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;

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

-OCH ₃ ;

1 represents: -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

R' and R" are independently of each other selected from

-OCH ₃ ;

R'" represents: -H or -CH ₃ ; A represents -NH-, -O- or -S-;

R ² represents: -H, -CH ₃ or -C(=O)CH ₃ ;

R ⁶ , R ⁷ ; R ⁸ , R ⁹ and R ¹⁰ are independently of each other selected form : -H, -CH ₃ , -C2H _5, -C3H ₇ , -CH(CH ₃ ) ₂ , -C(CH ₃ )3-(CH2)n-CH ₃ , -(CH ₂ )n-C(CH ₃ ) ₂ , -CH[(CH ₂ )nCH ₃ ]-(CH ₂ ) _m -CH ₃₎ -CH[(CH ₂ ) _n CH ₃ ]-(CH ₂ ) _m -C(CH ₃ ) ₂ , -CH=CH ₂ , -(CH ₂ )n-CH=CH-(CH ₂ ) _k -CH _3, -CH≡CH, -(CH ₂ ) _n -C≡C-(CH ₂ ) _k -CH ₃ , -Ph, -(CH ₂ ) _n -Ph, _(CH ₂ )n-OH, -(CH ₂ )n-NH ₂ , -(CH ₂ ) _n -O-(CH ₂ ) _k -CH ₃ , (CH ₂ )n-NH(CH ₂ ) _k -CH3, -(CH ₂ )n-N(CH ₃ )2, -(CH ₂ )n-N(C ₂ H5)2

R ¹¹ represents: = =C(CH ₃ ) ₂ ,

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;

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 Q ¹ 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 R ² , R ³ , Q ¹ - Q ⁴ , 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 R ² , R ³ , Q ¹ - Q ⁴ , 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)

wherein the residues R ³ , Q ¹ - Q ⁴ , y and z have the meanings as defined herein. 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)

wherein the residues R ² , R ³ , Q ² - Q ⁴ , 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 R ² , R ³ , Q ¹ - Q ⁴ , 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 R ¹ , R ³ , Q ¹ - Q ⁴ , 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)

wherein the residues R ¹ , R ³ , Q ¹ - Q ⁴ , 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 (IX)

(IX)

wherein the residues R ¹ , R ³ , Q ² - Q ⁴ , 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 R ¹ , R ³ , Q ¹ - Q ⁴ , 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 R ¹ , R ³ , Q ² - Q ⁴ , 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)

wherein the residues R ¹ - R ³ , Q ² - Q ⁴ , 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 (XIII)

wherein the residues R ¹ - R ³ , Q ² - Q ⁴ , 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 (XIV)

wherein the residues R ¹ - R ³ , Q ¹ - Q ⁴ , 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 (XV)

(XV)

wherein the residues R ¹ - R ³ , Q ¹ - Q ⁴ , 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 R ¹ - R ³ , and Q ¹ - Q ⁴ 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 R ² , R ³ and Q ¹ - Q ⁴ 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 R ³ , Q ¹ - Q ⁴ , 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 R ¹ - R ³ and Q ¹ - Q ⁴ 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 R ³ , Q ¹ - Q ⁴ , 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 R ² , R ³ , Q ¹ - Q ⁴ , 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 R ³ , Q ¹ - Q ⁴ , 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 R ² , R ³ and Q ² - Q ⁴ 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 R ³ and Q ¹ - Q ⁴ 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 R ³ and Q ² - Q ⁴ 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 R ⁴ , Q ² - Q ⁴ , 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 R ¹ represents: — CH2CH3,— CH(CH3)2,

wherein 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-.

Furthermore, 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 .

Moreover, 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 ,

X represents: =O, =S;

