyl- methyl-amino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-cyano-acetic acid
Dissolve 170 mg of the raw product described under intermediate INTA1) (approx. 0.42 mmol) in 10 ml dimethylformamide, add 248 mg sodium hydrogencarbonate, 62 μl 2-amino-2-methyl-propane-1-ol, and 200 mg TBTU and stir for 18 hours at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with dichlormethane. Wash the organic solution with saturated sodium chloride, dry over sodium sulfate, press and, after purification through chromatography in silica gel, 61 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.30 (t, 3H); 1.36 (s, 6H); 1.74 (m, 4H); 2.54 (m, 4H); 2.69 (m, 2H); 2.79 (m, 2H); 3.43 (d, 2H); 4.27 (q, 2H); 5.27 (t, 1H); 6.74 (s, 1H); 7.00 (d, 1H); 7.18 (d, 1H); 7.25-7.35 (m, 2H); 8.19 (s, 1H); 10.31 (s, 1H) ppm.
Dissolve 42 mg tetrahydropyran-4-carboxylic acid in 10 ml tetrahydrofurane. At 0° C., add 80 μl triethylamine and 42 μl isobutylchloroformate to it. Stir for 30 minutes at room temperature. Then add 100 mg of the compound described under Example 6). Stir for 12 hours at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with dichlormethane. Wash the organic solution with saturated sodium chloride, dry over sodium sulfate, press and, after purification through chromatography in silica gel, 49 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
(DMSO-d6, stored via K2CO3, primary isomer): δ=1.07 (t, 3H); 1.22 (t, 3H); 1.68 (m, 4H); 2.58 (m, 2H); 3.19 (pentuplet, 2H); 3.39 (m, 1H); 3.90 (m, 1H); 4.21 (q, 2H); 6.90 (s, 1H); 7.12-7.31 (m, 2H); 7.50-7.80 (m, 2H); 8.04 (s, 1H); 9.81-9.99 (s, b, 1H); 10.39 (s, 1H) ppm.
Dissolve 150 mg of the compound described under Example 19) in 5 ml tetrahydrofurane. Add 0.25 ml triethylamine and 62 mg Piperidin-4-yl-methanol. Stir for 12 hours under re-flow. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with dichlormethane. Wash the organic solution with saturated sodium chloride, dry over sodium sulfate, press and, after purification through chromatography in silica gel, 37 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
(DMSO-d6, stored via K2CO3, primary isomer): δ=0.97-1.40 (m, 9H); 1.64 (d, 2H); 1.90 (t, 2H); 2.45 (m, 2H); 2.60 (t, 2H); 2.89 (m, 2H); 3.11-3.29 (m, 4H); 4.21 (q, 2H); 4.49 (t, 1H); 6.92 (s, 1H); 7.13 (d, 1H); 7.24 (t, 1H); 7.56-7.80 (m, 2H); 8.02 (s, 1H); 10.18 (s, 1H); 10.40 (s, 1H) ppm.
Dissolve 50 mg of the compound described under Intermediate INT9) in 5 ml triethylorthoformiate. Add 148 mg 3-aminobenzyl alcohol and 100 μl triethylorthoformiate. Stir for 3 hours under re-flow. Filter off the excluded product after the cooling of the reaction mixture. After purification through the re-crystallizing of ethanol, 56 mg of the compound in the title is obtained.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.24 (t, 3H); 3.07 (s, b, 1H); 3.92 (m, 2H); 4.23 (q, 2H); 4.49 (d, 2H); 5.25 (t, 1H); 7.00 (d, 1H); 7.13 (d, 1H); 7.21-7.35 (m, 2H); 7.95-8.20 (m, 2H); 10.40 (s, 1H) ppm.
Dissolve 50 mg of the compound described under Intermediate INTT7) in 10 ml ethanol. Add 140 mg of the compound described under Intermediate INT20) and 100 μL triethylorthoformiate to it. Stir for 3 hours under re-flow. Press the reaction mixture. After purification through the re-crystallizing of ethanol, 26 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.07 (t, 1H); 1.25 (t, 3H); 1.41 (m, 2H); 1.59 (m, 4H); 2.44 (m, 4H); 3.06 (s, 2H); 3.20 (pentuplet, 2H); 4.23 (q, 2H); 6.96 (d, 1H); 7.20-7.33 (m, 2H); 7.60-7.77 (m, 2H); 8.03 (s, 1H); 9.70 (s, 1H); 10.39 (s, 1H) ppm.
Suspend 7.75 g of the compound manufactured under Example 79) in 120 ml dichlormethane. Add 70 ml trifluoro acetic acid to it. Stir for one hour at room temperature. Press the reaction mixture, add dichlormethane and hexane and press anew. After drying well in vacuum, 11.2 g of the compound in the title is obtained as a trifluoro acetic acid salt. This raw product is used without further purification for the following reactions.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.07 (t, 3H); 1.26 (t, 3H); 3.20 (m, 2H); 4.22 (q, 2H); 6.80 (d, 1H); 7.01 (s, 1H); 7.05 (d, 1H); 7.30 (t, 1H); 7.74 (t, 1H); 8.01 (d, 1H); 9.20 (s, b, 3H); 10.35 (d, 1H) ppm.
Suspend approx. 16.9 mmol of the raw product of the compound manufactured under Example 6) (11.2 g) in 500 ml tetrahydrofurane. Add 5.15 ml triethylamine at room temperature and 3.28 g chloro-acetic acid anhydride in portions following this at 15° C. Stir for two hours at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with a saturated sodium chloride solution, dry over sodium sulfate, press and, after purification through re-crystallization from ethanol, 5.26 g of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.09 (t, 3H); 1.26 (t, 3H); 3.21 (pentuplet, 2H); 4.21 (q, 2H); 4.28 (s, 2H); 7.00 (d, 1H); 7.20 (d, 1H); 7.29 (t, 1H); 7.58-7.77 (m, 1H); 8.01 (s, 1H); 10.35 (s, 1H); 10.41 (s, 1H) ppm.
Dissolve 100 mg of the compound described under Example 7) in 5 ml dimethylformamide. Add 0.15 ml triethylamine, 6 mg potassium iodide and 38 μl 4-methylpiperidine to it. Stir for 4 hours at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with saturated sodium chloride, dry over sodium sulfate, press and, after purification through chromatography in silica gel, 62 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=0.91 (d, 3H); 1.08 (t, 3H); 1.14-1.40 (m, 6H); 1.59 (d, 2H); 2.12 (t, 2H); 2.83 (d, 2H); 3.09 (s, 2H); 3.21 (m, 2H); 4.22 (q, 4H); 6.96 (d, 2H); 7.20-7.33 (m, 2H); 7.58-7.78 (m, 2H); 8.04 (s, 1H); 9.69 (s, 1H); 10.40 (s, 1H) ppm.
Suspend 94 mg of the compound manufactured under Example 80) in 5 ml dichlormethane. Add 2.5 ml trifluoro-acetic acid to it. Stir for 30 minutes at room temperature. Press the reaction mixture, add dichlormethane and hexane and press anew. After drying well in vacuum, the residue thus obtained is suspended in 5 ml dimethylformamide. Add 50 μL acetic acid, 67 mg sodium hydrogencarbonate and 62 mg TBTU 5A to it. Stir for 12 hours at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with a saturated sodium chloride solution, dry over sodium sulfate, press and, after purification through re-crystallization from ethanol, 48 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.07 (t, 3H); 1.25 (t, 3H); 2.00 (s, 3H); 2.41-2.60 (m, 4H); 3.14-3.28 (m, 4H); 3.50 (m, 4H); 4.22 (q, 2H); 6.98 (m, 1H); 7.21-7.31 (m, 2H); 7.63-7.76 (m, 2H); 8.00 (s, 1H); 9.81 (s, 1H); 10.40 (s, 1H) ppm.
Suspend 120 mg of the compound manufactured under Example 80) in 5 ml dichlormethane. Add 2.5 ml trifluoro-acetic acid to it. Stir for 30 minutes at room temperature. Press the reaction mixture, add dichlormethane and hexane and press anew. After drying well in vacuum, the residue thus obtained is suspended in 5 ml tetrahydrofurane. Add 50 μL triethylamine, 20 μL methano-sulfonic acid chloride to it. Stir for 3 hours at room temperature. Add semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with a saturated sodium chloride solution, dry over sodium sulfate, press and, after purification through re-crystallization from ethanol, 46 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.08 (t, 3H); 1.24 (t, 3H); 2.63 (m, 4H); 2.91 (s, 3H); 3.10-3.28 (m, 8H); 4.22 (q, 2H); 6.95 (s, 1H); 7.20-7.30 (m, 2H); 7.56-7.75 (m, 2H); 8.05 (s, 1H); 9.80 (s, 1H); 10.40 (s, 1H) ppm.
Dissolve 100 mg of the compound manufactured under Example 95) in 10 ml methanol. Add 1 ml water and 30 mg potassium carbonate to it. Stir for 2 hours at room temperature. Add water to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with a saturated sodium chloride solution, dry over sodium sulfate, press and, after purification through re-crystallization from ethanol, 72 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.26 (t, 3H); 4.01 (d, 1H); 4.17 (d, 2H); 4.25 (q, 2H); 5.70 (t, 1H); 6.99 (d, 2H); 7.28 (t, 1H); 7.40 (d, 1H); 7.81 (s, 1H); 8.09 (s, 1H); 8.35 (s, 1H); 9.73 (s, 1H); 10.53 (s, 1H) ppm.
Dissolve 1.0 g of the compound manufactured under Example 71) in 10 ml dimethylformamide and 200 ml tetrahydrofurane. Add 0.9 ml triethylamine and 0.31 ml methane sulfonic acid chloride to it at −10° C. Stir for 1 hour at room temperature. Add a semi-saturated sodium hydrogencarbonate solution to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with a saturated sodium chloride solution, dry over sodium sulfate and press. Add dichlormethane to the solid obtained, stir for one hour at room temperature and filter off. 1.0 g of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.26 (t, 3H); 3.00 (t, 2H); 3.11 (s, 3H); 4.17 (m, 2H); 4.24 (q, 2H); 4.45 (t, 2H); 7.01 (d, 1H); 7.19 (d, 1H); 7.25-7.36 (m, 2H); 8.19 (s, 1H); 8.34 (t, 1H); 10.41 (s, 1H) ppm.
