WO2016131789A1 - Benzopyrrolidone derivatives possessing antiviral and anticancer properties - Google Patents
Benzopyrrolidone derivatives possessing antiviral and anticancer properties Download PDFInfo
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- WO2016131789A1 WO2016131789A1 PCT/EP2016/053204 EP2016053204W WO2016131789A1 WO 2016131789 A1 WO2016131789 A1 WO 2016131789A1 EP 2016053204 W EP2016053204 W EP 2016053204W WO 2016131789 A1 WO2016131789 A1 WO 2016131789A1
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- Prior art keywords
- phenyl
- amino
- methylene
- carboxamide
- indoline
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
Definitions
- the present invention relates to benzopyrrolidone derivatives and/or pharmaceutically acceptable salts thereof for use in the treatment of infection diseases, and pharmaceutical composition containing at least one of the said benzopyrrolidone derivatives and/or pharmaceutically acceptable salt thereof.
- influenza infections still make a huge impact on human health worldwide.
- seasonal infections and also the recurring threat of influenza virus pandemics, there is an acute need to develop effective and lasting drugs.
- the seasonal occurrence of influenza causes between 5,000 and 20,000 deaths per year (source: Robert Koch Institute).
- WHO opportunistic infections
- the recurring big influenza pandemics however, present the greatest threat.
- the first great pandemic, the so-called "Spanish Flu" cost 40 million lives in the years 1918-1920, including a high percentage of healthy, middle-aged people.
- pandemic A similarly devastating pandemic could still be initiated by the recently arisen avian H5N1 influenza virus, if acquired mutations enable the virus to be transmitted from human-to-human. With mortality rates of approximately 60%, the H5N1 virus represents an unprecedented risk to human health. While the threat of a H5N1 pandemic still exists, the world is currently in the throes of yet another novel influenza strain, the pandemic (H1 N1 ) 2009 virus. Although highly transmissible, the H1 N1 virus appears, currently, to be less hazardous, as mortality rates are still low (less than -1 %) and comparable to seasonal epidemics. However, uncertainty exists about a possible acquisition of increased pathogenicity during its unavoidable adaptation process.
- influenza viruses consists of eight genome segments that can be quickly re-assorted upon viral co-infections, a process called antigenic shift. If such viral recombinants are derived from animal reservoirs they may exhibit surface antigens that are unknown to the human immune system.
- virus replication supports the generation of point mutations, giving rise to a steady 'antigenic drift' and viral escape.
- These two mechanisms of influenza virus variation necessitate the generation of new anti-influenza vaccines every yearly season.
- vaccine development is inherently afflicted with uncertainty about the emerging strain because the viral antigen has to be decided upon months before the virus is established in the human population.
- pandemic threat as the new virus has to be isolated and amplified prior to vaccine generation, a lag time of several months is unavoidable. Since pandemic strains have the potential to spread rapidly across the globe, vaccination strategies necessitate the concurrent development and availability of effective complementary options to treat already infected individuals.
- Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both gender. Localized tumors may be curable with surgery, but those that have spread widely are usually not curable. Therefore, there is a need for more effective treatment regimes for advanced and metastatic disease. Besides cytotoxic chemotherapy patients may take advantage of so far limited targeted therapies (e. g. anti-EGFR therapy).
- targeted therapies e. g. anti-EGFR therapy.
- Benzopyrrolidone derivatives are well known kinase inhibitors (e.g. VEGFR, FGFR, PDGFR, c-KIT, FLT3, Met, Src and Aurora B).
- VEGFR kinase inhibitor
- FGFR FGFR
- PDGFR phospholipase inhibitor
- c-KIT FLT3, Met, Src and Aurora B
- FLT3 Met, Src and Aurora B
- Benzopyrrolidone derivatives like sunitinib, nintedanib and toceranib have already been used as anticancer and anti-angiogenic agents.
- the present invention relates to benzopyrrolidone derivatives of the general formula (I) for use in the treatment of infectious diseases, preferably in the treatment of viral infection such as influenza infection.
- y is an integer number selected from: 0, 1 , and 2;
- z is an integer number selected from: 0, 1 , and 2;
- Q 1 represents: -H or -CH 3 ;
- Q 2 represents: -H, -CH 3 or -CH 2 CH 3 ;
- Q 3 and Q 4 are independently of each other selected from
- R' and R" are independently of each other selected from
- R'" represents: -H or -CH 3 ;
- A represents -NH-, -O- or -S-;
- R 14 represents: -H, -F, -CI, - -I, -OH or -OCH 3 ;
- k and I are integer numbers and independently of each other selected from: 0, 1 2, 3, 4 and 5;
- n, and q are integer numbers and independently of each other selected from: 1 2, 3, 4 and 5;
- p is an integer number selected from: 0 and 1 and stereoisomeric forms, E/Z isomers, enantiomers, mixtures of enantiomers, anomers, deoxyforms, diastereomers, mixtures of diastereomers, prodrugs, tautomers, hydrates, solvates and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof, for the use in the treatment of infectious diseases and cancer.
- the term 'prodrug' describes a precursor of the active ingredient containing a compound according to general formula (I) and further comprises groups which can be cleaved under physiological conditions or releases a compound according to general formula (I) under physiological conditions.
- tautomer' is defined as an organic compound that is interconvertible by a chemical reaction called tautomerization. Tautomerization can be catalyzed preferably by bases or acids or other suitable compounds.
- the compounds of general formula (I) are basic and form salts with various organic and inorganic acids.
- suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p- aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluen
- the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
- a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
- the free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.
- a preferred embodiment of this invention is directed to compounds of general formula (II)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (III)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (IV)
- the amide moiety preferably is bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (V)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (VI)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (VII)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (VIII)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (IX)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XI)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XIV)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XV)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XVI)
- a preferred embodiment of this invention is directed to compounds of general formula (XVII)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XIX)
- the amide moiety is preferably bound at the 5-position of the indol backbone. 5
- a preferred embodiment of this invention is directed to compounds of general formula (XXI)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XXII)
- the amide moiety is preferably preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XXIII)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XXV)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- a preferred embodiment of this invention is directed to compounds of general formula (XXVII)
- the amide moiety is preferably bound at the 5-position of the indol backbone.
- Another preferred embodiment of the present invention relates to compounds of the general formulas (VII)-(XVI), (XIX) and (XXVII), wherein R 1 represents: — CH2CH3,— CH(CH3)2,
- R' and R" are independently of each other selected from: -H, -F, -CH 3 and -OCH 3 ; R'" represents: -CH 3 ; A represents: -O- or -S-.
- a preferred embodiment refers to inventive compounds of general formulas (l)-(lll), (V), (VI), (IX), (XII)-(XVII), (XIX), (XXI), and (XXVII), wherein R 2 represents: -H or -COCH 3 .
- a preferred embodiment according to the invention comprises compounds of general formulas (l)-(XXV), wherein
- R represents:
- R 4 represents: -R 12 , -NH 2 , -N(CH 3 ) 2 ,
- R 5 represents: -R 6 ,
- R 13 represents: -OH , -CI, or
- R 10 has the meanings as disclosed herein and preferably R 10 represents hydrogen
- k, m and n have the meanings as disclosed herein;
- p is an integer number selected from: 0 and 1 .
- a further preferred embodiment according to the invention refers to the compounds of the general formulas (l)-(XXVII), wherein Q 3 is in para-position and Q 4 in meta-position of the benzene ring.
- Q 3 represents: -H and Q 4 is selected from: -H, -F, -CI, -CH 3, or Q 4 represents: -H and Q 3 is selected from: -H, -F, -CI, or -CH 3 .
- a preferred embodiment of this invention is directed to compounds of general ffoorrmmuullaass (()XII), (XIV), (XV), and (XIX)-(XVII), wherein Q 2 is selected from: -CH 3 and -C2H5.
- a preferred embodiment refers to inventive compounds of general formulas (I), (lll)-(VI), (VII)-(XIII), (XV), (XVIII), (XX), and (XXI), wherein z represents 0.
- a preferred embodiment of the invention comprises the compounds according to the general formula (I) as depicted in the following Table 1
- inventive compounds (I) according to the present invention can be prepared by methods known to one skilled in the art.
- the synthesis is preferably carried out according to the general synthetic routes, shown in scheme 1.
- Suitable amines are: (1 R)-1 -(4-chlorophenyl)ethanamine, (1 R)-1 -phenylpropan-1 - amine, (1 R)-1 - phenylethanamine, (1 S)-1 -phenylethanamine, (1 R)-1 -(4- methoxyphenyl)-ethanamine, (1 R)-1 -(3-methoxyphenyl)-ethanamine, (1 R)-1 - cyclohexylethanamine (1 R)-1 -(3-chlorophenyl)-ethanamine, (1 R)-1 -(2- naphthyl)ethanamine, (1 S)-indan-1 -amine, (1 R)-indan-1 -amine, (1 R)-/V-methyl-1 - phenylethanamine, (1 R)-1 -(4-methylphenyl)-ethanamine, (1 S)-1 -(4-methylphenyl)- ethanamine, (1 R)-1 -(4-ch
- Amide bond formation involves activation of the carboxylic group, followed by nucleophile attack of the amino group.
- Activation of the carboxylic acid includes conversion of the carboxylic acid to the corresponding active ester, carboxyl chloride or bromide, or anhydride.
- the activation of the carboxylic acid performed in situ by treatment of the mixture of carboxylic acid and amine with an activating agent.
- Activating agents include carbodiimides such as DCC ( ⁇ /, ⁇ /'-dicyclohexylcarbodiimide), DIC ( ⁇ /, ⁇ / ' -diisopropylcarbodiimide) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), phosphonium salts such as BOP (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, PyBOP
- Amide bond formation is conducted preferably in presence of a base, such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine.
- a base such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine.
- TEA triethylamine
- DIPEA diisopropylethyl amine
- Compound 5 * can be made from 3 * with commercially available trimethoxymethyl or triethoxymethyl derivatives 4 * , such as (trimethoxymethyl)benzene, (triethoxymethyl)benzene, 2-(trimethoxymethyl)pyridine,
- THF tetrahydrofurane
- dioxane dioxane
- DMF dimethylformamide
- MeOH methanol
- EtOH ethanol
- propanol iso
- anilines and amines are: 4- [(dimethylamino)methyl]aniline, 3-[(dimethylamino)methyl]aniline, 4- [(diethylamino)methyl]aniline, 3-[(diethylamino)methyl]aniline, 4-(piperidin-1 - ylmethyl)aniline, 3-(piperidin-1 -ylmethyl)aniline, 2-(piperidin-1 -ylmethyl)aniline, 4- (pyrrolidin-1 -ylmethyl)aniline, 3-(pyrrolidin-1 -ylmethyl)aniline, 2-(pyrrolidin-1 - ylmethyl)aniline, 4-[(4-methylpiperazin-1 -yl)methyl]aniline, 3-[(4-methylpiperazin-1 - yl)methyl]aniline, 2-[(4-methylpiperazin-1 -yl)methyl]aniline, 2-[4-(3- aminobenzyl)piperazin-1 -yl]ethanol, 2-[4-[(4
- reaction a * and b * during the synthesis of 5 * is reversible, as shown in scheme 1 . If one would chose the other synthetic route, than one should react 1 * (oxindole carboxylic acid or oxindole carboxylic acid ester) with 4 * in reaction b * first, gaining compound 6 * . Reacting the vinyl ether 6 * with anilines and amines in the presence of DMF, MeOH, EtOH, DMSO (dimethyl sulfoxid), or in their appropriate mixtures, via reaction c * gives 5B.
- inventive compounds (I) according to the present invention can also (but not limited to) be prepared according to the general synthetic routes, shown in Scheme 2.
- compound 12a,b* can be prepared from 10* and 11* reacted with commercially avaible acyl-derivatives, especially acyl-chlorides: isonicotinoyl chloride, nicotinoyl chloride, thiophene-3-carbonyl chloride, thiophene-2-carbonyl chloride, 1 -methyl-1 H-pyrazole-4-carbonyl chloride, 1 -methyl-1 H-indole-5-carbonyl chloride, 3-furoyl chloride, 2-furoyl chloride, cyclohexanecarbonyl chloride, cyclopropanecarbonyl chloride, propanoyl chloride, 2-methylpropanoyl chloride, etc. in the presence of N,N-dimethylpyridin-4-amine and TEA or DIEA in any aprotic solvents, especially dichloromethane, chloroform or dichororoethane
- Compounds 12b* were obtained via procedure B2, where 2 molequivalent activated acyl-derivatives are needed for simultenously protection of acyl NH.
- Compound 13A* and 13B* can be obtained by activation of vinyl-OH and reacted by amines (N-C bond formation) in procedure c*.
- Amide bond formation involves activation of the hydroxy group by known methods via silylation, especially chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, via mesylation by methanesulfonyl chloride or activation by trifluoromethanesulfonic anhydride in any aprotic solvent like dioxane, tetrahydrofurane.
- N-acyl groups were cleaved from the oxindole NH, giving the desired 14* compounds.
- N-acyl type protecting groups must be cleaved under acidic (especially aqueous HCI) or basic (especially aqueous LiOH, NaOH, or KOH) conditions (procedure D)
- procedure E the activation of the carboxylic acid performed in situ by treatment of the mixture of the amine and compound 14* with an activating agents, such as DCC ( ⁇ /, ⁇ /'-dicyclohexylcarbodiimide), DIC ( ⁇ /, ⁇ / ' -diisopropylcarbodiimide) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), phosphonium salts such as BOP (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, PyBOP
- an activating agents such as DCC ( ⁇ /, ⁇ /'-dicyclohexylcarbodiimide), DIC ( ⁇ /, ⁇ / ' -diisopropylcarbodiimide) and EDCI (N-(3-dimethylaminopropyl)-N'-ethy
- Amide bond formation is conducted preferably in presence of a base, such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine.
- a base such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine.
- TEA triethylamine
- DIPEA diisopropylethyl amine
- acylation agents especially acetic-anhydride
- the present invention refers further to use of the compounds according to the general formula (I) are in the manufacture of a medicament for the treatment of infectios diseases.
- Another aspect of the present invention relates to a method comprising administering to a patient suffering from an infectious disease a therapeutically effective amount of at least one compound according to general formula (I) as defined herein in order to treat that infectious disease.
- infectious diseases comprises selected from the group comprising or consisting of virally induced infectious diseases, bacterially induced infectious diseases, and parasitic induced infectious diseases. Within the present invention it is preferred that the infectious diseases are virally induced infectious diseases, including opportunistic diseases.
- a preferred embodiment of the present invention refers to the compounds of general formula I for use in the treatment of virally induced infectious diseases, including opportunistic diseases, being infections with dsDNA viruses, ssDNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, or dsDNA-RT viruses.
- the infection with (-)ssRNA viruses are an infection with Orthomyxoviridae, Bornaviridae, Filoviridae, Paramyxoviridae, or Rhabdoviridae.
- Another aspect of the present invention refers to the compounds of general formula I for use in the treatment of an infection with Orthomyxoviridae selected from the group comprising or consisting of an infection with Influenza virus A, 5
- Influenza virus B or Influenza virus C.
- compounds of general formula I for use in the treatment of an infection with Influenza virus A.
- opportunistic diseases refers to infections caused by pathogens, particularly opportunistic pathogens that usually do not cause disease or symptoms in a healthy host, one with a healthy immune system but in a host with a damaged or weakened immune system. This is because a healthy immune system is able to successfully fight off the disease, or keep it under control.
- opportunistic diseases are caused by an infection with aspergillus sp., Candida albicans, cytomegalovirus, polyomavirus, kaposi's sarcoma caused by human herpesvirus 8 (HHV8), pseudomonas aeruginosa, staphylococcus aureus, streptococcus pneumonia and toxoplasma gondii.
- aspergillus sp. Candida albicans
- cytomegalovirus cytomegalovirus
- polyomavirus polyomavirus
- kaposi's sarcoma caused by human herpesvirus 8 (HHV8)
- pseudomonas aeruginosa pseudomonas aeruginosa
- staphylococcus aureus streptococcus pneumonia
- streptococcus pneumonia streptococcus pneumonia
- toxoplasma gondii toxoplasma gondii.
- cancer is selected from the group consisting of adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumour, bladder cancer, bronchial carcinoma, non-small cell lung cancer, breast cancer, Burkitt's lymphoma, corpus cancer, colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic ne
- cancer is selected from the group consisting of adenocarcinoma, choroidal melanom
- compositions comprising at least one compound according to general formula (I) as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents.
- the pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
- the preferred preparations are adapted for oral application or for injection.
- These administration forms include, for example, liquids, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits.
- the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound as described herein and/or a pharmaceutical acceptable salt thereof as active ingredient.
- compositions according to the present invention containing at least one compound as described in the present invention, especially one pure optical isomer, and/or a pharmaceutically acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices.
- suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices.
- suitable formulations are gels, elixirs, dispersable granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like.
- Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components 7 and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
- excipient and/or diluents can be used carriers such as preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).
- an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).
- Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate.
- Suitable lubricants are selected from the group comprising boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
- Disintegrating agents such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures may be added.
- disintegrating agents such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium
- coloring agents are coloring agents, sweetening agents, flavoring agents, preservatives, glidents such as silicon dioxide and talc, and adsorbent such as clay, aluminum oxide.
- Suitable diluents are water or water/propylene glycol solutions for parenteral injections, juice, sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
- Compounds of general formula (I) may be administered as the sole active agent or in combination with one or more additional therapeutic agents, wherein the combination causes no unacceptable adverse effects.
- a compound of general formula (I) and an active agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate dosage formulations.
- the compound of general formula (I) and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).
- the compounds of the present invention may be used in fixed or separate combination with other anti-viral agents such as interferons, acyclovir, neuraminidase inhibitors (oseltamivir and zanamivir) and M2 protein inhibitors (rimantadine).
- another aspect of the present invention relates to drug combinations comprising at least one compound according to general formula (I) and/or pharmaceutically acceptable salts thereof together with at least one additional antiviral agent, especially at least one of the active agents mentioned above. Description of the figures:
- Figure 1 shows an overview of the virus screening process to identify chemical compounds that inhibit influenza virus replication
- TMS 0 ppm
- the chemical shifts are expressed in ppm using the residual solvent as internal standard.
- Splitting patterns are designated as s (singlet), d (doublet), dd (double-doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), and bs (broad singlet).
- Electrospray MS spectra were obtained on a Waters LC-MS system Acquity SQD detector, Waters 2795 Alliance HPLC equipped with Waters 996 PDA Detector (HPLC column: Waters XBridge, RP C18, 3.5 ⁇ , 4.6 mm x 50 mm; gradient MeCN/H2O, containing 0.1 % HCOOH: 5% MeCN (0.5 min), 5% to 95% MeCN (5 min), 95% MeCN (0.5 min); flow rate: 2.0 ml/min.
- Step A (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline-5-carboxylic acid
- step A (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid
- Step B (3Z)-2-oxo-3-(phenyl ⁇ [3-(piperidin-1 -ylmethyl)phenyl]amino ⁇ methylene) indoline-5-carboxylic acid
- step B The following compounds were obtained according to the procedure described by example 1 , step B:
- Step C (3Z)-2-oxo-3-(phenyl ⁇ [3-(piperidin-1 -ylmethyl)phenyl]amino ⁇ methylene)- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
- step C The following compounds were obtained according to the procedure described by example 1 , step C:
- reaction mixture was poured into 30 ml 10 % Na 2 CO3 and extracted with 3x60 ml ethyl-acetate. The organic layer was separated and dried over MgSO 4 . The dessicant was filtered off and the solvent was removed under reduced pressure to give methyl-(3Z)-3-[( ⁇ 4-[(4-methylpiperazin-1 -yl)methyl]phenyl ⁇ amino)(pyridin-4- yl)methylene]-2-oxoindoline-5-carboxylate as dark brown oil. This product was used in the next step without purification.
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Abstract
The present invention relates to benzopyrrolidone derivatives and/or pharmaceutically acceptable salts thereof for the use in the treatment of infectious diseases or cancer, and pharmaceutical compositions containing at least one of said benzopyrrolidone derivatives and/or pharmaceutically acceptable salts thereof for the use in the treatment of infectious diseases or cancer.
Description
BENZOPYRROLIDONE DERIVATIVES POSSESSING ANTIVIRAL AND
ANTICANCER PROPERTIES
Specification
The present invention relates to benzopyrrolidone derivatives and/or pharmaceutically acceptable salts thereof for use in the treatment of infection diseases, and pharmaceutical composition containing at least one of the said benzopyrrolidone derivatives and/or pharmaceutically acceptable salt thereof.
