WO2017135901A1

WO2017135901A1 - Heterocyclic compounds, methods of synthesis and uses thereof

Info

Publication number: WO2017135901A1
Application number: PCT/SG2017/050054
Authority: WO
Inventors: Boon Tin Chua; Gyorgy Keri; Laszlo Orfi; Gábor NÉMETH; Frigyes Wáczek; Zoltán VARGA; Peter Marko
Original assignee: Agency For Science, Technology And Research; Vichem Chemie Research Ltd
Priority date: 2016-02-05
Filing date: 2017-02-06
Publication date: 2017-08-10

Abstract

The present invention relates to 3-quinolinecarbonitrile compounds of formula (I) disclosed herein, methods for their synthesis, and uses thereof. Advantageously, the disclosed heterocyclic compounds may demonstrate enhanced efficacy in antitumor properties. Hence, the present disclosure also relates to the use of the disclosed 3-quinolinecarbonitrile compounds or pharmaceutical compositions thereof in cancer treatment.

Description

Title of Invention: Heterocyclic Compounds, Methods of Synthesis and Uses thereof

Technical Field

The present invention generally relates to heterocyclic compounds, methods for their synthesis and uses thereof. The disclosed compounds may be useful in the treatment of cancer.

Background Art

Bosutinib is a tyrosine kinase inhibitor that has received FDA and EMA approval for use in Philadelphia chromosome-positive (Ph+) Chronic Myeloid Leukemia (CML). In addition, it has also demonstrated inhibitory effect on growth of solid tumours such as pancreas, breast, prostate, and melanoma in preclinical models.

Nonetheless, patients with Ph+ CML may encounter side effects when undergoing treatment with Bosutinib. Some examples of commonly encountered side effects are elevated risk of contracting an infection as a result of a reduction in white blood cells level, breathlessness and tiredness as a result of a reduction in red blood cells level, diarrhoea, fatigue, and etc. Furthermore, in cases where patients on Bosutinib treatment do not elicit a desired therapeutic response, it may be necessary to increase the dose of Bosutinib. Such a measure is undesirable as patients may experience more severe side effects associated with the increased use of Bosutinib.

There is therefore a need to provide alternative compounds that overcome, or at least ameliorate, one or more of the disadvantages described above.

Importantly, it is desirable to provide alternative compounds which possesses enhanced inhibitory effect on solid tumours at reduced drug dosage which may advantageously alleviate any potential side effects encountered by patients undergoing Ph+ CML treatment or may even advantageously lead to a lower likelihood of a patient experiencing any potential side effects. There is also a need to provide alternative compounds that are less toxic to a human or animal body. Summary of Invention

One aspect of the present disclosure relates to a compound of general formula (I) and/or its solvates, hydrates and pharmaceutically acceptable salts

Y

(I) wherein

R represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH₂, -CO-O-alkyl or -CO-alkyl;

R², R³ and R⁴ independently of each other represent alkyl, thioalkyi, alkylcarbonyl, halogen, - COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO- heterocyclyl and R² can also represent hydrogen;

Q represents a heterocyclyl group;

W represents optionally substituted aromatic or non-aromatic heterocyclyl group or an optionally substituted aryl group;

X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;

Y represents an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyi, alkylthioalkyi, cycloalkyi, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro- heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ or-CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

I is the number of R⁵ substituents independently selected and is itself a number selected from 0, 1 , 2, 3, 4 or 5;

n is a number selected from 1 , 2, 3, 4, 5 or 6;

m is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

p is a number selected from 0 or 1 ;

r is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

s is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

t is a number selected from 0 or 1 ; and

u is a number selected from 0 or 1.

Advantageously, the disclosed compounds surprisingly demonstrate significantly higher inhibitory effect on tumour growth, Bcr-AbI and Src kinases, and Ack1 inhibitory activities when compared to Bosutinib.

In another aspect, the present disclosure relates to a process for making a compound of formula (I) as disclosed herein, comprising

(a) reacting a compound of formula (II),

wherein

R⁵, X, W, Y, I, u, r, t, s and k are as defined herein and Hal stands for halogen; or (b) reacting a compound of formula (II),

wherein R , R², R³, R⁴, Q, n, m and p are as defined herein,

in an organic solvent in the presence of a base with a compound of formula (IV),

Y (IV)

wherein

R⁵, X, W, Y, I, u, r, t, s and k are as defined herein;

or (c) reacting a compound of formula (V),

(V) wherein R¹ , R², R³, R⁴, n, m and p are as defined herein and Hal stands for chlorine or bromine,

in an organic solvent in the presence of an alkali or ammonium iodide, preferably sodium i

Y (VI)

wherein

R⁵, X, W, Y, Q, I, u, r, t, s and k are as defined herein.

In another aspect, the present disclosure provides a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof for use as a medicament.

In a further aspect, the present disclosure relates to a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof for use in the treatment of diseases, disorders and conditions which are caused by cancer cells.

In yet another aspect, the present disclosure relates to a use of a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from any cancer form.

In another aspect, the present disclosure relates to a method of treating an oncological disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof.

In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates and solvates thereof and a pharmaceutical acceptable excipient. In yet another aspect, the present disclosure relates to a pharmaceutical composition as disclosed herein for use in the treatment of cancer.

Advantageously, the compounds or pharmaceutical compositions of the present disclosure may demonstrate enhanced efficacy in anti-tumour properties. Further advantageously, the compounds of the present disclosure may show superior anti-cell viability effect on breast, pancreatic, ovarian, hepatocellular carcinoma and neuroblastoma cell lines. In addition, the compounds of the present disclosure may be more effective in reducing proliferative and survival signalling in carcinoma cells when compared to Bosutinib.

Definitions

In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined. The following words and terms used herein shall have the meaning indicated:

In the definitions of a number of substituents below it is stated that "the group may be a terminal group or a bridging group". This is intended to signify that the use of the term is intended to encompass a situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.

"Alkenyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight, linear or branched preferably having 2-20 carbon atoms, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. The group may be a terminal group or a bridging group.

"Alkenoyl" refers to a -C(=0)-alkenyl group in which alkenyl is as defined herein. The group may be a terminal group or a bridging group. "Alkenyloxy" refers to an alkenyl-O- group in which alkenyl is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, vinyloxy, 1 -propenyloxy and 2-butenyloxy.

"Alkenylamine" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an amino group as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, 2-butenylamine, 2-propenylamine and 3-pentenylamine.

"Alkyl" as a group or part of a group refers to a straight, linear or branched aliphatic hydrocarbon group, preferably a Ci-C₂₀ alkyl, e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13,

14, 15, 16, 17, 18, 19, 20 carbon atoms, more preferably a Ci-Ci₆ alkyl, even more preferably a C₁-C₁₂ alkyl, most preferably d-C₆ unless otherwise noted. Examples of suitable straight and branched Ci-C₆ alkyl substituents include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.

"Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight, linear or branched preferably having from 2-20 carbon atoms, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14,

15, 16, 17, 18, 19, 20 carbon atoms, more preferably 2-18 carbon atoms, more preferably 5-16 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl. The group may be a terminal group or a bridging group.

"Alkynylamino" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an amino group as defined herein. The group may be a terminal group or a bridging group.

"Alkoxy" refers to an alkyl-O- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert- butoxy.

"Alkoxyalkyl" refers to an alkyl-O-alkyl group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, 2-methoxyethyl, 3-methoxy propyl, and 1 -methyl-2- methoxyethyl. "Acyl" refers to groups of the form RC(=0) wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted cycloalkyl groups, optionally substituted heterocyclyl groups, or optionally substituted heteroalkenyl groups, wherein C may refer to a carbon atom belonging to the R group when R is an optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted cycloalkyl group, optionally substituted heterocyclyl group, or optionally substituted heteroalkenyl group.

"Amino" refers to groups of the form -NR_aR_b wherein R_a and R_b are individually selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

"Acylamino" refers to groups of the form RC(=0)-amino- -in which amino is as defined herein. "Diacylamino" refers to an amino group in which two of the hydrogen atoms have been replaced with two acyl groups as defined herein, which may be same or different.

"Acyloxy" refers to the groups of the form RC(=0)-0- wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

"Acylthio" refers to the groups of the form R-C(=0)-S- wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

"Alkylamino" refers to -NH-alkyl group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, -NHCH₃, -NHCH₂CH₃ and -NH(CH₂)₂CH₃. "Dialkylamino" means - N(alkyl)(alkyl) group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, - N(CH₃)₂, -N(CH₃)(CH₂CH₃) and -N(CH₂CH₃)₂.

"Alkylcarbonyl" refers to an alkyl-C(=0)- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, acetyl, propionyl, butyryl and isobutyryl. "Alkylcarbonyloxy" refers to an alkylcarbonyl-O- group in which the alkylcarbonyl group is as defined herein. The group may be a terminal group or a bridging group.

"Alkylsulfenyl" refers to an alkyl-S(O) group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group.

"Alkylsulfonyloxy" refers to an alkyl-S(0)₂-0- group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group.

"Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring, e.g. 5, 6, 7, 8, 9, 10, 1 1 , 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C_5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C₆-C₁₈ aryl group.

"Alkylaryl" refers to an aryl group as defined herein in which one or more of the hydrogen atoms has been replaced with an alkyl group as defined herein.

"Carbonyl" refers to a -C(=0)- group.

"Alkoxycarbonyl" refers to groups of the form alkoxy-C(=0)- wherein the alkoxy group is as defined herein. Exemplary structures include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.

"Oxo" as a substituent refers to a double-bonded oxygen group of the formula =0. When "oxo" refers to a substituent, it is understood that the oxygen atom is double-bonded to the molecule of interest. For instance, when R⁵ is an oxo group, the oxygen atom is attached to the W or X-W moiety via a double bond.

"Halogen" refers to chlorine, fluorine, bromine or iodine.

"Haloalkyi" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyi group typically has the formula C_nH(₂n+i-m) m wherein each X is independently selected from the group consisting of F, CI, Br and I . In groups of this type n is typically from 1 to 10 (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10), more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyi include fluoromethyl, difluoromethyl and trifluoromethyl.

"Haloalkoxy" refers to a haloalkyl-O- group in which the haloalkyi is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, difluoromethoxy, trifluoromethoxy and chlorodifluoromethoxy.

"Haloalkynyl" refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.

"Haloalkenyl" refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.

"Haloalkenyloxy" refers to a haloalkenyl-O- group in which haloalkenyl is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, 2-chloro-2-propenyl, 3-chloro-2-propenyl and 3,3-difluoro- 2-propenyl.

"Fused" when used herein refers to two or more cyclic rings are joined or bonded covalently via at least one pair of adjacent atoms included in adjacent rings. The term "benzofused" when used herein refers to at least one cyclic ring is joined or bonded covalently with a benzene ring. Exemplary benzofused structures include, but are not limited to, benzimidazole, benzoxazole and benzothiazole.

"Thioalkyl" or "thioalkoxy" or "alkylthio" refers to a -S-alkyl group in which the alkyl group is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, -S-CH₃, -S-CH₂CH₃ and -S-(CH₂)₂CH₃.

"Alkylthioalkyl" means a -alkyl-S-alkyl group in which the -S-alkyl and alkyl groups are as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, methylthiomethyl, ethylthiomethyl, n- propyl thiomethyl and isopropylthio methyl.

"Cycloalkyl" refers to a saturated monocyclic or fused or bridged or spiro polycyclic, carbocycle preferably containing from 3 to 12 carbons per ring (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12 carbon atoms per ring), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-12 carbon atoms per ring (e.g. 5, 6, 7, 8, 9, 10, 1 1 , 12 carbon atoms per ring). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituent groups The group may be a terminal group or a bridging group.

"Heterocyclyl" refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Each ring is preferably from 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10), more preferably 4 to 7 membered. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.

"Heterocycloalkyl" refers to a saturated monocyclic, fused or bridged or spiro polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10), more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4 oxathiapane. A heterocycloalkyl group may comprise 3 to 9 ring atoms. A heterocycloalkyl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group.

"Heterocyclyloxy" refers to -O-heterocyclyl group in which the heterocyclyl group is as defined herein.

"Heterocyclylamino" refers to an amino group as defined herein in which one or more of the hydrogen atoms has been replaced with a heterocyclyl group as defined herein.

"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1 -, 3-, 4-, or 5- isoquinolinyl 1 -, 2-, or 3- indolyl, and 2-, or 3 thienyl. A heteroaryl group is typically a Ci-Ci₈ heteroaryl group (e.g. d, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, Cn , C₁₂, Ci₃, Ci₄, Ci5, Ci₆, Ci₇, or Cis). A heteroaryl group may comprise 3 to 8 ring atoms. A heteroaryl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group.

"Alky I heteroaryl" refers to a heteroaryl group as defined herein in which one or more of the hydrogen atoms has been replaced with an alkyl group as defined herein.

"Haloheterocycloallkyl" refers to a hetercycloalkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.

"Nitro" when used herein to describe a chemical structure refers to one containing -N0₂. Examples of nitro moiety include nitroalkyl, nitroalkenyl and nitroalkynyl. "Nitroalkyl" means N0₂-alkyl- in which the alkyl group is as defined herein. "Nitroalkenyl" means N0₂-alkenyl- in which the alkenyl group is as defined herein. "Nitroalkynyl" means N0₂- alkynyl- in which the alkynyl group is as defined herein.

"Cyano" or "cyanide" when used herein to describe a chemical structure refers to one containing -C≡N group. "Isocyanate" when used herein to describe a chemical structure refers to one containing -N=C=0 group.

"Phosphono" when used herein to describe a chemical structure refers to one containing -P0₃H₂.

"Phosphinyl" when used herein to describe a chemical structure refers to one containing -PRR' wherein R and R' are each independently selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

A "bond" is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond. It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.

Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.