Dissolve 4.5 g of the compound manufactured under Example 12) in 400 ml butanon. Add 1.72 g sodium iodide to it. Stir for 8 hours under re-flow. Add water to the reaction mixture and extract with acetic acid ethylester. 1.6 g of the initial material is re-obtained from the watery phase through filtration. Dry the organic solution over sodium sulfate and press. 3.0 g of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.27 (t, 3H); 3.12 (t, 2H); 3.50 (t, 2H); 4.16 (d, 2H); 4.24 (q, 2H); 6.98 (d, 1H); 7.18 (d, 1H); 7.22-7.34 (m, 2H); 8.20 (d, 1H); 8.35 (t, 1H); 10.41 (d, 1H) ppm.
Dissolve 120 mg of the compound manufactured under Example 13) in 5 ml dimethylformamide. Add 42 mg morpholine and 65 mg potassium carbonate to it. Stir for 12 hours at room temperature. Add water to the reaction mixture and extract with acetic acid ethylester. Wash the organic solution with saturated sodium chloride, dry over sodium sulfate, press and, after purification through chromatography in silica gel, 40 mg of the compound in the title is obtained as a pH dependent 5-(E/Z)-isomer mixture.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.27 (t, 3H); 2.43 (m, 4H); 2.52 (m, 2H); 2.74 (m, 2H); 3.59 (m, 4H); 4.17 (m, 2H); 4.23 (q, 2H); 6.95 (d, 1H); 7.11 (d, 1H); 7.19-7.30 (m, 2H); 8.18 (s, 1H); 8.32 (s, 1H); 10.39 (s, 1H) ppm.
The following compounds are manufactured according to the process described above.
1H-NMR
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-{3- [2-((S)-2-hydroxymethyl-pyrrolidin- 1-yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1-Cyano-cyclopropanecarboxylic acid (3-{[2-[1-cyano-1- ethylcarbamoyl-meth-(E or Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5-(E/Z))-ylidenemethyl]-amino}- phenyl)-amide
Tetrahydro-furan-2-carboxylic acid (3-{[2-[1-cyano-1-ethylcarbamoyl- meth-(E or Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5-(E/Z))- ylidenemethyl]-amino}-phenyl)- amide
(3-{[2-[1-Cyano-1-ethylcarbamoyl- meth-(E or Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5-(E/Z))- ylidenemethyl]-amino}-phenyl)- carbamic acid isobutyl ester
N-(3-{[2-[1-Cyano-1- ethylcarbamoyl-meth-(E or Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5-(E/Z))-ylidenemethyl]-amino}- phenyl)-acrylamide
2-[5-[1-{3-[2-(2-Butoxy-ethoxy)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-ethyl-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(2,2,2-trifluoro- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-(3-propionylamino- phenylamino)-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2[5-[1-(3-Acetylamino- phenylamino)-meth-(E/Z)-ylidene]- 2-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-2-cyano-N-ethyl- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[3- (2-methoxy-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[3- (3-methoxy-propionylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(3-pyrrolidin-1-yl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(2-pyrrolidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-pyrrolidin-1-yl- ethyl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-N-cyanomethyl-2-[5-[1-[3- (2,2-dimethyl-propionylamino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- hydroxy-2-methyl-propionylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(2-hydroxy-2-methyl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- hydroxy-2-methyl-propionylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[3- (2-hydroxy-2-methyl- propionylamino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[2-(2- methoxy-ethoxy)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[22-(2- methoxy-ethoxy)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(2-methoxy-ethoxy)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-[5-[1-[6-(2,2-dimethyl- propionylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- ethyl-acetamide
2-Cyano-2-[5-[1-[6-(2,2-dimethyl- propionylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyano-2-[5-[1-[6-(2,2-dimethyl- propionylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-N-cyanomethyl-2-[5-[1-[6- (2,2-dimethyl-propionylamino)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-{6- [2-(2-methoxy-ethoxy)- acetylamino]-pyridin-2-ylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-2-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-Cyano-2-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{6-[2-(2-methoxy-ethoxy)- acetylamino]-pyridin-2-ylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-(2- ethylamino-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-2-[3-ethyl-5-[1-(2- ethylamino-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene-N- prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-5-[1-(2- ethylamino-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2trifluoro-ethyl)-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(2-ethylamino-pyridin-4- ylamino)-meth-(E/Z)-ylidene]-4- ox-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-(3- hydroxymethyl-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-acetamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-piperidin-1-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(2-pyrrolidin-1-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-pyrrolidin-1-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(2-morpholin-4-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[3- (2-morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-2-[5-[1-[3-(2,2-dimethyl- propionylamino)-4-fluoro- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-Cyano-N-cyanomethyl-2-[5-[1-[3- (2,2-dimethyl-propionylamino)-4- fluoro-phenylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[5-[1-[3-(2,2-dimethyl- propionylamino)-4-fluoro- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-Cyano-2-[5-[1-[3-(2,2-dimthyl- propionylamino)-4-fluoro- phenylamino]-meth-(E/Z()-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene-N-ethyl-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- hydroxy-ethyl)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-prop-2-ynyl- acetamide
Methanesulfonic acid 2-[(3-{[2-[1- cyano-1-prop-2-ynylcarbamoyl- meth-(E or Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5-(E/Z))- ylidenemethyl]-amino}-phenyl)- ethyl ester
2-Cyano-2-[3-ethyl-5-[1-[3-(2-iodo- ethyl)-phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl--2-[3-ethyl- 5-[1-[3-(2-hydroxy-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-piperidin-1-yl- ethyl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-]3-ethyl- 5[1-{3-[2-(4-methyl-piperidin-1-yl)- ethyl]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-thiomorpholin-4-yl- ethyl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[5-[1-{3- [2-(4,4-difluoro-piperidin-1-yl)- ethyl]-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-{3-[2-(4-trifluoromethyl- piperidin-1-yl)-ethyl]-phenylamino}- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-{3-[2-(4-phenyl- piperidin-1-yl)-ethyl]-phenylamino}- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-(3-vinyl-phenylamino)- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
(3-{[2-[1-Cyano-1-ethylcarbamoyl- meth-(E/Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5-(E/Z))- ylidenemethyl]-amino}-phenyl)- carbamic acid tert-butyl ester
4-[(3-{[2-[1-Cyano-1- ethylcarbamoyl-meth-(E or Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5-(E/Z))-ylidenemethyl]-amino}- phenylcarbamoyl)-methyl]- piperiazine-1-carboxylic acid tert- butyl ester
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-{3-[2-(4-propionyl-piperazin-1- yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-[5-[1-(3-{2-[4-(2,2- dimethyl-propionyl)-piperazin-1-yl]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- ethyl-acetamide
2-[5-[1-{3-[2-(4-Benzenesulfonyl- piperazin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-2-Cyano-N-ethyl- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(2-thiomorpholin-4-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-ethyl-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-{3-[2-(4-trifluoromethyl- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
(3-{[2-[1-Cyano-1-prop-2- ynylcarbamoyl-meth-(E or Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5-(E/Z))-ylidenemethyl]-amino}- phenyl)-carbamic acid tert-butyl ester
2-[5-[1-(3-Amino-phenylamino)- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2,2,2-trifluoro-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-[5-[1-[3-(2-Chloro-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-2-cyano-N-prop-2-ynyl- acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-thiomorpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-Cyan-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 2-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-{3- [2-(4-trifluoromethyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
Acetic acid (3-{[2-[1-cyano-1- (cyanomethyl-carbamoyl)-meth-(E or Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(5-(E/Z))-ylidenemethyl]- amino}-phenylcarbamoyl)-methyl ester
Methanesulfonic acid (3-{[2-[1- cyano-1-(cyanomethyl-carbamotl)- meth-(E or Z)-yliene]-3-ethyl-4- oxo-thiazolidin-(5-(E/Z))- ylidenemethyl]-amino}- phenylcarbamoyl)-methyl ester
2-Cyano-2-[3-ethyl-5-[1-{3-[2-(2- methoxy-ethoxy)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2-hydroxy-1,1-dimthyl- ethyl)-acetamide
2-Cyano-2-[3-ethyl-5-[1-{6-[2-(2- methoxy-ethoxy)-acetylamino]- pyridin-2-ylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2-hydroxy-1,1- dimethyl-ethyl)-acetylamide
2-Cyano-2-[3-ethyl-5-[1-(2- ethylamino-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2-hydroxy-1,1-dimethyl-ethyl)- acetamide
2-Cyano-2-[5-[1-[6-(2,2-dimethyl- propionylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2-hydroxy-1,1-dimethyl-ethyl)- acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-methyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin(2- (E or Z))-ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[(4a-(R or S),8a-(R or S))-2- (octahydro-isoquinolin-2-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.26 (m, 3H); 1.71 (m, 4H); 2.79 (m, 2H); 3.06 (m, 1H); 3.94 (m, 2H); 4.10 (m, 2H); 4.28 (m, 2H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.22 (m, 1H); 8.13 (m, 2H); 10.28 (s, 1H).
2-Cyano-N-ethyl-2-[3-ethyl-4-oxo- 5-[1-[3-(2-pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.02 (m, 3H); 1.25 (m, 3H); 1.68 (m, 4H); 2.79 (m, 2H); 3.21 (m, 2H); 4.09 (m, 2H); 4.22 (m, 2H); 6.62 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.70 (m, 1H); 8.10 (s, 1H); 10.18 (s, 1H).
2-Cyano-N-cyclopropylmethyl-2-[3- ethyl-4-oxo-5-[1-[3-(2-pyrrolidin-1- yl-ethoxy)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 0.22 (m, 2H); 0.40 (m, 2H); 1.02 (m, 1H); 1.26 (m, 3H); 1.69 (m, 4H); 2.79 (m, 2H); 3.03 (m, 2H); 4.09 (m, 2H); 4.22 (m, 2H); 6.62 (dd, 1H); 6.88 (m, 2H); 7.24 (m, 1H); 7.73 (m, 1H); 8.10 (s, 1H);10.19 (s, 1H).