Background of the invention
Medical need for novel innovative drugs for influenza treatment
Despite vaccination and currently available antiviral drugs, influenza infections still make a huge impact on human health worldwide. In light of the risk posed by seasonal infections and also the recurring threat of influenza virus pandemics, there is an acute need to develop effective and lasting drugs. In Germany alone, the seasonal occurrence of influenza causes between 5,000 and 20,000 deaths per year (source: Robert Koch Institute). Worldwide, up to 500,000 humans die annually due to seasonal influenza or accompanying opportunistic infections (source: WHO). The recurring big influenza pandemics, however, present the greatest threat. The first great pandemic, the so-called "Spanish Flu", cost 40 million lives in the years 1918-1920, including a high percentage of healthy, middle-aged people. A similarly devastating pandemic could still be initiated by the recently arisen avian H5N1 influenza virus, if acquired mutations enable the virus to be transmitted from human-to-human. With mortality rates of approximately 60%, the H5N1 virus represents an unprecedented risk to human health. While the threat of a H5N1 pandemic still exists, the world is currently in the throes of yet another novel influenza strain, the pandemic (H1 N1 ) 2009 virus. Although highly transmissible, the H1 N1 virus appears, currently, to be less hazardous, as mortality rates are still low (less than -1 %) and comparable to seasonal epidemics. However, uncertainty exists about a possible acquisition of increased pathogenicity during its unavoidable adaptation process. Historical data from 1918 are giving special cause for concern: the first infections with the H1 N1 "Spanish Flu" virus in March 1918 led to relatively mild symptoms compared to the deadly second wave of infections that spread worldwide several months later.
The current panel of preventive and therapeutic measures against influenza virus infections rests on (i) active vaccination and (ii) the use of conventional anti-viral drugs. Both strategies have their intrinsic limitations owing to the high variability of influenza viruses. The genome of influenza viruses consists of eight genome segments that can be quickly re-assorted upon viral co-infections, a process called antigenic shift. If such viral recombinants are derived from animal reservoirs they may exhibit surface antigens that are unknown to the human immune system. Moreover, virus replication supports the generation of point mutations, giving rise to a steady 'antigenic drift' and viral escape. These two mechanisms of influenza virus variation necessitate the generation of new anti-influenza vaccines every yearly season. However, vaccine development is inherently afflicted with uncertainty about the emerging strain because the viral antigen has to be decided upon months before the virus is established in the human population. Similarly, in the case of a pandemic threat, as the new virus has to be isolated and amplified prior to vaccine generation, a lag time of several months is unavoidable. Since pandemic strains have the potential to spread rapidly across the globe, vaccination strategies necessitate the concurrent development and availability of effective complementary options to treat already infected individuals.
The fact that treatment (and immediate prophylaxis) of influenza virus infections is hampered by the occurrence of viral escape mutants is not just theoretical, but has been impressively demonstrated with the growing emergence of, e.g. Tamiflu®, resistant virus mutants of seasonal influenza strains as well as the new H5N1 and H1 N1 strains. Considering that, in the case of a severe pandemic threat, these conventional drugs would be given to millions of people; a global manifestation of drug resistance will be likely.
Existing anti-viral drugs are typically directed against bona fide viral targets, so- called direct antiviral targets, bearing the usual risk of generating therapeutic resistance. However, a largely ignored fact is that viral infection and replication intimately depend on the cellular factors provided by the host. Blocking human functions to prevent infection may appear - at a first glance - counter-intuitive. However, this very approach is taken on a regular and sometimes long-lasting basis to successfully treat thousands of other human diseases. Application of this widely used approach should thus also be feasible to treat viral infection, but this approach has not been systematically developed.
Recently, suitable human genes have been identified in the process of a genome- wide RNAi screen for human factors essential for influenza virus replication in vitro (Karlas et al., Nature, 2010). This high-throughput analysis revealed hundreds of human factors involved in the replication of the influenza virus. Subsequent
validation yielded a panel of targets including many kinases (e.g. Clk1 , Akt1 and Ack1 ; Karlas et al., Nature, 2010)) that fulfilled crucial in vitro requirements with respect to safety (no toxicity of RNAi knock-down) and efficacy (substantially diminished viral replication). These validated host cell targets were the basis for the subsequent drug discovery project.
Anticancer application
Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both gender. Localized tumors may be curable with surgery, but those that have spread widely are usually not curable. Therefore, there is a need for more effective treatment regimes for advanced and metastatic disease. Besides cytotoxic chemotherapy patients may take advantage of so far limited targeted therapies (e. g. anti-EGFR therapy).
Many kinases have been found to be involved in the processes leading to tumor cell proliferation and survival. Benzopyrrolidone derivatives are well known kinase inhibitors (e.g. VEGFR, FGFR, PDGFR, c-KIT, FLT3, Met, Src and Aurora B). Several indolin-2-ones have been under preclinical or clinical study for cancer treatment. Benzopyrrolidone derivatives like sunitinib, nintedanib and toceranib have already been used as anticancer and anti-angiogenic agents.
Brief description of the invention
It is object of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof, which can be used as pharmaceutically active agents, especially for treatment of infection diseases, as well as compositions comprising at least one of these compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.
This object is solved by providing compounds and/or their pharmaceutically acceptable salts according to the general formula (I) for use in the treatment of infectious diseases and pharmaceutical compositions comprising at least one of said compounds. Therefore the present invention relates to benzopyrrolidone derivatives of the general formula (I) for use in the treatment of infectious diseases, preferably in the treatment of viral infection such as influenza infection.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
Description of the invention
Thus, the present invention relates to compounds of general formula (I)
wherein,
y is an integer number selected from: 0, 1 , and 2;
z is an integer number selected from: 0, 1 , and 2;
Q1 represents: -H or -CH3;
Q2 represents: -H, -CH3 or -CH2CH3;
Q3 and Q4 are independently of each other selected from
-OCH3;
1 represents: -CH2CH3, -CH(CH3)2,
R' and R" are independently of each other selected from
-OCH3;
R'" represents: -H or -CH3;
A represents -NH-, -O- or -S-;
R2 represents: -H, -CH3 or -C(=O)CH3;
R6, R7; R8, R9 and R10 are independently of each other selected form : -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3-(CH2)n-CH3, -(CH2)n-C(CH3)2, -CH[(CH2)nCH3]-(CH2)m-CH3) -CH[(CH2)nCH3]-(CH2)m-C(CH3)2, -CH=CH2, -(CH2)n-CH=CH-(CH2)k-CH3, -CH≡CH, -(CH2)n-C≡C-(CH2)k-CH3, -Ph, -(CH2)n-Ph, _(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-O-(CH2)k-CH3,
(CH2)n-NH(CH2)k-CH3, -(CH2)n-N(CH3)2, -(CH2)n-N(C2H5)2
R11 represents: = =C(CH3)2,
R14 represents: -H, -F, -CI, - -I, -OH or -OCH3;
k and I are integer numbers and independently of each other selected from: 0, 1 2, 3, 4 and 5;
m, n, and q are integer numbers and independently of each other selected from: 1 2, 3, 4 and 5;
p is an integer number selected from: 0 and 1 and stereoisomeric forms, E/Z isomers, enantiomers, mixtures of enantiomers, anomers, deoxyforms, diastereomers, mixtures of diastereomers, prodrugs, tautomers, hydrates, solvates and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof, for the use in the treatment of infectious diseases and cancer.
The term 'prodrug' describes a precursor of the active ingredient containing a compound according to general formula (I) and further comprises groups which can be cleaved under physiological conditions or releases a compound according to general formula (I) under physiological conditions.
The expression 'tautomer' is defined as an organic compound that is interconvertible by a chemical reaction called tautomerization. Tautomerization can be catalyzed preferably by bases or acids or other suitable compounds.
Compound according to claim 1 , wherein z represents 0 and Q1 is: -H.
The compounds of general formula (I) are basic and form salts with various organic and inorganic acids. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p- aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, tartronic acid, a-toluic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, amino acids such as glycone, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophane, lysine, arginine, histidine, asparaginic acid, glutamic acid, asparagines, glutamine, cysteine, methionine, proline, 4-hydroxyproline, Ν,Ν,Ν-trimethyllysine, 3-methylhistidine, 5- hydroxylysine, O-phosphoserine, g-carboxyglutamate, e-N-acetyllysine, w-N- methylarginine, citrulline and ornithine, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.
A preferred embodiment of this invention is directed to compounds of general formula (II)
(II)
wherein the residues R2, R3, Q1 - Q4, and y have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (III)
wherein the residues R2, R3, Q1 - Q4, y and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (IV)
A preferred embodiment of this invention is directed to compounds of general formula (V)
wherein the residues R2, R3, Q2 - Q4, y and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (VI)
wherein the residues R2, R3, Q1 - Q4, and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (VII)
(VII)
wherein the residues R1, R3, Q1 - Q4, and y have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (VIII)
A preferred embodiment of this invention is directed to compounds of general formula (IX)
(IX)
wherein the residues R1, R3, Q2 - Q4, y and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (X)
wherein the residues R1, R3, Q1 - Q4, and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XI)
(XI)
wherein the residues R1, R3, Q2 - Q4, and y have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone. A preferred embodiment of this invention is directed to compounds of general formula (XII)
A preferred embodiment of this invention is directed to compounds of general formula (XIV)
A preferred embodiment of this invention is directed to compounds of general formula (XV)
(XV)
wherein the residues R1 - R3, Q1 - Q4, and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XVI)
(XVI)
wherein the residues R1 - R3, and Q1 - Q4 have the meanings as defined herein The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XVII)
wherein the residues R2, R3 and Q1 - Q4 have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XVIII)
(XVIII)
wherein the residues R3, Q1 - Q4, and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XIX)
(XIX)
wherein the residues R1 - R3 and Q1 - Q4 have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone. A preferred embodiment of this invention is directed to compounds of general formula (XX)
(XX)
wherein the residues R3, Q1 - Q4, y and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
5
A preferred embodiment of this invention is directed to compounds of general formula (XXI)
(XXI)
wherein the residues R2, R3, Q1 - Q4, and z have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XXII)
(XXII)
wherein the residues R3, Q1 - Q4, and y have the meanings as defined herein. The amide moiety is preferably preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XXIII)
(XXIII)
wherein the residues R2, R3 and Q2 - Q4 have the meanings as defined herein. The amide moiety is preferably preferably bound at the 5-position of the indol backbone. A preferred embodiment of this invention is directed to compounds of general formula (XXIV)
(XXIV)
wherein the residues R3 and Q1 - Q4 have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XXV)
(XXV)
wherein the residues R3 and Q2 - Q4 have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone. A preferred embodiment of this invention is directed to compounds of general formula (XXVI)
7
(XXVI)
wherein the residues R4, Q2 - Q4, and p have the meanings as defined herein. The amide moiety is preferably bound at the 5-position of the indol backbone.
A preferred embodiment of this invention is directed to compounds of general formula (XXVII)
The amide moiety is preferably bound at the 5-position of the indol backbone.
Another preferred embodiment of the present invention relates to compounds of the general formulas (VII)-(XVI), (XIX) and (XXVII), wherein R1 represents: — CH2CH3,— CH(CH3)2,
wherein R' and R" are independently of each other selected from: -H, -F, -CH3 and -OCH3; R'" represents: -CH3; A represents: -O- or -S-.
Furthermore, a preferred embodiment refers to inventive compounds of general formulas (l)-(lll), (V), (VI), (IX), (XII)-(XVII), (XIX), (XXI), and (XXVII), wherein R2 represents: -H or -COCH3.
Moreover, a preferred embodiment according to the invention comprises compounds of general formulas (l)-(XXV), wherein
R represents:
R4 represents: -R12, -NH2, -N(CH3)2,
X represents: =O, =S;
R5 represents: -R6,
R13 represents: -OH , -CI,
or
R10 has the meanings as disclosed herein and preferably R10 represents hydrogen;
k, m and n have the meanings as disclosed herein; and
p is an integer number selected from: 0 and 1 . A further preferred embodiment according to the invention refers to the compounds of the general formulas (l)-(XXVII), wherein Q3 is in para-position and Q4 in meta-position of the benzene ring. Q3 represents: -H and Q4 is selected from: -H, -F, -CI, -CH3, or Q4 represents: -H and Q3 is selected from: -H, -F, -CI, or -CH3.
A preferred embodiment of this invention is directed to compounds of general ffoorrmmuullaass (()XII), (XIV), (XV), and (XIX)-(XVII), wherein Q2 is selected from: -CH3 and -C2H5.
Furthermore, a preferred embodiment refers to inventive compounds of general formulas (I), (lll)-(VI), (VII)-(XIII), (XV), (XVIII), (XX), and (XXI), wherein z represents 0. A preferred embodiment of the invention comprises the compounds according to the general formula (I) as depicted in the following Table 1
Table 1 :
No. Compound
(3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino} methylene)- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 -
13
ylmethyl)phenyl] amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V- 14
[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 -
15
ylmethyl) phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 -
16
ylmethyl )phenyl]amino} methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - 17
ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V- 18
[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-/V-methyl-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 - 19
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-benzyl-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino} 20
methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - 21
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - 22
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - 23
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - 24
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 - 25
ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - 26
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - 27
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Ζ)-Λ/-[(1 S)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-W^
[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenylethyl]indoline-5-carboxannide
(3Z)-/V-(3,4-dinnethoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-(3-methoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino} methylene)indoline-6-carboxannide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene
[(1 R)-1 -phenylpropyl]indoline-6-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-(3-methoxybenzyl)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}annino)
(phenyl)methylene]-2-oxoindoline-5-carboxannide
(3Z)-/V-(3,4-dimethoxybenzyl)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl} amino)(phenyl)nnethylene]-2-oxoindoline-5-carboxannid (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4-
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-/V-benzyl-3-[({4-[(4-methylpiperazin-1 -
136 yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxamide
(3Z)-/V-(4-fluorobenzyl)-3-[({4-[(4-nnethylpiperazin-1 -
137 yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-
138
yl)methylene]-2-oxo-A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- 139
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 140
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 141
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 142
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylen 143
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({4-[(diethylamino)methyl]phe^
144
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 145
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]am
146
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-^ 147
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- 148
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- 149
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 150
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 151
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 152
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 153
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 154
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 155
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 - 156
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 -
157
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 158
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 159
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4- 160
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 161
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 162
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 163
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 164
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylen 165
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylen 166
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2- 167
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2- 168
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - 169
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - 170
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(pyrrolidin-1 - 171
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(pyrrolidin-1 - 172
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 173
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 174
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2- 175
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methyl^
176
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 177
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 178
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Ζ)-2-οχο-Λ/-[(1 R)-1 -phenylethyl]-3-[{[3-(pyrrolidin-1 -
179
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(pyrrolidin-1 - 180
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 181
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 182
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 183
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 184
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amm^
185
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amm^
186
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(3-fur7l{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- 187
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(3-fur7l{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-W^
188
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(2-furYl{[4-(piperidin-1 -ylmethyl)ph
189
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 -
190 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 -
191 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 -
192 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 -ylmethyl)phenyl]-
193
amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 -
194 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 -
195 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 -
196 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 -
197 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
5
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -ylmethyl)phenyl]- amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene) indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene)indoline-5-carboxamide
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]-
217
2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 218
A/-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]^ 219
A/-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - 220
ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - 221
ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 222
A/-[(1 R)-1 -(4-methylphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-/V-[1 -(3,4-difluorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - 223
ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[1 -(3-chlorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - 224
ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[({2-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2- 225
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-{[(2-{[(ethylamino)carbonothioyl]amino}phenyl)amino]
226
(phenyl)methylene}-2-oxoindoline-5-carboxannide
(3Z)-3-{[(2-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl) 227
methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl) 228
methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(4-
229 hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[2-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(phenyl)methylene]-
230
2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({2-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - 231 yl]phenyl}amino)(phenyl)nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[({3-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-
232
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(3-
233 chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(3-
234 {[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)methylene}-2- oxo-A/-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(4-
235 hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[3-({[4-(2,5-dioxoimidazolidin-1 -
236 yl)phenyl]carbamoyl}annino)phenyl]annino}
(phenyl)methylene]-2-oxo-/V-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
7
(3Z)-3-[({3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-3-ylmethylene)imidazolidin-1 ^ yl]phenyl}carbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-oxo-/V- [(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(4- {[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)methylene}-2- oxo-/V-[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(4-{[(3- chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(4-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl) methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(pyridin-4- yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4Z)-4-benzylidene-2,5-dioxoimidazolidin-1 - yl]phenyl}amino)(pyridin-4-yl)nnethylene]-2-oxo-/\/-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(ethylamino)carbonothioyl]amino}benzyl)annino](3- thienyl)methylene}-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({2-[(1 ,3-benzodioxol-5- ylcarbamoyl)amino]benzyl}amino)(phenyl)methylene] -2-oxo-/V-[(1 R)-1 - phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({3-[(ethylcarbamoyl)amino]benzyl}amino)(pyridin-3-yl)methyle 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}benzyl)amino](pyridin-3- yl)methylene}-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[3-(2,5-dioxoimidazolidin-1 -yl)benzyl]amino}(pyridin-3- yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]benzyl}amino)(pyridin-3-yl)nnethylene]-2-oxo-/\/-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-[{[4-({[(3- chlorophenyl)amino]carbonothioyl}amino)benzyl]amino}
(phenyl)methylene]-2-oxoindoline-5-carboxannide
(3Z)-/V-benzyl-3-[{[4-(2,5-dioxoimidazolidin-1 - yl)benzyl]amino}(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)benzy^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-6-carboxamide
(3Z)-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]benzyl}amino)(phenyl)nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 6-carboxamide
(3Z)-/V-benzyl-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin- 1 -yl]benzyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide (3Z)-3-{[(2-{2- [(ethylcarbamoyl)amino]phenyl}ethyl)^
[(1 R)-1 -phenylpropyl]indoline-7-carboxamide
(3Z)-3-[{[2-(2-{[(3-
255 chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(pyridin-4- yl)methylene]-2-oxo-/V-[(1 S)-1 -phenylpropyl]indoline-7-carboxamide (3Z)-3-{[(2-{3-
256 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](pheny^
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(2-{3-
257 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](pheny^
[(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[2-(3-{[(3-
258 chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(phenyl)met^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-{[(2-{3-[(4Z)-2,5-dioxo-4-(pyridin-4-
259 ylmethylene)imidazolidin-1 -yl]phenyl}ethyl)amino](phenyl)me
oxoindoline-5-carboxamide
(3Z)-3-{[(2-{4-
260 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylen
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[2-(4-{[(3-chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}
261
(phenyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]in^
(3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 262
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 263
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-/V- 264
benzyl-2-oxoindoline-5-carboxamide
(3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 265
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 266
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 267
A/-[(1 R)-1 -phenylpropyl]indoline-6-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](pyridin-4-yl)methylene}-2- 268
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-6-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](3-thienyl)methylene}-/V- 269
benzyl-2-oxoindoline-6-carboxamide
and prodrugs, tautomers, hydrates, solvates of the above mentioned compounds and pharmaceutically acceptable salts thereof, for the use in the treatment of infectious diseases and cancer. Chemical synthesis
The inventive compounds (I) according to the present invention can be prepared by methods known to one skilled in the art. The synthesis is preferably carried out according to the general synthetic routes, shown in scheme 1.
Scheme 1 . Synthesis of the inventive compounds of general formula (I). The residues have the meanings as disclosed herein. Compound 3* can be synthesised from the commercially available carboxy- oxindoles 1 * and commercially available amines 2* via amide bond formation a*. Conveniently, many amines of general formula 2* are commercially available or can be easily prepared by a person skilled in the art following known synthetic procedures that are disclosed in patent or non-patent literature. Examples of suitable amines are: (1 R)-1 -(4-chlorophenyl)ethanamine, (1 R)-1 -phenylpropan-1 - amine, (1 R)-1 - phenylethanamine, (1 S)-1 -phenylethanamine, (1 R)-1 -(4- methoxyphenyl)-ethanamine, (1 R)-1 -(3-methoxyphenyl)-ethanamine, (1 R)-1 - cyclohexylethanamine (1 R)-1 -(3-chlorophenyl)-ethanamine, (1 R)-1 -(2- naphthyl)ethanamine, (1 S)-indan-1 -amine, (1 R)-indan-1 -amine, (1 R)-/V-methyl-1 - phenylethanamine, (1 R)-1 -(4-methylphenyl)-ethanamine, (1 S)-1 -(4-methylphenyl)- ethanamine, (1 R)-1 -(4-chlorophenyl)-ethanamine, (1 R)-1 -(3-bromophenyl)- ethanamine, (1 R)-1 -(3-chlorophenyl)propan-1 -amine, (1 R)-1 -(4- chlorophenyl)propan-1 -amine, (1 R)-1 -(3,4-difluorophenyl)propan-1 -amine, 1 -(4- methoxyphenyl)propan-1 -amine,, (1 R)-1 -(4-methoxyphenyl)propan-1 -amine, (1 R)- 1 -(4-methylphenyl)propan-1 -amine, (1 R)-1 -(3-methylphenyl)propan-1 -amine, (1 R)-1 -(3-methoxyphenyl)propan-1 -amine, etc.