Further, it is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

The term "optionally substituted" as used herein means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkenyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkyloxy, cycloalkenyloxy, cycloamino, halo, carboxyl, oxo, haloalkyl, haloalkenyl, haloalkynyl, alkynyloxy, heteroalkyl, heteroalkyloxy, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, aminoalkyl, alkynylamino, acyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxycarbonyl, alkyloxycycloalkyl, alkyloxyheteroaryl, alkyloxyheterocycloalkyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocyclyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylheteroalkyl, heterocycloalkyloxy, heterocycloalkenyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, aminosulfonyl, phosphorus-containing groups such as phosphono and phosphinyl, sulfinyl, sulfinylamino, sulfonyl, sulfonylamino, aryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroaryl heteroalky I, heteroarylamino, heteroaryloxy, arylalkenyl, arylalkyl, alkylaryl, alkylheteroaryl, aryloxy, arylsulfonyl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), and -C(0)N(alkyl)₂.

When compounded chemical names, e.g. "arylalkyl" and "arylimine" are used herein, they are understood to have a specific connectivity to the core of the chemical structure. The group listed farthest to the right (e.g. alkyl in "arylalkyl"), is the group that is directly connected to the core. Thus, an "arylalkyl" group, for example, is an alkyl group substituted with an aryl group (e.g. phenylmethyl (i.e., benzyl)) and the alkyl group is attached to the core. An "alkylaryl" group is an aryl group substituted with an alkyl group (e.g., p-methylphenyl (i.e., p-tolyl)) and the aryl group is attached to the core.

Any carbon or heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cydoaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present disclosure and specified formulae.

The term "pharmaceutically acceptable excipient" refers to a excipient that is generally safe, non-toxic that may be useful in the preparation of a pharmaceutical composition.

The term "oncology" or "oncological" when used herein to describe a disease, disorder or condition, means the disease, disorder or condition is related

The word "subject" when used herein refers to a human or an animal. The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.

Unless specified otherwise, the terms "comprising" and "comprise", and grammatical variants thereof, are intended to represent "open" or "inclusive" language such that they include recited elements but also permit inclusion of additional, unrecited elements.

As used herein, the term "about", in the context of concentrations of components of the formulations, typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1 % of the stated value, and even more typically +/- 0.5% of the stated value.

Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Certain embodiments may also be described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the embodiments with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Detailed Disclosure of Embodiments

The present disclosure relates to a compound of general formula (I) and/or its solvates, hydrates and pharmaceutically acceptable salts

wherein

Q represents a heterocyclyl group;

Y represents an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyi, alkylthioalkyi, cycloalkyi, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro- heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkyl heteroaryl, cyano, cyanate, isocyanate, -C(0)NH (alkyl), -C(0)N(alkyl)₂ or-CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

I is the number of R⁵ substituents independently selected and is itself a number selected from 0, 1 , 2, 3, 4 or 5; n is a number selected from 1 , 2, 3, 4, 5 or 6;

m is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

p is a number selected from 0 or 1 ;

r is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

s is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

t is a number selected from 0 or 1 ; and

u is a number selected from 0 or 1.

R may be a hydrogen; cyano; alkylamino comprising 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms; alkoxy comprising 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms; -COOH; -CO-NH₂; -CO-O-alkyl comprising 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms or -CO-alkyl comprising 1 to 20 (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms) carbon atoms, 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. R may be hydrogen or a cyano group. R may represent hydrogen, cyano, C C₄-alkylamino, C C₄- alkoxy, -COOH, -CO-NH₂, -CO-0-C C₄-alkyl or -CO-C C₄-alkyl. ^ may represent hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH, -CO-NH₂, -CO-0-CH₃ or -CO-CH₃. Ri may represent hydrogen or a cyano group.

R² may represent hydrogen, alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO-heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. R² may represent hydrogen, CrC₆-alkyl, thio-CrC₆-alkyl, CrC₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo-CrC₆-alkyl, hydroxyl, CrC₆-alkoxy, nitro, amino, CrC₆- alkylamino, di-CrC₆-alkylamino, C C₆-acyl, cyano, or -N H R⁶ wherein R⁶ represents C C₄- alkyl-CO-O-d-Cs-alkyl, CrC₄-alkyl-CO-C3-C₈-cycloalkyl or C C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R₂ may represent C C₆-alkyl, thio-C C₆-alkyl, C C₆-alkylcarbonol, halo, -COOH , -CON H₂, halo-C C₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, C C₆- acyl, cyano or -N H R⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C₃-C₈- cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O). R₂ may represent CrC₆-alkyl, halo, -COOH , halo-CrC₆-alkyl, C C₆-alkoxy, nitro, or cyano. R₂ may represent halo, or CrC₆-alkoxy. R₂ may represent methoxy.

R³ may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH , -CON H₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -N H R⁶ wherein R⁶ may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO-heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. R³ may represent CrC₆-alkyl, thio-CrC₆-alkyl, CrC₆-alkylcarbonyl, halogen, -COOH , -CON H₂, halo- CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, C C₆-acyl, cyano, or -N H R⁶ wherein R⁶ represents C C₄-alkyl-CO-0-CrC₈-alkyl, C C₄-alkyl- CO-C₃-C₈-cycloalkyl or C C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R³ may represent CrC₆-alkyl, thio-CrC₆-alkyl, C C₆- alkylcarbonol, halo, -COOH , -CON H₂, halo-CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, CrC₆-acyl, cyano or -N H R⁶ wherein R⁶ represents - CH₂-CO-0-C C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O) . R³ may represent CrC₆-alkyl, halo, -COOH , halo-CrC₆-alkyl, C C₆-alkoxy, nitro, or cyano. R³ may represent halo, or C C₆-alkoxy. R³ may represent methoxy.

R⁴ may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH , -CON H₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -N H R⁶ wherein R⁶ may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO-heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. R⁴ may represent C C₆-alkyl, thio-C C₆-alkyl, C C₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo- CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, C C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents CrC₄-alkyl-CO-0-CrC₈-alkyl, C C₄-alkyl- CO-C₃-C₈-cycloalkyl or C C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R⁴ may represent CrC₆-alkyl, thio-Ci-C₆-alkyl, C C₆- alkylcarbonol, halo, -COOH, -CONH₂, halo-C C₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, CrC₆-acyl, cyano or -NHR⁶ wherein R⁶ represents - CH₂-CO-0-CrC₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O). R⁴ may represent CrC₆-alkyl, halo, -COOH, halo-CrC₆-alkyl, C C₆-alkoxy, nitro, or cyano. R⁴ may represent halo, or C C₆-alkoxy. R⁴ may represent methoxy.

R², R³ and R⁴ may be the same or different. R³ and R⁴ may be the same but different from R². R³ and R⁴ may each be a halogen independently selected from chlorine, fluorine, bromine or iodine. R³ and R⁴ may be identical halogens selected from chlorine, fluorine, bromine or iodine. R³ and R⁴ may both be chlorine. When R² is different, R² may be an alkoxy group comprising 1 to 20 carbon atoms (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. R² may be an alkoxy group comprising 1 to 4 carbon atoms. R² may be a methoxy, ethoxy or isopropoxy group. R² may be a methoxy group. R² may be a methoxy group when R³ and R⁴ are each chloro.

In one embodiment, R may be a cyano group, R² may be a methoxy group, and R³ and R⁴ may both be chlorine. In another embodiment, R may be hydrogen, R² may be a methoxy group, and R³ and R⁴ may both be chlorine.

R₂, R₃ and R₄ may independently of each other represent halo, or CrC₆-alkoxy.

Q may represent a heterocyclyl group. Q may be selected from 3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures. Q may contain at least one heteroatom selected from nitrogen, sulfur or oxygen. Q may be a 5 membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen, or a 6 membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen. Q may be 5 membered or 6 membered ring structure containing at least one sulfur atom, or Q may be 5 membered or 6 membered ring structure containing at least one oxygen atom, or a 5 membered or 6 membered ring structure containing at least one nitrogen atom. Q may be a 6 membered ring structure containing at least one nitrogen atom, or a 6 membered ring structure containing two nitrogen atoms. Q may be a piperidinyl, tetrahydropyridinyl, or piperazinyl group.

W may represent optionally substituted aromatic or non-aromatic heterocyclyl group or an optionally substituted aryl group. W may be a substituted aromatic or non-aromatic heterocyclyl group or a substituted aryl group. W may be an unsubstituted aromatic or non- aromatic heterocyclyl group or an unsubstituted aryl group. W may be an unsubstituted aryl group. W may be an optionally substituted benzene ring. W may be substituted with at least one R⁵ substituent as disclosed herein.

W may represent an optionally substituted aromatic or non-aromatic heterocyclyl group. W may be selected from 3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures. W may contain at least one heteroatom selected from nitrogen, sulfur or oxygen. W may be a 5- or 6- membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen. W may be 5- or 6- membered ring structure containing at least one sulfur atom. W may be 5- or 6- membered ring structure containing at least one oxygen atom. W may be 5- or 6- membered ring structure containing at least one nitrogen atom. .

W may be an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non-aromatic heterocyclyl group or an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aryl group. W represents a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or represents a phenyl group. W may represent a succinimide, phenyl, 5- dioxo-2,5-dihydro-pyrrol-1-yl, 2,5-dioxo-2,5-dihydro-dihydro pyrrol-1-yl, 2,5-dioxo-pyrrolidin-1- yl group, or together with X represents a 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl group, a 5,7- dioxo-2,3,5,7-tetrahydro-[1 ,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazinyl group.

X may represent no further substituent or may represent a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W.

X may be an optionally substituted benzene ring or a 1 ,4-dithiane group. X may be an optionally substituted benzene ring. X may be substituted with at least one R⁵ as defined herein. X may be a moiety that is benzofused, partially saturated benzofused or heterocyclic fused to W to form a X-W moiety. X and W may be individually selected from 3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures. The X-W moiety may contain at least one heteroatom selected from nitrogen, sulfur or oxygen. The X portion of the X-W moiety may be a 6 membered ring structure and the W portion of the X-W moiety may be a 5 membered ring structure. The X portion and/or W portion of the X-W moiety may be substituted with at least one R⁵ substituent as defined herein. The X-W moiety may be an optionally substituted phthalimide, or a phthalimide group substituted with at least one R⁵ substituent as defined herein.

X may represent no further substituent, or represent a moiety that is benzofused to the heterocyclic ring or represents a C₃ to C₆ -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-. X may represent no further substituent or may represent a moiety that is benzofused to the pyrrolyl group or represents a bridge selected from -0-CH₂-CH₂-0-, -S-CH₂-CH₂-S-, -CH₂-CH=CH-CH₂-, -CH=NH-CH₂- CH₂-, -NH=CH-CH₂-CH₂- -CH=CH-S- or -CO-NH-CO-.

In another preferred embodiment, the X-W moiety may be a 1 ,4-dithiane group (X) heterocyclic fused to succinimide group (W). Advantageously, this X-W moiety may surprisingly result in improved biological effect. u may be 0 or 1. When u is 1 , X may represent no further substituent. When u is 1 , W may be an optionally substituted benzene ring, a benzene ring that may be substituted at least with R₅ or a 1 ,4-dithiane.

In an embodiment, u may be 1 , X may represent no further substituent, W may be an optionally substituted benzene ring. Advantageously, having an acyl group in place of the phthamlimide (acyl-c-Bosutinib) may surprisingly increase activity, however this modification may increase the biological effect on normal epithelial cells also.

When u is 0, W may be a succinimide, phenyl, 5-dioxo-2,5-dihydro-pyrrol-1-yl, 2,5-dioxo-2,5- dihydro-dihydro pyrrol-1-yl, 2,5-dioxo-pyrrolidin-1-yl group, or together with X represents a 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl group, or a 5,7-dioxo-2,3,5,7-tetrahydro-[1 ,4]dithiino[2,3- c]pyrrol-6-yl)-butyryl]-piperazinyl group. When u is 0, X may be a benzene ring benzofused to W. When u is 0, the X-W moiety may be an optionally substituted phthalimide group. When u is 0, the X-W moiety may be a phthalimide group substituted with at least one R⁵ substituent as defined herein.

R⁵ may be selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus- containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ or-CH₂N(alkyl)₂.

R⁵ may be selected from oxo, halogen and alkyl groups comprising 1 to 20 carbon (i.e. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms) atoms, 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms. R⁵ may be selected from fluoride, chlorine, methyl, ethyl, iso-propyl and tert-butyl groups. k may be 0 or 1. When k is 1 , Q may be a piperazine group. When k is 1 , Q may be a piperazine group, u may be 0 and X-W may be a phthalimide group.

When k is 1 , Q may be a piperazine group, r, t and u may be 0, s may be 4 and X-W may be a phthalimide group. When k is 1 , Q may be a piperazine group, s, t and u may be 0, r may be 4 and X-W may be a phthalimide group. s may be a number selected from 0, 1 , 2, 3, 4, 5 and 6. s may be a number selected from 2, 3, 4 and 5. s may be 2 or 4. r may be a number selected from 0, 1 , 2, 3, 4, 5 and 6. r may be a number selected from 2, 3, 4 and 5. r may be 2 or 4.

When s is 2 or 4, r may be 2 or 4. I represents the number of R⁵ substituents on the W or X-W moiety. I may be a number selected from 0, 1 , 2, 3, 4 and 5. I may be 0, 1 or 2. When I is greater than 1 , the more than one R⁵ substituent may be independently selected to be the same or different. For instance, when I is 2, the first R⁵ substituent may be an oxo group and the second R⁵ substituent may be an oxo group or a substituent other than oxo group. n may be a number selected from 1 , 2, 3, 4, 5 and 6. m may be a number selected from 0, 1 , 2, 3, 4, 5 and 6. t may be 0 or 1. p may be 0 or 1. Both t and p may be 0. Both t and p may be 1. k and u may be 0, t and p may be 1 , m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group. K, t and u may be 0, p may be 1 , m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group, k, p and u may be 0, p may be 1 , m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group. k, m, p, r and t may be 0, s may be 4 and R may be hydrogen. In another embodiment, k, m, p, s and t may be 0, r may be 4 and R may be hydrogen.