N-Allyl-2-cyano-2-[3-ethyl-4-oxo-5- [1-[3-(2-pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.23 (m, 3H); 1.68 (m, 4H); 2.80 (m, 2H); 3.79 (m, 2H); 4.09 (m, 2H); 4.21 (m, 2H); 5.08 (dd, 1H); 5.11 (dd, 1H); 5.83 (m, 1H); 6.62 (dd, 1H); 6.88 (m, 1H); 7.22 (m, 1H); 7.98 (m, 1H); 8.12 (s, 1H); 10.20 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2-fluoro-ethyl)-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.27 (m, 3H); 1.70 (m, 4H); 2.81 (m, 2H); 3.42 (m, 1H); 3.50 (m, 1H); 4.10 (m, 2H); 4.20 (m, 2H); 4.42 (m, 1H); 4.54 (m, 1H); 6.63 (dd, 1H); 6.88 (m, 2H); 7.21 (m, 1H); 7.80 (m, 1H); 8.12 (s, 1H);10.22 (s, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-4-oxo-5-[1-[3-(2-pyrrolidin-1- yl-ethoxy)-phenylamino]-meth- (e/Z)-ylidene]hiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.27 (m, 3H); 1.69 (m, 4H); 2.79 (m, 2H); 3.58 (m, 2H); 4.10 (m, 2H); 4.25 (m, 2H); 6.09 (tt, 1H); 6.65 (dd, 1H); 6.89 (m, 2H); 7.24 (m, 1H); 7.97 (m, 1H); 8.14 (s, 1H); 10.28 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-pyrrolidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
1H-NMR (DMSO-d d6, 300 MHz) (selected peaks) δ = 1.22 (m, 3H); 1.70 (m, 4H); 2.81 (m, 2H); 3.96 (m, 2H); 4.09 (m, 2H); 4.22 (m, 2H); 6.66 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 8.18 (m, 2H); 10.29 (s, 1H).
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-pyrrolidin-1-yl- ethoxy)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.26 (m, 3H); 1.70 (m, 4H); 2.81 (m, 2H); 4.09 (m, 2H); 4.19 (d, 2H); 4.23 (m, 2H); 6.64 (dd, 1H); 6.89 (m, 2H); 7.25 (m, 1H); 8.18 (s, 1H); 8.35 (m, 1H); 10.32 (s, 1H).
2-Cyano-2-[3-ethyl-5-[1-[4-methyl- 3-(2-morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
1H-NMR (CDCl3, 300 MHz) δ = 1.40 (m, 3H); 2.17 (s, 3H); 2.61 (m, 4H); 2.87 (m, 2H); 3.71 (m, 4H); 3.97 (m, 2H); 4.07 (m, 2H); 4.35 (m, 2H); 6.60 (m, 3H); 7.09 (d, 1H); 7.57 (m, 1H); 10.50 (d, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[4-(3-hydroxy-2- piperidin-2-yl-ethyl)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (DMSO- d6,300 MHz) (selected peaks) δ = 1.22 (m, 3H); 2.10 (s, 3H); 2.72 (m, 2H); 3.58 (m, 4H); 4.11 (m, 2H); 4.21 (m, 2H); 6.05 (tt, 1H); 6.79 (dd, 1H); 6.91 (s, 1H); 7.08 (d, 1H); 7.95 (m, 1H); 8.16 (s, 1H); 10.27 (s, 1H).
2-Cyano-N-(2-difluoro-ethyl)-2-[3- ethyl-5-[1-[4-(-3-hydroxy-2- piperidin-1-yl-ethyl)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (CDCl3, 300 MHz) δ = 1.39 (m, 3H); 2.17 (s, 3H); 2.58 (m, 4H); 2.86 (m, 2H); 3.72 (m, 4H); 3.95 (m, 2H); 4.07 (m, 2H); 4.36 (m, 2H); 5.20 (m, 2H); 5.86 (m, 1H); 6.27 (m, 1H); 6.50 (d, 1H); 6.58 (m, 1H); 7.08 (d, 1H); 7.56 (d,1H); 10.45 (d, 1H).
2-Cyano-N-cyclopropylmethyl-2-[3- ethyl-5-[1-[4-methyl-3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
1H-NMR (CDCl3, 300 MHz) (selected peaks) δ = 0.19 (m, 2H); 0.50 (m, 2H); 0.99 (m, 1H); 1.38 (m, 3H); 2.12 (s, 3H); 2.60 (m, 4H); 3.17 (m, 2H); 3.70 (m, 4H); 4.09 (m, 2H); 4.32 (m, 2H); 6.30 (m, 1H); 6.60 (m, 2H); 7.05 (m, 1H); 7.55 (d, 1H); 10.42 (d, 1H).
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[4- methyl-3-(2-morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.10 (m, 3H); 1.22 (m, 3H); 2.11 (s, 3H); 2.73 (m, 2H); 3.21 (m, 2H); 3.60 (m, 4H); 4.11 (m, 2H); 4.21 (m, 2H); 6.78 (dd, 1H); 6.91 (d, 1H); 7.08 (d, 1H); 7.68 (m, 1H); 8.11 (d, 1H); 10.16 (d, 1H).
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[4-methyl-3-(2-morpholin-4-yl- ethoxy)-phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.26 (m, 3H); 2.18 (s, 3H); 3.60 (m, 2H); 3.92 (m, 4H); 4.11 (s, 2H); 4.28 (m, 2H); 4.49 (m, 2H); 6.88 (dd, 1H); 6.97 (s, 1H); 7.13 (d, 1H); 8.21 (d, 1H); 10.43 (d, 1H); 11.11 (s, 1H).
2-Cyan-2-[3-ethyl-5-[1-[4-methyl- 3-(2-morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
1H-NMR (CDCl3, 300 MHz) δ = 1.40 (m, 3H); 2.19 (s, 3H); 2.28 (s, 1H); 2.65 (m, 4H); 2.88 (m, 2H); 3.72 (m, 4H); 4.15 (m, 4H); 4.37 (m, 2H); 6.36 (m, 1H); 6.50 (d, 1H); 6.11 (dd, 1H); 7.09 (d, 1H); 7.53 (d, 1H); 10.48 (d, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
1H-NMR (DMSO- d6, 200 MHz) (selected peaks) δ = 1.28 (m, 3H); 1.38 (m, 2H); 1.50 (m, 4H); 2.40 (m, 4H); 2.68 (m, 2H); 3.92 (m, 2H); 4.03 (m, 2H); 4.21 (m, 2H); 6.63 (dd, 1H); 6.90 (m, 2H); 7.24 (m, 1H); 8.20 (m, 2H); 10.30 (s, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-4-oxo-5-[1-[3-(2-piperidin-1- yl-ethoxy)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.29 (m, 3H); 1.38 (m, 2H); 1.49 (m, 4H); 2.42 (m, 4H); 2.68 (m, 2H); 3.57 (m, 2H); 4.10 (m, 2H); 4.23 (m, 2H); 6.08 (tt, 1H); 6.62 (dd, 1H); 6.98 (m, 2H); 7.22 (m, 1H); 7.98 (m, 1H); 8.12 (s,1H); 10.27 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- (2-fluoro-ethyl)-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.28 (m, 3H); 1.38 (m, 2H); 1.50 (m, 4H); 2.42 (m, 4H); 2.68 (m, 2H); 3.47 (m, 1H); 3.54 (m, 1H); 4.09 (m, 2H); 4.21 (m, 2H); 4.42 (m, 1H); 4.59 (m, 1H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.24 (m, 1H);7.82 (m, 1H); 8.10 (s, 1H); 10.22 (s, 1H).
N-Allyl-2-cyano-2-[3-ethyl-4-oxo-5- [1-[3-(2-piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.28 (m, 3H); 1.39 (m, 2H); 1.50 (m, 4H); 2.47 (m, 4H); 2.68 (m, 2H); 3.80 (m, 2H); 4.09 (m, 2H); 4.25 (m, 2H); 5.09 (dd, 1H); 5.12 (dd, 1H); 5.85 (m, 1H); 6.62 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.85 (m,1H); 8.10 (s, 1H); 10.19 (s, 1H).
2-Cyano-N-cyclopropylmethyl-2-[3- ethyl-4-oxo-5-[1-[3-(2-piperidin-1- yl-ethoxy)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 0.21 (m, 2H); 0.40 (m, 2H); 1.00 (m, 1H); 1.22 (m, 3H); 1.38 (m, 2H); 1.50 (m, 4H); 2.41 (m, 4H); 2.62 (m, 2H); 3.04 (m, 2H); 4.09 (m, 2H); 4.21 (m, 2H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.22 (m, 1H);7.77 (m, 1H); 8.09 (s, 1H); 10.20 (s, 1H).
2-Cyano-N-ethyl-2-[3-ethyl--oxo- 5-[1-[3-(2-piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.09 (m, 3H); 1.23 (m, 3H); 1.39 (m, 2H); 1.49 (m, 4H); 2.41 (m, 4H); 2.67 (m, 2H); 3.21 (m, 2H); 4.09 (m, 2H); 4.20 (m, 2H); 6.62 (dd, 1H); 6.87 (m, 2H); 7.21 (m, 1H); 7.70 (m, 1H); 8.10 (s, 1H); 10.18 (s,1H).
2-Cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-piperidin-1-yl- ethoxy)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.28 (m, 3H); 1.38 (m, 2H); 1.49 (m, 4H); 2.44 (m, 4H); 2.67 (m, 2H); 4.08 (m, 2H); 4.15 (d, 2H); 4.21 (m, 2H); 6.64 (dd, 1H); 6.90 (m, 2H); 7.22 (m, 1H); 8.17 (s, 1H); 8.38 (m, 1H); 10.31 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-[3- (2-piperidin-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 1.37 (m, 2H); 1.47 (m, 4H); 2.68 (m, 2H); 3.07 (m, 1H); 3.91 (m, 2H); 4.05 (m, 2H); 4.20 (m, 2H); 6.64 (dd, 1H); 6.89 (m, 2H); 7.24 (m, 1H); 8.11 (m, 2H); 10.27 (s, 1H).