Amide bond formation involves activation of the carboxylic group, followed by nucleophile attack of the amino group. Activation of the carboxylic acid includes
conversion of the carboxylic acid to the corresponding active ester, carboxyl chloride or bromide, or anhydride. For facility reasons, the activation of the carboxylic acid performed in situ by treatment of the mixture of carboxylic acid and amine with an activating agent. Activating agents include carbodiimides such as DCC (Λ/,Λ/'-dicyclohexylcarbodiimide), DIC (Λ/,Λ/'-diisopropylcarbodiimide) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), phosphonium salts such as BOP (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, PyBOP
(benzotriazol-l -yloxy)tripyrrolidinophosphonium 5 hexafluorophosphate, PyAOP ((7-azabenzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyCloP (chlorotripyrrolidinophosphonium hexafluorophosphate), DEPBT (3- (diethoxyphosphoryloxy)-l ,2,3-benzotriazin-4(3H)-one), uranium and guanidinium salts such as HBTU (0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), HATU (O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBPyU (O-(benzotriazol-1 -yl)-N,N,N',N'- bis(tetramethylene)uranium hexafluorophosphate), HCTU (O-(6- chlorobenzotriazol-1 -yl)-N,N,N',N'- 8 tetramethyluronium hexafluorophosphate). Amide bond formation is conducted preferably in presence of a base, such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine. Thus, the amide bond formation can be carried out using reagent systems such as HATU/DIPEA, HBTU/TEA or EDCI/HOBT/TEA.
Compound 5* can be made from 3* with commercially available trimethoxymethyl or triethoxymethyl derivatives 4*, such as (trimethoxymethyl)benzene, (triethoxymethyl)benzene, 2-(trimethoxymethyl)pyridine,
2- (triethoxymethyl)pyridine, 3-(trimethoxymethyl)pyridine,
3- triethoxymethyl)pyridine, 4-trimethoxymethyl)pyridine, 4-triethoxymethyl)pyridine, 2-(trimethoxymethyl)thiophene, 2-(triethoxymethyl)thiophene, 3-trimethoxymethyl)thiophene, 3-(triethoxymethyl)thiophene, by reacting them via an aldol reaction b* at reflux, in acetic anhydride or in the mixture of acetic anhydride and other appropriate solvent such as THF (tetrahydrofurane), dioxane, DMF (dimethylformamide), MeOH (methanol), EtOH (ethanol), propanol, iso- propanol, butanol, terf-BuOH, forming an α,β-unsaturated vinyl ether.
Reacting the vinyl ether 5* with anilines and amines, in the presence of DMF, MeOH, EtOH, DMSO (dimethyl sulfoxid), or in their appropriate mixtures, via reaction c* gives the inventive compounds (I).
Anilines and amines are commercially available or can be easily prepared by a person skilled in the art following known synthetic procedures that are disclosed in patent or non-patent literature. Some examples for the anilines and amines are: 4- [(dimethylamino)methyl]aniline, 3-[(dimethylamino)methyl]aniline, 4- [(diethylamino)methyl]aniline, 3-[(diethylamino)methyl]aniline, 4-(piperidin-1 - ylmethyl)aniline, 3-(piperidin-1 -ylmethyl)aniline, 2-(piperidin-1 -ylmethyl)aniline, 4- (pyrrolidin-1 -ylmethyl)aniline, 3-(pyrrolidin-1 -ylmethyl)aniline, 2-(pyrrolidin-1 - ylmethyl)aniline, 4-[(4-methylpiperazin-1 -yl)methyl]aniline, 3-[(4-methylpiperazin-1 - yl)methyl]aniline, 2-[(4-methylpiperazin-1 -yl)methyl]aniline, 2-[4-(3- aminobenzyl)piperazin-1 -yl]ethanol, 2-[4-(3-aminobenzyl)piperazin-1 -yl]ethanol, 2- [4-(4-aminobenzyl)piperazin-1 -yl]ethanol, 2-[4-(2-aminobenzyl)piperazin-1 - yl]ethanol, 4-(morpholin-4-ylmethyl)aniline, 3-(morpholin-4-ylmethyl)aniline, 2- (morpholin-4-ylmethyl)aniline, [1 -(4-aminobenzyl)piperidin-2-yl]methanol, [1 -(3- aminobenzyl)piperidin-2-yl]methanol, [1 -(2-aminobenzyl)piperidin-2-yl]methanol, 3- (thiomorpholin-4-ylmethyl)aniline, 2-(thiomorpholin-4-ylmethyl)aniline, 4- (thiomorpholin-4-ylmethyl)aniline, A/-(4-aminophenyl)-2-piperidin-1 -ylacetamide, N- (3-aminophenyl)-2-piperidin-1 -ylacetamide, A/-(2-aminophenyl)-2-piperidin-1 - ylacetamide, A/-(3-aminophenyl)-/V-methyl-2-piperidin-1 -ylacetamide, A/-(4- aminophenyl)-/V-methyl-2-piperidin-1 -ylacetamide, A/-(2-aminophenyl)-/V-methyl-2- piperidin-1 -ylacetamide, A/-(4-aminophenyl)-/V-methyl-2-(4-methylpiperazin-1 - yl)acetamide, A/-(3-aminophenyl)-/V-methyl-2-(4-methylpiperazin-1 -yl)acetamide, A/-(2-aminophenyl)-/V-methyl-2-(4-methylpiperazin-1 -yl)acetamide, A/-(3- aminophenyl)-2-[4-(2-hydroxyethyl)piperazin-1 -yl]-/V-methylacetamide, A/-(4- aminophenyl)-2-[4-(2-hydroxyethyl)piperazin-1 -yl]-/V-methylacetamide, A/-(3- aminophenyl)-/V-methyl-2-pyrrolidin-1 -ylacetamide, A/-(4-aminophenyl)-/V-methyl-2- pyrrolidin-1 -ylacetamide, A/-(4-aminophenyl)-2-pyrrolidin-1 -ylacetamide, etc.
1 -[2-(aminomethyl)phenyl]-3-ethylurea, 1 -[2-(aminomethyl)phenyl]-3-phenylurea, 1 -[2-(aminomethyl)phenyl]-3-(3-chlorophenyl)urea, 1 -[2-(aminomethyl)phenyl]-3- (4-hydroxyphenyl)urea, 1 -[3-(aminomethyl)phenyl]-3-ethylurea, 1 -[3- (aminomethyl)phenyl]-3-phenylurea, 1 -[3-(aminomethyl)phenyl]-3-(3- chlorophenyl)urea, 1 -[3-(aminomethyl)phenyl]-3-(4-hydroxyphenyl)urea, 1 -[3- (aminomethyl)phenyl]-3-(1 ,3-benzodioxol-5-yl)urea, 1 -[4-(aminomethyl)phenyl]-3- ethylurea, 1 -[4-(aminomethyl)phenyl]-3-phenylurea, 1 -[4-(aminomethyl)phenyl]-3- (3-chlorophenyl)urea, 1 -[4-(aminomethyl)phenyl]-3-(4-hydroxyphenyl)urea, 1 -[2-(2- aminoethyl)phenyl]-3-ethylurea, 1 -[2-(2-aminoethyl)phenyl]-3-phenylurea, 1 -[2-(2- aminoethyl)phenyl]-3-(3-chlorophenyl)urea, 1 -[2-(2-aminoethyl)phenyl]-3-(4- hydroxyphenyl)urea, 1 -[3-(2-aminoethyl)phenyl]-3-ethylurea, 1 -[3-(2- aminoethyl)phenyl]-3-phenylurea, 1 -[3-(2-aminoethyl)phenyl]-3-(3-
chlorophenyl)urea, 1 -[3-(2-aminoethyl)phenyl]-3-(4-hydroxyphenyl)urea, 1 -[3-(2- aminoethyl)phenyl]-3-(1 ,3-benzodioxol-5-yl)urea, 1 -[4-(2-aminoethyl)phenyl]-3- ethylurea, 1 -[4-(2-aminoethyl)phenyl]-3-phenylurea, 1 -[4-(2-aminoethyl)phenyl]-3- (3-chlorophenyl)urea, 1 -[4-(2-aminoethyl)phenyl]-3-(4-hydroxyphenyl)urea, (3S)- quinuclidin-3-amine, (3R)-quinuclidin-3-amine. The order of reaction a* and b* during the synthesis of 5* is reversible, as shown in scheme 1 . If one would chose the other synthetic route, than one should react 1 *(oxindole carboxylic acid or oxindole carboxylic acid ester) with 4* in reaction b* first, gaining compound 6*. Reacting the vinyl ether 6* with anilines and amines in the presence of DMF, MeOH, EtOH, DMSO (dimethyl sulfoxid), or in their appropriate mixtures, via reaction c* gives 5B.
In addition, the inventive compounds (I) according to the present invention can also (but not limited to) be prepared according to the general synthetic routes, shown in Scheme 2.
Compounds 12b* were obtained via procedure B2, where 2 molequivalent activated acyl-derivatives are needed for simultenously protection of acyl NH. Compound 13A* and 13B* can be obtained by activation of vinyl-OH and reacted by amines (N-C bond formation) in procedure c*. Amide bond formation involves activation of the hydroxy group by known methods via silylation, especially chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, via mesylation by methanesulfonyl chloride or activation by trifluoromethanesulfonic anhydride in any aprotic solvent like dioxane, tetrahydrofurane.
In some cases under condition of this reaction, N-acyl groups were cleaved from the oxindole NH, giving the desired 14* compounds. In other cases, N-acyl type protecting groups must be cleaved under acidic (especially aqueous HCI) or basic (especially aqueous LiOH, NaOH, or KOH) conditions (procedure D)
In procedure E the activation of the carboxylic acid performed in situ by treatment of the mixture of the amine and compound 14* with an activating agents, such as DCC (Λ/,Λ/'-dicyclohexylcarbodiimide), DIC (Λ/,Λ/'-diisopropylcarbodiimide) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), phosphonium salts such as BOP (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, PyBOP
(benzotriazol-l -yloxy)tripyrrolidinophosphonium 5 hexafluorophosphate, PyAOP ((7-azabenzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyCloP (chlorotripyrrolidinophosphonium hexafluorophosphate), DEPBT (3- (diethoxyphosphoryloxy)-l ,2,3-benzotriazin-4(3H)-one), uranium and guanidinium salts such as HBTU (0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate), TBTU (0-(Benzotriazol-1 -yl)-N,N,N',N'-tetrannethyluroniunn tetrafluoroborate), HATU (O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBPyU (O-(benzotriazol-1 -yl)-N,N,N',N'- bis(tetramethylene)uranium hexafluorophosphate), HCTU (O-(6- chlorobenzotriazol-1 -yl)-N,N,N',N'- 8 tetramethyluronium hexafluorophosphate). Amide bond formation is conducted preferably in presence of a base, such as tertiary amines including TEA (triethylamine) and (DIPEA) diisopropylethyl amine. Thus, the amide bond formation can be carried out using reagent systems such as HATU/DIPEA, HBTU/TEA or EDCI/HOBT/TEA.
Acylation of NH of the benzopyrrolidones was carried out by acylation agents (especially acetic-anhydride) at 80 °C - 140 °C obtained the compounds covered by general formula (I). The present invention refers further to use of the compounds according to the general formula (I) are in the manufacture of a medicament for the treatment of infectios diseases. Another aspect of the present invention relates to a method comprising administering to a patient suffering from an infectious disease a therapeutically effective amount of at least one compound according to general formula (I) as defined herein in order to treat that infectious disease.
As used herein the term infectious diseases comprises selected from the group comprising or consisting of virally induced infectious diseases, bacterially induced infectious diseases, and parasitic induced infectious diseases. Within the present invention it is preferred that the infectious diseases are virally induced infectious diseases, including opportunistic diseases.
A preferred embodiment of the present invention refers to the compounds of general formula I for use in the treatment of virally induced infectious diseases, including opportunistic diseases, being infections with dsDNA viruses, ssDNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, or dsDNA-RT viruses. Within the present invention it is preferred that the infection with (-)ssRNA viruses are an infection with Orthomyxoviridae, Bornaviridae, Filoviridae, Paramyxoviridae, or Rhabdoviridae.
Another aspect of the present invention refers to the compounds of general formula I for use in the treatment of an infection with Orthomyxoviridae selected from the group comprising or consisting of an infection with Influenza virus A,
5
Influenza virus B, or Influenza virus C. Especially preferred are compounds of general formula I for use in the treatment of an infection with Influenza virus A.
The term "opportunistic diseases" as used herein refers to infections caused by pathogens, particularly opportunistic pathogens that usually do not cause disease or symptoms in a healthy host, one with a healthy immune system but in a host with a damaged or weakened immune system. This is because a healthy immune system is able to successfully fight off the disease, or keep it under control. Examples for opportunistic diseases are caused by an infection with aspergillus sp., Candida albicans, cytomegalovirus, polyomavirus, kaposi's sarcoma caused by human herpesvirus 8 (HHV8), pseudomonas aeruginosa, staphylococcus aureus, streptococcus pneumonia and toxoplasma gondii.
Another preferred embodiment of the present invention refers to compounds of the general formula (I) for the use in treatment of cancer, wherein cancer is selected from the group consisting of adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumour, bladder cancer, bronchial carcinoma, non-small cell lung cancer, breast cancer, Burkitt's lymphoma, corpus cancer, colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors, brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors, colon carcinoma, craniopharyngiomas, oral cancer, cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer, lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, spinalioms, T-cell lymphoma, thymoma, tube carcinoma, eye
tumours, urethral cancer, urologic tumours, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumours, soft tissue sarcoma, Wilm's tumour, cervical carcinoma and tongue cancer. A more preferred embodiment of the present invention refers to compounds of the general formula (I) for the use in treatment of cancer, wherein the cancer is a colorectal cancer.
Still another aspect of the present invention deals with pharmaceutical compositions comprising at least one compound according to general formula (I) as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. The preferred preparations are adapted for oral application or for injection. These administration forms include, for example, liquids, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits.
Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound as described herein and/or a pharmaceutical acceptable salt thereof as active ingredient.
The pharmaceutical compositions according to the present invention containing at least one compound as described in the present invention, especially one pure optical isomer, and/or a pharmaceutically acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices. Other suitable formulations are gels, elixirs, dispersable granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components
7 and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
As pharmaceutically acceptable carrier, excipient and/or diluents can be used carriers such as preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).
Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate.
Suitable lubricants are selected from the group comprising boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Disintegrating agents (disintegrates) such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures may be added.
Further suitable additives are coloring agents, sweetening agents, flavoring agents, preservatives, glidents such as silicon dioxide and talc, and adsorbent such as clay, aluminum oxide.
Suitable diluents are water or water/propylene glycol solutions for parenteral injections, juice, sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
Compounds of general formula (I) may be administered as the sole active agent or in combination with one or more additional therapeutic agents, wherein the combination causes no unacceptable adverse effects. For example, a compound of general formula (I) and an active agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate dosage formulations. Where separate dosage formulations are used, the compound of general formula (I) and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially). In particular, the compounds of the present invention may be used in fixed or separate combination with other anti-viral agents such as interferons, acyclovir, neuraminidase inhibitors (oseltamivir and zanamivir) and M2 protein inhibitors (rimantadine). Thus, another aspect of the present invention relates to drug combinations comprising at least one compound according to general formula (I) and/or pharmaceutically acceptable salts thereof together with at least one additional antiviral agent, especially at least one of the active agents mentioned above. Description of the figures:
Figure 1 : shows an overview of the virus screening process to identify chemical compounds that inhibit influenza virus replication
EXAMPLES
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the
purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
Part A: Chemical Synthesis,
Genaral chemical procedures
All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Reagent grade solvents were used in all other cases, unless otherwise specified, respectively. Silica gel generally used for column chromatography was Fisher silica gel (60A, 35-70 micron). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). The 1H-NMR spectra were recorded on a Bruker Avance 300 NMR spectometer controlled by TopSpin software package in deuterodimethylsulfoxide (DMSO-c/6) solution at 30 °C. The data were processed by TopSpin software. The chemical shifts are referred to tetramethylsilane (5TMS = 0 ppm).The chemical shifts are expressed in ppm using the residual solvent as internal standard. Splitting patterns are designated as s (singlet), d (doublet), dd (double-doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), and bs (broad singlet). Electrospray MS spectra were obtained on a Waters LC-MS system Acquity SQD detector, Waters 2795 Alliance HPLC equipped with Waters 996 PDA Detector (HPLC column: Waters XBridge, RP C18, 3.5 μπτι, 4.6 mm x 50 mm; gradient MeCN/H2O, containing 0.1 % HCOOH: 5% MeCN (0.5 min), 5% to 95% MeCN (5 min), 95% MeCN (0.5 min); flow rate: 2.0 ml/min.
Example 1 :
Step A: (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline-5-carboxylic acid
A mixture of 2-oxoindoline-5-carboxilic acid (5.221 g, 29.50 mmol) and triethylorthobenzoate (20.16 g, 90 mmol) in acetic anhydride (75 ml) were stirred at 100 °C for 8 h.The solvent was removed under reduced pressure. The residue was stirred with i-Pr2O (250 ml) for 2 h to give a solid which was filtered and washed with i-Pr2O to provide (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2- oxoindoline-5-carboxylic acid (3.5 g, 33 %)
1H-NMR in DMSO-c/6 12.3(bs,1 H); 8.61 (d,1 H); 8.22(d,1 H); 7.90(dd,1 H); 7.54(m,5H); 3.99(q,2H); 2.45(s,3H); 1 .35(t,3H).
tR: 3.82 min, MS(ESI):m/z (M+H)+ 352' (M+H)" 350.
The following compound was obtained according to the procedure described by examplel , step A: (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid
Starting from 2-oxoindoline-6-carboxilic acid and triethylorthobenzoate compound 2 was obtained (3.8 g, 36 %).
Step B: (3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid
3
C28H27N3O3, Mw calc: 453.2
A mixture of compound (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2-oxoindoline- 5-carboxylic acid (4.35g ,12.39 mmol) and 3-(piperidine-1 -ylmethyl)aniline (2.47 g,
13 mmol) in dry DMF were stirred at 100 C for 6 h. After cooling down the reaction mixture, MeOH (70 ml) and NaOMe (30 % wt solution in MeOH , 5 ml) were added and the reaction mixture was further stirred overnight. The resulting solid was filtered and washed with cold MeOH to provide (3Z)-2-oxo-3-(phenyl{[3-(piperidin- 1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid (3.27 g, 58 %)
1H-NMR in DMSO-c/6 δ: 12.01 (s, 1 H), 10.71 (s, 1 H), 7.55 (dd, J = 7.9 and 1 .5 Hz, 1 H), 7.47-7.54 (ovl. m, 3H), 7.44 (m, 2H), 7.08 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.89 (dm, J = 7.6 Hz, 1 H), 6.78 (d, J = 1 .5 Hz, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 6.68 (dm, J = 7.8 Hz, 1 H), 6.61 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 3.18 (s, 2H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (m, 2H)
tR: 2.51 min; MS(ESI): m/z (M+H)+ 454; (M+HV 452.
The following compounds were obtained according to the procedure described by example 1 , step B:
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5- carboxylic acid
4
Compound 4 (3.17 g, 56% ) was obtained satrting from (3Z)-1 -acetyl-3- [ethoxy(phenyl)methylene]-2-oxoindoline-5-carboxylic acid and 4-(piperidine-1 - ylmethyl)aniline:
C28H27N3O3, Mw calc: 453.2
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 1 1 .01 (s, 1 H), 7.56 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.50-7.62 (ovl. m, 3H), 7.47 (ovl. m, 2H), 7.05 (dm, J = 8.3 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1 H), 6.76 (dm, J = 8.3 Hz, 2H), 6.58 (d, J = 1 .5 Hz, 1 H), 3.28 (s, 2H), 2.22 (m, 4H), 1 .43 (m, 4H), 1 .36 (m, 2H)
tR: 2.48 min ; MS(ESI): m/z (M+H)+ 454; (M+HV 452.