Q may be a piperazine group, X-W may be a phthalimide group, k may be 1 or 0, s, t and u may be 0, r may be selected from 1 , 2 and 3 and Y may represent no further substituent or Y may be a methyl group. Q may be a piperazine group, X-W may be a phthalimide group, k may be 1 or 0, t and u may be 0, r may be 0 or 1 , Y may represent no further substituent or Y may be a methyl group, and s may be selected from 0, 1 , 2 and 3.

Y may be an optional substituent of the -(CH₂)_r- chain selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, - C(0)NH(alkyl), -C(0)N(alkyl)₂ or-CH₂N(alkyl)₂. In an embodiment, Y may be absent.

The disclosed compound and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

R may be hydrogen, cyano, C C₄-alkylamino, C C₄-alkoxy, -COOH, -CO-NH₂, -CO-0-C C₄-alkyl or -CO-C C₄-alkyl;

R², R³ and R⁴ may independently of each other be CrC₆-alkyl, thio-CrC₆-alkyl, C C₆- alkylcarbonyl, halogen, -COOH, -CONH₂, halo-CrC₆-alkyl, hydroxyl, CrC₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, C C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-CrC₈-alkyl, CrC₄-alkyl-CO-C₃-C₈-cycloalkyl or C C₄-alkyl-CO- heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O) and R² may also be hydrogen;

Q may be a heterocyclyl group;

W may be an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non-aromatic heterocyclyl group or an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aryl group;

X may represent no further substituent or may be a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;

Y may represent an optional substituent of the -(CH₂)_r- chain and R⁵ may represent an optional substituent of the W or X-W moiety and Y and R⁵ may independently of another be selected from CrC₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, d-C₄-alkyl-thio-Cr C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, CrC₆-alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, C C₄-alkoxy-CrC₄-alkyl, thio-C C₆-alkoxy, C₂- C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-CrC₆-alkyl, nitro- C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro- heterocyclyl, C C₄-alkylamino-CrC₄-alkyl, CrC₆-alkylamino, di-CrC₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, C C₆- acylamino, di-Ci-C₆-acylamino, C C₆-acyloxy, C C₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-C C₄-alkyl, five to six ring membered optionally benzofused heterocyclyloxy, five to six ring membered optionally benzofused heterocyclylamino, five to six ring membered optionally benzofused haloheterocycloalkyl, C C₆-alkylsulfenyl, C C₆-alkylcarbonyloxy, C C₆-alkylthio, C C₆-acylthio, phosphorus- containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl, C C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused d-C₆-alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(C C₆-alkyl), -C(0)N(Ci-C_e-alkyl)₂ or -CH₂N(C C₆- alkyl)₂.

The compound of the present disclosure and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t and p may both be 0.

The compound of the present disclosure and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), m and s may both be 0 or 1 and n and r may each selected from 3, 4, 5, and 6.

The compound of the present disclosure and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), Y may be absent.

The disclosed compound and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), u may be 0.

Ri may represent hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH, -CO-NH₂, -CO-0-CH₃ or - CO-CH₃;

R₂, R₃ and R₄ may independently of each other represent CrC₆-alkyl, thio-Ci-C₆-alkyl, C C₆- alkylcarbonol, halo, -COOH, -CONH₂, halo-CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, CrC₆-acyl, cyano or -NHR⁶ wherein R⁶ represents - CH₂-CO-0-C C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO-heterocyclyl(having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O);

Q may represent a piperidin, tetrahydropyridin or piperazinyl group;

W may represent a heterocyclic ring having 5 to 6 ring members and 1 to 3 hetero atoms selected from N, O, or S or may represent phenyl;

X may represent no further substituent or may be a moiety that is benzofused to the heterocyclic ring or may be a C₃ to C₆ -bridge formed by two substituents of W in which 1 to 3 carbon atoms may be replaced by O, N, S or -C(O)-;

Y may be an optional substituent of the -(CH₂)_r chain and R⁵ may be an optional substituent of the W or X-W moiety and Y and R⁵ may independently of another be selected from C C₆- alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-C C₆-alkyl, CrC₄-alkyl-thio-C C₄-alkyl, C₃-C₈- cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, oxo, fluorine, chlorine, bromine, iodine, - COOH, -CONH₂, d-Ce-alkoxycarbonyl, halo-C C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆- alkoxy, CrC₄-alkyl-oxy-CrC₄-alkyl, thio-C C₆-alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-CrC₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl and 1 to 3 hetero atoms selected from N, O, or S, C C₆-alkylamino, di-C C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆- alkynylamino, CrC₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, CrC₆-acylamino, di-C C₆- acylamino, C C₆-acyloxy, CrC₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-CrC₄-alkyl- and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloxy and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloamino and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused haloheterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, CrC₆-alkylsulfenyl, CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, CrC₆-acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl and 1 to 3 hetero atoms selected from N, O, or S, C C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused CrC₆-alkylheteroaryl and 1 to 3 hetero atoms selected from N, O, or S, cyano, cyanate, isocyanate, -C(0)NH(CrC₆-alkyl), and -C(0)N(C C₆-alkyl)₂;

k may be a number selected from 0 and 1 ;

I may be a number selected from 0, 1 , and 2;

n may be a number selected from 1 , 2, 3, and 4;

m may be a number selected from 0, 1 , 2, 3, and 4;

p may be a number selected from 0 and 1 ;

r may be a number selected from 0, 1 , 2 and 3;

s may be a number selected from 2, 3, 4 and 5;

t may be a number selected from 0 and 1 ; and

u may be a number selected from 0 and 1.

The compound of the present disclosure and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

Ri may represent hydrogen or a cyano group;

R₂, R₃ and R₄ may independently of each other represent C C₆-alkyl, halo, -COOH, halo-C C₆-alkyl, C C₆-alkoxy, nitro, or cyano; Q may represent a piperidin or piperazinyl group;

W may represent a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or may represent a phenyl group;

X may represent no further substituent or may represent a moiety that is benzofused to the heterocycle or may represent a C₃ or C₄ bridge formed by two substituents of W in which 1 to 3 C-atoms may be replaced by O, N, S or -CO-;

R₅ may represent a substituent of the W or X-W moiety and may be selected from d-C₆- alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-C C₆-alkyl, oxo, halo, -COOH, -CONH₂, C C₆- alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, thio-C C₆- alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-C C₆- alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , CrC₆-alkylamino, di-CrC₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, C C₆- acylamino, di-CrC₆-acylamino, C C₆-acyloxy, CrC₆-alkylsulfonyloxy, CrC₆-alkylsulfenyl,

CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, C C₆-acylthio, nitro , cyano, cyanate, isocyanate, -

C(0)NH(C C₆-alkyl), and -C(0)N(C C₆-alkyl)₂;

k may be a number selected from 0 and 1 ;

I may be a number selected from 0, 1 , and 2;

n may be a number selected from 1 , 2, and 3;

m may be a number selected from 0, 1 , 2, and 3;

p may be a number selected from 0 and 1 ;

r may be a number selected from 0 and 1 ;

s may be a number selected from 2, 3, 4, and 5;

t may be a number selected from 0 and 1 ; and

u may be a number selected from 0 and 1.

The disclosed compound and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t, r und u may be 0, k may be 0 or 1 and s may be 3, 4 or 5.

may represent hydrogen or a cyano group;

R₂, R₃ and R₄ may independently of each other represent halo, or C C₆-alkoxy;

Q may represent a piperidin-, or piperazinyl group;

W may represent a 2,5-dioxo-2,5-dihydro-pyrrol-1-yl group or may represent a phenyl group; X may represent no further substituent or may represent a moiety that is benzofused to the pyrrolyl group or may represent a bridge selected from -0-CH₂-CH₂-0-, -S-CH₂-CH₂-S-, - CH₂-CH=CH-CH₂-, -CH=NH-CH₂-CH₂-, -NH=CH-CH₂-CH₂- -CH=CH-S- and -CO-NH-CO-; R₅ may represent a substitutent of the W or X-W moiety and may be selected from C C₆- alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-C C₆-alkyl, oxo, halo, -COOH, -CONH₂, C C₆- alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, thio-C C₆- alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-C C₆- alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , CrC₆-alkylamino, di-CrC₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, C C₆- acylamino, di-CrC₆-acylamino, C C₆-acyloxy, CrC₆-alkylsulfonyloxy, CrC₆-alkylsulfenyl, CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, CrC₆-acylthio, cyano, cyanate, isocyanate, - C(0)NH(C C₆-alkyl), and -C(0)N(C C₆-alkyl)₂;

k may be 0 or 1 ;

I may be a number selected from 0, 1 and 2;

n may be a number selected from 1 and 2;

m may be a number selected from 0, 1 , 2, and 3;

p may be 0;

r may be a number selected from 0 and 1 ;

s may be a number selected from 2, 3 and 4;

t may be 0; and

u may be 0.

Ri may represent hydrogen or cyano;

R₂ may represent methoxy;

R₃ may represent chlorine;

R₄ may represent chlorine;

Q may represent a piperazinyl group;

W may represent a 2,5-dioxo-2,5-dihydro-dihydro pyrrol-1-yl group or a 2,5-dioxo-pyrrolidin-

1-yl group or together with X may represent a 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl group, a

5,7-dioxo-2,3,5,7-tetrahydro-[1 ,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazinyl group;

R₅ may represent hydrogen or may represent a substitutent of the W or X-W moiety and may be selected from CrC₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, oxo, halogen, C C₆- alkylcarbonyloxy, and nitro;

k may be 0 or 1 ; I may be a number selected from 0, 1 and 2;

n may be a number selected from 1 and 2;

m may be a number selected from 1 , 2 and 3;

p may be 0;

r may be a number selected from 0 and 1 ;

s may be a number selected from 2, 3 and 4;

t may be 0; and

u may be 0

and Y may be absent.

The disclosed compound may be selected from one of the following formulas and/or its solvates, hydrates and pharmaceutically acceptable salts:

The present disclosure relates to a process for making a compound of formula (I) as disclosed herein comprising reacting a compound of formula (II),

wherein

R may represent hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH₂, -CO-O-alkyl or -CO-alkyl;

R², R³ and R⁴ may independently of each other represent alkyl, thioalkyi, alkylcarbonyl, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl- CO-heterocyclyl

and R² may also represent hydrogen; Q may represent a heterocyclyl group;

n may be a number selected from 1 , 2, 3, 4, 5 and 6;

m may be a number selected from 0, 1 , 2, 3, 4, 5 and 6; and

p may be a number selected from 0 and 1 ;

in an organic solvent in the presence of a base with a compound of formula (III),

Y (III)

wherein

W may represent optionally substituted aromatic or non-aromatic heterocyclyl group or an optionally substituted aryl group;

X may represent no further substituent or may represent a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;

Y may represent an optional substituent of the -(CH₂)_r- chain and R⁵ may represent an optional substituent of the W or X-W moiety and Y and R⁵ may independently of another be selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkyl heteroaryl, cyano, cyanate, isocyanate, -C(0)NH (alkyl), -C(0)N(alkyl)₂ and -CH₂N(alkyl)₂;

k may a number selected from 0 and 1 ;

I may be the number of R⁵ substituents independently selected and may itself be a number selected from 0, 1 , 2, 3, 4 and 5;

r may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

s may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

t may be a number selected from 0 and 1 ; u may be a number selected from 0 and 1 ; and

Hal stands for halogen.

The present disclosure relates to a process for making a compound of formula (I) as disclosed herein comprising reacting a compound of formula (II) as disclosed herein in an organic solvent in the presence of a base with a compound of formula (III) as disclosed herein, wherein R¹, R², R³, R⁴, R⁵, R⁶, Q, W, X, Y, k, I, n, m, p, r, s, t and u may be as disclosed herein.

The organic solvent in a process comprising reacting a compound of formula (II) with a compound of formula (III) may be dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, acetonitrile or mixtures thereof.

The base in a process comprising reacting a compound of formula (II) with a compound of formula (III) may be Ν,Ν-diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine, morpholine or mixtures thereof.

The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (III) at a temperature of about 0 °C to about 153 °C, or about 5 °C to about 153 °C, about 10 °C to about 153 °C, about 15 °C to about 153 °C, about 20 °C to about 153 °C, about 25 °C to about 153 °C, about 30 °C to about 153 °C, about 35 °C to about 153 °C, about 40 °C to about 153 °C, about 45 °C to about 153 °C, about 50 °C to about 153 °C, about 55 °C to about 153 °C, about 60 °C to about 153 °C, about 65 °C to about 153 °C, about 70 °C to about 153 °C, about 75 °C to about 153 °C, about 80 °C to about 153 °C, about 85 °C to about 153 °C, about 90 °C to about 153 °C, about 95 °C to about 153 °C, about 100 °C to about 153 °C, about 105 °C to about 153 °C, about 1 10 °C to about 153 °C, about 115 °C to about 153 °C, about 120 °C to about 153 °C, about 120 °C to about 153 °C, about 125 °C to about 153 °C, about 130 °C to about 153 °C, about 135 °C to about 153 °C, about 140 °C to about 153 °C, about 145 °C to about 153 °C, about 150 °C to about 153 °C, about 0 °C to about 150 °C, about 0 °C to about 145 °C, about 0 °C to about 140 °C, about 0 °C to about 135 °C, about 0 °C to about 130 °C, about 0 °C to about 125 °C, about 0 °C to about 120 °C, about 0 °C to about 1 15 °C, about 0 °C to about 110 °C, about 0 °C to about 105 °C, about 0 °C to about 100 °C, about 0 °C to about 95 °C, about 0 °C to about 90 °C, about 0 °C to about 85 °C, about 0 °C to about 80 °C, about 0 °C to about 75 °C, about 0 °C to about 70 °C, about 0 °C to about 65 °C, about 0 °C to about 60 °C, about 0 °C to about 55 °C, about 0 °C to about 50 °C, about 0 °C to about 45 °C, about 0 °C to about 40 °C, about 0 °C to about 35 °C, about 0 °C to about 30 °C, about 0 °C to about 25 °C, about 0 °C to about 20 °C, about 0 °C to about 15 °C, about 0 °C to about 10 °C, about 0 °C to about 5 °C, about 5 °C to about 150 °C, about 10 °C to about 145 °C, about 15 °C to about 140 °C, about 20 °C to about 135 °C, about 25 °C to about 130 °C, about 30 °C to about 125 °C, about 35 °C to about 120 °C, about 40 °C to about 1 15 °C, about 45 °C to about 1 10 °C, about 50 °C to about 105 °C, about 55 °C to about 100 °C, about 60 °C to about 95 °C, about 65 °C to about 90 °C, about 70 °C to about 85 °C, about 75 °C to about 80 °C, about 80 °C to about 120 °C, about 85 °C to about 115 °C, about 90 °C to about 110 °C, about 95 °C to about 105 °C, or about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 153 °C, or any value and range therebetween.