R ⁵ represents: -R ⁶ ,

R ⁶ is selected form : -H , -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -C(CH ₃ )3-(CH2)n-CH _3j -(CH ₂ ) _n -C(CH ₃ ) ₂ , -CH [(CH ₂ )nCH3]-(CH2) _m -CH _3j -CH [(CH ₂ ) _n CH ₃ ]-(CH ₂ ) _m - C(CH ₃ ) ₂ , -CH=CH _2j -(CH ₂ ) _n -CH=CH-(CH ₂ ) _k -CH ₃ , -CH≡CH , -(CH ₂ ) _n -C≡C- (CH ₂ ) _k -CH ₃ , -Ph , -(CH ₂ ) _n -Ph , -(CH ₂ ) _n -OH , -(CH ₂ ) _n -N H ₂ , -(CH ₂ ) _n -O-(CH ₂ ) _k - CH _3j -(CH ₂ )n-N H(CH ₂ ) _k -CH ₃ , -(CH ₂ ) _n -N(CH ₃ ) ₂ , -(CH ₂ ) _n -N(C ₂ H ₅ ) ₂ and -(CH ₂ ) _n -N(CH ₃ )(C ₂ H ₅ ); preferably from : -H , -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ -(CH ₂ )n-CH ₃ , -(CH ₂ )n-C(CH ₃ ) ₂ , -CH=CH ₂ , -(CH ₂ ) _n -CH=CH-(CH ₂ ) _k - CH ₃ , -CH≡CH , -Ph , -(CH ₂ ) _n -Ph , -(CH ₂ ) _n -OH , -(CH ₂ ) _n -N H ₂ , -(CH ₂ ) _n -O-(CH ₂ ) _k - CH ₃ , -(CH ₂ )n-N(CH ₃ ) ₂ , and -(CH ₂ ) _n -N(C ₂ H ₅ ) ₂ ; more preferably from : -H , -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH=CH ₂ ,-CH≡CH , -Ph , -CH ₂ -Ph , -CH ₂ -OH , and -CH ₂ -N H ₂ ;

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; 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 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.

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-ca rboxamide

(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({4-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-ca rboxamide

(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-ca rboxamide

(3Z)-/V-(3-methoxybenzyl)-3-[({4-[(4-nnethylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-ca rboxamide

(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-ca rboxamide

(3Z)-/V-[(1 R)-1 -(3-chlorophenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-ca rboxamide

(3Z)-/V-[(1 R)-1 -(3-methoxyphenyl)ethyl]-3-[({3-[(4-methylpiperazin-1 - yl)methyl]phenyl}amino)(phenyl)methylene]-2-oxoindoline-5-ca rboxamide

(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-oxoindolin e-5- carboxamide

(3Z)-/V-(4-fluorobenzyl)-3-[({4-[(4-nnethylpiperazin-1 -

137 yl)methyl]phenyl}amino)(pyridin-3-yl)methylene]-2-oxoindolin e-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-car boxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 141

ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 142

ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxamide (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-car boxamide (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-car boxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 151

ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxamide (3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 152

ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 153

ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 154

ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-car boxamide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 155

ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-car boxamide (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-car boxamide

(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 159

ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-car boxamide

(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-car boxamide

(3Z)-2-oxo-/V-[(1 S)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 162

ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxamide

(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 163

ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxamide

(3Z)-2-oxo-/V-[(1 S)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 164

ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxamide

(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-carbox amide

(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(pyrrolidin-1 - 172

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide

(3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[4-(piperidin-1 - 173

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide

(3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[4-(piperidin-1 - 174

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide

(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)me thyl^

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-carbox amide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(pyrrolidin-1 - 180

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide (3Z)-2-oxo-/V-[(1 R)-1 -phenylethyl]-3-[{[3-(piperidin-1 - 181

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide (3Z)-2-oxo-/V-[(1 R)-1 -phenylpropyl]-3-[{[3-(piperidin-1 - 182

ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox amide (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-(piperid in-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)meth ylene]-2- 225

oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide

(3Z)-/V-benzyl-3-{[(2-{[(ethylamino)carbonothioyl]amino}phen yl)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)imidazo lidin-1 - 231 yl]phenyl}amino)(phenyl)nnethylene]-2-oxo-/\/-[(1 R)-1 -phenylethyl]indoline- 5-carboxamide

(3Z)-3-[({3-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)meth ylene]-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)methy lene}-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)methy lene}-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)ami no](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-y l)methyle 2-oxo-/V-[(1 R)-1 -phenylethyl]indoline-5-carboxamide

(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}benzyl)amin o](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)imid azolidin-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-carboxami de

(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)imid azolidin-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-ylmethyle ne)imidazolidin- 1 -yl]benzyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxam ide (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)ethy l]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.