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2- oxoindoline-5-carboxylic acid
Compound 5 (3.24 g, 55 %) was obtained from (3Z)-1 -acetyl-3-[ethoxy(phenyl) methylene]-2-oxoindoline-5-carboxylic acid and 4-[(4-methylpiperazin-1 - yl)methyl]aniline:
C28H28N4O3, Mw calc: 468.2
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.99 (s, 1 H), 7.55 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.51 -7.62 (ovl. m, 3H), 7.48 (m, 2H), 7.05 (dm, J = 8.2 Hz, 2H), 6.89 (dm, J = 8.1 Hz, 1 H), 6.75 (dm, J = 8.2 Hz, 2H), 6.60 (d, J ~ 1 .5 Hz, 1 H), 3.31 (s, 2H), 2.17- 2.38 (m, 8H), 2.1 1 (s, 3H)
tR: 2.17 min; MS(ESI): m/z (M+H)+ 469; (M+H)" 467.
Compound 6: (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl) methylene]-2-oxoindoline-5-carboxylic acid
C28H28N4O3, Mw calc: 468.2
MS(ESI): m/z (M+H)+ 469
Compound 7: (3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino} methylene)indoline-6-carboxylic acid
C28H27N3O3, Mw calc: 453.2
MS(ESI): m/z (M+H)+ 454
Compound 8: (3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino} methylene)indoline-6-carboxylic acid
C28H27N3O3, Mw calc: 453.2
MS(ESI): m/z (M+H)+ 454
Compound 9: (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)
(phenyl)methylene]-2-oxoindoline-6-carboxylic acid
C28H28N4O3, Mw calc: 468.2
MS(ESI): m/z (M+H)+ 469;
Compound 10: (3Z)-3-{[(4-{[4-(2-hydroxyethyl)piperazin-1 - yl]methyl}phenyl)amino](phenyl)methylene}-2-oxoindoline-5-carboxylic acid
C29H30N4O4 MW cal.:498.2
MS(ESI): m/z (M+H)+ 499
Compound 11 : (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino) (phenyl)methylene]-2-oxoindoline-6-carboxylic acid
C28H28N4O3, Mw calc: 468.2
MS(ESI): m/z (M+H)+ 469;
Step C: (3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino} methylene)- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
12
C37H38N4O2, Mw calc: 570.3
A solution of (3Z)-2-oxo-3-(phenyl{[3-(pipehdin-1 -ylmethyl)phenyl]amino} methylene) indoline-5-carboxylic acid (0.1 13 g, 0.25 mmol), HBTU (0.1 13 g, 0.30mmol), DIEA (0.1 16g, 0.9 mmol) and (1 R)-1 -phenylpropane-1 -amine ( 0.040g, 0.30 mmol) in dry DMF (3 ml) were stirred overnight. The reaction mixture was poured into saturated sodium carbonate solution((100 ml), ) and extracted with EtOAc (3X30 ml).Washed with brine,dried(MgSO4), filtered and concentrated in vacuo. Residue was chromatographed on silica gel eluted with CHCI3-MeOH- TEA(15:1 :0.1 ) provide the . (3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl] amino} methylene)-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (0.62 mg, 44 %)
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.94 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.50- 7.57 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .6 Hz, 1 H), 7.46 (m, 2H), 7.23-7.35 (ovl. m, 4H), 7.20 (m, 1 H), 7.13 (dd, J = 7.8 and 7.5 Hz, 1 H), 6.95 (dm, J = 7.5 Hz, 1 H), 6.89 (d, J = 8.1 Hz, 1 H), 6.77 (dm, J = 7.8 Hz, 1 H), 6.71 (m, 1 H), 6.47 (d, J = 1 .6 Hz, 1 H), 4.73 (ddd, J = 8.5, 7.3 and 7.3 Hz, 1 H), 3.30 (s, 2H), 2.14 (m, 4H), 1 .61 - 1 .81 (m, 2H), 1 .45 (m, 4H), 1 .36 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H)
tR: 3.3 min; MS(ESI): m/z (M+H)+ 571 ; (M+HV 569.
The following compounds were obtained according to the procedure described by example 1 , step C:
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl] amino}methylene)indoline-5-carboxamide
13
Compound 13 (64 mg, 46%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid and (1 R)-1 -phenylethanamine C36H36N4O2 , Mw calc, : 556.2
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 (m, 1 H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.93 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.76 (dm, J = 7.8 Hz, 1 H), 6.69 (m, 1 H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.98 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.22 (s, 2H), 2.1 1 (m, 4H), 1 .43 (m, 4H), 1 .36 (d, J = 7.0 Hz, 3H), 1 .35 (m, 2H),
tR: 3.17 min; MS(ESI): m/z (M+H)+ 557; (M+HV 555.
(3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V-[(1 S)-1 - phenylpropyl]indoline-5-carboxamide
14
5
Compound 14 (64 mg, 45%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid and (1 S)-1 -phenylpropan-1 -amine
C37H38N4O2, Mw calc. : 570.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.94 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.49 (dd, J = 8.2 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 (m, 1 H), 7.12 (dd, J = 7.8 and 7.7 Hz, 1 H), 6.93 (dm, J = 7.7 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.47 (d, J = 1 .5 Hz, 1 H), 4.73 (ddd, J = 8.5, 7.2 and 7.2 Hz, 1 H), 3.21 (s, 2H), 2.10 (m, 4H), 1 .60-1 .80 (m, 2H), 1 .43 (m, 4H), 1 .34 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H)
tR: 3.29 min; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569.
(3Z)-/V-[(1 S)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 -yimethyl) phenyl]amino}methylene)indoline-5-carboxamide
15
Compound 15 (57 mg, 38%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid and (1 S)-1 -(4-chlorophenyl)ethanamine
C36H35CIN4O2 Mw calc: 590.2 1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.94 (s, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.49- 7.56 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.35 (dm, J = 8.5 Hz, 2H), 7.30 (dm, J = 8.5 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.92 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.45 (d, J = 1 .5 Hz, 1 H), 4.96 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.20 (s, 2H), 2.10 (m, 4H), 1 .40 (m, 4H), 1 .35 (d, J = 7.0 Hz, 3H), 1 .34 (m, 2H) tR: 3.37 min; MS(ESI): m/z (M+H)+ 591 ; (M+H)" 589.
(3Ζ)-Λ/-[(1 R)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]annino} methylene)indoline-5-carboxannide
16
Connpound 16 (69 mg, 46%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid and (1 R)-1 -(4-chlorophenyl)ethanamine
C36H35CIN4O2, Mw calc. : 590.2
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.94 (s, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.49- 7.56 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.35 (dm, J = 8.5 Hz, 2H), 7.30 (dm, J = 8.5 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.92 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.45 (d, J = 1 .5 Hz, 1 H), 4.96 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.20 (s, 2H), 2.10 (m, 4H), 1 .40 (m, 4H), 1 .35 (d, J = 7.0 Hz, 3H), 1 .34 (m, 2H) tR: 3.35 min; MS(ESI): m/z (M+H)+ 591 ; (M+H)" 589.
(3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
17
Compound 17 (65 mg, 45%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid and (1 R)-1 -(4-fluorophenyl)ethanamine
C36H35FN4O2, Mw calc. : 574.2
7
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.94 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.49- 7.57 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.31 (ddm, J = 8.6 and 5.6 Hz, 2H), 7.12 (ddm, J = 9.0 and 8.6 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.93 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.76 (dm, J = 7.8 Hz, 1 H), 6.69 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.98 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.21 (s, 2H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (d, J = 7.0 Hz, 3H), 1 .34 (m, 2H)
tR: 3.16 min; MS(ESI): m/z (M+H)+ 575; (M+H)" 573. (3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V-[(1 f?)-1 - phenyl propyl]indoline-5-carboxamide
18
Compound 18 (65 mg, 45%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -phenylpropan-1 -amine
C37H38N4O2, Mw calc.: 570.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.92 (s, 1 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.49- 7.57 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.21 (m, 1 H), 7.04 (dm, J = 8.2 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 8.2 Hz, 2H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.73 (ddd, J = 8.3, 7.3 and 7.3 Hz, 1 H), 3.30 (s, 2H), 2.23 (m, 4H), 1 .60-1 .80 (m, 2H), 1 .44 (m, 4H), 1 .36 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H)
tR: 3.26 min; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-/V-methyl-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
19
Connpound 19 (75 mg, 52%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- W-methyl-1 -phenylethanamine
C37H38N4O2, Mw calc.: 570.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.88 (s, 1 H), 7.42-7.58 (ovl. m, 5H), 7.37 (ddm, J = 7.5 and 7.0 Hz, 2H), 7.38 (tm, J ~ 7.0 Hz, 1 H), 7.13 (dm, J ~ 7.5 Hz, 2H), 7.1 1 (dd, J = 7.8 and 7.6 Hz, 1 H); 7.03 (dd, J = 8.00 and 1 .3 Hz, 1 H), 6.92 (dm, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.70 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 5.81 (d, J ~ 1 .5 Hz, 1 H), 5.40 (br, 1 H), 3.20 (br. s, 2H), 2.36 (s, 3H), 2.10 (m, 4H), 1 .43 (m, 4H), 1 .39 (d, J ~ 7.0 Hz, 3H), 1 .35 (m, 2H) tR: 3.21 min ; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-/V-benzyl-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}
methylene)indoline-5-carboxamide
20
Compound 20 (70 mg, 51 %) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and 1 - phenylmethanamine
C35H34N4O2, Mw calc: 542.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.93 (s, 1 H), 8.42 (t, J = 5.9 Hz, 1 H), 7.50- 7.60 (ovl. m, 3H), 7.47 (m, 2H), 7.46 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.31 (ddm, J ~ 7.5 and 7.0 Hz, 2H), 7.16-7.26 (ovl. m, 3H), 7.05 (dm, J = 8.2 Hz, 2H), 6.88 (d, J =
8.1 Hz, 1 H), 6.75 (dm, J = 8.2 Hz, 2H), 6.53 (d, J ~ 1 .0 Hz, 1 H), 4.32 (d, J Hz, 2H), 3.28 8s, 2H), 2.22 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H)
tR: 3.03 min ; MS(ESI): m/z (M+H)+ 543; (M+H)" 541
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
21
Compound 21 (60 mg, 41 %) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(4-methoxyphenyl)ethanamine
Cs/HssNUOs, Mw calc. : 586.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.92 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.50- 7.57 (ovl. m, 3H), 7.48 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.45 (m, 2H), 7.19 (dm, J = 8.6 Hz, 2H), 7.04 (dm, J = 8.3 Hz, 2H), 6.87 (d, J = 8.1 Hz, 1 H), 6.86 (dm, J = 8.6 Hz, 2H), 6.75 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .5 Hz, 1 H), 4.94 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.72 (s, 3H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H), 1 .34 d, J = 7.0 Hz, 3H)
tR: 3.08 min; MS(ESI): m/z (M+H)+ 587; (M+H)" 585
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
22
5
Compound 22 (67 mg, 46%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(3-methoxyphenyl)ethanamine C37H38N4O3, Mw calc.: 586.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.92 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.21 (dd, J = 8.0 and 7.8 Hz, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.87 (dd, J ~ 1 .5 and 1 .5 Hz, 1 H), 6.85 (dm, J = 7.8 Hz, 1 H), 6.78 (dm, J = 8.0 Hz, 1 H); 6.75 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .0 Hz, 1 H), 4.95 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.73 (s, 3H), 3.28 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H), 1 .35 d, J = 7.0 Hz, 3H)
tR: 3.1 1 min; MS(ESI): m/z (M+H)+ 587; (M+H)" 585 (3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
23
Compound 23 (71 mg, 49%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(4-fluorophenyl)ethanamine
C36H35FN4O2, Mw calc: 574.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.92 (s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.31 (ddm, J = 8.6 and 5.5 Hz, 2H), 7.12 (ddm, J = 9.1 and 8.6 Hz, 2H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 8.3 Hz, 2H), 6.45 (d, J = 1 .0 Hz, 1 H), 4.98 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.28 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H), 1 .35 d, J = 7.0 Hz, 3H)
tR: 3.16 min ; MS(ESI): m/z (M+H)+ 575; (M+H)" 573
5
(3Ζ)-Λ/-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
24
Connpound 24 (57 mg, 39%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(3-methoxyhenyl)ethanamine
C37H38N4O3, Mw calc.: 586.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.21 (dd, J = 8.0 and 7.5 Hz, 1 H), 7.1 1 (dd, J = 7.8 and 7.8 Hz, 1 H), 6.92 (dm, J = 7.8 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.86 (dd, J = 1 .5 and 1 .5 Hz, 1 H), 6.85 (dm, J = 8.0 Hz, 1 H), 6.78 (dm, J = 7.5 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.69 (dd, J ~ 1 .5 and 1 .5 Hz, 1 H), 6.45 (d, J = 1 .0 Hz, 1 H), 4.95 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.73 (s, 3H), 3.20 (s, 2H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 d, J = 7.0 Hz, 3H)1 .34 (m, 2H),
tR: 3.13 min ; MS(ESI): m/z (M+H)+ 587; (M+H)" 585
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
25
Compound 25 (51 mg, 37%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -phenylethanamine
C36H36N4O2, Mw calc. : 556.3
5
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 (m, 1 H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.93 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.76 (dm, J = 7.8 Hz, 1 H), 6.69 (m, 1 H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.98 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.22 (s, 2H), 2.1 1 (m, 4H), 1 .43 (m, 4H), 1 .36 (d, J = 7.0 Hz, 3H), 1 .35 (m, 2H)
tR: 3.12 min; MS(ESI): m/z (M+H)+ 557; (M+H)" 555
(3Z)-/V-[(1 S)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
26
Compound 26 (67 mg, 47%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -(4-fluorophenyl)ethanamine
C36H35FN4O2, Mw calc. : 574.3
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.93 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.49- 7.57 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.31 (ddm, J = 8.6 and 5.6 Hz, 2H), 7.12 (ddm, J = 9.0 and 8.6 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.93 (dm, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.76 (dm, J = 7.8 Hz, 1 H), 6.69 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.98 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.20 (s, 2H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (d, J = 7.0 Hz, 3H), 1 .34 (m, 2H)
tR: 3.17 min; MS(ESI): m/z (M+H)+ 575; (M+H)" 573
(3Z)-/V-[(1 R)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
5
27
Connpound 27 (67 mg, 47%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(4-methylphenyl)ethanamine
C37H38N4O2, Mw calc.: 570.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.49- 7.55 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.16 (dm, J = 8.0 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 7.10 (dm, J = 8.0 Hz, 2H), 6.92 (dm, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.46 (d, J ~ 1 .0 Hz, 1 H), 4.94 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.21 (s, 2H), 2.26 (s, 3H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (m, 2H), 1 .34 (d, J = 7.0 Hz, 3H)
tR: 3.16 min; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-/V-[(1 S)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
28
Compound 28 (58 mg, 38%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -(4-methylphenyl)ethanamine
C37H38N4O2, Mw calc: 570.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.49- 7.55 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.16 (dm, J = 8.0 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 7.10 (dm, J = 8.0 Hz, 2H), 6.92
5
(dm, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.46 (d, J ~ 1 .0 Hz, 1 H), 4.94 (dq, J = 7.8 and 7.0 Hz, 1 H), 3.21 (s, 2H), 2.26 (s, 3H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (m, 2H), 1 .34 (d, J = 7.0 Hz, 3H)
tR: 3.26 min; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
29
Compound 29 (72 mg, 49%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -(4-methoxyphenyl)ethanamine
Cs/HssNUOs, Mw calc 586.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.49- 7.55 (ovl. m, 3H), 7.48 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.20 (dm, J = 8.6 Hz, 2H), 7.12 (dd, J = 7.8 and 7.6 Hz, 1 H), 6.93 (dm, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.86 (dm, J = 8.6 Hz, 2H), 6.75 (dm, J = 7.8 Hz, 1 H), 6.68 (dd, J ~ 2.5 and 2.0 Hz, 1 H), 6.45 (d, J ~ 1 .0 Hz, 1 H), 4.94 (dq, J = 8.0 and 7.0 Hz, 1 H), 3.72 (s, 3H), 3.20 (s, 2H), 2.10 (m, 4H), 1 .42 (m, 4H), 1 .35 (m, 2H), 1 .34 (d, J = 7.0 Hz, 3H)
tR: 3.02 min; MS(ESI): m/z (M+H)+ 587; (M+H)" 585
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
30
Connpound 30 (60 mg, 43%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -phenylethanamine
C36H36N4O2, Mw calc: 556.3
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.91 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.50- 7.56 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 8m, 1 H), 7.04 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 8.3 Hz, 2H), 6.45 (d, J = 1 .0 Hz, 1 H), 4.98 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 d, J = 7.0 Hz, 3H)1 .35 (m, 2H), tR: 3.16 min; MS(ESI): m/z (M+H)+ 557; (M+H)" 555 (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
31
Compound 31 (66 mg, 47%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -phenylethanamine
C36H36N4O2, Mw calc: 556.3
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.91 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.50- 7.56 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 8m, 1 H), 7.04 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75
5
(dm, J = 8.3 Hz, 2H), 6.45 (d, J = 1 .0 Hz, 1 H), 4.98 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 d, J = 7.0 Hz, 3H)1 .35 (m, 2H), tR: 3.16 min; MS(ESI): m/z (M+H)+ 557; (M+H)" 555 (3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V-[(1 S)-1 - phenyl propyl]indoline-5-carboxamide
32
Compound 32 (65 mg, 45%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -phenylpropan-1 -amine
C37H38N4O2, Mw calc.: 570.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.91 (s, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.49- 7.57 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.21 (m, 1 H), 7.04 (dm, J = 8.2 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.75 (dm, J = 8.2 Hz, 2H), 6.46 (d, J = 1 .5 Hz, 1 H), 4.73 (ddd, J = 8.3, 7.3 and 7.3 Hz, 1 H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .60-1 .80 (m, 2H), 1 .44 (m, 4H), 1 .36 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H)
tR: 3.25 min; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-/V-[(1 S)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
33
Compound 33 (70 mg, 48%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -(4-methoxyphenyl)ethanamine C37H38N4O3, Mw calc.: 586.3
1H-NMR in DMSO-c/6 δ: 12.02 (s, 1 H), 10.91 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.50- 7.57 (ovl. m, 3H), 7.48 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.45 (m, 2H), 7.19 (dm, J = 8.6 Hz, 2H), 7.04 (dm, J = 8.3 Hz, 2H), 6.87 (d, J = 8.1 Hz, 1 H), 6.86 (dm, J = 8.6 Hz, 2H), 6.75 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .5 Hz, 1 H), 4.94 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.72 (s, 3H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H), 1 .34 d, J = 7.0 Hz, 3H)