The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (III) for about 1 to about 72 hours, or about 5 to about 72 hours, or about 10 to about 72 hours, or about 15 to about 72 hours, or about 20 to about 72 hours, or about 25 to about 72 hours, or about 30 to about 72 hours, or about 35 to about 72 hours, or about 40 to about 72 hours, or about 45 to about 72 hours, or about 50 to about 72 hours, or about 55 to about 72 hours, or about 60 to about 72 hours, or about 65 to about 72 hours, or about 70 to about 72 hours, or about 1 to about 70 hours, about 1 to about 65 hours, about 1 to about 60 hours, about 1 to about 55 hours, about 1 to about 50 hours, about 1 to about 45 hours, about 1 to about 40 hours, about 1 to about 35 hours, about 1 to about 30 hours, about 1 to about 25 hours, about 1 to about 20 hours, about 1 to about 15 hours, about 1 to about 10 hours, about 1 to about 5 hours, about 10 to about 65 hours, about 15 to about 60 hours, about 20 to about 55 hours, about 25 to about 50 hours, about 30 to about 45 hours, about 35 to about 40 hours, about 12 to about 24 hours, about 14 to about 22 hours, about 16 to about 20 hours, about 18 to about 22 hours, or about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 72 hours, or any range or value therebetween. The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (III) under constant agitation, mixing or stirring.

Water may be added to the disclosed process after the reaction of the compound of formula (II) with the compound of formula (III) is completed.

The disclosed process may comprise reacting a compound of formula (II) in the presence of DMF and DIPEA with a compound of formula (III) at about 100 °C for about 16 hours.

The disclosed process may be allowed to cool to room temperature prior to purification.

The present disclosure also relates to a process for making a compound of formula (I) as disclosed herein, comprising reacting a compound of formula (II) as disclosed herein in an f formula (IV),

Y (IV)

wherein

Y may represent an optional substituent of the -(CH₂)_r- chain and R⁵ may represent an optional substituent of the W or X-W moiety and Y and R⁵ may independently of another be selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ and -CH₂N(alkyl)₂;

k may be a number selected from 0 and 1 ;

r may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

s may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

t may be a number selected from 0 and 1 ; and

u may be a number selected from 0 and 1.

The present disclosure relates to a process for making a compound of formula (I) as disclosed herein, comprising reacting a compound of formula (II) as disclosed herein in an organic solvent in the presence of a base with a compound of formula (IV), wherein W, X, Y, k, I, r, s, t, u and R⁵ may be as disclosed herein.

The organic solvent in the process comprising reacting a compound of formula (II) with a compound of formula (IV) may be dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dichloromethane, chloroform, or mixtures thereof.

The base in a process comprising reacting a compound of formula (II) with a compound of formula (IV) may be Ν,Ν-diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine, morpholine or mixtures thereof.

The process comprising reacting a compound of formula (II) with a compound of formula (IV) may further comprise a coupling agent. The coupling agent may be 1- [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), Ν,Ν'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), carbonyldiimidazole (CDI), or 2-(1 H-benzotriazol- 1-yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU).

The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (IV) at about 20 °C to about 35 °C, or about 20 °C to about 30 °C, about 20 °C to about 25 °C, about 25 °C to about 35 °C, about 30 °C to about 35 °C, or about 20 °C, about 25 °C, about 30 °C, about 35 °C, or any range or value therebetween. The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (IV) for about 1 to about 72 hours, or about 5 to about 72 hours, or about 10 to about 72 hours, or about 15 to about 72 hours, or about 20 to about 72 hours, or about 25 to about 72 hours, or about 30 to about 72 hours, or about 35 to about 72 hours, or about 40 to about 72 hours, or about 45 to about 72 hours, or about 50 to about 72 hours, or about 55 to about 72 hours, or about 60 to about 72 hours, or about 65 to about 72 hours, or about 70 to about 72 hours, or about 1 to about 70 hours, about 1 to about 65 hours, about 1 to about 60 hours, about 1 to about 55 hours, about 1 to about 50 hours, about 1 to about 45 hours, about 1 to about 40 hours, about 1 to about 35 hours, about 1 to about 30 hours, about 1 to about 25 hours, about 1 to about 20 hours, about 1 to about 15 hours, about 1 to about 10 hours, about 1 to about 5 hours, about 10 to about 65 hours, about 15 to about 60 hours, about 20 to about 55 hours, about 25 to about 50 hours, about 30 to about 45 hours, about 35 to about 40 hours, about 12 to about 24 hours, about 14 to about 22 hours, about 16 to about 20 hours, about 18 to about 22 hours, or about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 72 hours, or any range or value therebetween.

The disclosed process may comprise reacting a compound of formula (II) in the presence of DMF, DIPEA and 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), with a compound of formula (IV), at room temperature selected from about 20 °C, about 25 °C, about 30 °C and about 35 °C for about 16 hours.

The disclosed process may comprise reacting the compound of formula (II) with the compound of formula (IV) under constant agitation, mixing or stirring.

Water may be added to the disclosed process after the reaction of the compound of formula (II) with the compound of formula (IV) is completed.

The present disclosure relates to a process for making a compound of formula (I) as disclosed herein, comprising reacting a compound of formula (V),

wherein

R², R³ and R⁴ may independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl- CO-heterocyclyl

and R² may also represent hydrogen;

n may be a number selected from 1 , 2, 3, 4, 5 and 6;

m may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

p may be a number selected from 0 and 1 ; and

Hal stands for chlorine or bromine,

Y (VI)

wherein

Q may represent a heterocyclyl group;

k may be a number selected from 0 and 1 ;

I may be the number of R⁵ substituents may independently be selected and may itself be a number selected from 0, 1 , 2, 3, 4 and 5;

r may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

s may be a number selected from 0, 1 , 2, 3, 4, 5 and 6;

t may be a number selected from 0 and 1 ; and

u may be a number selected from 0 and 1.

The present disclosure relates to a process for making a compound of formula (I) as disclosed herein, comprising reacting a compound of formula (V) as disclosed herein in an organic solvent in the presence of an alkali or ammonium iodide, preferably sodium iodide, with a compound of formula (VI), wherein R¹, R², R³, R⁴, R⁵, n, m, p, W, X, Y, Q, k, I, r, s, t, u may be as disclosed herein.

The alkali iodide of the process comprising reacting a compound of formula (V) with a compound of formula (VI) may be sodium iodide or potassium iodide. The alkali iodide may be a catalyst.

The organic solvent in the process comprising reacting a compound of formula (V) with a compound of formula (VI) may be acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran and a mixture thereof. The organic solvent of the disclosed process may be a mixture of acetone and acetonitrile. The acetone and acetonitrile mixture may comprise 1 part acetone to 1 part acetonitrile by volume. The base in the process comprising reacting a compound of formula (V) with a compound of formula (VI) may be Ν,Ν-diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine, morpholine, or mixtures thereof.

The process comprising reacting a compound of formula (V) with a compound of formula (VI) may comprise an inorganic baseThe inorganic base may be potassium carbonate (K₂C0₃), sodium carbonoate (Na₂C0₃), or caesium carbonate (Cs₂C0₃).

The process comprising reacting a compound of formula (V) with a compound of formula (VI) may comprise reacting a compound of formula (V) in the presence of acetone, acetonitrile, K₂C0₃ and sodium iodide with a compound of formula (VI).

The process may comprise reacting the compound formula (V) with the compound of formula (VI) at reflux temperature. The temperature may be about 80 °C to about 120 °C, about 85 °C to about 120 °C, about 90 °C to about 120 °C, about 95 °C to about 120 °C, about 100 °C to about 120 °C, about 105 °C to about 120 °C, about 110 °C to about 120 °C, about 115 °C to about 120 °C, about 80 °C to about 1 15 °C, about 80 °C to about 1 10 °C, about 80 °C to about 105 °C, about 80 °C to about 100 °C, about 80 °C to about 95 °C, about 80 °C to about 90 °C, about 80 °C to about 85 °C, about 85 °C to about 115 °C, about 90 °C to about 1 10 °C, about 95 °C to about 105 °C, or about 80 °C, about 85 °C, about, or any value and range therebetween.

The disclosed process may comprise reacting the compound formula (V) with the compound of formula (VI) for about 1 to about 72 hours, or about 5 to about 72 hours, or about 10 to about 72 hours, or about 15 to about 72 hours, or about 20 to about 72 hours, or about 25 to about 72 hours, or about 30 to about 72 hours, or about 35 to about 72 hours, or about 40 to about 72 hours, or about 45 to about 72 hours, or about 50 to about 72 hours, or about 55 to about 72 hours, or about 60 to about 72 hours, or about 65 to about 72 hours, or about 70 to about 72 hours, or about 1 to about 70 hours, about 1 to about 65 hours, about 1 to about 60 hours, about 1 to about 55 hours, about 1 to about 50 hours, about 1 to about 45 hours, about 1 to about 40 hours, about 1 to about 35 hours, about 1 to about 30 hours, about 1 to about 25 hours, about 1 to about 20 hours, about 1 to about 15 hours, about 1 to about 10 hours, about 1 to about 5 hours, about 10 to about 65 hours, about 15 to about 60 hours, about 20 to about 55 hours, about 25 to about 50 hours, about 30 to about 45 hours, about 35 to about 40 hours, about 12 to about 24 hours, about 14 to about 22 hours, about 16 to about 20 hours, about 18 to about 22 hours, or about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours, about 72 hours, or any range or value therebetween.

The disclosed process may comprise reacting the compound of formula (V) with the compound of formula (VI) under constant agitation, mixing or stirring.

Water may be added to the disclosed process after the reaction of the compound of formula (V) with the compound of formula (VI) is completed.

The disclosed process may comprise reacting a compound of formula (V) in the presence of acetone, acetonitrile, K₂C0₃ and sodium iodide, with a compound of formula (VI), at reflux temperature for about 72 hours.

The disclosed compound of formula (I) or pharmaceutically acceptable salts, hydrates or solvates thereof may be used as a medicament.

The disclosed compound of formula (I) or pharmaceutically acceptable salts, hydrates or solvates thereof may be used in the treatment of diseases, disorders and conditions which are caused by cancer cells. In an embodiment, the cancer may be selected from lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma. In another embodiment, the cancer may be selected from breast cancer and neuroblastoma.

The present disclosure relates to the use of a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from any cancer form. In an embodiment, the cancer form may be selected from lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma. In another embodiment, the cancer may be selected from breast cancer and neuroblastoma.

In another embodiment, the present disclosure relates to a method of treating an oncological disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a compound of formula (I) as disclosed herein or pharmaceutically acceptable salts, hydrates or solvates thereof. In an embodiment, the an oncological disease, disorder or condition may be selected from lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma. In another embodiment, the cancer may be selected from breast cancer and neuroblastoma.

The compounds as disclosed herein may be adminsistered in an effective amount to treat a disease as disclosed herein. The compounds may be administered at a dosage of about 30 mg/kg to about 100 mg/kg every other day (i.e. every about 48 hours). The compounds may be administered at a dosage of about 30 mg/kg to about 100 mg/kg, or about 40 mg/kg to about 100 mg/kg, or about 50 mg/kg to about 100 mg/kg, or about 60 mg/kg to about 100 mg/kg, or about 70 mg/kg to about 100 mg/kg, or about 80 mg/kg to about 100 mg/kg, or about 90 mg/kg to about 100 mg/kg, or about 40 mg/kg to about 90 mg/kg, or about 40 mg/kg to about 80 mg/kg, or about 40 mg/kg to about 70 mg/kg, or about 40 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 50 mg/kg, or about or about 50 mg/kg to about 90 mg/kg, or about 60 mg/kg to about 80 mg/kg, or about 60 mg/kg, about 65 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or any range or value therebetween.

Advantageously, administering at the dosages disclosed herein may result in enhanced inhibitory effect. As shown in Fig. 6, compounds of the present invention showed greater reduction in tumour size when administered in the dosages of 30mg/kg to about 100 mg/kg every other day when compared to treatment with bosutinib at 100 mg mg/kg daily (percentage reduction at day 21 compared to vehicle treated: bosutinib (32%), V3-030 (36%), V1 1-008 (47%) and V1 1-010 (55%)). Therefore, advantageously, the compounds of the present invention may possess enhanced inhibitory effect on solid tumours at reduced drug dosage which may advantageously alleviate any potential side effects encountered by patients undergoing bosutinib treatment. Brief Description of Drawings

The accompanying drawings illustrate a disclosed embodiment and serves to explain the principles of the disclosed embodiment. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

Key:

SKI-606: Bosutinib

V3-030: fc-Bosutinib (also known as phthalimide-protected Bosutinib) Fig.lA

[Fig. 1A] shows a kinase inhibitory profile of Bosutinib (SKI-606) on a 130-member kinase panel (DiscoveRx: 1 μΜ of bosutinib was tested on scanTK^™ Kinase Assay Panel. The panel includes 130 receptor and non-receptor tyrosine kinases and important mutant forms).