Scheme 2. Synthesis of the inventive compounds of the general formula (I). The definition of the groups are the same as disclosed herein, and B is selected from: -H, -CH ₃ and -C2H ₅ . R ¹ has the meaning as disclosed herein. Compound 11* can be synthesised from the commercially available carboxy- oxindoles (acid or ester) 10* according to procedure A. In procedure B or B2 (aldol-reaction) 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.

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 ¹ H-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-carboxyl ic acid

1

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-Pr ₂ O (250 ml) for 2 h to give a solid which was filtered and washed with i-Pr ₂ O to provide (3Z)-1 -acetyl-3-[ethoxy(phenyl)methylene]-2- oxoindoline-5-carboxylic acid (3.5 g, 33 %)

¹ H-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).

t _R : 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-carboxyl ic 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 %)

¹ H-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)

t _R : 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)

t _R : 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:

C28H ₂ 8N ₄ O ₃ , Mw calc: 468.2

¹ H-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)

t _R : 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

C ₂ 8H ₂ 8N ₄ O ₃ , 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

C ₂ 8H ₂ 8N ₄ O ₃ , 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-ca rboxylic acid

C ₂ 9H ₃₀ N ₄ O ₄ 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

C28H ₂ 8N ₄ O ₃ , 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

C ₃ 7H ₃ 8N ₄ O ₂ , 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 CHCI ₃ -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 %)

¹ H-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) t _R : 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 C ₃ 6H ₃ 6N ₄ O ₂ , Mw calc, : 556.2

¹ H-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),

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , 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)

t _R : 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

C ₃ 6H ₃ 5CIN ₄ O ₂ Mw calc: 590.2 ¹ H-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) t _R : 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

C ₃ 6H ₃ 5CIN ₄ O ₂ , 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) t _R : 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

C ₃ 6H ₃ 5FN ₄ O ₂ , Mw calc. : 574.2 7

¹ H-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)

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , Mw calc.: 570.3

¹ H-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)

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , Mw calc.: 570.3

¹ H-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) t _R : 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

C ₃ 5H ₃₄ N ₄ O ₂ , 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)

t _R : 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

¹ H-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)

t _R : 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 C ₃ 7H ₃ 8N ₄ O ₃ , Mw calc.: 586.3

¹ H-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)

t _R : 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

C ₃ 6H ₃ 5FN ₄ O ₂ , Mw calc: 574.3

¹ H-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)

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₃ , 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),

t _R : 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

C ₃ 6H ₃ 6N ₄ O ₂ , Mw calc. : 556.3 5

¹ H-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)

t _R : 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

C ₃ 6H ₃ 5FN ₄ O ₂ , Mw calc. : 574.3

¹ H-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)

t _R : 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

C37H ₃ 8N ₄ O ₂ , Mw calc.: 570.3

¹ H-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)

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , 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)

t _R : 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

¹ H-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)

t _R : 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

C36H ₃ 6N ₄ O ₂ , Mw calc: 556.3

¹ H-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), t _R : 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

C ₃ 6H ₃ 6N ₄ O ₂ , Mw calc: 556.3

¹ H-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), t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , Mw calc.: 570.3

¹ H-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)

t _R : 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 C ₃ 7H ₃ 8N ₄ O ₃ , Mw calc.: 586.3

¹ H-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)

t _R : 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

¹ H-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)

t _R : 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-ca rboxamide

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) t _R : 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-ca rboxamide

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

¹ H-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)

t _R : 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

¹ H-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)

t _R : 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

¹ H-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)

t _R : 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-ca rboxamide

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

C ₃ 7H ₃ 9N ₅ O ₄ , Mw calc: 617.3

¹ H-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)

t _R : 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-ca rboxamide

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

¹ H-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)

t _R : 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 C36H ₃ 6N ₄ O ₂ , Mw calc.: 556.3

¹ H-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)

t _R : 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

C ₃ 7H ₃ 8N ₄ O ₂ , Mw calc: 570.3

¹ H-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) t _R : 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-ca rboxamide 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-ca rboxamide

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

C ₃ 7H ₃ 9N ₅ O ₄ , 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 MgSO ₄ . 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-c arboxylate 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-carb oxylate 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-carbox ylate 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-carbox ylate 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 % 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.