tR: 3.07 min; MS(ESI): m/z (M+H)+ 587; (M+H)" 585
(3Z)-/V-[(1 S)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
34
Compound 34 (70 mg, 48%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 S)- 1 -(3-methoxyphenyl)ethanamine
C37H38N4O3, Mw calc: 586.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.92 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.50- 7.55 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.21 (dd, J = 8.0 and 7.8 Hz, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.87 (dd, J ~ 1 .5 and 1 .5 Hz, 1 H), 6.85 (dm, J = 7.8 Hz, 1 H), 6.78 (dm, J = 8.0 Hz, 1 H); 6.75 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .0 Hz, 1 H), 4.95 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.73 (s, 3H), 3.28 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .36 (m, 2H), 1 .35 d, J = 7.0 Hz, 3H)
tR: 3.09 min; MS(ESI): m/z (M+H)+ 587; (M+H)" 585
5
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
35
Compound 35 (84 mg, 56%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -(3-methoxyphenyl)ethanamine
C37H39N5O3, Mw calc: 601 .3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.50- 7.56 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.21 (dd, J = 8.1 and 7.8 Hz, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J ~ 8.1 Hz, 1 H), 6.87 (dd, J ~ 2.0 and 1 .5 Hz, 1 H), 6.85 (dm, J = 7.8 Hz, 1 H), 6.78 (dm, J = 8.1 Hz, 1 H), 6.76 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .0 Hz, 1 H), 4.95 (dq, J = 8.0 and 7.0 Hz, 1 H), 3.73 (s, 3H), 3.32 (s, 2H), 2.22-2.42 (m, 8H), 2.18 (s, 3H), 1 .35 (d, J = 7.0 Hz, 3H) tR: 2.8 min; MS(ESI): m/z (M+H)+ 602; (M+H)" 600
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
36
Compound 36 (72 mg, 47%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -(3-chlorophenyl)ethanamine
C36H36CIN5O2, Mw calc: 605.2
5
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.18 (6, J = 1.1 Hz, 1 H), 7.50- 7.57 (ovl. m, 3H), 7.50 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.35 (dd, J ~ 1 .5 and 1 .5 Hz, 1 H), 7.33 (dd, J ~ 7.5 and 7.5 Hz, 1 H), 7.27 (dm, J ~ 7.5 Hz, 1 H), 7.24 (dm, J ~ 7.5 Hz, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.89 (d, J ~ 8.1 Hz, 1 H), 6.76 (dm, J = 8.3 Hz, 2H), 6.44 (d, J = 1 .0 Hz, 1 H), 4.96 (dq, J = 7.7 and 7.0 Hz, 1 H), 3.31 (s, 2H), 2.19-2.39 (m, 8H), 2.14 (s, 3H), 1 .36 (d, J = 7.0 Hz, 3H)
tR: 3.00 min; MS(ESI): m/z (M+H)+ 606; (M+H)" 604
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
37
Compound 37 (57 mg, 39%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -phenylpropan-1 -amine
C37H39N5O2, MW calc.: 585.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.93 (s, 1 H), 8.06 (d, J = 8.2 Hz, 1 H), 7.50- 7.57 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.20 (m, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J ~ 8.1 Hz, 1 H), 6.75 (dm, J = 8.3 Hz, 2H), 6.46 (d, J = 1 .0 Hz, 1 H), 4.73 (ddd, J = 8.2, 7.4 and 7.4 Hz, 1 H), 3.29 (s, 2H), 2.21 -2.41 (m, 8H), 2.16 (s, 3H), 1 .60-1 .80 (ovl. m, 2H), 0.81 (t, J = 7.0 Hz, 3H)
tR: 2.91 min; MS(ESI): m/z (M+H)+ 586; (M+H)" 584
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
38
Compound 38 (60 mg, 42%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -phenylethanamine
C36H37N5O2, Mw calc.: 571 .3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.12 (d, J = 8.1 Hz, 1 H), 7.50- 7.56 (ovl. m, 3H), 7.49 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.24-7.34 (ovl. m, 4H), 7.21 (m, 1 H), 7.06 (dm, J = 8.3 Hz, 2H), 6.88 (d, J ~ 8.1 Hz, 1 H), 6.76 (dm, J = 8.3 Hz, 2H), 6.45 (d, J = 1 .0 Hz, 1 H), 4.98 (dq, J = 8.1 and 7.0 Hz, 1 H), 3.32 (s, 2H), 2.23-2.43 (m, 8H), 2.18 (s, 3H), 1 .36 (d, J = 7.0 Hz, 3H)
tR: 2.78 min; MS(ESI): m/z (M+H)+ 572; (M+H)" 570 (3Z)-/V-(3,4-dimethoxybenzyl)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
39
Compound 39 (74 mg, 48%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and 1 -(3,4-dimethoxyphenyl)methanamine
C37H39N5O4, Mw calc: 617.3
1H-NMR in DMSO-c/6 δ: 12.04 (s, 1 H), 10.92 (s, 1 H), 8.32 (t, J = 5.5 Hz, 1 H), 7.49- 7.57 (ovl. m, 3H), 7.46 (m, 2H), 7.45 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.06 (dm, J = 8.0 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.87 (d, J ~ 8.0 Hz, 1 H), 6.86 (d, J ~ 1 .5 Hz, 1 H), 6.76 (dm, J = 8.0 Hz, 2H), 6.73 (dd, J ~ 8.0 and 1 .5 Hz, 1 H), 6.51 (d, J = 1 .0
Hz, 1 H), 4.25 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.36 (s, 2H), 2
(m, 8H), 2.30 (s, 3H)
tR: 2.50 min; MS(ESI): m/z (M+H)+ 618; (M+H)" 616
(3Z)-/V-(3-methoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
40
Compound 40 (72 mg, 49%) was obtained starting from (3Z)-3-[({4-[(4- methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5- carboxylic acid and 1 -(3-methoxyphenyl)methanamine
C36H37N5O3, Mw calc.: 587.3
1H-NMR in DMSO-c/6 δ: 12.03 (s, 1 H), 10.93 (s, 1 H), 8.40 (t, J = 5.6 Hz, 1 H), 7.49- 7.55 (ovl. m, 3H), 7.47 (dd, J = 8.1 and 1 .0 Hz, 1 H), 7.46 (m, 2H), 7.21 (dd, J = 8.4 and 8.0 Hz, 1 H), 7.05 (dm, J = 8.3 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1 H), 6.76-6.80 (ovl. m, 3H), 6.75 (dm, J = 8.3 Hz, 2H), 6.52 (d, J = 1 .0 Hz, 1 H), 4.29 (d, J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.28 (s, 2H), 2.19-2.33 (m, 8H), 2.12 (s, 3H)
tR: 2.68 min; MS(ESI): m/z (M+H)+ 588; (M+H)" 586
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino} methylene)indoline-6-carboxamide
41
Compound 41 (72 mg, 49%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-6-carboxylic acid and (1 R)- 1 -phenylethanamine C36H36N4O2, Mw calc.: 556.3
1H-NMR in DMSO-c/6 δ: 12.1 1 (s, 1 H), 10.85 (s, 1 H), 8.50 (d, J = 8.0 Hz, 1 H), 7.52- 7.62 (ovl. m, 3H), 7.48 (m, 2H), 7.37 (d, J ~ 1 .5 Hz, 1 H), 7.34 (dm, J ~ 7.5 Hz, 2H), 7.29 (ddm, J ~ 7.5 and 7.0 Hz, 2H), 7.19 (tm, J ~ 7.0 Hz, 1 H), 7.15 (dd, J = 8.1 and 1 .5 Hz, 1 H), 7.06 (dm, J = 8.2 Hz, 2H), 6.80 (dm, J = 8.2 Hz, 2H), 5.71 (d, J = 8.1 Hz, 1 H), 5.1 1 (dq, J = 8.0, and 7.0 Hz, 1 H), 3.29 (s, 2H), 2.23 (m, 4H), 1 .44 (m, 4H), 1 .42 (d, J = 7.0 Hz, 3H)1 .36 (m, 2H)
tR: 3.15 min.; MS(ESI): m/z (M+H)+ 557; (M+H)" 555
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V-[(1 R)-1 - phenylpropyl]indoline-6-carboxamide
42
Compound 42 (77 mg, 54%) was obtained starting from (3Z)-2-oxo-3-(phenyl{[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene)indoline-6-carboxylic acid and (1 R)- 1 -phenylpropan-1 -amine
C37H38N4O2, Mw calc: 570.3
1H-NMR in DMSO-c/6 δ: 12.10 (s, 1 H), 10.85 (s, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 7.52-7.62 (ovl. m, 3H), 7.48 (m, 2H), 7.35 (d, J ~ 1 .5 Hz, 1 H), 7.34 (dm, J ~ 7.5 Hz, 2H), 7.28 (ddm, J ~ 7.5 and 7.0 Hz, 2H), 7.19 (tm, J ~ 7.0 Hz, 1 H), 7.14 (dd, J = 8.2 and 1 .5 Hz, 1 H), 7.06 (dm, J = 8.3 Hz, 2H), 6.80 (dm, J = 8.3 Hz, 2H), 5.70 (d, J = 8.1 Hz, 1 H), 4.84 (ddd, J = 8.0, 7.5 and 7.5 Hz, 1 H), 3.28 (s, 2H), 2.22 (m, 4H), 1 .66-1 .86 (ovl. m, 2H), 1 .44 (m, 4H), 1 .36 (m, 2H)0.85 (t, J = 7.3 Hz, 3H) tR: 3.24 min ; MS(ESI): m/z (M+H)+ 571 ; (M+H)" 569
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(phenyl)methylene]-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
43
C36H37N5O2, Mw calc.:571 .3
MS(ESI): m/z (M+H)+ 572
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)me
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
44
C37H39N5O2, Mw calc.:585.3
MS(ESI): m/z (M+H)+ 586
(3Z)-A/-benzyl-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amin arboxamide
45
C35H35N5O2, Mw calc.:557.3
MS(ESI): m/z (M+H)+ 558
(3Z)-/V-[(1 R)A -(3-chlorophenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
46
C36H36CIN5O2, Mw calc.:605.2
MS(ESI): m/z (M+H)+ 606 (3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
47
C37H39N5O3, Mw calc. :601 .3
MS(ESI): m/z (M+H)+ 602
(3Z)-/V-(3-methoxybenzyl)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amin (phenyl)methylene]-2-oxoindoline-5-carboxannide
48
C36H37N5O3, Mw calc.:587.3
MS(ESI): m/z (M+H)+588
(3Z)-/V-(3,4-dimethoxybenzyl)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]ph amino)(phenyl)nnethylene]-2-oxoindoline-5-carboxannide
C37H39N5O4, Mw calc.:617.3
5
MS(ESI): m/z (M+H)+618
Example 2
Step A
50
l O mmol (1 .91 g) methyl-2-oxoindoline-5-carboxylate was suspended in 20 ml acetic-anhydnde and stirred for 2-3 hours at 130-140 °C. The reaction mixture was cooled to rt and poured into crushed ice (100-150 g) then the precipitated product was filtered off.
2.17 g (93 %) Rt: 3.21 min.
MS (ESI) [M+H]+: 234 MS (ESI) [M+H]" : 232 Step B
Methyl-(3Z)-1 -acetyl-3-[hydroxy(pyridin-4-yl)methylene]-2-oxoindoline-5- carboxylate
51
10 mmol (methyl-1 -acetyl-2-oxoindoline-5-carboxylate) was dissolved in 40 ml dry dichloromethane and 100 mmol DIPEA, 0.1 mmol DMAP (4- Dimethylaminopyridine) were added to the reaction mixture under inert atmosphere and stirred for 5-10 mins. 1 .1 mmol isonicotinoyl chloride was added in one portion and stirred for 2 hours. The reaction was monitored by TLC. After the completion, the reaction mixture was washed with 20-30 ml sat. aq. NaHCO3 and the organic layer was separated and dried over MgSO4. The dessicant was filtered off and the solvent was removed under reduced pressure to give methyl- (3Z)-1 -acetyl-3-[hydroxy(pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylate as brown foamy solid.
C18H14N2O5 calc. 338.32
MS (ESI) [M+H]+: 339 MS (ESI) [M+H]" : 337
The following compounds were obtained according to the procedure described by example 2, step B Compound 52:
Methyl-(3Z)-1 -acetyl-3-[hydroxy(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxylate
C18H14N2O5 calc. 338.32
MS (ESI) [M+H]+: 339 MS (ESI) [M+H]" : 337
Compound 53:
Methyl-(3Z)-1 -acetyl-3-[hydroxy(pyridin-2-yl)methylene]-2-oxoindoline-5- carboxylate
C18H14N2O5 calc. 338.32
MS (ESI) [M+H]+: 339 MS (ESI) [M+H]" : 337
Compound 54:
Methyl-(3Z)-1 -acetyl-3-[hydroxy(3-thienyl)methylene]-2-oxoindoline-5-carboxylate C17H13NO5S calc. 343.36
MS (ESI) [M+H]+: 344 MS (ESI) [M+H]" : 342
Compound 55:
Methyl-(3Z)-1 -acetyl-3-[3-furyl(hydroxy)methylene]-2-oxoindoline-5-carboxylate C17H13NO6 calc. 327.30
MS (ESI) [M+H]+: 328 MS (ESI) [M+H]" : 326
Compound 56:
Methyl-(3Z)-1 -acetyl-3-[2-furyl(hydroxy)methylene]-2-oxoindoline-5-carboxylate C17H13NO6 calc. 327.30
MS (ESI) [M+H]+: 328 MS (ESI) [M+H]" : 326
Compound 57:
Methyl-(3Z)-3-[hydroxy(1 -methyl-1 /-/-pyrazol-4-yl)methylene]-2-oxoindoline-5- carboxylate
C17H15N305 calc. 341 .33
MS (ESI) [M+H]+: 342 MS (ESI) [M+H]" : 340
Compound 58:
Methyl-(3Z)-1 -acetyl-3-[hydroxy(1 -methyl-1 H-indol-5-yl)methylene]-2-oxoindoline-
5-carboxylate
C22H18N2O5 calc. 390.40
MS (ESI) [M+H]+: 391 MS (ESI) [M+H]" : 389
Compound 59:
Methyl-(3Z)-1 -acetyl-3-[cyclopropyl(hydroxy)methylene]-2-oxoindoline-5- carboxylate
C16H15NO5 calc. 301 .30
MS (ESI) [M+H]+: 302 MS (ESI) [M+H]" : 300
Compound 60:
Methyl-(3Z)-1 -acetyl-3-[cyclohexyl(hydroxy)methylene]-2-oxoindoline-5- carboxylate
C19H21 NO5 calc. 343.38
MS (ESI) [M+H]+: 342 MS (ESI) [M+H]" : 344
Compound 61 :
Methyl-(3Z)-1 -acetyl-3-(1 -hydroxypropylidene)-2-oxoindoline-5-carboxylate
C15H15NO5 calc. 289.29
MS (ESI) [M+H]+: 288 MS (ESI) [M+H]" : 287
Compound 62: Methyl (3Z)-1 -acetyl-3-(1 -hydroxy-2-methylpropylidene)-2- oxoindoline-5-carboxylate C16H17NO5 calc. 303.32
MS (ESI) [M+H]+: 304 MS (ESI) [M+H]" : 302
Step C
Methyl-(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4- yl)methylene]-2-oxoindoline-5-carboxylate
63
10 mmol (3.38 g) methyl-(3Z)-1 -acetyl-3-[hydroxy(pyridin-4-yl)methylene]-2- oxoindoline-5-carboxylate intermediate was suspended in 40 ml dry dioxane and 20 mmol (3.22 g, 4.18 ml) HMDS (hexamethyldisilazane), 20 mmol (2.17 g, 2.54 ml) trimethylsilyl chloride and 4-[(4-methylpiperazin-1 -yl)methyl]aniline were added to the reaction mixture under inert atmosphere and refluxed overnight. The reaction mixture was poured into 30 ml 10 % Na2CO3 and extracted with 3x60 ml ethyl-acetate. The organic layer was separated and dried over MgSO4. The dessicant was filtered off and the solvent was removed under reduced pressure to give methyl-(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4- yl)methylene]-2-oxoindoline-5-carboxylate as dark brown oil. This product was used in the next step without purification.
C28H29N5O3 calc. 483.58
MS (ESI) [M+H]+: 484 MS (ESI) [M+H]" : 482 The following compounds were obtained according to the procedure described by example 2, step C
Compound 64:
Methyl-(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxoindoline-5-carboxylate
C28H29N5O3 calc. 483.58
MS (ESI) [M+H]+: 484 MS (ESI) [M+H]" : 482
Compound 65:
Methyl-(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-2- oxoindoline-5-carboxylate
C27H26N4O4 calc. 470.53
MS (ESI) [M+H]+: 471 MS (ESI) [M+H]" : 469 Compound 270:
Methyl-(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-3- yl)methylene]indoline-5-carboxylate
C28H28N4O3 calc. 468.56
MS (ESI) [M+H]+: 469 MS (ESI) [M+H]" : 470
Compound 66:
Methyl-(3Z)-2-oxo-3-(pyridin-3-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene) indoline-5-carboxylate
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]" : 453
Compound 67:
Methyl-(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin yl)methylene]-2-oxoindoline-5-carboxylate
C28H29N5O3 calc. 483.58
MS (ESI) [M+H]+: 484 MS (ESI) [M+H]" : 482 Compound 68:
Methyl-(3Z)-2-oxo-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-3- yl)methylene]indoline-5-carboxylate
C28H28N4O3 calc. 468.56
MS (ESI) [M+H]+: 469 MS (ESI) [M+H]" : 467
Compound 69:
Methyl-(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2- oxoindoline-5-carboxylate
C27H28N4O3 calc. 456.55
MS (ESI) [M+H]+: 457 MS (ESI) [M+H]" : 455
Compound 70:
Methyl-(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-2- yl)methylene]indoline-5-carboxylate
C28H28N4O3 calc. 468.56
MS (ESI) [M+H]+: 469 MS (ESI) [M+H]" : 467
Compound 71 :
Methyl-(3Z)-2-oxo-3-(pyridin-2-yl{[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxylate
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]" : 453
Compound 72:
Methyl-(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-4- yl)methylene]indoline-5-carboxylate
C28H28N4O3 calc. 468.56
MS (ESI) [M+H]+: 469 MS (ESI) [M+H]" : 467
7
Compound 73:
Methyl-(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)m
oxoindoline-5-carboxylate
C27H26N4O4 calc. 470.53
MS (ESI) [M+H]+: 471 MS (ESI) [M+H]" : 469
Compound 74:
Methyl-(3Z)-2-oxo-3-(pyridin-4-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene) indoline-5-carboxylate
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]" : 452
Compound 75:
Methyl-(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2- oxoindoline-5-carboxylate
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]": 452 Compound 76:
Methyl-(3Z)-2-oxo-3-[{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylate
C26H25N3O3S calc. 459.57
MS (ESI) [M+H]+: 460 MS (ESI) [M+H]": 458
Compound 77:
Methyl-(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylate
C27H27N3O3S calc. 473.60
MS (ESI) [M+H]+: 474 MS (ESI) [M+H]": 472
Compound 78:
Methyl-(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2- oxoindoline-5-carboxylate
C26H25N3O4S calc. 475.57
MS (ESI) [M+H]+: 476 MS (ESI) [M+H]": 474
Compound 79:
7
Methyl-(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- thienyl)methylene]-2-oxoindoline-5-carboxylate
C27H28N4O3S calc. 488.61
MS (ESI) [M+H]+: 489 MS (ESI) [M+H]" : 487
Compound 80:
Methyl-(3Z)-2-oxo-3-[{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylate
C26H25N3O3S calc. 459.57
MS (ESI) [M+H]+: 460 MS (ESI) [M+H]": 468
Compound 81 :
Methyl-(3Z)-2-oxo-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylate
C27H27N3O3S calc. 473.60
MS (ESI) [M+H]+: 474 MS (ESI) [M+H]": 472
Compound 82:
Methyl-(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- thienyl)methylene]-2-oxoindoline-5-carboxylate
C27H28N4O3S calc. 488.61
MS (ESI) [M+H]+: 489 MS (ESI) [M+H]": 487
Compound 83:
Methyl-(3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2- oxoindoline-5-carboxylate
C26H25N3O4S calc. 475.57
MS (ESI) [M+H]+: 475 MS (ESI) [M+H]": 473 Compound 84:
Methyl-(3Z)-3-(3-furyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylate
C26H25N3O4 calc. 443.51
MS (ESI) [M+H]+: 444 MS (ESI) [M+H]": 442
Compound 85:
Methyl-(3Z)-3-(3-fur7l{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
7
C27H27N3O4 calc. 457.53
MS (ESI) [M+H]+: 458 MS (ESI) [M+H]": 456
Compound 86:
Methyl-(3Z)-3-(2-fur7l{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene oxoindoline-5-carboxylate
C27H27N3O4 calc. 457.53
MS (ESI) [M+H]+: 458 MS (ESI) [M+H]": 456 Compound 87:
Methyl-(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate
C26H27N5O3 calc. 457.54
MS (ESI) [M+H]+: 458 MS (ESI) [M+H]": 456
Compound 88:
Methyl-(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate C27H29N5O3 calc. 471 .56
MS (ESI) [M+H]+: 472 MS (ESI) [M+H]": 470
Compound 89:
Methyl-(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate C26H27N5O3 calc. 457.54
MS (ESI) [M+H]+: 458 MS (ESI) [M+H]": 456
Compound 90:
Methyl-(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate C31 H30N4O3 calc. 506.61
MS (ESI) [M+H]+: 507 MS (ESI) [M+H]": 505
Compound 91 :
Methyl-(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate
C32H32N4O3 calc. 520.64
MS (ESI) [M+H]+: 521 MS (ESI) [M+H]": 519
7
Compound 92:
Methyl-(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate
C31 H30N4O3 calc. 506.61
MS (ESI) [M+H]+: 507 MS (ESI) [M+H]": 505
Compound 93:
Methyl-(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylate
C32H32N4O3 calc. 520.64
MS (ESI) [M+H]+: 521 MS (ESI) [M+H]": 519
Compound 94:
Methyl-(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylate
C25H27N3O3 calc. 417.51
MS (ESI) [M+H]+: 418 MS (ESI) [M+H]": 416 Compound 95:
Methyl-(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylate
C26H29N3O3 calc. 431 .54
MS (ESI) [M+H]+: 432 MS (ESI) [M+H]": 430
Compound 96:
Methyl-(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylate
C29H35N3O3 calc. 473.62
MS (ESI) [M+H]+: 474 MS (ESI) [M+H]": 472
Compound 97:
Methyl-(3Z)-2-oxo-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene)indoline-5-carboxylate
C25H29N3O3 calc. 419.53
MS (ESI) [M+H]+: 420 MS (ESI) [M+H]" : 419
Compound 98:
7
Methyl-(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amin
oxoindoline-5-carboxylate
C26H31 N3O3 calc. 433.56
MS (ESI) [M+H]+: 434 MS (ESI) [M+H]": 432
Step D
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)m
2-oxoindoline-5-carboxylic acid
99
10 mmol (4.83g) Methyl-(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amin (pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylate was suspended in mixture of 50 ml metanol and 10 ml water and 20 mmol (0.80 g) NaOH was added and stirred at 60 °C for 4-6 hours. The reaction was monitored by TLC. After the completion the pH was adjusted to pH = 4-5 and the precipitated product was filtered off.