Fig.l B

[Fig. 1 B] shows the kinase inhibitory profile of phthalimide protected Bosutinib (fc- Bosutinib) on a 130-member kinase panel (DiscoveRx: 1 μΜ of fc-bosutinib was tested on scanTK^™ Kinase Assay Panel. The panel includes 130 receptor and non-receptor tyrosine kinases and important mutant forms). The binding affinity difference between fc-Bosutinib and Bosutinib (Fig. 1A) was higher than 10% in 32 kinases.

Fig.2

[Fig. 2] is a series of graph plots showing the results of flow cytometry examinations of MDA-MB-436 cells stained with Annexin V (FL1 -A) and Propidium iodide (FL2-A) after treatment with (A) DMSO, (B) 0.1 μΜ Staurosporine and (C) 5 μΜ fc-Bosutinib (V3-030) for 24 hours. Apoptotic cells are defined as Annexin V positive and PI positive cells (Q1 - LR and Q1 -UR).

Fig.3

[Fig. 3] is a Western Blot profile showing the inhibition of ERK and AKT phosphorylation by V3-030. MDA-MB 436 and MDA-MB 453 cells were treated with SKI-606 or V3-030 for 2 hours at 1 μΜ concentration. Cell lysates were harvested and separated on SDS-PAGE gel. Westen blot were performed with respective antibodies.

Fig.4

[Fig. 4] is a series of graphs showing that V3-030 induces cell death. MDA-MB 453 cells were treated with (A) SKI-606 and (B) V3-030 for at various concentrations over 1 , 2 and 3 days. Cells were stained with Trypan blue following by cell counting for stained (dead) and unstained (viable) cells. Percentage of cell death was calculated by number of dead cells over total number of cells x 100%.

Fig.5

[Fig. 5] is a series of graphs showing (A) the change in the tumor volume in MDA-MB 361 xenograft model over time with increasing dose of V3-030; Animals were inoculated with 1x10⁷ MDA-MB 361 cells subcutaneously; Animals were randomised to group of 6 at tumor volume ~200mm³; Treatment commenced with either vehicle, 10, 30 or 100 mg/kg of V3-030 via intraperitoneal injection once every other day; Tumors were measured twice per week and volume was calculated with formula (LxW²)/2; and (B) the change in weight of the animals (subjects) over time with increasing dose of V3-030 (vehicle, 10, 30 or 100 mg/kg, once every other day); Animals were weighed twice per week after the commencement of the treatment. V3-030 reduced tumor volume in MDA-MB 361 xenograft model.

Fig.6

[Fig. 6] is a series of graphs showing (A) the change in the tumor tumor volume in MDA- MB 361 xenograft model over time with different dosing of Bosutinib, V3-030, V1 1-008 and V11 -010; Animals were inoculated with 1x10⁷ MDA-MB 361 cells subcutaneously; Animals were randomised to group of 5 at tumor volume ~200mm³; Treatment commenced with either vehicle, 60 mg/kg of V3-030 or V1 1-008 or V1 1-010 via intraperitoneal injection once every other day or 100mg/kg Bosutinib via oral administration (P.O.) every day; Tumors were measured twice per week and volume was calculated with formula (LxW²/2); and (B) the change in weight of the animals (subjects) over time with increasing dose of V3-030. Every other day dosing with 60mg/kg of V3-030, V1 1-008 and V1 1-010 is superior to daily dosing of 100mg/kg of Bosutinib.

Examples

Non-limiting examples of the invention and a comparative example will be further described in greater detail by reference to specific Examples, which should not be construed as in any way limiting the scope of the invention.

Example 1 - Analytical Characterization

All of the prepared compounds were characterized by two independent analytical methods. NMR

The 300 MHz ¹H-NMR analysis was performed with an apparatus of type Bruker AVANCE-300 at 25 °C, exact frequency was 300.14 MHz. Generally DMSO-d₆ was used as solvent, exceptions given. Chemical shifts are given in parts per million (δ) referenced to TMS (5 = 0.00 ppm). LCMS

The LCMS analysis was performed with a liquid chromatography mass-spectrometer

Waters chromatograph with the following parameters:

Waters HPLC/MS:

MS detector: Waters SQD

UV detector: Waters 996 DAD

Separation module: Waters Alliance 2795

HPLC:

Column: Waters XBridge C18, 50 mm x 4.6 mm, 3.5 μηι

Solvent I: Water / 0.1 % HCOOH (Method A)

Solvent I: Water / 0.4% NaHC0₃ (Method B)

Solvent II: MeCN-Sigma

Acetonitrile: Riedel-deHaen; G Chromasolv (34998)

Water: MilliQ- Merck Millipore

Formic acid: Riedel-deHaen; extra pure (27001 )

Flow rate: 2 ml/min

Injection: 5ug (1-50ul)

Gradient:

MS: Ionization: ES⁺/ES^"

Source block temperature: 110 °C

Desolvation temperature: 250 °C

Desolvation gas: 500 L/h

Cone gas: 80 L/h

Capillary voltage: 3000 V

Cone voltage: 30 V

Extractor voltage: 6 V Rf lens voltage: 0.1 V

Scan: 80 to 1000 m/z in 1 sec.

Inter-scan delay: 0.1 s

Example 2 - Methods of Synthesis

Example 2.1 - Synthesis of V3-030

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2- yl)-butyl]-piperazin-1 -yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

The solution of (0.130 g, 0.251 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)-

6- methoxy-7-(3-piperazin-1-yl-propoxy)-quinoline-3-carbonitrile, DIPEA (0.17 mL, 1.255 mmol 5.00 equiv) in 8 mL DMF was treated with 2-(4-Bromo-butyl)-isoindole-1 ,3-dione (0.05 g, 0.276 mmol, 1.1 equiv). The reaction mixture was stirred at 100 °C overnight. The mixture was cooled down to room temperature and poured onto water, extracted with 2 x 15 mL of ethyl acetate. The combined organic layers were washed with brine, dried over MgS0₄ and concentrated under vacuum. The residue was purified by preparative layer with chloroform/methanol (10: 1) to provide the desired 4-(2,4-Dichloro-5-methoxy-phenylamino)-

7- (3-{4-[4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-6-methoxy- quinoline-3-carbonitrile (0.075 g, 42%) as a pale yellow solid.

Mw calc: 716.23 m/z 717.1 [M+H]⁺ 715.1 [M-H]^" Rt = 3.05 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1 H), 8.40 (s, 1 H), 7.82-7-91 (ovl. m, 4H), 7.81 (s, 1 H), 7.72 (s, 1 H), 7.30 (s, 1 H), 7.29 (s, 1 H), 4.18 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.58 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 7.0 Hz. 2H), 2.29-2.39 (ovl. m, 8H), 2.26 (t, J = 7.0 Hz, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.42 (m, 2H)

The title compound was made 2xHCI salt. The solution of (0.150 g 0.209 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- butyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile in 10 ml dry ethyl acetate was treated with 4N HCI/Dioxan (0.105 ml 0.418 mmol, 2.00 equiv). The mixture was cooled down and filtered off, washed with acetonitrile and dried, give the pure 2xHCI salt of title compound. (0.135 g, 81 %) as a light yellow solid.

Mw calc: 716.23 m/z 717.4 [M+H]⁺ 715.4 [M-H]^" Rt = 2.81 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 11.85 (br. s, 1 H), 1 1.33 (br. s, 1 H), 8.98 (s, 1 H), 8.31 (s, 1 H), 7.83-7-90 (ovl. m, 4H), 7.83 (s, 1 H), 7.58 (s, 1 H), 7.50 (s, 1 H), 4.33 (t, J ~ 5.5 Hz, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 3.65-3.88 (ovl. m, 4H), 3.61 (t, J = 6.7 Hz, 2H), 3.25-3.57 (ovl. m, 6H), 3.17 (m, 2H), 2.35 (m, 2H), 1.75 (m, 2H), 1.66 (m, 2H)

Example 2.2 - Synthesis of V9-002, V9-003, V9-004, V9-005, V9-006, V9-007, V9- 008, V9-009, V9-011 , V9-019, V9-020, V9-022, V9-027, V9-028, V9-029, V11-005 and V11-008.

The following compounds were prepared as described in Example 2.1 for V3-030.

V9-002

7-(3-{4-[2-(4-Chloro-butyl)-6-nitro-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-5-yl]-piperazin-1-yl}- propoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile (0.042 g, 21 %) yellow solid

Mw calc: 795.17 m/z 796.2 [M+H]⁺ 794.2 [M-H]^" Rt = 3.60 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.75 (br. s, 1 H), 8.34 (s, 1 H), 8.18 (s, 1 H), 7.82 (s, H), 7.69 (s, 1 H), 7.67 (s, 1 H), 7.29 (s, 1 H), 7.23 (s, 1 H), 4.21 (t, J = 5.8 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.53-3.70 (ovl. m, 4H), 3.28 (m, 4H), 2.47-2.62 (ovl. m, 6H), 2.00 (m, 2H), 1.66- 1.77 (ovl. m, 4H)

V9-003

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(2,5-dioxo-pyrrolidin-1-yl)-butyl]- piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.038 g, 28%) white solid

Mw calc: 668.23 m/z 669.4 [M+H]⁺ 667.4 [M-H]^" Rt = 2.63 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.59 (br. s, 1 H), 8.40 (s, 1 H), 7.82 (s, 1 H), 7.72 (s, H), 7.32 (s, 1 H), 7.31 (s, 1 H), 4.19 (t, J ~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.35 (m, 2H), 2.61 (s, 4H), 2.45 (m, 2H), 2.30-2.43 (ovl. m, 8H), 2.25 (m, 2H), 1.95 (m, 2H), 1.45 (m, 2H), 1.38 (m, 2H)

V9-004 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(5-fluoro-1,3-dioxo-1,3-dihydro-isoin

2-yl)-butyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.051 g, 35%) pale yellow solid

Mw calc: 734.22 m/z 735.4 [M+H]⁺ 733.4 [M-H]^" Rt = 2.95 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.59 (br. s, 1H), 8.40 (s, 1H), 7.93 (dd, J= 8.0 and 4.4 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J= 10.2 and 1.8 Hz, 1H), 7.73 (s, 1H), 7.65 (ddd, J= 9.6, 8.0 and 1.8 Hz, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 4.18 (t, J~ 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.57 (t, J= 6.6 Hz, 2H), 2.45 (t, J= 7.0 Hz.2H), 2.31-2.42 (ovl. m, 8H), 2.28 (t, J= 7.0 Hz, 2H), 1.94 (m, 2H), 1.59 (m, 2H), 1.42 (m, 2H)

V9-005

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[4-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.030 g, 21%) off white solid

Mw calc: 730.24 m/z 731.4 [M+H]⁺ 729.4 [M-H]^" Rt = 3.11 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.59 (br. s, 1H), 8.39 (s, 1H), 7.81 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J= 1.8 Hz, 1H), 7.63 (dd, J= 7.8 and 1.8 Hz, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 4.18 (t, J~ 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.56 (t, J= 6.8 Hz, 2H), 2.48 (s, 3H), 2.44 (t, J~ 7.5 Hz.2H), 2.29-2.41 (ovl. m, 8H), 2.26 (t, J~ 7.0 Hz, 2H), 1.94 (m, 2H), 1.59 (m, 2H), 1.40 (m, 2H)

V9-006

7-(3-{4-[4-(5-tert-Butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-4^

(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

(0.020 g, 13%) off white solid

Mw calc: 772.29 m/z 773.4 [M+H]⁺ 771.4 [M-H]^" Rt = 3.50 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.62 (br. s, 1H), 8.38 (s, 1H), 7.86 (dd, J 8.0 and 1.5 Hz, 1H), 7.85 (d, J~ 1.5 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J~ 8.0 Hz, 1H), 7.70 (s, 1H), 7.29 (s, 1H), 7.28 (s, 1H), 4.17 (t, J~ 5.5 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.57 (t, J= 6.8 Hz, 2H), 2.43 (t, J~ 7.5 Hz.2H), 2.29-2.41 (ovl. m, 8H), 2.26 (t, J~ 7.0 Hz, 2H), 1.93 (m, 2H), 1.59 (m, 2H), 1.40 (m, 2H), 1.35 (s, 9H)

V9-007

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-m

butyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-5-yl]-piperazin-1-yl}-propoxy)-quinoline- 3-carbonitrile (0.050 g, 30%) pale yellow solid

Mw calc: 852.07 m/z 853.1 [M+H]⁺ 851.1 [M-H]^" Rt = 3.90 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1 H), 8.41 (s, 1 H), 7.84 (s, 1 H), 7.74 (s, 1 H), 7.35 (s, 1 H), 7.33 (s, 1 H), 4.26 (t, J ~ 5.5 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 3H), 3.66 (m, 2H), 3.60 (m, 2H), 3.32 (m, 4H), 2.52-2.64 (ovi. m, 6H), 2.03 (m, 2H), 1.62-1.80 (ovi. m, 4H)

V9-008

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[4-(4-methyl-1 ,3-dioxo-1 ,3- dihydro-isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.040 g, 28%) off white solid

Mw calc: 730.24 m/z 731.3 [M+H]⁺ 729.3 [M-H]^" Rt = 4.35 min (Method B).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.58 (br. s, 1 H), 8.40 (s, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.63-7.70 (ovi. m, 2H), 7.61 (m, 1 H), 7.31 (s, 1 H), 7.30 (s, 1 H), 4.18 (t, J ~ 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.56 (t, J = 6.8 Hz, 2H), 2.62 (s, 3H), 2.43 (t, J = 7.5 Hz, 2H), 2.29-2.41 (ovi. m, 8H), 2.26 (t, J = 7.0 Hz, 2H), 1.94 (m, 2H), 1.59 (m, 2H), 1.41 (m, 2H)