2-Cyano-2-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-prop-2-ynyl-acetamide
1H-NMR (CDCl3, 300 MHz) δ = 1.40 (m, 3H); 2.25 (m, 1H); 2.34 (s, 6H); 2.71 (m, 2H); 4.03 (m, 2H); 4.11 (m, 2H); 4.38 (m, 2H); 6.39 (m, 1H); 6.62 (dd, 1H); 6.69 (m, 1H); 7.21 (d, 1H); 7.56 (s, 1H); 10.48 (s, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[5- [1-[3-(2-dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.21 (m, 3H); 2.28 (s, 6H); 2.63 (m, 2H); 3.58 (m, 2H); 4.05 (m, 2H); 4.25 (m, 2H); 6.08 (tt, 1H); 6.62 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.99 (m, 1H); 8.13 (s, 1H); 10.29 (s, 1H).
2-Cyano-2-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
1H-NMR (DSMO- d6, 300 MHz) (selected peask) δ = 1.22 (m, 3H); 2.25 (s, 6H); 2.67 (m, 2H); 3.96 (m, 2H); 4.09 (m, 2H); 4.26 (m, 2H); 6.63 (dd, 1H); 6.90 (m, 2H); 7.23 (m, 1H); 8.13 (s, 1H); 8.22 (m, 1H); 10.30 (s, 1H).
N-Allyl-2-cyano-2-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DSMO- d6, 300 MHz) (selected peaks) δ = 1.23 (m, 3H); 2.22 (s, 6H); 2.61 (m, 2H); 3.79 (m, 2H); 4.08 (m, 2H); 4.22 (m, 2H); 5.08 (dd, 1H); 5.12 (dd, 1H); 5.81 (m, 1H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.22 (m, 1H); 7.83 (m, 1H); 8.10 (s, 1H); 10.20 (s, 1H).
2-Cyano-N-cyanomethyl-2-[5-[1-[3- (2-dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.27 (m, 3H); 2.26 (s, 6H); 2.62 (m, 2H); 4.07 (m, 2H); 4.16 (m, 2H); 4.22 (m, 2H); 6.63 (dd, 1H); 6.90 (m, 2H); 7.25 (m, 1H); 8.18 (s, 1H); 8.37 (m, 1H); 10.33 (s, 1H).
2-Cyano-2-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-(2-fluoro-ethyl)- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.26 (m, 3H); 2.24 (s, 6H); 2.62 (m, 2H); 3.45 (m, 1H); 3.51 (m, 1H); 4.09 (m, 2H); 4.21 (m, 2H); 4.42 (m, 2H); 4.58 (m, 2H); 6.62 (dd, 1H); 6.89 (m, 2H); 7.22 (m, 1H); 7.81 (m, 1H); 8.11 (s, 1H);10.23 (s, 1H).
2-Cyano-N-cyclopropylmethyl-2-[5- [1-[3-(2-dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 0.21 (m, 2H); 0.41 (m, 2H); 1.00 (m, 1H); 1.25 (m, 3H); 2.21 (s, 6H); 2.61 (m, 2H); 3.04 (m, 2H); 4.07 (m, 2H); 4.21 (m, 2H); 6.62 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.77 (m, 1H); 8.09 (s, 1H);10.19 (s, 1H).
2-Cyano-2-[5-[1-[3-(2- dimethylamino-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-ethyl-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.05 (m, 3H); 1.22 (m, 3H); 2.22 (s, 6H); 2.65 (m, 2H); 3.21 (m, 2H); 4.03 (m, 2H); 4.20 (m, 2H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.21 (m, 1H); 7.70 (m, 1H); 8.10 (s, 1H); 10.20 (s, 1H).
2-Cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth(E/Z ylidene]-4- oxo-thiazolidin-(2Z or E)-ylidene]- N-(2,2,2-trifluoro-ethyl)-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.29 (m, 3H); 2.71 (m, 2H); 3.58 (m, 4H); 3.95 (m, 2H); 4.10 (m, 2H); 4.22 (m, 2H); 6.65 (dd, 1H); 6.90 (m, 2H); 7.22 (m, 1H); 8.20 (m, 2H); 10.31 (d, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[3-(2-morpholin-4-yl- ethoxy)-phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 2.70 (m, 2H); 3.60 (m, 6H); 4.11 (m, 2H); 4.22 (m, 2H); 6.08 (tt, 1H); 6.64 (ddm 1H); 6.89 (m, 2H); 7.21 (m, 1H); 7.98 (m, 1H); 8.12 (s, 1H); 10.29 (s, 1H).
2-Cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl- ethoxy)phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-(2-fluoro-ethyl)- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ 1.26 (m, 3H); 2.70 (m, 2H); 3.48 (m, 1H); 3.51 (m, 1H); 3.60 (m, 4H); 4.11 (m, 2H); 4.22 (m, 2H); 4.40 (m, 1H); 4.58 (m, 1H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.21 (m, 1H); 7.81 (m, 1H); 8.11 (d, 1H); 10.26 (d, 1H).
N-Allyl-2-cyano-2-[3-ethyl-5-[1-[3- (2-morpholin-4-yl-ethoxy)- henylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2Z or E)-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.27 (m, 3H); 2.70 (m, 2H); 3.58 (m, 4H); 3.80 (m, 2H); 4.11 (m, 2H); 4.22 (m, 2H); 5.08 (dd, 1H); 5.12 (dd, 1H); 5.82 (m, 1H); 6.63 (dd, 1H); 6.88 (m, 2H); 7.21 (m, 1H); 7.87 (m, 1H); 8.10 (s, 1H); 10.20 (s, 1H).
2-Cyano-N-cyclopropylmethyl-2-[3- ethyl-5-[1-[3-(2-morpholin-4-yl- ethoxy)phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 0.21 (m,2 H); 0.42 (m, 2H); 1.02 (m, 1H); 1.27 (m, 3H); 2.70 (m, 2H); 3.03 (m, 2H); 3.61 (m, 4H); 4.10 (m, 2H); 4.27 (m, 2H); 6.66 (dd, 1H); 6.88 (m, 2H); 7.22 (m, 1H); 7.78 (m, 1H); 8.11 (s,1H); 10.19 (s, 1H).
2-Cyano-N-2-[3-ethyl-5-[1-[3- (2-morpholin-4-yl-ethoxy)- henylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2Z or E)-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.08 (m, 3H); 1.28 (m, 3H); 2.70 (m, 2H); 3.20 (m, 2H); 3.59 (m, 4H); 4.11 (m, 2H); 4.22 (m, 2H); 6.62 (dd, 1H); 6.97 (m, 2H); 7.23 (m, 1H); 7.72 (m, 1H); 8.10 (s, 1H), 10.20 (s, 1H).
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(2-morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 2.71 (m, 2H); 3.60 (m, 4H); 4.13 (m, 2H); 4.16 (m, 2H); 4.21 (m, 2H); 6.69 (dd, 1H); 6.90 (m, 2H); 7.21 (m, 1H); 8.18 (d, 1H); 8.37 (m, 1H); 10.32 (d, 1H).
2-Cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethoxy)- phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-prop-2-ynyl-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.25 (m, 3H); 2.71 (m, 2H); 3.09 (m, 1H); 3.58 (m, 4H); 3.93 (m, 2H); 4.10 (m, 2H); 4.22 (m, 2H); 6.63 (dd, 1H); 6.89 (m, 2H); 7.22 (m, 1H); 8.12 (m, 1H); 10.27 (s, 1H).
(3-{[2-[1-Cyano-1-(2,2-difluoro- ethylcarbamoyl)-meth-(Z or E)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5E/Z)-ylidenemethyl]-amino}- phenyoxy)-acetic acid methyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ 1.18 (m, 3H); 3.48 (m, 2H); 3.69 (s, 3H); 4.19 (m, 2H); 4.50 (s, 2H); 5.98 (tt, 1H); 6.60 (dd, 1H); 6.83 (m, 2H); 7.19 (m, 1H); 8.18 (s, 1H); 8.40 (m, 1H); 10.50 (s, 1H).
(3-{[2-[1-Cyano-1-(2-fluoro- ethylcarbamoyl)-meth-(Z or E)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5E or Z)-ylidenemethyl]-amino}- phenoxy)-acetic acid methyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ 1.25 (m, 3H); 3.50 (m, 1H); 3.78 (s, 3H); 4.23 (m, 2H); 4.40 (m, 1H); 4.57 (m, 3H); 6.70 (dd, 1H); 6.93 (m, 2H); 7.28 (m, 1H); 8.21 (s, 1H); 8.32 (m, 1H); 10.57 (s, 1H).
(3-{[2-[1-Allylcarbamoyl-1-cyano- meth-(Z or E)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5E/Z)- ylidenemethyl]-amino}-phenoxy)- acetic acid methyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.24 (m, 3H); 3.79 (m, 5H); 4.27 (m, 2H); 4.58 (s, 2H); 5.07 (dd, 1H); 5.11 (dd, 1H); 5.81 (m, 1H); 6.70 (dd, 1H); 6.92 (m, 2H); 7.28 (m, 1H); 8.22 (s, 1H); 8.30 (m, 1H); 10.58 (s, 1H).
(3-{[2-[1-Cyano-1- cyclopropylmethyl-carbamoyl)-eth- (Z or E)-ylidene]-3-ethyl-4-oxo- thiazlolidin-(5E/Z)-ylidenemethyl]- amino}-phenyoxy)-acetic acid methyl ester
1H-NMR (DMSO- d6, 300 Mhz) (selected peaks) δ = 0.19 (m, 2H); 0.39 (m, 2H); 0.45 (m, 1H); 1.21 (m, 3H); 3.02 (m, 2H); 3.79 (s, 3H); 4.25 (m, 2H); 4.51 (s, 2H); 6.70 (dd, 1H); 6.94 (m, 2H); 7.29 (m, 1H); 8.18 (m, 1H); 8.26 (s, 1H); 10.58 (s, 1H).
(3-{[2-[1-Cyano-1-ethylcarbamoyl- meth-(E or Z)-ylidene]-3-ethyl-4- oxo-thiazolidin-(5E/Z)- ylidenemethyl]-amino}-phenoxy)- acetic acid methyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.02 (m, 3H); 1.22 (m, 3H); 3.18 (m, 2H); 3.79 (s, 3H); 4.28 (m, 2H); 4.50 (s, 2H); 6.71 (dd, 1H); 6.98 (m, 2H); 7.28 (m, 1H); 8.11 (m, 1H); 8.22 (s, 1H); 10.48 (s, 1H).