C27H27N5O3 calc. 469.55
MS (ESI) [M+H]+: 470 MS (ESI) [M+H]": 468 The following compounds were obtained according to the procedure described by example 2, step D
Compound 100:
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]- 2-oxoindoline-5-carboxylic acid
C27H27N5O3 calc. 469.55
MS (ESI) [M+H]+: 470 MS (ESI) [M+H]" : 468
Compound 101 :
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-2- oxoindoline-5-carboxylic acid
C26H24N4O4 calc. 456.51
MS (ESI) [M+H]+: 457 MS (ESI) [M+H]": 455 Compound 102:
(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyndin-3- yl)methylene]indoline-5-carboxylic acid
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 456 MS (ESI) [M+H]": 453
Compound 103:
(3Z)-2-oxo-3-(pyridin-3-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid
C26H24N4O3 calc. 440.51
MS (ESI) [M+H]+: 441 MS (ESI) [M+H]": 439 Compound 104:
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-
2-oxoindoline-5-carboxylic acid
C27H27N5O3 calc. 469.55
MS (ESI) [M+H]+: 470 MS (ESI) [M+H]": 468
Compound 105:
(3Z)-2-oxo-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-3- yl)methylene]indoline-5-carboxylic acid
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]": 453
Compound 106:
(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-2- yl)methylene]indoline-5-carboxylic acid
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]": 456
Compound 107:
(3Z)-2-oxo-3-(pyridin-2-yl{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene) indoline-5-carboxylic acid
C26H24N4O3 calc. 440.51
MS (ESI) [M+H]+: MS (ESI) [M+H]":
7
Compound 108:
(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-4-yl)methylen indoline-5-carboxylic acid
C27H26N4O3 calc. 454.53
MS (ESI) [M+H]+: 455 MS (ESI) [M+H]": 453
Compound 109:
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2- oxoindoline-5-carboxylic acid
C26H24N4O4 calc. 456.51
MS (ESI) [M+H]+: 457 MS (ESI) [M+H]": 455
Compound 110:
(3Z)-2-oxo-3-(pyridin-4-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid
C26H24N4O3 calc. 440.51
MS (ESI) [M+H]+: 441 MS (ESI) [M+H]": 439
Compound 111 :
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2- oxoindoline-5-carboxylic acid
C26H26N4O3 calc. 442.52
MS (ESI) [M+H]+: 443 MS (ESI) [M+H]": 441
Compound 112:
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2- oxoindoline-5-carboxylic acid
C26H26N4O3 calc. 442.52
MS (ESI) [M+H]+: 443 MS (ESI) [M+H]": 441 Compound 113:
(3Z)-2-oxo-3-[{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylic acid
C25H23N3O3S calc. 445.54
MS (ESI) [M+H]+: 446 MS (ESI) [M+H]": 444
Compound 114:
(3Z)-2-oxo-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline- 5-carboxylic acid
C26H25N3O3S calc. 459.57
MS (ESI) [M+H]+: 460 MS (ESI) [M+H]": 458
Compound 115:
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylen
oxoindoline-5-carboxylic acid
C25H23N3O4S calc. 461 .54
MS (ESI) [M+H]+: 462 MS (ESI) [M+H]" : 460 Compound 116:
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3-thienyl)methylene]-2- oxoindoline-5-carboxylic acid
C26H26N4O3S calc. 474.59
MS (ESI) [M+H]+: 475 MS (ESI) [M+H]" : 473
Compound 117:
(3Z)-2-oxo-3-[{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxylic acid
C25H23N3O3S calc. 445.54
MS (ESI) [M+H]+: 446 MS (ESI) [M+H]" : 444
Compound 118:
(3Z)-2-oxo-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline- 5-carboxylic acid
C26H25N3O3S calc. 459.57
MS (ESI) [M+H]+: 460 MS (ESI) [M+H]" : 458
Compound 119:
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3-thienyl)methylene]-2- oxoindoline-5-carboxylic acid
C26H26N4O3S calc. 474.59
MS (ESI) [M+H]+: 475 MS (ESI) [M+H]" : 473
Compound 120:
(3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2- oxoindoline-5-carboxylic acid
C25H23N3O4S calc. 461 .54
MS (ESI) [M+H]+: 462 MS (ESI) [M+H]" : 460
7
Compound 121 :
(3Z)-3-(3-furYl{[4-(pyrrolidin-1 -ylm
carboxylic acid
C25H23N3O4 calc. 429.48
MS (ESI) [M+H]+: 430 MS (ESI) [M+H]" : 431
Compound 122:
(3Z)-3-(3-furyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxoindoline-5- carboxylic acid
C26H25N3O4 calc. 443.51
MS (ESI) [M+H]+: 444 MS (ESI) [M+H]" : 442
Compound 123:
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid
C25H25N5O3 calc. 443.51
MS (ESI) [M+H]+: 444 MS (ESI) [M+H]" : 442
Compound 124:
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid
C26H27N5O3 calc. 457.54
MS (ESI) [M+H]+: 458 MS (ESI) [M+H]" : 456 Compound 125:
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid
C25H25N5O3 calc. 443.51
MS (ESI) [M+H]+: 444 MS (ESI) [M+H]" : 442
Compound 126:
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxoindoline-5-carboxylic acid
C30H28N4O3 calc. 492.58
MS (ESI) [M+H]+: 493 MS (ESI) [M+H]" : 491
Compound 127:
7
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene]-
2-oxoindoline-5-carboxylic acid
C31 H30N4O3 calc. 506.61
MS (ESI) [M+H]+: 507 MS (ESI) [M+H]" : 504
Compound 128:
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxoindoline-5-carboxylic acid
C30H28N4O3 calc. 492.58
MS (ESI) [M+H]+: 493 MS (ESI) [M+H]" : 491
Compound 129:
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxoindoline-5-carboxylic acid
C31 H30N4O3 calc. 506.61
MS (ESI) [M+H]+: 507 MS (ESI) [M+H]" : 505
Compound 130:
(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylic acid
C24H25N3O3 calc. 403.49
MS (ESI) [M+H]+: 404 MS (ESI) [M+H]" : 402
Compound 131 :
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylic acid
C25H27N3O3 calc. 417.51
MS (ESI) [M+H]+: 418 MS (ESI) [M+H]" : 416 Compound 132:
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxoindoline-5-carboxylic acid
C28H33N3O3 calc. 459.59
MS (ESI) [M+H]+: 460 MS (ESI) [M+H]" : 458
Compound 133:
(3Z)-2-oxo-3-(1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)indoline-5- carboxylic acid
C24H27N3O3 calc. 405.50
MS (ESI) [M+H]+: 406 MS (ESI) [M+H]" : 404
Compound 134:
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2- oxoindoline-5-carboxylic acid
C25H29N3O3 calc. 419.53
MS (ESI) [M+H]+: 420 MS (ESI) [M+H]" : 418 Step E
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4-yl)methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
135
0.5 mmol (230 mg) (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino) (pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylic acid, 0.5 mmol (68 mg) (1 R)-1 - phenylpropan-1 -amine, 0.6 mmol (0.450 g) HATU/HBTU , 1 .5 mmol (0.19 g, 0.26 ml)DIPEA were stirred in 8 ml dry DMF at 50 °C for 2-5 hours. The solvent was removed under reduced pressure and the residue was taken up with 20-30 ml sat. K2CO3 and extracted with 3x30 ml ethyl-acetate. The organic layer was separated and and dried over MgSO4. The dessicant was filtered off and the solvent was removed under reduced pressure. The product was purified by column chromatography (Kieselgel, chloroform/methanol (sat. with NH3 15:1 )
C36H38N6O2 calc: 586.74
MS (ESI) [M+H]+: 587 MS (ESI) [M+H]" : 585
The following compounds were obtained according to the procedure described by example 2, step E (3Z)-/V-benzyl-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxoindoline-5-carboxamide
136
Connpound 136 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and benzyl-amine according to Step E.
C34H34N6O2 calc: 558.69
MS (ESI) [M+H]+: 559 MS (ESI) [M+H]" : 557
(3Z)-/V-(4-fluorobenzyl)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5-carboxamide
137 C34H33FN6O2 calc: 576.68
MS (ESI) [M+H]+: 577 MS (ESI) [M+H]" : 575
Connpound 137 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and benzyl-amine according to Step E.
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)m
2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
138
Compound 138 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl} amino)(pyridin-3-yl)nnethylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C35H36N6O2 calc: 572.72
MS (ESI) [M+H]+: 573 MS (ESI) [M+H]" : 571
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)meth
2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
139
Connpound 139 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl} amino)(pyridin-3-yl)nnethylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C36H38N6O2 calc: 586.74
MS (ESI) [M+H]+: 587 MS (ESI) [M+H]" : 585
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
Compound 140 was obtained by reaction (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
141
Compound 141 was obtained by reaction (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 S)-1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556 (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
142
Compound 142 was obtained by reaction (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]- : 570
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
Connpound 143 was obtained by reaction (3Z)-3-
[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H37N5O2 calc: 559.72
MS (ESI) [M+H]+: 560 MS (ESI) [M+H]" : 558
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-ox
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
144
Connpound 144 was obtained by reaction (3Z)-3-[({4-[(diethylamino)methyl]phenyl} amino)(pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C34H35N5O2 calc: 545.69
MS (ESI) [M+H]+: 546 MS (ESI) [M+H]" : 544
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
Connpound 145 was obtained by reaction (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 S)-1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570
5
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-2
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
146
Compound 146 was obtained by reaction and (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C34H33N5O3 calc: 559.67
MS (ESI) [M+H]+: 560 MS (ESI) [M+H]" : 558
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
147
Compound 147 was obtained by reaction of (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H35N5O3 calc: 573.70
MS (ESI) [M+H]+: 574 MS (ESI) [M+H]" : 572
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
148
Connpound 148 was obtained by reaction of (3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl} amino)(pyridin-3-yl)nnethylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C35H36N6O2 calc: 572.72
MS (ESI) [M+H]+: 573 MS (ESI) [M+H]" : 571
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3-yl)meth
2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
149
Connpound 149 was obtained by reaction of (3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C36H38N6O2 calc: 586.74
MS (ESI) [M+H]+: 587 MS (ESI) [M+H]" : 585 (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
150
Compound 150 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]annino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
151
Compound 151 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 S)-1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide
152
Compound 152 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 S)-1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Ζ)-2-οχο-Λ/-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxam
153
Connpound 153 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxylic acid and (1 R)- 1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
154
Connpound 154 was obtained by reaction of and and according to (3Z)-2-oxo-3 [{[4-(piperidin-1 -ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5- carboxylic acid and (1 R)-1 -phenylethanamine Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]"
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
155
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570
Compound 155 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)nriethylene]indoline-5-carboxylic acid and (1 R)- 1 -phenylpropan-1 -amine according to Step E. (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
156
Compound 156 was obtained by reaction of (3Z)-2-oxo-3-(pyridin-2-yl{[3- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R)- 1 -phenylethanamine according to Step E.
C34H33N5O2 calc: 543.67
MS (ESI) [M+H]+: 544 MS (ESI) [M+H]"
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
157
Compound 157 was obtained by reaction of (3Z)-2-oxo-3-(pyridin-2-yl{[3- (pyrrolidin-1 -ylmethyl)phenyl]annino}nnethylene)indoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556 (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
158
Compound 158 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino} (pyridin-2-yl)methylene]indoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide
Connpound 159 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxylic acid and (1 R)- 1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4-yl)me
2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
160
Connpound 160 was obtained by reaction of and (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C35H36N6O2 calc: 572.72
MS (ESI) [M+H]+: 573 MS (ESI) [M+H]" : 571
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
161
Connpound 161 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxylic acid and (1 R)- 1 -phenylethanamine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]"
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
162
Compound 162 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]annino} (pyridin-4-yl)methylene]indoline-5-carboxylic acid and (1 S)-1 -phenylpropan-1 -amine according to Step E.
C36H37N5O2 calc: 571 .73
MS (ESI) [M+H]+: 572 MS (ESI) [M+H]" : 570 (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
163
Compound 163 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxylic acid and (1 R)- 1 -phenylethanamine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide
164
Compound 164 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxylic acid and (1 S)- 1 -phenylpropan-1 -amine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
165
Compound 165 was obtained by reaction of (3Z)-3-[({4-
[(diethylamino)methyl]phenyl}amino) (pyridin-4-yl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C34H35N5O2 calc: 545.69
MS (ESI) [M+H]+: 546 MS (ESI) [M+H]" : 544
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
166
Compound 166 was obtained by reaction of (3Z)-3-[({4- [(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methylene]-2-oxoindoline-5- carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E. C35H37N5O2 calc. 559.72
MS (ESI) [M+H]+: 560 MS (ESI) [M+H]" : 558
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
167
Compound 167 was obtained by reaction of (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C34H33N5O3 calc: 559.67
MS (ESI) [M+H]+: 560 MS (ESI) [M+H]" : 558
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
168
Compound 168 was obtained by reaction of (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H35N5O3 calc: 573.70
5
MS (ESI) [M+H]+: 574 MS (ESI) [M+H]" :572
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
169
Compound 169 was obtained by reaction of (3Z)-2-oxo-3-(pyridin-4-yl{[4 (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R) 1 -phenylpropan-1 -amine according to Step E.
C35H35N5O2 calc: 557.70
MS (ESI) [M+H]+: 558 MS (ESI) [M+H]" : 556
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
170
Compound 170 was obtained by reaction of (3Z)-2-oxo-3-(pyridin-4-yl{[4 (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)indoline-5-carboxylic acid and (1 R) 1 -phenylethanamine according to Step E.
C34H33N5O2 calc: 543.67
MS (ESI) [M+H]+: 544 MS (ESI) [M+H]"
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxamide
171
Compound 171 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C33H32N4O2S calc: 548.71
MS (ESI) [M+H]+: 549 MS (ESI) [M+H]" : 547 (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxannide
172
Compound 172 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E.
C34H34N4O2S calc.:562.74
MS (ESI) [M+H]+: 563 MS (ESI) [M+H]" : 561
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxamide
173
Compound 173 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C34H34N4O2S calc: 562.74
MS (ESI) [M+H]+: 563 MS (ESI) [M+H]" : 561
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxannide
174
Compound 174 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and(1 R)-1 phenylpropan-1 -amine according to Step E.
C35H36N4O2S calc: 576.77
MS (ESI) [M+H]+: 577 MS (ESI) [M+H]" : 575
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
175
Compound 175 was obtained by reaction of (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C33H32N4O3S calc: 564.71
MS (ESI) [M+H]+: 565 MS (ESI) [M+H]"
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxo- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
176
Connpound 176 was obtained by reaction of (3Z)-3-[{[4-(morpholin-4- ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C34H34N4O3S calc: 578.74
MS (ESI) [M+H]+: 579 MS (ESI) [M+H]" : 577
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phe^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
177
Connpound 177 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C34H35N5O2S calc: 577.75
MS (ESI) [M+H]+: 578 MS (ESI) [M+H]" : 576
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phe^
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
178
Connpound 178 was obtained by reaction of (3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H37N5O2S calc: 591 .78
MS (ESI) [M+H]+: 592 MS (ESI) [M+H]" : 590 (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxannide
179
Connpound 179 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(pyrrolidin-1 ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 phenylethanamine according to Step E.
C33H32N4O2S calc: 548.71
MS (ESI) [M+H]+: 549 MS (ESI) [M+H]" : 547
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxamide
180
Compound 180 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E. C34H34N4O2S calc: 562.74
MS (ESI) [M+H]+: 563 MS (ESI) [M+H]" : 561
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxamide
181
Compound 181 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 phenylethanamine according to Step E.
C34H34N4O2S calc: 562.74
MS (ESI) [M+H]+: 563 MS (ESI) [M+H]" : 561
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 -ylmethyl)phenyl]amino}(3- thienyl)methylene]indoline-5-carboxamide
182
Compound 182 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxylic acid and (1 R)-1 phenylpropan-1 -amine according to Step E.
C35H36N4O2S calc: 576.77
MS (ESI) [M+H]+: 577 MS (ESI) [M+H]"
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)me
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxannide
183
Connpound 183 was obtained by reaction of (3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E. C34H35N502S calc: 577.75
MS (ESI) [M+H]+: 578 MS (ESI) [M+H]" : 576
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]^^
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
184
Connpound 184 was obtained by reaction of (3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H37N5O2S calc: 591 .78
MS (ESI) [M+H]+: 592 MS (ESI) [M+H]" : 590
(3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]arnino}(3-thienyl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
185
Compound 185 was obtained by reaction of (3Z)-3-[{[3-(morpholin-4- ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C33H32N4O3S calc: 564.71
MS (ESI) [M+H]+: 565 MS (ESI) [M+H]" : 563 (3Z)-3-[{[3-(morpholin-4-ylmethyl)pheny^
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
186
Compound 186 was obtained by reaction of (3Z)-3-[{[3-(morpholin-4- ylmethyl)phenyl]amino}(3-thienyl)methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C34H34N4O3S calc: 578.74
MS (ESI) [M+H]+: 579 MS (ESI) [M+H]"
(3Z)-3-(3-furyl{[4-(py rrol id in- 1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
187
Compound 187 was obtained by reaction of (3Z)-3-(3-furyl{[4-(pyrrolidin-1 - ylmethyl)phenyl]annino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C34H34N4O3 calc: 532.65
MS (ESI) [M+H]+: 533 MS (ESI) [M+H]": 531 (3Z)-3-(3-furyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
188
Compound 188 was obtained by reaction of (3Z)-3-(3-furyl{[4-(piperidin-1 ylmethyl)phenyl]amino}methylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 phenylpropan-1 -amine according to Step E.
C35H36N4O3 calc: 560.70
MS (ESI) [M+H]+: 561 MS (ESI) [M+H]" : 559
(3Z)-3-(2-furyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
Connpound 189 was obtained by reaction of (3Z)-3-(2-furyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)-2-oxoindoline-5-carboxylic acid and according to (1 R)-1 -phenylpropan-1 -amine preparation of according to, Step E.
C35H36N4O3 calc: 560.70
MS (ESI) [M+H]+: 561 MS (ESI) [M+H]" : 559
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline-5- carboxamide
190
Connpound 190 was obtained by reaction of and according to preparation of (3Z)- 3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2- oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine, according to Step E.
C33H34N6O2 calc: 546.68
MS (ESI) [M+H]+: 547 MS (ESI) [M+H]" : 545
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5- carboxamide
191
Compound 191 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
5
C34H36N6O2 calc: 560.71
MS (ESI) [M+H]+: 560 MS (ESI) [M+H]" : 558 (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]in
carboxamide
192
Connpound 192 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C34H36N6O2 calc: 560.71
MS (ESI) [M+H]+: 561 MS (ESI) [M+H]" : 559
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5- carboxamide
193
Compound 193 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H38N6O2 calc: 574.73
MS (ESI) [M+H]+: 575 MS (ESI) [M+H]" : 573
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]in
carboxamide
194
Connpound 194 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E. C33H34N6O2 calc: 546.68
MS (ESI) [M+H]+: 547 MS (ESI) [M+H]" : 545
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5- carboxamide
195
Compound 195 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C34H36N6O2 calc: 560.71
MS (ESI) [M+H]+: 561 MS (ESI) [M+H]" : 559 (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5- carboxamide
7
196
Connpound 196 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid (1 R)-1 -phenylethanamine and according to Step E.