V9-009

2-[4-(4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoli

propyl}-piperazin-1-yl)-butyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid ethyl ester (0.031 g, 20%) light yellow solid

Mw calc: 788.25 m/z 789.3 [M+H]⁺ 787.3 [M-H]^" Rt = 4.41 min (Method B).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.59 (br. s, 1H), 8.41 (s, 1H), 8.37 (dd, J~ 7.5 and 1.5 Hz, 1H), 8.24 (d, J~ 1.5 Hz, 1H), 8.00 (d, J~ 7.5 Hz, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 4.39 (q, J= 7.0 Hz, 2H), 4.18 (t, J~ 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.61 (t, J= 6.8 Hz, 2H), 2.43 (t, J~ 7.5 Hz, 2H), 2.29-2.41 (ovl. m, 8H), 2.26 (t, J~ 7.0 Hz, 2H), 1.94 (m, 2H), 1.62 (m, 2H), 1.44 (m, 2H), 1.36 (t, J= 7.0 Hz, 3H)

V9-011

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-{3-[4-(2-methyl-thiazol-4-ylrnethyl)- piperazin-1-yl]-propoxy}-quinoline-3-carbonitrile (0.036 g, 23%) light yellow solid

Mw calc: 626.16 m/z 627.4 [M+H]⁺ 625.4 [M-H]^" Rt = 2.86 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.65 (br. s, 1 H), 8.42 (s, 1 H), 7.86 (s, 1 H), 7.73 (s, 1 H), 7.34 (s, 1 H), 7.33 (s, 1 H), 7.32 (s, 1 H), 4.22 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 3H), 3.66 (m, 2H), 2.64 (s, 3H), 2.35-2.85 (ovl. m, 10H), 2.08 (m, 2H)

V9-019

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(1 ,3-dioxo-1 ,3,3a,4,7,7a-hexahydro- isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.027 g, 15%) off white solid

Mw calc: 720.26 m/z 721.4 [M+H]⁺ 719.4 [M-H]^" Rt = 3.30 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.50 (br. s, 1 H), 8.36 (s, 1 H), 7.82 (s, 1 H), 7.68 (s, 1 H), 7.27 (s, 1 H), 7.25 (s, 1 H), 5.84 (m, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.34 (t, J ~ 6.5 Hz, 2H), 3.12 (m, 2H), 2.44 (m, 2H), 2.40 (m, 2H), 2.27-2.42 (ovl. m, 8H), 2.21 (m, 2H), 2.16 (m, 2H), 1.95 (m, 2H), 1.43 (m, 2H), 1.30 (m, 2H)

V9-020

7-(3-{4-[3-(5-tert-Butyl-1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propyl]-piperazin-1-yl}-propoxy)-4^

(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

(0.099 g, 52%) white solid

Mw calc: 758.28 m/z 759.5 [M+H]⁺ 757.5 [M-H]^" Rt = 3.56 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1 H), 8.39 (s, 1 H), 7.84 (s, 1 H), 7.75-7.85 (ovl. m, 3H), 7.71 (s, 1 H), 7.28 (s, 1 H), 7.27 (s, 1 H), 4.12 (t, J ~ 6.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.64 (t, J ~ 6.0 Hz, 2H), 2.30 (m, 2H), 2.26 (m, 2H), 1.97-2.30 (ovl. m, 8H), 1.85 (m, 2H), 1.72 (m, 2H), 1.34 (s, 9H)

V9-022

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(3,4-dimethyl-2,5-dioxo-2,5

pyrrol-1-yl)-butyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.066 g, 38%) pale yellow solid Mw calc: 694.24 m/z 695.4 [M+H]⁺ 693.4 [M-H]^" Rt = 2.88 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 8.33 (s, 1 H), 7.80 (s, 1 H), 7.66 (s, 1 H), 7.26 (s, 1 H), 7.22 (s, 1 H), 4.16 (t, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.37 (m, 2H), 2.43 (t, J ~ 7.0 Hz, 2H), 2.26-2.42 (ovl. m, 8H), 2.22 (t, J ~ 7.0 Hz, 2H), 1.92 (m, 2H), 1.88 (s, 6H), 1.47 (m, 2H), 1.34 (m, 2H)

V9-027

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[3-(3,4-dimethyl-2,5-dioxo-2,5-dihydro- pyrrol-1-yl)-propyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.047 g, 27%) off white solid

Mw calc: 680.23 m/z 681.2 [M+H]⁺ 679.3 [M-H]^" Rt = 2.86 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.57 (br. s, 1 H), 8.40 (s, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.31 (s, 1 H), 7.30 (s, 1 H), 4.18 (t, J ~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.42 (t, J = 7.0 Hz, 2H), 2.44 (t, J ~ 7.0 Hz, 2H), 2.32 (ovl. m, 8H), 2.25 (t, J ~ 7.0 Hz, 2H), 1.94 (m, 2H), 1.89 (s, 6H), 1.62 (m, 2H)

V9-028

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[2-(2-{4-[4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-y butyl]-piperazin-1-yl}-ethoxy)-ethoxy]-6-methoxy-quinoline-3-carbonitrile

(0.022 g, 18%) light brown solid

Mw calc: 746.24 m/z 747.3 [M+H]⁺ 745.3 [M-H]^" Rt = 2.98 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.63 (br. s, 1 H), 8.37 (s, 1 H), 7.77-7.90 (ovl. m, 5H), 7.69 (s, 1 H), 7.32 (s, 1 H), 7.27 (s, 1 H), 4.27 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.80 (m, 2H), 3.53-3.62 (ovl. m, 4H), 2.46 (t, J = 6.0 Hz, 2H), 2.38 (m, 4H), 2.28 (m, 4H), 2.23 (t, J = 7.3 Hz, 2H), 1.59 (m, 2H), 1.39 (m, 2H)

V9-029

4-(2,4-Dichloro-5-methoxy-phenylarnino)-7-[3-(4-{2-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- ethoxy]-ethyl}-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile

(0.028 g, 15%) light brown solid Mw calc: 732.22 m/z 733.2 [M+H]⁺ 731.3 [M-H]^" Rt = 2.95 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.62 (br. s, 1 H), 8.41 (s, 1 H), 7.79-7.91 (ovl. m, 5H), 7.72 (s, 1 H), 7.31 (s, 1 H), 7.30 (s, 1 H), 4.15 (t, J = 6.0 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 3H), 3.75 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.5 Hz, 2H), 3.47 (t, J = 5.5 Hz, 2H), 2.36 (t, J = 5.5 Hz, 2H), 2.24 (t, J = 7.0 Hz, 2H), 2.29 (m, 4H), 2.20 (m, 4H), 1.87 (m, 2H)

V11-005

7-(3-{4-[4-(5-Chloro-1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-butyl]-piperazin-1-yl}-propoxy)-4-

(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

(0.012 g, 6%) yellow solid

Mw calc: 750.19 m/z 751.3 [M+H]⁺ 749.2 [M-H]^" Rt = 3.14 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.61 (br. s, 1 H), 8.40 (s, 1 H), 7.93 (s, 1 H), 7.85-7.90 (ovl. m, 2H), 7.82 (m, 1 H), 7.72 (s, 1 H), 7.30 (s, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.57 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.30-2.40 (ovl. m, 8H), 2.26 (t, J = 7.0 Hz, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.42 (m, 2H)

V11-008

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(5,7-dioxo-2,3,5,7-tetrahydro-

[1 ,4]dithiino[2,3-c]pyrrol-6-yl)-butyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3- carbonitrile

(0.074 g, 39%) vivid yellow solid

Mw calc: 756.17 m/z 757.3 [M+H]⁺ 755.3 [M-H]^" Rt = 2.99 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.61 (br. s, 1 H), 8.40 (s, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.30 (s, 1 H), 7.29 (s, 1 H), 4.18 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.41 (t, J = 7.0 Hz, 2H), 3.38 (s, 4H), 2.44 (t, J = 7.0 Hz, 2H), 2.28-2.43 (ovl. m, 8H), 2.23 (t, J = 6.9 Hz, 2H), 1.95 (m, 2H), 1.50 (m, 2H), 1.35 (m, 2H)

Example 2.3 - Synthesis of V9-023

7-(3-{4-[3-(5-tert-Butyl-1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propionyl]-piperazin-1-yl}- propoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

The solution of (0.130 g, 0.251 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)- 6-methoxy-7-(3-piperazin-1-yl-propoxy)-quinoline-3-carbonitrile, 3-(5-tert-Butyl-1 ,3-dioxo-1 ,3- dihydro-isoindol-2-yl)-propionic acid (0.070 g, 0.251 mmol, 1.00 equiv), HATU (0.106 g, 0.276 mmol, 1.10 equiv) in 12 mL DMF, was added the DIPEA (0.135 mL, 0.753 mmol 3.00 equiv) The reaction mixture was stirred at rt overnight. The mixture was poured onto water, extracted with 2 x 25 mL of ethyl acetate. The combined organic layers were washed with brine, dried over MgS0₄ and concentrated under vacuum. The residue was purified by preparative layer with chloroform/methanol (10:1) to provide the desired 7-(3-{4-[3-(5-tert- Butyl-1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-propionyl]-piperazin-1-yl}-propoxy)-4-(2,4-dichloro- 5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile. (0.030 g, 15%) as a off white solid.

Mw calc: 772.25 m/z 773.4 [M+H]⁺ 771.4 [M-H]^" Rt = 3.51 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.64 (br. s, 1 H), 8.39 (s, 1 H), 7.85 (dd, J ~ 8.5 and 1.5 Hz, 1 H), 7.84 (s, 1 H), 7.82 (d, J ~ 1.5 Hz, 1 H), 7.79 (d, J ~ 8.5 Hz, 1 H), 7.71 (s, 1 H), 7.31 (s, 1 H), 7.28 (s, 1 H), 4.20 (t, J ~ 6.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.77 (t, J = 7.0 Hz, 2H), 3.43 (m, 4H), 2.68 (t, J = 7.0 Hz, 2H), 2.47 (t, J ~ 7.0 Hz, 2H), 2.30-2.43 (ovl. m, 4H), 1.97 (m, 2H), 1.34 (s, 9H)

Example 2.4 - Synthesis of V9-024, V9-025, V9-026, V9-030, V9-031 , V9-032, V9- 033, V9-034, V9-035, V9-036, V9-037, V9-038, V9-039, V9-040, V9-041 , V11-004, V11- 006, V11 -007, V11 -009 and V11 -010. 9-023.

V9-024

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-4- methyl-pentanoyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.112 g, 59%) off white solid

Mw calc: 758.24 m/z 759.5 [M+H]⁺ 757.5 [M-H]^" Rt = 3.43 min (Method A). H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1H), 8.38 (s, 1H), 7.84-7.96 (ovl. m, 4H), 7.81 (s, 1H), 7.72 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 5.06 (dd, J= 11.2 and 4.2 Hz, 1H), 4.19 (t, J~ 6.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.41 (m, 4H), 2.44 (t, J~ 7.0 Hz, 2H), 2.37 (m, 1H), 2.25-2.41 (ovl. m, 4H), 1.94 (m, 2H), 1.64 (m, 1H), 1.50 (m, 1H), 0.90 (d, J= 7.0 Hz, 3H), 0.88 (d, J= 7.0 Hz, 3H)

V9-025

N-[4-(4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]- propyl}-piperazin-1-yl)-butyl]-3-methyl-benzamide

(0.023 g, 13%) white solid

Mw calc: 704.27 m/z 705.4 [M+H]⁺ 703.4 [M-H]^" Rt = 2.91 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.59 (br. s, 1H), 8.40 (s, 1H), 8.36 (t, J~ 5.5 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.65 (dd, J~ 1.5 and 1.5 Hz, 1H), 7.61 (m, 1H), 7.27-7.36 (ovl. m, 4H), 4.19 (t, J~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.24 (m, 2H), 2.44 (t, J~ 7.0 Hz, 2H), 2.38 (m, 8H), 2.35 (s, 3H), 2.28 (m, 2H), 1.94 (m, 2H), 1.41-1.56 (ovl. m, 4H)

V9-026

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- butyryl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.063 g, 34%) white solid

Mw calc: 730.21 m/z 731.3 [M+H]⁺ 729.3 [M-H]^" Rt = 3.04 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.59 (br. s, 1 H), 8.40 (s, 1 H), 7.77-7.91 (ovl. m, 5H), 7.72 (s, 1 H), 7.33 (s, 1 H), 7.32 (s, 1 H), 4.21 (t, J ~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.60 (t, J = 6.5 Hz, 2H), 3.39 (m, 4H), 2.48 (t, J ~ 7.0 Hz, 2H), 2.25-2.42 (ovl. m, 6H), 1.97 (m, 2H), 1.84 (m, 2H)

V9-030

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-3- methylsulfanyl-propionyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile (0.053 g, 25%) pale yellow solid

Mw calc: 762.18 m/z 763.3 [M+H]⁺ 761.3 [M-H]^" Rt = 3.30 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.59 (br. s, 1H), 8.36 (s, 1H), 7.86-7.98 (ovl. m, 4H), 7.80 (s, 1H), 7.72 (s, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 5.20 (dd, J= 10.2 and 5.2 Hz, 1H), 4.17 (t, J= 6.0 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.48 (m, 2H), 3.37 (m, 2H), 3.24 (dd, J= 14.2 and 10.2 Hz, 1H), 3.09 (dd, J= 14.2 and 5.2 Hz, 1H), 2.33-2.44 (ovl. m, 4H), 2.28 (m, 1H), 2.19 (m, 1H), 2.05 (s, 3H), 1.90 (m, 2H)

V9-031

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3- methyl-butyryl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.058 g, 31%) light yellow solid