(3-{[2-[1-Cyano-1-(cyanomethyl- carbamoyl)-meth-(Z or E)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(5E or Z)- ylidenemethyl]-amino}-phenoxy)- acetic acid methyl ester
1H-NMR (DMSO- d6, 300 Mhz) (selected peaks) δ 1.22 (m, 3H); 3.79 (s, 3H); 4.22 (m, 4H); 4.68 (s, 2H); 6.71 (dd, 1H); 6.95 (m, 2H); 7.30 (m, 1H); 8.22 (s, 1H); 8.86 (m, 1H); 10.53 (s, 1H).
2-Cyano-2-[3-ethyl-5-[1-{3-[(2- fluoro-ethoxycarbamoyl)-methoxy]- phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-N-(2-fluoro-ethyl)- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.24 (m, 3H); 3.50 (m, 4H); 4.24 (m, 2H); 4.40 (m, 2H); 4.57 (m, 4H); 6.68 (dd, 1H); 6.92 (m, 2H); 7.28 (m, 1H); 7.80 (m, 1H); 8.10 (s, 1H); 8.32 (m, 1H); 10.31 (s, 1H).
N-Allyl-2-[5-[1-(3- allylcarbamoylmethoxy- phenylamino)-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2Z or E)-ylidene]-2-cyano- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.28 (m, 3H); 3.78 (m, 4H); 4.26 (m, 2H); 4.54 (s, 2H); 5.10 (m, 4H); 5.81 (m, 2H); 6.69 (dd, 1H); 6.91 (m, 2H); 7.27 (m, 1H); 7.88 (m 1H); 8.10 (d, 1H); 8.30 (m, 1H); 10.28 (d, 1H).
2-Cyano-N-cyclopropylmethyl-2-[5- ]1-{3-[(cyclopropylmethyl- carbamoyl)-methoxy]- phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2Z or E)-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 0.20 (m, 4H); 0.39 (m, 4H); 0.97 (m, 2H); 1.27 (m, 3H); 3.04 (m, 4H); 4.21 (m, 2H); 4.50 (s, 2H); 6.68 (dd, 1H); 6.91 (m, 2H); 7.22 (m, 1H); 7.75 (s, 1H); 8.09 (s, 1H); 8.16(m, 1H); 10.27 (s, 1H).
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-(3- ethylcarbamoylmethoxy- phenylamino)-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2Z or E)- ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.09 (m, 6H); 1.28 (m, 3H); 3.20 (m, 4H); 4.21 (m, 2H); 4.50 (s, 2H); 6.68 (dd, 1H); 6.92 (m, 2H); 7.27 (m, 1H); 7.70 (m, 1H); 8.10 (d, 1H); 10.26 (d, 1H).
2-Cyano-N-cyanomethyl-2-[5-[1-{3- [(cyanomethyl-carbamoyl)- methoxy]-phenylamino}-meth-(E/ Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2Z or E)-ylidene]- acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.29 (m, 3H); 4.10 (m, 6H); 4.57 (s, 2H); 6.60 (dd, 1H); 6.88 (m, 2H); 7.19 (m, 1H); 8.08 (s, 1H); 8.26 (s, 1H); 8.78 (m, 1H); 10.33 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-(3- prop-2-ynylcarbamoylmethoxy- phenylamino)-meth-(E/Z)- ylidene]-thiazolidin-(2Z or E)- ylidene]-N-prop-2-ynyl-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.28 (m, 3H); 3.08 (m, 1H); 3.13 (m, 1H); 3.92 (m, 4H); 4.22 (m, 2H); 4.55 (s, 2H); 6.69 (dd, 1H); 6.92 (m,2 H); 7.28 (m, 1H); 8.11 (d, s, 1H); 8.60 (m, 1H); 10.31 (s, 1H).
2-Cyano-2-[3-ethyl-4-oxo-5-[1-{3- [(2,2,2-trifluoro-ethylcarbamoyl)- methoxy]-phenylamino}-meth-(E/ Z)-ylidene]-thiazolidin-(2Z or E)- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
1H-NMR (DMSO- d6,300 MHz) (selected peaks) δ = 1.28 (m, 3H); 3.97 (m, 4H); 4.22 (m, 2H); 4.63 (s, 2H); 6.69 (dd, 1H); 6.93 (m, 2H); 7.28 (m, 1H); 8.20 (m, 2H); 8.78 (m,1 H); 10.40 (s, 1H).
2-Cyano-N-(2,2-difluoro-ethyl)-2-[5- [1-{3-[(2,2-difluoro- ethylcarbamoyl)-methoxy]- phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2Z or E)-ylidene]-acetamide
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.20 (m, 3H); 3.47 (m, 4H); 4.15 (m, 2H); 4.50 (s, 2H); 5.97 (tm, 2H); 6.60 (dd, 1H); 6.82 (m, 2H); 7.19 (m, 1H); 7.88 (s, 1H); 8.03 (s, 1H); 8.40 (m, 1H); 10.26 (s, 1H).
(3-{[2-[1-Cyano-1-(2,2,2-trifluoro- ethylcarbamoyl)-meth-(Z or E)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5E/Z)-ylidenemethyl]-amino}- phenoxy)-acetic acid methyl ester
1H-NMR (DMSO- d6, 300 MHz) (selected peaks) δ = 1.19 (m, 3H); 3.68 (s, 3H); 3.89 (m, 2H); 4.18 (m, 2H); 4.57 (s, 2H); 6.60 (d, 1H); 6.83 (m, 2H); 7.69 (m, 1H); 8.15 (s, 1H); 8.70 (m, 1H); 10.50 (s, 1H).
(3-{[2-[1-Cyano-1-prop-2- ynylcarbamoyl-meth-(Z or E)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5E/Z)-ylidenemethyl]-amino}- phenoxy)-acetic acid methyl ester
1H-NMR (DMSO- d6,300 MHz) (selected peaks) δ = 1.27 (m, 3H), 3.11 (m, 1H); 3.79 (s, 3H); 3.93 (m, 2H); 4.25 (m, 2H); 4.58 (s, 2H); 6.71 (dd, 1H); 6.97 (m, 2H); 7.29 (m, 1H); 8.22 (s, 1H); 8.60 (m, 1H); 10.57 (s, 1H).
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-(3- isobutyrylamino-phenylamino)-eth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-{3-ethyl-5-[1-(3- isobutyryl-amino-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-2-{3-ethyl-5-[1-(3- isobutyryl-amino-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- prop-2-ynyl-acetamide
2-Cyano-2-{3-ethyl-5-[1-(3- isobutyryl-amino-phenylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- (2-fluoro-ethyl)-acetamide
2-Cyano-N-cyanomethyl-2-{3-ethyl- 5-[1-(3-isobutyrylamino- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene}-acetamide
2-Cyano-N-(2,2-difluoro-ethyl)-2- {3-ethyl-5-[1-(3-isobutyrylamino- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene}-acetamide
2-{5-[1-[3-(Acetyl-methyl-amino)- phenyl-amino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N-ethyl- acetamide
2-{5-[1-[3-(Acetyl-methyl-amino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N-(2,2,2- trifluoro-ethyl)-acetamide
2-{5-[1-[3-(Acdtyl-methyl-amino)- phenyl-amino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N-prop-2-ynyl- acetamide
2-{5-[1-[3-(Acetyl-methyl-amino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N- cyanomethyl-acetamide
2-{5-[1-[3-(Acetyl-methyl-amino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N-(2-fluoro- ethyl)-acetamide
2-{5-[1-[3-(Acetyl-methyl-amino)- phenyl-amino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-2-cyano-N-(2,2- difluoro-ethyl)-acetamide
2-Cyano-2-{5-[1-[3-(2-dimethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- ethyl-acetamide
2-Cyano-2-{5-[1-[3-(2-dimethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-2-{5-[1-[3-(2-dimethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-{5-[1-[3- (2-dimethylamin-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene}-acetamide
2-Cyano-2-{5-[1-[3-(2-dimethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- (2-fluoro-ethyl)-acetamide
2-Cyano-N-(2,2-difluoro-ethyl)-2- {5-[1-[3-(2-dimethylamino- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene}- acetamide
2-Cyano-2-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]-phenyl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-ethyl-acetamide
2-Cyano-2-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]-phenyl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-Cyano-2-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]-phenyl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]-phenyl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[5-[1-{3-[(2,2-dimethyl- propionyl)-methyl-amino]-phenyl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2-trifluoro-ethyl)- acetamide
2-Cyano-N-(2,2-difluoro-ethyl)-2-[5- [1-{3-[(2,2-dimethyl-propionyl)- methyl-amino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-Cyano-N-ethyl-2-{3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)-phenyl- amino]-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}- acetamide
2-Cyano-2-{[3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)-phenyl- amino]-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- (2,2,2-trifluoro-ethyl)-acetamide
2-Cyano-2-{3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene}-N-prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-{3-methyl- 5-[1-[3-(isobutyryl-methyl-amino)- phenylamino]-methyl-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-2-{3-ethyl-5-[1-[3- (isobutyryl-methyl-amino)-phenyl- amino]-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}-N- 2-(fluoro-ethyl)-acetamide
2-Cyano-N-(2,2-difluoro-ethyl)-2- {3-ethyl-5-[1-[3-(isobutyryl-methyl- amino)-phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-E or Z))-ylidene}-acetamide
2-Cyano-N-ethyl-2-{3-ethyl-5-[1-[3- (2-methoxy-ethylamino)-phenyl- amino]-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene}- acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(2-methoxy-methylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[3-(2-methoxy- ethylamino)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(2- methoxy-ethylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2-fluoro-ethyl)- acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-{3- [2-(ethyl-methyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[2- (ethyl-methyl-amino)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[2- (ethyl-methyl-amino)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1{3-[2-(ethyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyan-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-{3-[2-(ethyl-methyl- amino)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-E or Z))-ylidene]- acetamide
2-Cyan-2-[3-ethyl-5-[1-{3-[2- (ethyl-methyl-amino)-acetylamino]- phenylamino}-methyl-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2-fluoro-ethyl)- acetamide
Dissolve 2.5 g of the compound described under Intermediate INTE44 in 160 ml tetrahydrofurane, add 1.66 g N,N-dimethyl barbituric acid and 614 mg Pd(PPh3)4 to it and stir for two hours at room temperature. Following this 3.68 ml triethylamine, add 1.09 ml propargylamine and 5.12 g TBTU and stir for a further 15 hours at room temperature. Add 250 ml acetic acid ethylester and wash once again with 100 ml water. Dry the organic phase over sodium sulfate. After purification through re-crystallization from dichlormethane and additional re-crystallization from ethanol, 1.68 g of the compound in the title is obtained.