C34H36N6O2 calc: 560.71
MS (ESI) [M+H]+: 561 MS (ESI) [M+H]" (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5- carboxamide
197
Connpound 197 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3- (piperidin-1 -ylmethyl)phenyl]amino}nnethylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C35H38N6O2 calc: 574.73
MS (ESI) [M+H]+: 575 MS (ESI) [M+H]" : 573
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
198
Connpound 198 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C38H37N5O2 calc: 595.75
MS (ESI) [M+H]+: 596 MS (ESI) [M+H]" : 594 (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
199
Connpound 199 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C39H39N5O2 calc: 609.78
MS (ESI) [M+H]+: 610 MS (ESI) [M+H]" : 608
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
Connpound 200 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C39H39N5O2 calc: 609.78
MS (ESI) [M+H]+: 610 MS (ESI) [M+H]" : 608
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
201
Connpound 201 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4- (piperidin-1 -ylmethyl)phenyl]amino}nnethylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C40H41 N5O2 calc: 623.81
MS (ESI) [M+H]+: 624 MS (ESI) [M+H]" : 622 (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
202
Compound 202 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C38H37N5O2 calc: 595.75
MS (ESI) [M+H]+: 596 [M+H]" : 594
(3Z)-3-[(1 -methyl-1 /-/-indol-5-yl){[3-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
203
Connpound 203 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3- (pyrrolidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylpropan-1 -amine according to Step E.
C39H39N5O2 calc: 609.78
MS (ESI) [M+H]+: 610 [M+H]" : 608
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
204
Compound 204 was obtained by reaction of (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid and (1 R)-1 -phenylethanamine according to Step E.
C39H39N5O2 calc: 609.78
MS (ESI) [M+H]+: 610 [M+H]" (3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
205
Connpound 205 was obtained by reaction of (3Z)-3-[(1 -methyl-1 /-/-indol-5-yl){[3- (piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxylic acid (1 R)-1 -phenylpropan-1 -amine according to Step E.
C40H41 N5O2 calc: 623.81
MS (ESI) [M+H]+: 624 [M+H]- : 622 (3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
206
Connpound 206 was obtained by reaction of (3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 ylmethyl)phenyl]amino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 phenylethanamine according to Step E.
C32H34N4O2 calc: 506.65
MS (ESI) [M+H]+: 507 [M+H]" : 505
(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
Connpound 207 was obtained by reaction of (3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 - ylmethyl)phenyl]amino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E.
C33H36N4O2 calc: 520.68
MS (ESI) [M+H]+: 521 [M+H]" : 519 (3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
208
Connpound 208 was obtained by reaction of (3Z)-3-(cyclopropyl{[4-(piperidin-1 ylmethyl)phenyl]amino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 phenylethanamine according to Step E.
C33H36N4O2 calc: 520.68
MS (ESI) [M+H]+: 521 [M+H]" : 519
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
209
Connpound 209 was obtained by reaction of (3Z)-3-(cyclopropyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E.
C34H38N4O2 calc: 534.71
MS (ESI) [M+H]+: 535 [M+H]" : 533 (3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylm
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
210
Connpound 210 was obtained by reaction of (3Z)-3-(cyclohexyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C36H42N4O2 calc: 562.76
MS (ESI) [M+H]+: 563 [M+H]" : 561
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethy^
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
211
Connpound 211 was obtained by reaction of (3Z)-3-(cyclohexyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}nnethylene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E.
C37H44N4O2 calc: 576.79
MS (ESI) [M+H]+: 577 [M+H]" : 575
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene) indoline-5-carboxamide
212
Connpound 212 was obtained by reaction of (3Z)-2-oxo-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]annino}propylidene)indoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C32H36N4O2 calc. 508.67
MS (ESI) [M+H]+ 509 [M+H]" :507 (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene)indoline-5-carboxamide
213
Connpound 213 was obtained by reaction of (3Z)-2-oxo-3-(1 -{[4-(piperidin-1 ylmethyl)phenyl]amino}propylidene)indoline-5-carboxylic acid and (1 R)-1 phenylpropan-1 -amine according to Step E.
C33H38N4O2, calc: 522.70
MS (ESI) [M+H]+: 523 [M+H]" : 521
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2-oxo-W^ [(1 R)-1 -phenylethyl]indoline-5-carboxamide
214
Compound 214 was obtained by reaction of (3Z)-3-(2-methyl-1 -{[4-(piperidin-1 - ylmethyl)phenyl]annino}propylidene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylethanamine according to Step E.
C33H38N4O2, calc. 522.70
MS (ESI) [M+H]+: 523 [M+H]" : 521
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethy^
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
215
Compound 215 was obtained by reaction of (3Z)-3-(2-methyl-1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene)-2-oxoindoline-5-carboxylic acid and (1 R)-1 - phenylpropan-1 -amine according to Step E.
C34H40N4O2, calc. 536.72
MS (ESI) [M+H]+: 537 [M+H]" : 535 (3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
216
C36H35FN4O2, Mw calc. :574.3
MS(ESI): m/z (M+H)+575
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
217
C37H37FN4O2, Mw cal. :588.3
MS(ESI): m/z (M+H)+589
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -y^
1 -(4-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
C37H37FN4O3, Mw calc. :604
MS(ESI): m/z (M+H)+605
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -y^
1 -(3-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
219
C37H37FN4O3, Mw calc.:604.3
MS(ESI): m/z (M+H)+605
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperid ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
7
220
C36H34CIFN4O2, Mw calc. :608.2
MS(ESI): m/z (M+H)+609
(3Z)-/V-[(1 R)-1 -(4-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperid ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
221
C36H34CIFN4O2, Mw calc. :608.2
MS(ESI): m/z (M+H)+609
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -y^
1 -(4-methylphenyl)ethyl]-2-oxoindoline-5-carboxannide
C37H37FN4O2, Mw calc. :588.3
MS(ESI): m/z (M+H)+589
(3Z)-/V-[1 -(3,4-difluorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperid ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
223
C37H37FN4O2, Mw calc. : 624.3
MS(ESI): m/z (M+H)+625
(3Z)-/V-[1 -(3-chlorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
224
C37H36CIFN4O2, Mw calc. :622.2
MS(ESI): m/z (M+H)+623
(3Z)-3-[({2-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
225
MS (ESI) [M+H]+: 547
(3Z)-/V-benzyl-3-{[(2-{[(ethylamino)carbonothioyl]amino}phenyl)amino]
(phenyl)methylene}-2-oxoindoline-5-carboxannide
226
MS (ESI) [M+H]+: 549
(3Z)-3-{[(2-{[(3-chlorophenyl)carb^
2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
MS (ESI) [M+H]+: 629
(3Z)-3-{[(2-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](ph
methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
228
MS (ESI) [M+H]+: 625
(3Z)-3-{[(2-{[(4- hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-/V^ 1 -phenylpropyl]indoline-5-carboxamide
229
MS (ESI) [M+H]+: 625 (3Z)-3-[{[2-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(phenyl)nnethylene]-2-oxo-/\/- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
230
MS (ESI) [M+H]+: 559
(3Z)-3-[({2-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indol carboxamide
231
MS (ESI) [M+H]+: 648
(3Z)-3-[({3-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide
232
MS (ESI) [M+H]+: 561
(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)methy^ 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
233
MS (ESI) [M+H]+: 643
(3Z)-3-{[(3-{[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)met^ oxo-/V-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
234
MS (ESI) [M+H]+: 563
(3Z)-3-{[(3-{[(4- hydroxyphenyl)carbamoyl]amino}phenyl)amino](ph^
1 -phenylpropyl]indoline-5-carboxamide
235
MS (ESI) [M+H]+: 625
(3Z)-3-[{[3-({[4-(2,5-dioxoimidazolidin-1 -yl)phenyl]carbamoyl}amino)phenyl]^ (phenyl)methylene]-2-oxo-/V-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
236
MS (ESI) [M+H]+: 693
(3Z)-3-[({3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-3-ylmethylene)imidazolidin-1 - yl]phenyl}carbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 S)-1 - phenylethyl]indoline-5-carboxamide
MS (ESI) [M+H]+: 782 (3Z)-3-{[(4-{[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)meth oxo-/V-[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
238
MS (ESI) [M+H]+: 577 (3Z)-3-{[(4-{[(3-chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)m
2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
239
MS (ESI) [M+H]+: 643
(3Z)-3-{[(4-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](ph
methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
240
MS (ESI) [M+H]+: 625
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(pyridin-4-yl)methylene]-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
241
MS (ESI) [M+H]+: 560
(3Z)-3-[({4-[(4Z)-4-benzylidene-2,5-dioxoimidazolidin-1 -yl]phenyl}amino)(p yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
242
MS (ESI) [M+H]+: 648
(3Z)-3-{[(2-{[(ethylamino)carbonothioyl]am
2-οχο-Λ/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
243
MS (ESI) [M+H]+: 583
(3Z)-3-[({2-[(1 ,3-benzodioxol-5- ylcarbamoyl)amino]benzyl}annino)(phenyl)methylene] -2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
244
MS (ESI) [M+H]+: 667 (3Z)-3-[({3-[(ethylcarbamoyl)amino]benzyl}amino)(pyridin-3-yl)methylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
245
MS (ESI) [M+H]+: 562
(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}benzyl)amino](pyridin-3- yl)methylene}-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
246
MS (ESI) [M+H]+: 644
(3Z)-3-[{[3-(2,5-dioxoimidazolidin-1 -yl)be^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
247
MS (ESI) [M+H]+: 574
1 ο
(3Z)-3-[({3-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]benzyl}amino)(pyridin-3-yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoli carboxamide
MS (ESI) [M+H]+: 663
(3Z)-/V-benzyl-3-[{[4-({[(3-chlorophenyl)amino]carbonothioyl}annino)benzyl] (phenyl)methylene]-2-oxoindoline-5-carboxannide
249
MS (ESI) [M+H]+: 645 (3Z)-/V-benzyl-3-[{[4-(2,5-dioxoinnidazolidin-1 -yl)benzyl]amino}(phenyl)methylene]- 2-oxoindoline-5-carboxamide
250
MS (ESI) [M+H]+: 559
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)benzyl]amino}(phenyl)methylene]-2-ox
[(1 R)-1 -phenylethyl]indoline-6-carboxamide
251
MS (ESI) [M+H]+: 573
(3Z)-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]benzyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indol carboxamide
252
MS (ESI) [M+H]+: 662
(3Z)-/V-benzyl-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]benzyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
253
MS (ESI) [M+H]+: 648
7
(3Z)-3-{[(2-{2-[(ethylcarbamoyl)amino]
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-7-carboxamide
254
MS (ESI) [M+H]+: 589
(3Z)-3-[{[2-(2-{[(3-chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(pyridi yl)methylene]-2-oxo-/V-[(1 S)-1 -phenylpropyl]indoline-7-carboxannide
255
MS (ESI) [M+H]+: 672
(3Z)-3-{[(2-{3-[(ethylcarbamoyl)amino]phe^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
256
MS (ESI) [M+H]+: 575
(3Z)-3-{[(2-{3-[(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylene oxo-/V-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
257
MS (ESI) [M+H]+: 575
(3Z)-3-[{[2-(3-{[(3- chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(phenyl)methylene]-2-oxo-/V^ [(1 R)-1 -phenylethyl]indoline-5-carboxamide
258
MS (ESI) [M+H]+: 657
(3Z)-/V-benzyl-3-{[(2-{3-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 yl]phenyl}ethyl)amino](phenyl)methylene}-2-oxoindoline-5-carboxamide
259
MS (ESI) [M+H]+: 662
(3Z)-3-{[(2-{4-[(ethylcarbamoyl)amino^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
260
MS (ESI) [M+H]+: 575
(3Z)-3-[{[2-(4-{[(3-chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}
(phenyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
261
MS (ESI) [M+H]+:657
(3Z)-3-{[(3S)-1 -azabicyclo[2.2 ]oct-3-ylamino](phenyl)methylene}-2-oxo-/V-[(1 R)- 1 -phenylethyl]indoline-5-carboxamide
262
MS (ESI) [M+H]+: 536
(3Z)-3-{[(3R)-1-azabicyclo[2 .2]oct-3-ylamino](phenyl)methylene}-2-oxo-/V-[(1R)- 1-phenylethyl]indoline-5-carboxamide
263
MS (ESI) [M+H]+: 536
(3Z)-3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-/V-benzyl-2- oxoindoline-5-carboxamide
264
MS (ESI) [M+H]+:522
(3Z)-3-{[(3S)-1-azabicyclo[2.2 ]oct-3-ylamino](phenyl)methylene}-2-oxo-/V-[(1R)- 1-phenylethyl]indoline-5-carboxamide
265
MS (ESI) [M+H]+: 494
(3Z)-3-{[(3R)-1-azabicyclo[2 .2]oct-3-ylamino](phenyl)methylene}-2-oxo-/V-[(1R)- 1-phenylethyl]indoline-5-carboxamide
MS (ESI) [M+H]+: 494
(3Z)-3-{[(3S)-1 -azabicyclo[2.2 ]oct-3-ylamino](phenyl)methylene}-2-oxo-/V-[(1 R)- 1 -phenylpropyl]indoline-6-carboxamide
MS (ESI) [M+H]+: 508 (3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](pyridin-4-yl)methylene}-2-oxo-A/- [(1 R)-1 -phenylpropyl]indoline-6-carboxamide
MS (ESI) [M+H]+: 509
(3Z)-3-{[(3/?)-1 -azabicyclo[2.2.2]oct-3-ylamino](3-thienyl)methylene}-A/-benzyl-2- oxoindoline-6-carboxamide
Part B: Biological evaluation Part B: Biological evaluation
Methods and Material
The activity of the compounds described in the present invention was determined by the following kinase assays.
In vitro Akt1 assay
The inhibition of Akt1 by the compounds described in the present invention were determined measuring the phosphorylation of a fluorescently-labeled peptide (TAMRA-peptide) by human Akt1 kinase by fluorescent polarization using a commercially available IMAP Screening Express Assay Kit (Molecular Devices).
Akt1 kinase assays were performed in low protein binding 384-well plates (Corning). Test compounds were diluted in 100% DMSO to 5 mM stock concentration and then further dilutions were made in H2O or 100% DMSO to desirable concentrations.
Each reaction consisted of 5 nM enzyme: Akt1 kinase, 400 nM TAMRA-peptide (5- TAMRA-GRTGRRNSI-COOH; Genecust), 40 μΜ ATP and kinase buffer: 20 mM MES pH6, 1 mM DTT, 10 mM MgCI2, 2 mM MnCI2, 0.01 VA/% TritonX (all reagents from Sigma-Aldrich).
For each reaction, 4 or 6 μΙ containing TAMRA-peptide, ATP and kinase buffer were combined with 2 μΙ diluted compound in H2O or 0.02 μΙ compound in 100% DMSO. The kinase reaction was started by the addition of 2 μΙ diluted enzyme. The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 15 μΙ IMAP beads (1 :400 beads in progressive (75% buffer A,
25% buffer B) 1x buffer). After an additional hour, fluorescent polarization (Ex: 550-10 nm, Em: 590-10 nm, Dich: 561 nm) was measured using an Analyst GT (Molecular Devices). In vitro Ack1 assay
The activity of the compounds described in the present invention can be determined by the following kinase assay, which measures the generation of ADP by human Ack1 kinase by fluorescent polarization using a commercially available TranScreener ADP2 FP Assay Kit (BellBrook Labs).
Ack1 kinase assays were performed in low protein binding 384-well plates (Corning). Test compounds were diluted in 100% DMSO to 5 mM stock concentration and then further dilutions were made in H2O or 100% DMSO to desirable concentrations.
Each reaction consisted of 5 nM enzyme: Ack1 kinase, Poly Glu-Tyr (4:1 ) (Sigma), 3.5 μΜ ATP and kinase buffer: 20 mM HEPES pH7.5, 1 mM DTT, 2 mM MgCI2, 0.4 mM MnCI2, 0.01 V7V% Tween20 (all reagents from Sigma-Aldrich)
For each reaction, 4 or 6 μΙ containing Poly Glu-Tyr (4:1 ), ATP and kinase buffer were combined with 2 μΙ diluted compound in H2O or 0.02 μΙ compound in 100% DMSO. The kinase reaction was started by the addition of 2 μΙ diluted enzyme. The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by addition of 8 μΙ ADP detection mixture (1 x) (1 x Detection buffer + 4.78 Mg/ml ADP2 Ab + 4 nM ADP Alexa633 Tracer). After an additional hour, fluorescent polarization (Ex: 630-35 nm, Em: 680-30 nm, Dich: 650 nm) was measured using an Analyst GT (Molecular Devices).
In vitro Clk1 assay
The activity of the compounds described in the present invention can be determined by the following kinase assay, which measures the phosphorylation of a fluorescently-labeled peptide by human Clk1 kinase by fluorescent polarization using a commercially available IMAP Screening Express Assay Kit (Molecular Devices).
Clk1 kinase assays were performed in low protein binding 384-well plates (Corning). Test compounds were diluted in 100% DMSO to 5 mM stock concentration and then further dilutions were made in H2O or 100% DMSO to desirable concentrations.
Each reaction consisted of 4 nM enzyme: Clk1 kinase domain, 400 nM TAMRA- AFRREWSPGKEAKK-NH2 (Genecust), 0.45 μΜ ATP (Sigma) and kinase buffer: 20 mM TRIS pH 8, 1 mM DTT, 0.4 mM MgCI2, 0.4 mM MnCI2, 0.01 VA/% Tween20 (all reagents from Sigma-Aldrich)
For each reaction, 4 or 6 μΙ containing TAMRA-peptide, ATP and kinase buffer were combined with 2 μΙ diluted compound in H2O or 0.02 μΙ compound in 100% DMSO. The kinase reaction was started by the addition of 2 μΙ diluted enzyme. The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 15 μΙ IMAP beads (1 :600 beads in progressive (80 % buffer A, 20% buffer B) 1x buffer). After an additional hour, fluorescent polarization (Ex: 550-10 nm, Em: 590-10 nm, Dich: 561 nm) was measured using an Analyst GT (Molecular Devices).
Example 3: High throughput screening of chemical compounds to identify small molecules that inhibit influenza virus replication
Human lung epithelial A549 cells were pre-treated on 384 well plates with the various substances in eight different 1 :3 dilutions two hours before infection. Infection was performed using 130 plaque forming units (PFU) of the H1 N1 influenza virus strain A/WSN/33. Subsequently, compounds were re-added at the same concentrations. 36 hours post infection virus-containing supernatants were transferred to Madin-Darby Canine Kidney Epithelial (MDCK) cells, seeded the day before, to quantify the virus titer. The MDCK cells were fixed with formaldehyde 7 hours post infection and the percentage of infected to non-infected cells was quantified by staining cells with an influenza virus specific antibody (recognizing the viral nucleoprotein) and with Hoechst dye (to label all cell nuclei), followed by automated microscopy and single object analysis. Based on the results of the eight different dilutions dose-response-curves could be calculated and the IC50 values of each compound were determined. All experiments were performed within the BSL-3 lab using the FXP Laboratory Automation Workstation (Beckman Coulter). The whole screening process is illustrated in Fig. 1 .
To be able to exclude possible cytotoxic effects all compounds were additionally tested using the 'Cell Proliferation Reagent WST-1 ' (Roche Diagnostics). Therefore, A549 cells were treated with the same concentrations of the various substances and 36 hours later the WST-1 was added to the cells. Finally, the read-out of this test was conducted at 48 hours post treatment using the EnVision Multilabel Reader (PerkinElmer).
5
Cell line
A549 human lung carcinoma cells were cultured in RPMI 1640 medium (Sigma) supplemented with 10% fetal bovine serum (Sigma) and Antibiotic-Antimycotic (Sigma) in tissue culture flasks at 37°C in a humidified 5% CO2 atmosphere. Cells were routinely assayed for mycoplasma contamination.
Cell-based EC50 determination
Two thousand cells were plated in 384-well tissue culture plates, and treated after 24 hours with a 10-point dilution series of the compounds (1 .5 nM-30 uM), using the vehicle, DMSO as control. Cells were incubated for 24 hours after which the relative cell density was determined by CellTiter-Glo Luminescent Cell Viability Assay (Promega). This method determines the number of metabolically active cells in the culture based on quantitation of the ATP present. The luminescent signal was measured with an Analyst GT multimode reader (Molecular Devices).
Table 2: Inhibition of influenza virus replication and relevant kinase activity of different compounds of general formula (I).