Mw calc: 744.22 m/z 745.3 [M+H]⁺ 743.3 [M-H]^" Rt = 3.27 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.58 (br. s, 1H), 8.37 (s, 1H), 7.84-7.96 (ovl. m, 4H), 7.81 (s, 1H), 7.73 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 4.69 (d, J= 9.7 Hz, 1H), 4.16 (t, J~ 6.0 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.47 (m, 2H), 3.39 (m, 2H), 2.83 (m, 1H), 2.30-2.44 (ovl. m, 4H), 2.26 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 0.98 (d, J= 6.6 Hz, 3H), 0.81 (d, J= 6.7 Hz, 3H)

V9-032

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[6-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- hexanoyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.072 g, 38%) white solid

Mw calc: 758.24 m/z 759.3 [M+H]⁺ 757.3 [M-H]^" Rt = 3.17 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.68 (br. s, 1 H), 8.37 (s, 1 H), 7.77-7.90 (ovl. m, 5H), 7.70 (s, 1 H), 7.30 (s, 1 H), 7.27 (s, 1 H), 4.20 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.56 (t, J = 7.0 Hz, 2H), 3.42 (m, 4H), 2.46 (t, J = 7.0 Hz, 2H), 2.29-2.40 (ovl. m, 4H), 2.27 (t, J = 7.0 Hz, 2H), 1.97 (m, 2H), 1.60 (m, 2H), 1.51 (m, 2H), 1.27 (m, 2H)

V9-033

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-3- (1 H-indol-3-yl)-propionyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile (0.085 g, 41%) light yellow solid

Mw calc: 831.23 m/z 832.3 [M+H]⁺ 830.3 [M-H]^" Rt = 3.37 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 10.75 (d, J =2.0 Hz, 1H), 9.58 (br.s, 1H), 8.37 (s, 1H), 7.78-7.84 (ovl. m, 5H), 7.72 (s, 1H), 7.50 (dm, J= 7.8 Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.26 (dm, J= 8.1 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 7.00 (dd, J= 8.1 and 7.5 Hz, 1H), 6.90 (dd, J= 7.8 and 7.5 Hz, 1H), 5.31 (dd, J= 9.6 and 5.6 Hz, 1H), 4.16 (t, J~ 6.0 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.64 (dd, J= 14.7 and 9.6 Hz, 1H), 3.47 (m, 2H), 3.43 (dd, J= 14.7 and 5.6 Hz, 1H), 3.34 (m, 2H), 2.34 (t, J~ 7.0 Hz, 2H), 2.22-2.34 (ovl. m, 3H), 2.17 (m, 1H), 1.91 (m, 2H)

V9-034

N-[2-(4-{2-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]- ethyl}-piperazin-1-yl)-ethyl]-3,5-dimethyl-benzamide

(0.011 g, 8%) light brown solid

Mw calc: 676.23 m/z 677.3 [M+H]⁺ 675.3 [M-H]^" Rt = 3.10 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.62 (br. s, 1H), 8.40 (s, 1H), 8.25 (t, J~ 5.0 Hz, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.42 (s, 2H), 7.35 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 4.26 (t, J~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.35 (m, 2H), 2.77 (m, 2H), 2.40-2.57 (m, 8H), 2.45 (m, 2H), 2.31 (s, 6H)

V9-035

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[3-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-propionyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.044 g, 24%) off white solid

Mw calc: 730.21 m/z 731.3 [M+H]⁺ 729.3 [M-H]^" Rt = 3.11 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.58 (br. s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J~ 1.5 Hz, 1H), 7.63 (dd, J~ 7.8 and 1.5 Hz, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 4.21 (t, J~ 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.77 (t, J= 7.1 Hz, 2H), 3.43 (m, 4H), 2.68 (t, J= 7.4 Hz, 2H), 2.49 (t, J~ 7.0 Hz, 2H), 2.48 (s, 3H), 2.39 (m, 2H), 2.34 (m, 2H), 1.97 (m, 2H)

V9-036

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[4-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-butyryl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile (0.043g, 23%) white solid

Mw calc: 744.22 m/z 745.3 [M+H]⁺ 743.3 [M-H]^" Rt = 3.18 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.60 (br. s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.73 (d, J~ 7.5 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J~ 1.5 Hz, 1H), 7.62 (dd, J~ 7.5 and 1.5 Hz, 1H, 7.32 (s, 1H), 7.31 (s, 1H), 4.21 (t, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.59 (t, J= 6.8 Hz, 2H), 3.34-3.42 (ovl. m, 4H), 2.47 (s, 3H), 2.46 (t, J~ 7.0 Hz, 2H), 2.37 (m, 2H), 2.34 (t, J~ 7.0 Hz, 2H), 2.30 (m, 2H), 1.97 (m, 2H), 1.83 (m, 2H)

V9-037

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[6-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-hexanoyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.038 g, 20%) white solid

Mw calc: 772.25 m/z 773.3 [M+H]⁺ 771.4 [M-H]^" Rt = 3.33 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.60 (br. s, 1H), 8.40 (s, 1H), 7.83 (s, 1H), 7.74 (d, J~ 7.5 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J~ 1.5 Hz, 1H), 7.62 (dd, J~ 7.5 and 1.5 Hz, 1H), 7.33 (s, 1H), 7.32 (s, 1H), 4.21 (t, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.54 (t, J= 6.9 Hz, 2H), 3.42 (m, 4H), 2.47 (s, 3H), 2.46 (t, J= 7.0 Hz, 2H), 2.36 (m, 2H), 2.31 (m, 2H), 2.26 (t, J = 7.4 Hz, 2H), 1.97 (m, 2H), 1.58 (m, 2H), 1.50 (m, 2H), 1.27 (m, 2H)

V9-038

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[3-methyl-2-(5-methyl-1,3-dioxo 1,3-dihydro-isoindol-2-yl)-butyryl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.028g, 15%) off white solid

Mw calc: 758.24 m/z 759.3 [M+H]⁺ 757.3 [M-H]^" Rt = 2.97 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.58 (br. s, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.79 (d, J~ 7.5 Hz, 1H), 7.73 (s, 1H), 7.72 (d, J~ 1.5 Hz, 1H), 7.67 (dd, J~ 7.5 and 1.5 Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 4.64 (d, J= 9.5 Hz, 1H), 4.16 (t, J~ 6.0 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.46 (m, 2H), 3.39 (m, 2H), 2.81 (m, 1H), 2.49 (s, 3H), 2.30-2.43 (m, 4H), 2.24 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 0.97 (d, J= 6.5 Hz, 3H), 0.79 (d, J= 6.7 Hz, 3H)

V9-039 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-me

1,3-dihydro-isoindol-2-yl)-pentanoyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.031 g, 16%) off white solid

Mw calc: 772.25 m/z 773.3 [M+H]⁺ 771.3 [M-H]^" Rt = 3.51 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.61 (br. s, 1H), 8.37 (s, 1H), 7.81 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.73 (d, J~ 1.5 Hz, 1H), 7.72 (s, 1H), 7.67 (dd, J= 7.8 and 1.5 Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 4.73 (d, J= 9.9 Hz, 1H), 4.16 (t, J~ 6.0 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.46 (m, 4H), 2.65 (m, 1H), 2.49 (s, 3H), 2.32-2.43 (ovl. m, 4H), 2.23 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.30 (m, 1H), 0.97 (m, 1H), 0.92 (d, J= 6.6 Hz, 3H), 0.79 (t, J= 7.2 Hz, 3H)

V9-040

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[6-(3,4-dimethyl-2,5-dioxo-2,5-dihydro- pyrrol-1-yl)-hexanoyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.046 g, 25%) off white solid

Mw calc: 736.25 m/z 737.3 [M+H]⁺ 735.3 [M-H]^" Rt = 3.14 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 4.21 (t, J= 5.8 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.43 (m, 4H), 3.36 (t, J= 7.0 Hz, 2H), 2.47 (t, J~ 7.0 Hz, 2H), 2.38 (m, 2H), 2.33 (m, 2H), 2.26 (t, J= 7.4 Hz, 2H), 1.98 (m, 2H), 1.89 (s, 6H), 1.40-1.54 (ovl. m, 4H), 1.23 (m, 2H)

V9-041

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[2-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-3-methylsulfanyl-propionyl]-piperazin-1-yl}-propoxy)-quinoline-3- carbonitrile

(0.024 g, 12%) white solid

Mw calc: 776.20 m/z 777.3 [M+H]⁺ 775.3 [M-H]^" Rt = 3.37 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.59 (br. s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.80 (d, J~ 7.5 Hz, 1H), 7.75 (d, J~ 1.5 Hz, 1H), 7.73 (s, 1H), 7.70 (dd, J~ 7.5 and 1.5 Hz, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 5.17 (dd, J= 10.2 and 4.9 Hz, 1H), 4.17 (t, J~ 6.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.47 (m, 2H), 3.38 (m, 2H), 3.22 (dd, J= 14.2 and 10.2 Hz, 1H), 3.07 (dd, J = 14.2 and 4.9 Hz, 1H), 2.50 (s, 3H), 2.35-2.47 (ovl. m, 4H), 2.28 (m, 1H), 2.16 (m, 1H), 2.04 (s, 3H), 1.92 (m, 2H)

V11-004 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[3-(1H-indo

dihydro-isoindol-2-yl)-propionyl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile (0.035 g, 16%) off white solid

Mw calc: 845.25 m/z 846.3 [M+H]⁺ 844.4 [M-H]^" Rt = 3.48 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 10.74 (s, 1H), 9.60 (br. s, 1H), 8.36 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.68 (d, J= 7.7 Hz, 1H), 7.63 (d, J= 1.5 Hz, 1H), 7.61 (d, J= 7.7 and 1.5 Hz, 1H), 7.50 (dm, J= 7.8 Hz, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 7.26 (dm, J= 8.1 Hz, 1H), 6.98-7-03 (ovl. m, 2H), 6.90 (ddm, J= 7.8 and 7.2 Hz, 1H), 5.28 (dd, J= 9.4 and 5.6 Hz, 1H), 4.16 (t, J= 5.6 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.63 (dd, J= 15.0 and 9.4 Hz, 1H), 3.47 (m, 2H), 3.40 (dd, J= 15.0 and 5.6 Hz, 1H), 3.36 (m, 2H), 2.45 (s, 3H), 2.39 (t, J= 7.0 Hz, 2H), 2.20-2.33 (ovl. m, 3H), 2.13 (m, 1H), 1.91 (m, 2H)

V11-006

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(5-ethynyl-1,3-dioxo-1,3-dihydro-isoindol-

2-yl)-butyryl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.059 g, 31%) light brown solid

Mw calc: 754.21 m/z 755.3 [M+H]⁺ 753.3 [M-H]^" Rt = 3.19 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.62 (br. s, 1H), 8.40 (s, 1H), 7.89 (dd, J= 7.5 and 1.5 Hz, 1H), 7.88 (d, J= 1.5 Hz, 1H), 7.85 (d, J= 7.5 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 4.59 (s, 1H), 4.21 (t, J= 6.3 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.61 (t, J = 6.6 Hz, 2H), 3.34-3.44 (ovl. m, 4H), 2.46 (t, J = 7.0 Hz, 2H), 2.25-2.42 (ovl. m, 6H), 1.97 (m, 2H), 1.84 (m, 2H)

V11-007

[1 ,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3- carbonitrile

(0.122 g, 62%) vivid yellow solid

Mw calc: 770.15 m/z 771.3 [M+H]⁺ 769.3 [M-H]^" Rt = 3.08 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.59 (br. s, 1 H), 8.40 (s, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.33 (s, 1 H), 7.31 (s, 1 H), 4.21 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.40-3.48 (ovl. m, 6H), 3.37 (s, 4H), 2.46 (t, J = 7.0 Hz, 2H), 2.32-2.42 (ovl. m, 4H), 2.30 (t, J = 7.0 Hz, 2H), 1.98 (m, 2H), 1.74 (m, 2H)

V11-009 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3^

piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.036 g, 22%) light brown solid

Mw calc: 655.17 m/z 656.3 [M+H]⁺ 654.3 [M-H]^" Rt = 4.03 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 10.52 (br. s, 1H), 9.70 (br. s, 1H), 8.39 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 4.17-4.26 (ovl. m, 3H), 3.94 (s, 3H), 3.85 (s, 3H), 3.39-3.51 (ovl. m, 4H), 2.79 (dd, J= 17.0 and 3.0 Hz, 1H), 2.70 (dd, J= 17.0 and 7.1 Hz, 1H), 2.48 (t, J= 7.0 Hz, 2H), 2.31-2.44 (ovl. m, 4H), 1.98 (m, 2H)

V11-010

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[5-(5-methyl-1,3-dioxo-1,3- dihydro-isoindol-2-yl)-pentanoyl]-piperazin-1-yl}-propoxy)-quinoline-3-carbonitrile

(0.117 g, 62%) pale yellow solid

Mw calc: 758.24 m/z 759.5 [M+H]⁺ 757.5 [M-H]^" Rt = 3.27 min (Method A).

H NMR (300 MHz, DMSO-d₆) δ ppm 9.66 (br. s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.70 (s, 1H), 7.69 (d, J= 1.5 Hz, 1H), 7.63 (dd, J= 7.5 and 1.5 Hz, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 4.20 (t, J= 6.2 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.56 (t, J= 6.7 Hz, 2H), 3.37-3.67 (ovl. m, 4H), 2.47 (s, 3H), 2.45 (t, J= 7.0 Hz, 2H), 2.27-2.38 (ovl. m, 6H), 1.96 (m, 2H), 1.60 (m, 2H), 1.48 (m, 2H)

Example 2.5 - Synthesis of V9-010

7-{3-[4-(Benzo[1,3]dioxole-5-carbonyl)-piperazin-1-yl]-propoxy}-4-(2,4-dichloro-5- methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

The solution of (0.1 g, 0.194 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)-6- methoxy-7-(3-piperazin-1-yl-propoxy)-quinoline-3-carbonitrile, TEA (0.035 ml_, 0.252 mmol, 1.30 equiv) in 10 ml_ dioxane was added the benzo[1 ,3]dioxole-5-carbonyl chloride (0.040 g, 0.213 mmol, 1.10). The reaction mixture was stirred at room temperature overnight. The mixture was evaporated at reduced pressure, iced water was added and stirred 20 minutes. The precipitated material was filtered off and was with water, DIPE, hexan and dried to provide the desired 7-{3-[4-(Benzo[1 ,3]dioxole-5-carbonyl)-piperazin-1-yl]-propoxy}-4-(2,4- dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile. (0.056 g, 43%) as a yellow solid.