1H-NMR (DMSO-d6, stored over K2CO3, primary isomer): δ=1.25 (t, 3H); 2.14 (s, 3H); 3.07 (t, 1H); 3.88-4.00 (m, 2H); 4.24 (q, 2H); 4.66 (s, 2H); 7.02 (d, 1H); 7.20 (d, 1H); 7.29 (t, 1H); 7.67 (s, 1H); 8.02 (d, 1H); 8.11 (t, 1H); 10.16 (s, 1H); 10.46 (d, 1H) ppm.
Dissolve 2.6 g of the compound described under Example 198 in 80 ml dimethylformamide and add 40 ml methanol and 40 ml water to it. Add 1.15 g of potassium carbonate and stir for two hours at room temperature. Add 1000 ml acetic acid ethylester, the organic phase is separated and washed thrice with 75 ml of a semi-saturated sodium chloride solution each time. Dry the organic phase over sodium sulfate. 2.19 g of the compound in the title is obtained.
(DMSO-d6, stored via K2CO3, primary isomer): δ=1.21 (t, 3H); 3.02 (b, 1H); 3.83-3.93 (m, 2H); 3.96 (d, 2H); 4.19 (q, 2H); 5.67 (t, 1H); 6.94 (d, 1H); 7.22 (t, 1H); 7.35 (d, 1H); 7.77 (s, 1H); 7.94-8.12 (m, 2H); 9.70 (s, 1H); 10.40 (d, b, 1H) ppm.
Dissolve 2.18 g of the compound described under Example 199 in 18 ml dimethylformamide and add 320 ml tetrahydrofurane to it. At 0° C., add 1.78 ml triethylamine and 0.60 ml methanesulfonic acid chloride and stir for one hour at room temperature. Add 500 ml acetic acid ethylester and 200 ml water, separate the organic phase and wash thrice with 75 ml of a semi-saturated sodium chloride solution each time. Dry the organic phase over sodium sulfate. After purification through a stirring out of the solids with dichlormethane, 2.02 g of the compound in the title is obtained.
(DMSO-d6, stored via K2CO3, primary isomer): δ=1.24 (t, 3H); 3.06 (b, 1H); 3.31 (s, 3H); 3.86-3.99 (m, 2H); 4.22 (q, 2H); 4.85 (s, 2H); 7.04 (d, 1H); 7.22 (d, 1H); 7.30 (t, 1H); 7.68 (s, 1H); 8.03 (d, 1H); 8.10 (t, 1H); 10.24 (s, 1H); 10.47 (d, b, 1H) ppm.
Suspend 60 mg of the compound described under INTT10 in 3 ml 1-propanol, add 138 mg of the compound described under INT62 and 0.16 ml triethylorthoformiate to it. Stir for 4 hours at 140° C. in a bomb tube. Allow the reaction mixture to gradually cool at room temperature and stir for 15 hours at room temperature. Filter off the excluded solids and wash successively with ethanol and diethylether. After purification through filtration through silica gel and subsequent re-crystallization from ethanol, 106 mg of the compound in the title are obtained.
(DMSO-d6, stored via K2CO3, primary isomer): δ=1.20 (t, 3H); 1.83-2.10 (m, 4H); 2.66 (m, 4H); 3.26 (s, 2H); 4.11 (d, 2H); 4.19 (q, 2H); 6.95-7.12 (m, 1H); 7.22 (t, 1H); 7.93 (s, b, 1H); 8.02 (s, 1H); 8.27 (s, b, 1H); 9.62 (s, 1H); 10.50 (s, b, 1H) ppm.
Suspend 1.6 g of the compound described under Example 204 in 40 ml dichlormethane. Add 24 ml trifluoro-acetic acid to it and stir for one hour at room temperature. Press reaction mixture, add dichlormethane and hexane and press anew. After drying well in vacuum, 1.7 g of the compound in the title is obtained in the form of trifluoro acetic acid salt. This raw product is used without further purification for the following reactions.
Dissolve 3.1 mmol of the trifluoro-acetic acid salts of the compound described under Example 202 in 45 ml tetrahydrofurane. At 0° C., add 0.64 ml pyridine and 0.60 mg chloro-acetic acid anhydride and stir for 30 minutes at room temperature. Add 200 ml acetic acid ethylester and 100 ml water, separate the organic phase and dry over sodium sulfate. After purification through the re-crystallizing of ethanol, 1.12 g of the compound in the title is obtained.
(DMSO-d6, stored via K2CO3, primary isomer): δ=1.27 (t, 3H); 3.98 (m, 2H); 4.19-4.31 (m, 4H); 7.04 (d, 1H); 7.22 (d, 1H); 7.31 (t, 1H); 7.70 (s, 1H); 8.06 (b, 1H); 8.21 (b, 1H); 10.40 (s, 1H); 10.54 (s, b, 1H) ppm.
Dissolve 95 mg of the compound described under INTA23 in 3 ml DMF and add HATU (194 mg) as well as allylamine (34 μl). Stir the reaction residue at room temperature under argon over night, diluted with water (approx. 20 ml), made alkaline through the addition of a sodium carbonate solution and extracted with acetic ester (3×10 ml). Dry the unified organic phases over sodium sulfate and distill the solvent on a rotary evaporator Purify the raw product chromatographically on the Flashmaster. The compound in the title (45 mg) is obtained in a 45% yield.
1H-NMR (CDCl3, primary isomer): δ=1.39 (m, 3H); 2.49 (m, 4H); 3.61 (m, 4H); 3.69 (m, 2H); 3.97 (m, 2H); 4.38 (m, 2H); 4.80 (s, 2H); 5.21 (m, 2H); 5.88 (m, 1H); 6.38 (t, 1H); 6.58 (m, 3H); 7.12 (t, 1H); 7.50 (m, 2H); 7.68 (m, 1H); 8.00 (d, 1H); 8.65 (d, 1H); 10.40 (d, 1H) ppm.
The following compounds are manufactured according to the process described above.
1H-NMR
(3-{[2-[1-Cyano-1-(2,2,2-trifluoro- ethylcarbamoyl)-meth-(E or Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (5-(E/Z))-ylidenemethyl]-amino}- phenyl)-carbamic acid tert-butyl ester
2-Cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[3-(1-hydroxy-2-piperidin- 1-yl-ethyl)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-Cyano-N-ethyl-2-[3-ethyl-5-[1-[3- (1-hydroxy-2-piperidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-Cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(1-hydroxy-2-piperidin-1-yl- ethyl)-phenylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-Cyano-2-[3-ethyl-5-[1-[3-(1- hydroxy-2-piperidin-1-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-5-[1-{3- [(4aR,8aS)-2-(octahydro- isoquinolin-2-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2-hydroxy-1,1-dimethyl- ethyl)-acetamide
2-Cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperidin-1-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-Cyano-2-[3-ethyl-4-oxo-5-[1-{3- [2-(4-phenyl-piperidin-1-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-ethyl]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-{3-[2- (4-trifluoromethyl-piperidin-1-yl)- ethyl]-phenylamino}-meth-(E/Z)- ylidene]-thiazolidin-(2-(E orZ))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(2- thiomorpholin-4-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-[5-[1-{3-[2-(4-benzyl-piperidin-1- yl)-ethyl]-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-2-cyano-N- prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-5-({3- [(4aR,8aS)-2-(octahydro- isoquinolin-2-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-5-[1-[3-(2- morpholin-4-yl-ethyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-hydroxy-piperidin-1- yl)-ethyl]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-methyl-piperazin-1-yl)- ethyl]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-[5-[1-{3-[2-(4-benzoyl-piperidin-1- yl)-ethyl]-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-2-cyano-N- cyanomethyl-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[(4aS,8aS)-2-(octahydro- isoquinolin-2-yl)-ethyl]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[4-fluoro-3-(2-morpholin- 4-yl-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[3-ethyl-5-[1-[4-fluoro-3- (2-morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-[4-fluoro-3- (2-morpholin-4-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[4-fluoro-3-(2-morpholin-4-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-[4- fluoro-3-(2-morpholin-4-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]-4- fluoro-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]-4- fluoro-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-N-(2,2,2- trifluoro-ethyl)-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[5- [1-{3-[2-(4,4-difluoro-piperidin-1-yl)- acetylamino]-4-fluoro- phenylamino}-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]-4- fluoro-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-N-ethyl- acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]-4- fluoro-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-N-(2-hydroxy- 1,1-dimethyl-ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-[3-(2- imidazol-1-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-[5-[1-[3-(2-benzoimidazol-1-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-{3-[2- (4-phenyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-[5-[1-{3-[2-(4-benzyl-piperidin-1- yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[5-[1-{3-[2-(4,4-difluoro- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-{3-[2- (4-trifluoromethyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- hydroxymethyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-{3-[2- (4-phenyl-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(2-thiomorpholin-4-yl- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-{3- [2-(4,4-difluoro-piperidin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-{3-[2-(4-trifluoromethyl- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-[5-[1-{3-[2-(4-benzyl-piperidin-1- yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-cyanomethyl-acetamide
2-[5-[1-{3-[2-(4-Benzoyl-piperidin- 1-yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-cyanomethyl-acetamide
2-cyano-N-cyanomethyl-2-(3-ethyl- 5-{[3-((4aS,8aS)-2-octahydro- isoquinolin-2-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene}- 4-oxo-thiazolidin-(2-(E or Z))- ylidene)-acetamide
2-cyano-N-cyanomethyl-2-(3-ethyl- 5-{[3-((4aR,8aS)-2-octahydro- isoquinolin-2-yl-acetylamino)- phenylamino]-meth-(E/Z)-ylidene}- 4-oxo-thiazolidin-(2-(E or Z))- ylidene)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-methyl-piperazin-1-yl)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-hydroxy-piperidin-1- yl)-ethyl]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-hydroxymethyl- piperidin-1-yl)-acetylamino]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-{3- [2-(4-cyano-4-phenyl-piperidin-1- yl)-acetylamino]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-[5-[1-[5-bromo-4-((R)-1- hydroxymethyl-2-methyl- propylamino)-pyrimidin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2,2-trifluoro-ethyl)- acetamide
2-[5-[1-[5-bromo-4-((R)-1- hydroxymethyl-2-methyl- propylamino)-pyrimidin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-cyanomethyl-acetamide
2-[5-[1-[5-bromo-4-((R)-1- hydroxymethyl-2-methyl- propylamino)-pyrimidin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-ethyl-acetamide
2-cyano-2-[5-[1-[6-(1,1-difluoro-2- pyrrolidin-1-yl-ethyl)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-ethyl-acetamide
2-cyano-2-[5-[1-[6-(1,1-difluoro-2- pyrrolidin-1-yl-ethyl)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-N-cyanomethyl-2-[5-[1-[6- (1,1-difluoro-2-pyrrolidin-1-yl-ethyl)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-cyano-2-[5-[1-[6-(1,1-difluoro-2- pyrrolidin-1-yl-ethyl)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-ethoxy]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperidin-1-yl)-ethoxy]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-[5-[1-[3-(2-azepan-1-yl-ethoxy)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-lidene]-2-cyano-N-(2,2,2- trifluoro-ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-ethyl-piperazin-1-yl)-2- oxo-ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-{3-[2-(4-ethyl-piperazin- 1-yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- ethyl-piperazin-1-yl)-2-oxo-ethoxy]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- ethyl-piperazin-1-yl)-2-oxo-ethoxy]- phenylamino}-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