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}(py ridin-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)(pyrid in-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}(pyrid in-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)(py ridin-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-thi enyl)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)me thylene]-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 MgSO ₄ . 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 NH ₃ 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-oxoindolin e-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-oxoindolin e-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-oxoindolin e-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-car boxamide

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-car boxamide

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-car boxamide

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

143

Connpound 143 was obtained by reaction (3Z)-3-

[(diethylamino)methyl]phenyl}amino)(pyridin-3-yl)methylen e]-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-car boxamide

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-oxoindolin e-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-car boxamide

7

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-car boxamide

151

Compound 151 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxylic 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-car boxamide

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-car boxam

153

Connpound 153 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-3-yl)methylene]indoline-5-car boxylic 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-car boxamide

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-car boxamide

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-c arboxylic 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-car boxamide

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-car boxamide

159

Connpound 159 was obtained by reaction of (3Z)-2-oxo-3-[{[3-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-2-yl)methylene]indoline-5-car boxylic 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-oxoindolin e-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-car boxamide

161

Connpound 161 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxylic 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-car boxamide

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-car boxamide

163

Compound 163 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxylic 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-car boxamide

164

Compound 164 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(pyridin-4-yl)methylene]indoline-5-car boxylic 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-carbox ylic 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-carbox ylic 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

7

173

Compound 173 was obtained by reaction of (3Z)-2-oxo-3-[{[4-(piperidin-1 - ylmethyl)phenyl]amino}(3-thienyl)methylene]indoline-5-carbox ylic 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-carbox ylic 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)me thylene]-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-carbox ylic 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-carbox ylic 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-carbox ylic 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-carbox ylic 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-thieny l)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-carboxyli c 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

189

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-carboxyli c 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

200

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-carboxyli c 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

207

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

5

214

Compound 214 was obtained by reaction of (3Z)-3-(2-methyl-1 -{[4-(piperidin-1 - ylmethyl)phenyl]annino}propylidene)-2-oxoindoline-5-carboxyl ic 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-carboxyli c 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

C ₃ 6H ₃ 5FN ₄ O ₂ , 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

C ₃ 7H ₃ 7FN ₄ O ₂ , 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

C ₃ 7H ₃ 7FN ₄ O ₃ , 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

C ₃₇ H ₃₇ FN ₄ O ₃ , 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

C ₃ 6H ₃₄ CIFN ₄ O _2, 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

C ₃ 6H ₃₄ CIFN ₄ O _2, 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

C ₃₇ H ₃₇ FN ₄ O ₂ , 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

C ₃₇ H ₃₇ FN ₄ O ₂ , 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

C ₃ 7H ₃ 6CIFN ₄ O _2, Mw calc. :622.2

MS(ESI): m/z (M+H) ⁺ 623

(3Z)-3-[({2-[(ethylcarbamoyl)amino]phenyl}amino)(phenyl)m ethylene]-2-oxo-/V- [(1 R)-1 -phenylethyl]indoline-5-carboxamide

225

MS (ESI) [M+H] ⁺ : 547

(3Z)-/V-benzyl-3-{[(2-{[(ethylamino)carbonothioyl]amino}phen yl)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

227

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)imidazo lidin-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)meth ylene]-2-oxo-/V- [(1 R)-1 -phenylpropyl]indoline-5-carboxamide

232

MS (ESI) [M+H] ⁺ : 561

(3Z)-3-{[(3-{[(3-chlorophenyl)carbamoyl]amino}phenyl)amin o](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)im idazolidin-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)ami no](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-y l)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)amin o](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)imid azolidin-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]carbonothi oyl}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)imid azolidin-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-ylmeth ylene)imidazolidin-1 - yl]benzyl}amino)(phenyl)methylene]-2-oxoindoline-5-carboxami de

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)e thyl]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)meth ylene]-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-ylm ethylene)imidazolidin-1 yl]phenyl}ethyl)amino](phenyl)methylene}-2-oxoindoline-5-car boxamide

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)e thyl]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)me thylene}-/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

266

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-o xo-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/-ben zyl-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 H ₂ O 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 MgCI ₂ , 2 mM MnCI ₂ , 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 H ₂ O 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 H ₂ O 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 MgCI ₂ , 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 H ₂ O 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 H ₂ O 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 MgCI ₂ , 0.4 mM MnCI ₂ , 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 H ₂ O 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)

Example 5: In vitro growth inhibition of colon carcinoma cells

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 EC ₅ 0 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