Influenza
patent Akt1 inh% Ack1 inh% replication A549 EC50
ID @12.5 uM Akt1 IC50 (uM) @12.5 uM Clk1 IC50 IC50 24h
12 75.1 7.98 18.1 0.21 0.01 6,89
13 60.6 5.94 13.7 0.03 0.16 9,34
18 92.1 0.57 85.9 0.03 <0.01 >30
20 91.6 0.91 72.7 0.01 <0.01 >30
21 78.2 1.70 87.0 0.02 1.48 >30
22 88.0 0.1 1 83.8 0.02 <0.01 >30
23 92.1 0.18 91.1 0.02 <0.01 15,27
24 76.8 0.88 13.7 0.08 0.42 1 1 ,79
27 81.3 2.96 9.9 0.20 2.46 25,35
30 93.0 1.30 80.5 0.01 <0.01 5,98
32 n.d. >12.5 n.d. 0.10 10.06 6,38
35 n.d. 2.51 n.d. 0.01 0.02 4,99
36 n.d. 0.33 n.d. 0.02 <0.01 1 ,77
37 n.d. 2.05 n.d. 0.01 <0.01 2,01
38 n.d. 1.83 n.d. 0.01 <0.01 3,67
39 n.d. 12.29 n.d. 0.01 0.10 18,76
40 n.d. 3.40 n.d. 0.01 <0.01 14,64
Example 4: Assessment of solubility
Samples were diluted in DMSO (control), phosphate buffer pH = 7.4 and pH = 2.0, from 5mM stock solutions (solved in DMSO), with a 120 μΜ final concentration. The samples were incubated for 24 hours at room temperature followed by 30 minutes centrifugation at 3700 rpm. 40 μΙ of the supernatants were injected into HPLC (Waters 2795 Alliance HPLC equipped with Waters 996 PDA Detector (HPLC column: Waters XBridge, RP C18, 3.5 μητι, 4.6 mm x 50 mm; gradient MeCN/H2O, containing 0.1 % HCOOH: 5% MeCN (0.5 min), 5% to 95% MeCN (5 min), 95% MeCN (0.5 min); flow rate: 2.0 ml/min)) and the AUC values (measured on sample specific wavelength) of the buffered samples were divided by the AUC values (same wavelength as buffered samples') of the DMSO control samples.
Table 3: Solubility in water for several compounds according to general formula (I)
Cell lines
HCT-1 16 and HKE3 human colon carcinoma cell lines (two completely identical cell lines that differ only in KRas mutation status) and HepG2 hepatoblastoma-
7 derived cell line were cultured in RPMI 1640 medium (Sigma) supplemented with 10% fetal bovine serum (Sigma) and Antibiotic-Antimycotic (Sigma) in tissue culture flasks at 37°C in a humidified 5% CO2 atmosphere. Cell lines were routinely assayed for mycoplasma contamination.
Cell-based EC50 determination
One thousand cells were plated in 384-well tissue culture plates, and treated after 24 hours with a 10-point dilution series of the compounds (1 .5 nM-30 μΜ), using the vehicle, DMSO as control. Cells were incubated for 72 hours after which the relative cell density was determined by CellTiter-Glo Luminescent Cell Viability Assay (Promega). This method determines the number of metabolically active cells in the culture based on quantitation of the ATP present. The luminescent signal was measured with an Analyst GT multimode reader (Molecular Devices). Table 4. Growth inhibition of human colon carcinoma cell lines
Claims
Claims The compound of general formula (I)
wherein,
y is an integer number selected from: 0, 1 , and 2;
z is an integer number selected from: 0, 1 , and 2;
Q1 represents: -H or -CH3;
Q2 represents: -H, -CH3 or -CH2CH3;
Q3 and Q4 are independently of each other selected from
-CH3, and -OCH3;
1 represents: -CH2CH3, -CH(CH3)2,
R' and R" are independently of each other selected from: -H, -F, -CH3 and -OCH3;
R'" represents: -H or -CH3;
A represents -NH- -O- or -S-;
R2 represents: -H, -CH3 or -C(=O)CH3;
R6, R7; R8, R9 and R10 are independently of each other selected form : -H -CH3, -C2H5, -C3H7) -CH(CH3)2, -C(CH3)3-(CH2)n-CH3) -(CH2)n-C(CH3)2 -CH[(CH2)nCH3]-(CH2)m-CH3, -CH[(CH2)nCH3]-(CH2)m-C(CH3)2 -CH=CH2, -(CH2)n-CH=CH-(CH2)k-CH3, -CH≡CH
-(CH2)n-C≡C-(CH2)k-CH3, -Ph, -(CH2)n-Ph, -(CH2)n-OH
-(CH2)n-NH2, -(CH2)n-O-(CH2)k-CH3, -(CH2)n-NH(CH2)k-CH3, -(CH2)n-N(CH3)2, -(CH2)n-N(C2H5)2 and -(CH2)n-N(CH3)(C2H5);
R11 represents: =CH2, =C(CH3)2,
R14 represents: -H, -F, -CI, -Br, -I, -OH or -OCH3;
k and I are integer numbers and independently of each other selected from: 0, 1 , 2, 3, 4 and 5;
m, n, and q are integer numbers and independently of each other selected from: 1 , 2, 3, 4 and 5;
p is an integer number selected from: 0 and 1 and stereoisomeric forms, E/Z isomers, enantiomers, mixtures of enantiomers, anomers, deoxyforms, diastereomers, mixtures of diastereomers, prodrugs, tautomers, hydrates, solvates and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof, for the use in the treatment of infectious diseases or cancer.
2. Connpound for use according to claim 1 , wherein z represents 0.
Compound for use according to claims 1 and 2, wherein R1 represents
Compound for use according to anyone of claims 1 - 3, wherein ; represents 0.
Compound for use according to anyone of claims 1 - 4, wherein Q represents: -CH3 or -C2H5 and the stereogenic center is (R) configurated.
Compound for use according to claim 1 , wherein y is 0, R2 is selected from
CH3 and R3 represents
Compound for use according to claim 1 , wherein the compound is selected from the following group:
Compound
(3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino} methylene)-
12
A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 -
13
ylmethyl)phenyl] amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V- 14 [(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 -
15
ylmethyl) phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-chlorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 -
16 ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - 17
ylmethyl)phenyl]amino} methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-/V- 18
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-/V-methyl-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 - 19 ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-benzyl-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}
20
methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - 21
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Ζ)-Λ/-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]annino} methylene)indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-fluorophenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-methylphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylme
[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(4-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 S)-1 -(3-methoxyphenyl)ethyl]-2-oxo-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-/V-(3,4-dinnethoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-(3-methoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(phenyl{[4-(piperidin-1 - ylmethyl)phenyl]annino} methylene)indoline-6-carboxannide
(3Z)-2-oxo-3-(phenyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene
[(1 R)-1 -phenylpropyl]indoline-6-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenylethyl]indoline-5-carboxannide
(3Z)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxo-/V-[(1 R)-1 - phenyl propyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide (3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide (3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide (3Z)-/V-(3-methoxybenzyl)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}annino)
(phenyl)methylene]-2-oxoindoline-5-carboxannide
(3Z)-/V-(3,4-dimethoxybenzyl)-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl} amino)(phenyl)methylene]-2-oxoindoline-5-carboxamid (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4- yl)methylene]-2-oxo-A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-/V-benzyl-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxamide
(3Z)-/V-(4-fluorobenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindoline-5- carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxo-A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylen oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({4-[(diethylamino)methyl]phe^
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]am
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]-2^ oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-3- yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[3-(piperidin-1 -
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[3-(piperidin-1 -
152
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 153
ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 154
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 155
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 - 156
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-2-yl{[3-(pyrrolidin-1 - 157
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 158
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 159
ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-carboxamide (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(pyridin-4- 160
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 161
yl methyl )phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 162
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 163
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 164
ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-carboxamide (3Z)-3-[({4-[(diethylamino)methyl]phe^
165
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(diethylamino)methyl]phenyl}amino)(pyridin-4-yl)methyl^ 166
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene 167
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(pyridin-4-yl)methylene 168
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - 169
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(pyridin-4-yl{[4-(pyrrolidin-1 - 170
ylmethyl)phenyl]amino}methylene)indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(pyrrolidin-1 - 171
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(pyrrolidin-1 - 172
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide 173 (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 -
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 -
174
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]amino}(3-thienyl)methylene]-2- 175
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[4-(morpholin-4-ylmethyl)phenyl]am
176
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 177
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({4-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 178
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(pyrrolidin-1 - 179
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(pyrrolidin-1 - 180
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 181
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 182
ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carboxamide (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 183
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({3-[(4-methylpiperazin-1 -yl)methyl]phenyl}amino)(3- 184
thienyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide (3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amm^
185
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[3-(morpholin-4-ylmethyl)phenyl]amm^
186
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(3-fur7l{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-/V- 187
[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(3-fur7l{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2-oxo-W^ 188
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(2-furYl{[4-(piperidin-1 -ylmethyl)ph
189
[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 -
190 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(pyrrolidin-1 -
191 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 -
192 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[4-(piperidin-1 -
193 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 -
194 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(pyrrolidin-1 -
195 ylmethyl)phenyl]annino}nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 -
196 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-pyrazol-4-yl){[3-(piperidin-1 -
197 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 -
198 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(pyrrolidin-1 -
199 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 -
200 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[4-(piperidin-1 -
201 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 -
202 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(pyrrolidin-1 -
203 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -
204 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[(1 -methyl-1 H-indol-5-yl){[3-(piperidin-1 -
205 ylmethyl)phenyl]amino}methylene]-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline- 5-carboxamide
(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2-
206
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(pyrrolidin-1 -ylmethyl)phenyl]amino}methylene)-2- 207
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- 208
oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclopropyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- 209
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(cyclohexyl{[4-(piperidin-1 -ylmethyl)phenyl]amino}methylene)-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]annino}propylidene) indoline-5-carboxamide
(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-(1 -{[4-(piperidin-1 - ylmethyl)phenyl]amino}propylidene)indoline-5-carboxamide
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-(2-methyl-1 -{[4-(piperidin-1 -ylmethyl)phenyl]amino}propylidene)-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- 2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- A/-[(1 R)-1 -(4-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- A/-[(1 R)-1 -(3-methoxyphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[(1 R)-1 -(4-chlorophenyl)ethyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[(4-fluorophenyl){[3-(piperidin-1 -ylmethyl)phenyl]amino}methylene]- A/-[(1 R)-1 -(4-methylphenyl)ethyl]-2-oxoindoline-5-carboxannide
(3Z)-/V-[1 -(3,4-difluorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-/V-[1 -(3-chlorophenyl)propyl]-3-[(4-fluorophenyl){[3-(piperidin-1 - ylmethyl)phenyl]amino}methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[({2-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2- oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-{[(2-{[(ethylamino)carbonothioyl]amino}phenyl)amino] (phenyl)methylene}-2-oxoindoline-5-carboxannide
(3Z)-3-{[(2-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl) methylene}-2-oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl) methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(4- hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[2-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(phenyl)methylen 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({2-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - yl]phenyl}amino)(phenyl)nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide
(3Z)-3-[({3-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-
232
oxo-/V-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(3-
233 chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(3-
234 {[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)methylene}-2- oxo-A/-[(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(4-
235 hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-[{[3-({[4-(2,5-dioxoimidazolidin-1 -
236 yl)phenyl]carbamoyl}annino)phenyl]annino}
(phenyl)methylene]-2-oxo-/V-[(1 S)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-3-ylmethylene)imidazolidin-1 -
237 yl]phenyl}carbamoyl)amino]phenyl}amino)(phenyl)methylene]-2-oxo-/V- [(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(4-
238 {[(ethylamino)carbonothioyl]amino}phenyl)amino](phenyl)methylene}-2- oxo-/V-[(1 S)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(4-{[(3-
239 chlorophenyl)carbamoyl]amino}phenyl)amino](phenyl)methylene}-2-oxo- A/-[(1 R)-1 -phenylpropyl]indoline-5-carboxamide
(3Z)-3-{[(4-{[(4-hydroxyphenyl)carbamoyl]amino}phenyl)amino](phenyl)
240
methylene}-2-oxo-/V-[(1 R)-1 -phenyl propyl]indoline-5-carboxamide
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)phenyl]amino}(pyridin-4- 241
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({4-[(4Z)-4-benzylidene-2,5-dioxoimidazolidin-1 -
242 yl]phenyl}amino)(pyridin-4-yl)nnethylene]-2-oxo-/\/-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(2-{[(ethylamino)carbonothioyl]amino}benzyl)annino](3-
243
thienyl)methylene}-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-[({2-[(1 ,3-benzodioxol-5- 244 ylcarbamoyl)amino]benzyl}amino)(phenyl)methylene] -2-oxo-/V-[(1 R)-1 - phenylpropyl]indoline-5-carboxamide
(3Z)-3-[({3-[(ethylcarbamoyl)amino]benzyl}amino)(pyridin-3-yl)methyle
245
2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}benzyl)amino](pyridin-3- 246
yl)methylene}-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[3-(2,5-dioxoimidazolidin-1 -yl)benzyl]amino}(pyridin-3- 247
yl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[({3-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - 248 yl]benzyl}amino)(pyridin-3-yl)nnethylene]-2-oxo-/\/-[(1 R)-1 - phenylethyl]indoline-5-carboxamide
(3Z)-/V-benzyl-3-[{[4-({[(3- 249 chlorophenyl)amino]carbonothioyl}amino)benzyl]amino}
(phenyl)nnethylene]-2-oxoindoline-5-carboxannide
(3Z)-/V-benzyl-3-[{[4-(2,5-dioxoimidazolidin-1 -
250
yl)benzyl]amino}(phenyl)methylene]-2-oxoindoline-5-carboxamide
(3Z)-3-[{[4-(2,5-dioxoimidazolidin-1 -yl)benzyl]amino}(phenyl)methylene]-2- 251
oxo-/V-[(1 R)-1 -phenylethyl]indoline-6-carboxamide
(3Z)-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-1 - 252 yl]benzyl}amino)(phenyl)nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 6-carboxamide
(3Z)-/V-benzyl-3-[({4-[(4Z)-2,5-dioxo-4-(pyridin-4-ylmethylene)imidazolidin-
253
1 -yl]benzyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxamide (3Z)-3-{[(2-{2-
254 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylene}-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-7-carboxamide
(3Z)-3-[{[2-(2-{[(3-
255 chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(pyridin-4- yl)methylene]-2-oxo-/V-[(1 S)-1 -phenylpropyl]indoline-7-carboxannide (3Z)-3-{[(2-{3-
256 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylene}-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(2-{3-
257 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylene}-2-oxo-/V- [(1 S)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[2-(3-{[(3-
258 chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}(phenyl)methylene]-2- oxo-/V-[(1 R)- -phenylethyl]indoline-5-carboxamide
(3Z)-A/-benzyl-3-{[(2-{3-[(4Z)-2,5-dioxo-4-(pyridin-4-
259 ylmethylene)imidazolidin-1 -yl]phenyl}ethyl)amino](phenyl)methylene}-2- oxoindoline-5-carboxamide
(3Z)-3-{[(2-{4-
260 [(ethylcarbamoyl)amino]phenyl}ethyl)amino](phenyl)methylene}-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-[{[2-(4-{[(3-chlorophenyl)carbamoyl]amino}phenyl)ethyl]amino}
261
(phenyl)methylene]-2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide (3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 262
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 263
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-/V- 264
benzyl-2-oxoindoline-5-carboxamide
(3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 265
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo- 266
A/-[(1 R)-1 -phenylethyl]indoline-5-carboxamide
267 (3Z)-3-{[(3S)-1 -azabicyclo[2.2.2]oct-3-ylamino](phenyl)methylene}-2-oxo-
Λ/-[(1 R)-1 -phenylpropyl]indoline-6-carboxamide
(3Z)-3-{[(3R)-1 -azabicyclo[2 .2]oct-3-ylamino](pyridin-4-yl)methylene}-2- oxo-/V-[(1 R)-1 -phenylpropyl]indoline-6-carboxamide and
(3Z)-3-{[(3R)-1 -azabicyclo[2.2.2]oct-3-ylamino](3-thienyl)methylene}-/V- benzyl-2-oxoindoline-6-carboxamide.
The compound for use according to anyone of claims 1 - 7, wherein the infectious diseases, are virally induced infectious diseases, including opportunistic diseases.
The compound for use according to claim 8, wherein the virally induced infectious diseases, including opportunistic diseases, are infections with dsDNA viruses, ssDNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, or dsDNA-RT viruses.
The compound for use according to claim 9, wherein the infection with (-)ssRNA viruses are an infection with Orthomyxoviridae, Bornaviridae, Filoviridae, Paramyxoviridae, or Rhabdoviridae.
The compound for use according to claim 10, wherein the infection with Orthomyxoviridae is an infection with Influenza virus A, Influenza virus B, or Influenza virus C.
The compound for use according to anyone of claims 1 - 7, wherein cancer is selected from the group consisting of adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumour, bladder cancer, bronchial carcinoma, non-small cell lung cancer, breast cancer, Burkitt's lymphoma, corpus cancer, colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors, brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer,
1 οΊ colorectal carcinoma, head and neck tumors, colon carcinoma, craniopharyngiomas, oral cancer, cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer, lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, spinalioms, T-cell lymphoma, thymoma, tube carcinoma, eye tumours, urethral cancer, urologic tumours, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumours, soft tissue sarcoma, Wilm's tumour, cervical carcinoma and tongue cancer.
The compound for use according to claim 12, wherein the cancer is a colorectal cancer.
A pharmaceutical compositions comprising at least one compound according to general formula (I) as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents for the use in the treatment of an infectious diseases or cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15155298.1 | 2015-02-16 | ||
| EP15155298.1A EP3056202A1 (en) | 2015-02-16 | 2015-02-16 | Benzopyrrolidone derivatives possessing antiviral and anticancer properties |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016131789A1 true WO2016131789A1 (en) | 2016-08-25 |
Family
ID=52573600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2016/053204 Ceased WO2016131789A1 (en) | 2015-02-16 | 2016-02-15 | Benzopyrrolidone derivatives possessing antiviral and anticancer properties |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP3056202A1 (en) |
| WO (1) | WO2016131789A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285872A (en) * | 2018-12-06 | 2020-06-16 | 北京志健金瑞生物医药科技有限公司 | Indole-2-ketone derivative and preparation method and application thereof |
| WO2024050297A1 (en) * | 2022-09-02 | 2024-03-07 | Deciphera Pharmaceuticals, Llc | Ulk inhibitors and methods of use thereof |
| US12071432B2 (en) | 2019-05-10 | 2024-08-27 | Deciphera Pharmaceuticals, Llc | Phenylaminopyrimidine amide autophagy inhibitors and methods of use thereof |
| US12377097B2 (en) | 2019-06-17 | 2025-08-05 | Deciphera Pharmaceuticals, Llc | Aminopyrimidine amide autophagy inhibitors and methods of use thereof |
| US12479833B2 (en) | 2019-05-10 | 2025-11-25 | Deciphera Pharmaceuticals, Llc | Heteroarylaminopyrimidine amide autophagy inhibitors and methods of use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000073297A1 (en) * | 1999-05-27 | 2000-12-07 | Boehringer Ingelheim Pharma Kg | Substituted indolinone as tyrosine kinase inhibitors |
| WO2004096224A2 (en) * | 2003-04-29 | 2004-11-11 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis |
| EP2837626A1 (en) * | 2013-08-16 | 2015-02-18 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Indolinone derivatives as GRK5 modulators |
-
2015
- 2015-02-16 EP EP15155298.1A patent/EP3056202A1/en not_active Withdrawn
-
2016
- 2016-02-15 WO PCT/EP2016/053204 patent/WO2016131789A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000073297A1 (en) * | 1999-05-27 | 2000-12-07 | Boehringer Ingelheim Pharma Kg | Substituted indolinone as tyrosine kinase inhibitors |
| WO2004096224A2 (en) * | 2003-04-29 | 2004-11-11 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis |
| EP2837626A1 (en) * | 2013-08-16 | 2015-02-18 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Indolinone derivatives as GRK5 modulators |
Non-Patent Citations (2)
| Title |
|---|
| KAR/AS ET AL., NATURE, 2010 |
| KARLAS ET AL., NATURE, 2010 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285872A (en) * | 2018-12-06 | 2020-06-16 | 北京志健金瑞生物医药科技有限公司 | Indole-2-ketone derivative and preparation method and application thereof |
| CN111285872B (en) * | 2018-12-06 | 2022-05-17 | 北京志健金瑞生物医药科技有限公司 | Indole-2-ketone derivative and preparation method and application thereof |
| US12071432B2 (en) | 2019-05-10 | 2024-08-27 | Deciphera Pharmaceuticals, Llc | Phenylaminopyrimidine amide autophagy inhibitors and methods of use thereof |
| US12479833B2 (en) | 2019-05-10 | 2025-11-25 | Deciphera Pharmaceuticals, Llc | Heteroarylaminopyrimidine amide autophagy inhibitors and methods of use thereof |
| US12377097B2 (en) | 2019-06-17 | 2025-08-05 | Deciphera Pharmaceuticals, Llc | Aminopyrimidine amide autophagy inhibitors and methods of use thereof |
| WO2024050297A1 (en) * | 2022-09-02 | 2024-03-07 | Deciphera Pharmaceuticals, Llc | Ulk inhibitors and methods of use thereof |
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|---|---|
| EP3056202A1 (en) | 2016-08-17 |
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