N-Allyl-2-cyano-2-[3-ethyl-5-[1-{3- [2-(4-methyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(4-methyl-piperazin-1-yl)- 2-oxo-ethoxy]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-{3-[2-(4-methyl-iperazin- 1-yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2-(4- methyl-piperazin-1-yl)-2-oxo- ethoxy]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-[5-[1-{3-[2-(4-benzyl-piperazin-1- yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-cyanomethyl-acetamide
2-[5-[1-{3-[2-(4-benzyl-piperazin-1- yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2-difluoro-ethyl)- acetamide
2-[5-[1-{3-[2-(4-benzyl-piperazin-1- yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-prop-2-ynyl-acetamide
2-[5-[1-{3-[2-(4-benzyl-piperazin-1- yl)-2-oxo-ethoxy]-phenylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[5-[1-[3-(2-diethylamino- acetylamino)-phenylamino]-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- ethyl-acetamide
2-cyano-2-[5-[1-[3-(2-diethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-cyano-2-[5-[1-[3-(2-diethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2-difluoro-ethyl)-acetamide
2-cyano-2-[5-[1-[3-(2-diethyl- amino-acetylamino)-phenylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2-fluoro-ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-[3- (2-diethylamino-acetylamino)- phenylamino]-meth-(E/Z)-ylidene]- 3-ethyl-4-oxo-thiazolidin-(2(E or Z))-ylidene]-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-{3- [2-(methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-tri- fluoro-ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2-difluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-(2-fluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-{3-[2- (methyl-propyl-amino)-acetyl- amino]-phenylamino}-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-{3-[2-(methyl-propyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acet-amide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-(3- {2-[(2-methoxy-ethyl)-methyl- amino]-acetylamino}-phenyl- amino)-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2-difluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2-fluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(3-{2-[(2-methoxy-ethyl)- methyl-amino]-acetylamino}- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-(3- {2-[ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2- [ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2- [ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2-difluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2- [ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2-fluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-(3-{2- [ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(3-{2-[ethyl-(2-methoxy-ethyl)- amino]-acetylamino}-phenyl- amino)-meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-[5-[1-{3-[2-(benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-ethyl-acetamide
2-[5-[1-{3-[2-(benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2,2-trifluoro-ethyl)- acetamide
2-[5-[1-{3-[2-(benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2,2-difluoro-ethyl)- acetamide
2-[5-[1-{3-[2-(Benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-(2-fluoro-ethyl)-acetamide
2-[5-[1-{3-[2-(Benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-prop-2-ynyl-acetamide
2-[5-[1-{3-[2-(benzyl-methyl-amino)- acetylamino]-phenylamino}-meth- (E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-cyanomethyl-acetamide
2-cyano-2-[5-[1-[6-(2-dimethyl- amino-acetylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-ethyl-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-{6- [2-(ethyl-methyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-2-[5-[1-[6-(2-diethyl- amino-acetylamino)-pyridin-2- ylamino]-meth-( E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-ethyl-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-{6- [2-(methyl-propyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-{6- [2-(isopropyl-methyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-[5-[1-{6-[2-(tert-butyl-methyl- amino)-acetylamino]-pyridin-2-yl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-2-cyano-N-ethyl- acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-(6- {2-[(2-methoxy-ethyl)-methyl- amino]-acetylamino}-pyridin-2- ylamino)-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-(6- {2-[ethyl-(2-methoxy-ethyl)-amino]- acetylamino}-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-[5-[1-{6-[2-(benzyl-methyl-amino)- acetylamino]-pyridin-2-ylamino}- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-2- cyano-N-ethyl-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-{6- [2-(methyl-phenethyl-amino)- acetylamino]-pyridin-2-ylamino}- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[5-[1-[6-(2-dimethyl- amino-acetylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[5-[1-[6-(2-diethyl- amino-acetylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-tri-fluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-{6-[2- (methyl-propyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-{6-[2-(iso- propyl-methyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-[5-[1-{6-[2-(tert-butyl-methyl- amino)-acetylamino]-pyridin-2-yl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-2-cyano-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(6-{2-[(2- methoxy-ethyl)-methyl-amino]- acetylamino}-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(6-{2- [ethyl-(2-methoxy-ethyl)-amino]- acetyl-amino}-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-[5-[1-{6-[2-(benzyl-methyl- amino)-acetylamino]-pyridin-2-yl- amino}-meth-(E/Z)-ylidene]-3-ethyl- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-2-cyano-N-(2,2,2-tri-fluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-{6-[2- (methyl-phenethyl-amino)-acetyl- amino]-pyridin-2-ylamino}-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-tri- fluoro-ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[6-(2-methoxy-ethylamino)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-[6-(2- methoxy-ethylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-[6-(2- methoxy-ethylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-[6- (2-methoxy-ethylamino)-pyridin-2- ylamino]-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[6-(2-methoxy- ethylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-2-[5-[1-[6-(2- dimethylamino-ethylamino)-pyridin- 2-ylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-[6- (2-dimethylamino-ethylamino)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(6- morpholin-4-yl-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-cyano-N-ethyl-2-[3-ethyl-5-[1-(6- morpholin-4-yl-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-(6-morpholin-4-yl-pyridin- 2-ylamino)-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(6- morpholin-4-yl-pyridin-2-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- (2,2,2-trifluoro-ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(6-morpholin-4-yl-pyridin-2- ylamino)-meth-(E/Z)-ylidene]-4-xo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(2-morpholin-4-yl-pyridin-4- ylamino)-meth-(E/Z)-ylidene]-4- oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(3- hydroxymethyl-phenylamino)-meth- (E/Z)-ylidene]-4-oxo-thiazolidin-(2- (E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(3-hydroxymethyl- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(3- morpholin-4-ylmethyl- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(4- trifluoromethyl-piperidin-1- ylmethyl)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-(2,2,2-trifluoro- ethyl)-acetamide
2-cyano-2-[3-ethyl-5-[1-(3- morpholin-4-ylmethyl- phenylamino)-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(4- trifluoromethyl-piperidin-1- ylmethyl)-phenylamino]-meth- (E/Z)-ylidene]-thiazolidin-(2-(E or Z))-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-(3-morpholin-4-ylmethyl- phenylamino)-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(4-trifluoromethyl- piperidin-1-ylmethyl)-phenylamino]- meth-(E/Z)-ylidene]-thiazolidin-(2- (E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-[3- (4,4-difluoro-piperidin-1-ylmethyl)- phenylamino]-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-(3-thiomorpholin-4- ylmethyl-phenylamino)-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(3-pyrrolidin-1-yl-prop- yl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(3-piperidin-1-yl- propyl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[3-(3-morpholin-4-yl-propyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(3- pyrrolidin-1-yl-propyl)-phenylamino]- meth-(E/Z)-ylidene]-thiazolidin- (2-(E or Z))-ylidene]-N-(2,2,2- trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-5-[1-[3-(3- morpholin-4-yl-propyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-(2,2,2-trifluoro-ethyl)- acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(3- pyrrolidin-1-yl-propyl)-phenylamino]- meth-(E/Z)-ylidene]-thiazolidin- (2Z)-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-2-[3-ethyl-4-oxo-5-[1-[3-(3- piperidin-1-yl-propyl)-phenylamino]- meth-(E/Z)-ylidene]-thiazolidin- (2Z)-ylidene]-N-prop-2-ynyl- acetamide
2-cyano-2-[3-ethyl-5-[1-[3-(3- morpholin-4-yl-propyl)- phenylamino]-meth-(E/Z)-ylidene]- 4-oxo-thiazolidin-(2-(E or Z))- ylidene]-N-prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[5-[1-{3- [3-(4,4-difluoro-piperidin-1-yl)-prop- yl]-phenylamino}-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 4-oxo-5-[1-[3-(3-thiomorpholin-4-yl- propyl)-phenylamino]-meth-(E/Z)- ylidene]-thiazolidin-(2-(E or Z))- ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[6-(4-methyl-piperazin-1-yl)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-2-[3-ethyl-5-[1-(2- morpholin-4-yl-pyridin-4-ylamino)- meth-(E/Z)-ylidene]-4-oxo- thiazolidin-(2-(E or Z))-ylidene]-N- prop-2-ynyl-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[2-(4-methyl-piperazin-1-yl)- pyridin-4-ylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-(2,2-difluoro-ethyl)-2-[3- ethyl-5-[1-[2-(4-methyl-piperazin-1- yl)-pyridin-4-ylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[3-ethyl- 5-[1-[2-(2-methoxy-ethylamino)- pyridin-4-ylamino]-meth-(E/Z)- ylidene]-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-acetamide
2-cyano-N-cyanomethyl-2-[5-[1- [3,5-difluoro-6-(2-methoxy- ethylamino)-pyridin-2-ylamino]- meth-(E/Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(2-(E or Z))-ylidene]- acetamide
(6-{[2-[1-Cyano-1-ethylcarbamoyl- meth-(Z)-ylidene]-3-ethyl-4-oxo- thiazolidin-(5-(E/Z))-ylidenemethyl]- amino}-pyridin-(2-(E oder Z))-yl)- carbamic acid tert-butyl ester
2-[5-[1-(6-Amino-pyridin-2- ylamino)-meth-(E/Z)-ylidene]-3- ethyl-4-oxo-thiazolidin-(2-(E oder Z))-ylidene]-2-cyano-N-ethyl- acetamide
2-[5-[1-[6-(2-Chloro-acetylamino)- pyridin-2-ylamino]-meth-(E/Z)- ylidene]-3-ethyl-4-oxo-thiazolidin- (2-(E oder Z))-ylidene]-2-cyano-N- ethyl-acetamide
2.6 g trifluoroethylamine, 8.4 g TBTU and 3.6 ml triethylamine are added to a solution of intermediate INTA37 in DMF (360 ml). The reaction mixture is stirred at ambient temperature for 12 hours. The solvent is distilled off and the raw product obtained mixed with a mixture of acetic acid ethyl ester and total NaHCO3 solution and extracted. The united organic phases are dried over sodium sulfate and the solvent is distilled on the rotary evaporator. The raw product is chromatographically purified. 7.9 g of title compound is obtained.
MW: 511; MS (ESI) [M+1]+: 512
1.3 ml propargylamine 6.2 g TBTU and 2.7 ml triethylamine are added to a solution of intermediate INTA37 in DMF (285 ml). The reaction mixture is stirred at ambient temperature for 12 hours. The solvent is distilled off and the raw product obtained mixed with a mixture of acetic acid ethyl ester and total NaHCO3 solution and extracted. The united organic phases are dried over sodium sulfate and the solvent is distilled off on the rotary evaporator. The raw product is chromatographically purified. 7.9 g of title compound is obtained.
MW: 467; MS (ESI) [M+1]+: 468
7.9 of the compound described under Example 370 is suspended in 175 ml dichloromethane. 19 ml trifluoroacetic acid is added. It is then stirred for 2.5 hours at ambient temperature. The reaction mixture is carefully admixed into 400 ml of cooled 1 M NaOH solution. It is then mixed and extracted with dichloromethane and acetic acid ethyl ester. The organic phase is dried over Na2SO4. 7 g of the title compound is obtained as trifluoroacetic acetic acid salt. That raw product is used without further purification for the next reactions.
5.8 g of the compound described under Example 371 is suspended in 140 ml dichloromethane. 15.4 ml trifluoroacetic acid is added. It is then stirred for 4 hours at ambient temperature. The reaction mixture is carefully admixed into 300 ml of cooled 1 M NaOH solution. It is then mixed and extracted with dichloromethane and acetic acid ethyl ester. The organic phase is dried over Na2SO4. 3 g of the title compound is obtained as trifluoroacetic acetic acid salt. That raw product is used without further purification for the next reactions.
0.71 mmol of the trifluoroacetic acid salt of the compound described under Example 372 is suspended in 9 ml tetrahydrofurane. After adding 113 μl pyridine and 157 mg chloroacetic acid anhydride it is stirred for 2.5 h at ambient temperature. 20 ml acetic acid ethyl ester and 10 ml total sodium hydrogen carbonate solution are added, the organic phase is separated off and dried over sodium sulfate. 0.4 g of the title compound is obtained.
MW: 501; MS (ESI) [M+1]+: 502
8 mmol of the trifluoroacetic acid salt of the compound described under Example 373 is suspended in 50 ml tetrahydrofurane. After adding 1.3 μl pyridine and 2 g chloroacetic acid anhydride dissolved in 50 ml THF it is stirred for 4 h at ambient temperature. 200 ml acetic acid ethyl ester and 100 total sodium hydrogen carbonate solution are added, the organic phase is separated off and dried over sodium sulfate. 3.1 g of the title compound is obtained.
MW: 457; MS (ESI) [M+1]+: 458
In an argon atmosphere a solution of 67 mg (0.15 mmol) 2-[5-[1-[3-(2-Chloro-acetylamino)-phenylamino]-meth-(E/Z)-ylidene]-3-ethyl-4-oxo-thiazolidin-(2-(E or Z))-ylidene]-2-cyano-N-prop-2-ynyl-acetamide and 6.5 mg (0.04 mmol) potassium iodide in 1.5 ml DMF a solution of 270 mg (0.38 mmol) 3,4-Dihydro-2H-benzo[1,4]oxazine were added in 0.5 ml DMF was added. After the addition of 170 μL (1.22 mmol) triethylamine, the mixture was stirred at room temperature for 12 hours.
The reaction mixture was separated from the solvent. The raw product so obtained was purified by HPLC. 5.1 mg (9%) of the desired product was isolated.
HPLC-MS (analytic) of the purified product (Detection: UV=254 nM; Column: Purospher STAR RP18e, 125×4 mm, 5μ (Merck KgGa, Darmstadt); Liquid: A: H2O/0.1% TFA, B: CH3CN/0.1% TFA, Gradient: 5 to 95% B in 10 min.; Flow rate: 1 ml/min): Retention time of the product=9.25 min.; MS of the product: m/z=560 ([M+H]+)
In an argon atmosphere a solution of 76 mg (0.15 mmol) Methanesulfonic acid (3-{[2-[1-cyano-1-(cyanomethyl-carbamoyl)-meth-(E oder Z)-ylidene]-3-ethyl-4-oxo-thiazolidin-(5-(E/Z))-ylidenemethyl]-amino}-phenylcarbamoyl)-methyl ester and 6.5 mg (0.04 mmol) potassium iodide in 1.5 ml DMF a solution of 278 mg (0.37 mmol) 3,4-Dihydro-2H-benzo[1,4]oxazine in 0.5 ml DMF is added. After the addition of 213 μL (1.22 mmol) diisopropylethylamine, the mixture was stirred at room temperature for 12 hours. The reaction mixture was separated from the solvent.
The raw product so obtained was purified by HPLC. 30 mg (37%) of the desired product was isolated.
HPLC-MS (analytic) of the purified product (Detection: UV=254 nM; Column: Purospher STAR RP18e, 125×4 mm, 5μ (Merck KgGa, Darmstadt); Liquid: A: H2O/0.1% TFA, B: CH3CN/0.1% TFA, Gradient: 5 to 95% B in 10 min.; Flow rate: 1 ml/min): Retention time of the product=9.09 min.; MS of the product: m/z=548 ([M+H]+)
In analogous fashion the following compounds can be created:
The following examples describe the biological effects of the invented compounds:
Recombinant human Plk-1 (6×His) was purified from insect cells (Hi5) infected with a baculovirus.
10 ng (recombinant created, purified) PLK enzyme is incubated for 90 minutes at room temperature with biotin casein and 33P-γ-ATP as a sub-stratum in a volume of 15 μl in 384 well Greiner Small Volume Microtiterplates (final concentration in buffer: 660 ng/ml PLK; 0.7 μM Casein, 0.5 μM ATP incl. 400 nCi/ml 33P-γ-ATP; 10 mM MgCl2, 1 mM MnCl2; 0.01% NP40; 1 mM DTT, Protease inhibitors; 0.1 mM Na2VO3 in 50 mM HEPES pH 7.5). At the end of the reaction a 5 μl stop solution (500 μM ATP; 500 mM EDTA; 1% triton X100; 100 mg/ml streptavidin coated SPA Beads in PBS) was added. After the microtiter plate is closed with foil, the beads are sedimented through centrifugation (10 min., 1500 rpm). The fixing of the 33P-γ-ATP in casein was set as a measure of the enzyme activity by β-Counting. The measure of inhibitor activity was referenced against a control solution (=unrestricted enzyme activity=0% inhibition) and the average value of several deposits that contained 300 μM Wortmannin (=fully restricted enzyme activity=100% inhibition).
Test substances were introduced in various concentrations (0 μM, and in the range of 0.01-30 μM). The final concentration of the dimethylsulfoxide solvent in all concentrations amounted to 1.5%.
Cultivated human MaTu breast tumor cells were spread on plates to a thickness of 5000 cells per measuring point in a 96-hole multititerplate in 200 μl of the appropriate growth medium. After 24 hours the cells of one plate (the zero-point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μl), to which was added the test substances in various concentrations (0 μM and in the range of 0.01 to 30 μm; the final concentration of the dimethylsulfoxide solvent was 0.5%). The cells were incubated for 4 days in the presence of the test substances. The cell proliferation was determined by the staining of the cells with crystal violet. The cells were fixed by the addition of 20 μl per measuring point of an 11% glutaraldehyde solution for 15 minutes at room temperature. After the fixed cells were washed three times with water, the plates were dried at room temperature. The cells were stained by the addition of 100 μl per measuring point of a 0.1% crystal violet solution (pH set at pH3 through the addition of acetic acid). After the fixed cells were washed three times with water, the plates were dried at room temperature. The coloring was dissolved by the addition of 100 μl per measuring point of a 10% acetic acid solution. Extinction was determined photometrically at a wave length of 595 nm. The percentage change of the cell growth was calculated by normalizing the measured values at the extinction value of the zero-point plate (=0%) and the extinction of the untreated cells (0 μM) (=100%).
The results of the PLK-1 enzyme assay and of the proliferation assay are shown in the following table 1.
From Table 1 it can be seen that the present invented compounds of general formula I inhibit PLK. Furthermore the expert can see from Tables 2 and 3 that the present invented substances are also better than the current state of technology.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 102004061503.9, filed Dec. 15, 2004 and U.S. Provisional Application Ser. No. 60/637,777, filed Dec. 22, 2004, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102004061503.9 | Dec 2004 | DE | national |
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/637,777 filed Dec. 22, 2004.
| Number | Date | Country | |
|---|---|---|---|
| 60637777 | Dec 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11302537 | Dec 2005 | US |
| Child | 12432213 | US |