Mw calc: 663.17 m/z 664.3 [M+H]⁺ 662.3 [M-H]^" Rt = 3.05 min (Method A).

H NMR (300 MHz, DMSO-cfe) δ ppm 9.58 (br. s, 1 H), 8.41 (s, 1 H), 7.83 (s, 1 H), 7.73 (s, 1 H), 7.34 (s, 1 H), 7.32 (s, 1 H), 6.95 (d, J = 8.2 Hz, 1 H), 6.94 (d, J = 1.3 Hz, 1 H), 6.90 (dd, J = 8.2 and 1.3 Hz, 1 H), 6.07 (s, 2H), 4.22 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.48 (m, 4H), 2.50 (t, J ~ 7.0 Hz. 2H), 2.42 (m, 4H), 1.98 (m, 2H)

The following compound was prepared as described in V9-010 (Method A).

7-{3-[4-(4-Chloromethyl-benzoyl)-piperazin-1-yl]-propoxy}-4-(2,4-dichloro-5-methoxy- phenylamino)-6-methoxy-quinoline-3-carbonitrile (0.210 g, 54%) white solid.

Mw calc: 667.15 m/z 668.4 [M+H]⁺ 666.5 [M-H]^" Rt = 3.19 min (Method A). Example 2.6 - Synthesis of V9-012

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-{3-[4-(4-pyrrolidin-1-ylmethyl^ benzoyl)-piperazin-1 -yl]-propoxy}-quinoline-3-carbonitrile

The solution of (0.09 g, 0.135 mmol, 1.00 equiv) 7-{3-[4-(4-Chloromethyl-benzoyl)-piperazin- 1-yl]-propoxy}-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile in 4 mL THF, was treated with pyrrolidine (0.12 mL, 1.35 mmol, 10 equiv). The reaction mixture was stirred in sealed tube at 80 °C for an hour. The mixture was cooled down to room temperature and precipitated material was filtered off and was with water, DIPE, hexan and dried to provide the desired 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-{3-[4-(4- pyrrolidin-1-ylmethyl-benzoyl)-piperazin-1-yl]-propoxy}-quinoline-3-carbonitrile. (0.090 g, 95%) as a off white solid.

Mw calc: 702.25 m/z 703.5 [M+H]⁺ 701.5 [M-H]^" Rt = 2.54 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 9.30 (br. s, 1 H), 8.40 (s, 1 H), 7.85 (s, 1 H), 7.72 (s, 1 H), 7.39 (dm, J ~ 7.5 Hz, 2H), 7.35 (s, 1 H), 7.34 (s, 1 H), 7.31 (dm, J ~ 7.5 Hz, 2H), 4.21 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.68 (s, 2H), 3.25-3.50 ( br. m, 4H), 3.08 (m, 4H), 2.35-2.55 (ovl. m, 6H), 1.98 (m, 2H), 1.83 (m, 4H) Example 2.7 - Synthesis of V9-018

The following compound was prepared as described in V9-012.

V9-018

4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(isopropylamino-methyl)-benzoyl]- piperazin-1-yl}-propoxy)-6-methoxy-quinoline-3-carbonitrile

(0.115 g, 93%) off white solid

Mw calc: 690.25 m/z 691.4 [M+H]⁺ 689.4 [M-H]^" Rt = 2.52 min (Method A).

¹H NMR (300 MHz, DMSO-cfe) δ ppm 9.60 (br. s, 1 H), 8.40 (s, 1 H), 7.84 (s, 1 H), 7.72 (s, 1 H),

7.54 (dm, J = 8.0 Hz, 2H), 7.40 (dm, J = 8.0 Hz, 2H), 7.32 (s, 1 H), 7.30 (s, 1 H), 4.22 (t, J ~

5.5 Hz, 2H), 3.99 (s, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.30-3.70 (ovl. m, 4H), 3.27 (ovl. m, 1 H),

3.06 (m, 1 H), 2.51 (ovl. m, 2H), 2.33-2.53 (ovl. m, 4H), 1.99 (m, 2H), 1.18 (d, J = 6.2 Hz, 6H)

Example 2.8 - Synthesis of 7-{2-[4-(2-Amino-ethyl)-piperazin-1-yl]-ethoxy}-4-(2,4- dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile

The solution of (0.3 g, 0.765 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- fluoro-6-methoxy-quinoline-3-carbonitrile and (0.663 g, 3.825 mmol, 5.00 equiv) in 7 mL DMSO, was added the NaH (0.185 g, 4.59 mmol, 6.00 equiv) with little portion. The reaction mixture was stirred at 100 °C for an hour. The mixture was cooled down to room temperature and iced water was added, NaCI and stirred 30 minutes. The precipitated material was filtered off and was with water, DIPE and dried to provide the desired 7-{2-[4-(2-Amino-ethyl)- piperazin-1-yl]-ethoxy}-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3- carbonitrile.

(0.14 g, 34%) brown solid

Mw calc: 544.17 m/z 545.2 [M+H]⁺ 543.2 [M-H]^" Rt = 2.35 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.66 (br. s, 1 H), 8.39 (s, 1 H), 7.89 (s, 1 H), 7.70 (s, 1 H), 7.33 (s, 1 H), 7.30 (s, 1 H), 4.26 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 2.86 (m, 2H), 2.78 (m, 2H), 2.38-2.62 (ovl. m, 10H)

Example 2.9 - Synthesis of V11 -001

2-[2-(4-{3-[4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]- propyl}-piperazin-1-yl)-ethyl]-isoindole-1 ,3-dione

Step A

(7-Benzyloxy-6-methoxy-quinolin-4-yl)-(2,4-dichloro-5-methoxy-phenyl)-amine

The title compound was prepared as described in V9-013.

(3.157 g, 69%) brown solid

Mw calc: 454.08 m/z 455.1 [M+H]⁺ 453.0 [M-H]^" Rt = 3.53 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.67 (br. s, 1 H), 8.24 (d, J = 5.2 Hz, 1 H), 7.74 (s, 1 H), 7.72 (s, 1 H), 7.52 (dm, J = 7.2 Hz, 2H), 7.43 (ddm, J = 7.5 and 7.2 Hz, 2H), 7.36 (m, 1 H), 7.36 (s, 1 H), 7.21 (s, 1 H), 6.20 (d, J = 5.2 Hz, 1 H), 5.27 (s, 2H), 3.95 (s, 3H), 3.86 (s, 3H) Step B

4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-ol (TFA salt)

The solution of (0.623 g, 1.36 mmol, 1.00 equiv) (7-Benzyloxy-6-methoxy-quinolin-4-yl)-(2,4- dichloro-5-methoxy-phenyl)-amine in 5 ml TFA was stirred at reflux temperature for 3.5 hours. The mixture was cooled down and evaporated at reduced pressure. The crude material was added diethyl ether, the resulting material was filtered off washed with ether to provide the desired 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-ol (TFA salt).

(0.448 g, 69%) beige solid

Mw calc: 364.04 m/z 365.0 [M+H]⁺ 363.0 [M-H]^" Rt = 2.95 min (Method A).

1H NMR (300 MHz, DMSO-d₆) δ ppm 11.36 (br. s, 1 H), 10.44 (br. s, 1 H), 8.31 (d, J = 6.8 Hz, 1 H), 8.00 (s, 1 H), 7.91 (s, 1 H), 7.44 (s, 1 H), 7.32 (s, 1 H), 6.31 (d, J = 6.8 Hz, 1 H), 3.99 (s, 3H), 3.90 (s, 3H)

Step C

[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yl]-(2,4-dichloro-5-methoxy-phenyl)-amine

The solution of (0.383 g, 0.8 mmol, 1.00 equiv) 4-(2,4-Dichloro-5-methoxy-phenylamino)-6- methoxy-quinolin-7-ol in 10 ml DMF, added the K₂C0₃ (0.221 g, 1.6 mmol, 2.00 equiv) after was added 1-Bromo-3-chloro-propane (0.12 mL, 1.2 mmol, 1.50 equiv) stirred at rt for 24 hours. The mixture was evaporated at reduced pressure after water was added. The crude material was extracted with CHCI₃, washed with water, brine and dried over MgS0₄ and evaporated under reduced pressure. The crude product was purified by coloumn chromatography with ethyl acetate to provide the desired [7-(3-Chloro-propoxy)-6-methoxy- quinolin-4-yl]-(2,4-dichloro-5-methoxy-phenyl)-amine.

(0.312 g, 88%) yellow solid

Mw calc. : 440.05 m/z 441.1 [M+H]⁺ 439.1 [M-H]^" Rt = 3.38 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.67 (br. s, 1 H), 8.25 (d, J = 4.1 Hz, 1 H), 7.73 (s, 1 H), 7.71 (s, 1 H), 7.28 (s, 1 H), 7.21 (s, 1 H), 6.20 (d, J = 4.1 Hz, 1 H), 4.24 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.84 (t, J = 6.5 Hz, 2H), 2.26 (tt, J = 6.5 and 6.0 Hz, 2H)

Step D V11-001

The solution of (0.15 g, 0.34 mmol, 1.00 equiv) [7-(3-Chloro-propoxy)-6-methoxy-quinolin-4- yl]-(2,4-dichloro-5-methoxy-phenyl)-amine in 30 ml mixture of aceton-acetonitril (1 :1), added the K2CO₃ (0.117g, 0.85 mmol, 2.50 equiv), Sodium iodide (0.051 g, 0.34 mmol 1.00 equiv) after was added 2-(2-Piperazin-1-yl-ethyl)-isoindole-1 ,3-dione (HCI salt ) (0.1 g, 0.34 mmol, 1.50 equiv) stirred at reflux temperature for 72 hours. The mixture was cooled down and evaporated at reduced pressure after water was added and filtered off. The crude product was purified by coloumn chromatography with (CHCI₃/MeOH 10:1) to provide the desired 2- [2-(4-{3-[4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]-propyl}- piperazin-1-yl)-ethyl]-isoindole-1 ,3-dione.

(0.041 g, 18%) pale yellow solid

Mw calc: 663.20 m/z 664.2 [M+H]⁺ 662.2 [M-H]^" Rt = 2.79 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.84 (br. s, 1 H), 8.23 (d, J = 5.4 Hz, 1 H), 7.79-7.93 (ovl. m, 4H), 7.74 (s, 1 H), 7.72 (s, 1 H), 7.24 (s, 1 H), 7.22 (s, 1 H), 6.19 (d, J = 5.4 Hz, 1 H), 4.13 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.70 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 2.49 (t, J ~ 7.0 Hz, 2H), 2.35-2.50 (ovl. m, 8H), 1.95 (m, 2H) Example 2.10 - Synthesis of V11-002 and V11-003

The following compounds were prepared as described in V11-001.

V11-002

2-[3-(4-{3-[4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]-propyl}- piperazin-1-yl)-propyl]-isoindole-1 ,3-dione

(0.061 g, 18%) pale yellow solid

Mw calc: 677.22 m/z 678.3 [M+H]⁺ 676.3 [M-H]^" Rt = 2.75 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.75 (br. s, 1 H), 8.22 (d, J = 4.6 Hz, 1 H), 7.79-7.91 (ovl. m, 4H), 7.73 (s, 1 H), 7.70 (s, 1 H), 7.21 (s, 1 H), 7.20 (s, 1 H), 6.19 (d, J = 4.6 Hz, 1 H), 4.09 (t, J = 6.2 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.65 (t, J = 6.5 Hz, 2H), 2.25-2.38 (ovl. m, 8H), 2.20 (m, 4H), 1.87 (m, 2H), 1.74 (m, 2H)

V11-003 2-[4-(4-{3-[4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]-pro piperazin-1-yl)-butyl]-isoindole-1 ,3-dione

(0.062 g, 18%) light yellow solid

Mw calc: 691.23 m/z 692.3 [M+H]⁺ 690.4 [M-H]^" Rt = 2.70 min (Method A).

1H NMR (300 MHz, DMSO-cfe) δ ppm 8.69 (br. s, 1 H), 8.23 (d, J = 4.2 Hz, 1 H), 7.79-7.91 (ovl. m, 4H), 7.73 (s, 1 H), 7.69 (s, 1 H), 7.23 (s, 1 H), 7.20 (s, 1 H), 6.18 (d, J = 4.2 Hz, 1 H), 4.13 (t, J = 6.4 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.58 (t, J = 6.9 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.32-7.42 (ovl. m, 8H), 2.28 (t, J = 6.6 Hz, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.41 (m, 2H)

Example 3 - Biological Data

Example 3.1 - Materials and methods

Cell culture All information on the cell lines source and culture media were listed in Table 1.

Table 1. Cell lines / cell culture media.

Tissue Cell Line Source Culture condition

Breast BT 474 ATCC RPMI-1640 medium supplemented with 10% FBS

Breast BT-483 ATCC RPMI-1640 medium supplemented with 20% FBS and 0.01 mg/ml bovine insulin

Breast BT-549 ATCC RPMI-1640 medium supplemented with 10% FBS and 0.023 lU/ml bovine insulin

Breast Hs 578T ATCC Dulbecco's Modified Eagle's medium supplemented with 10% FBS and 0.01 mg/ml bovine insulin

Breast MCF7 ATCC Dulbecco's Modified Eagle's Medium supplemented with 10% FBS

Breast MDA-MB-231 ATCC Dulbecco's Modified Eagle's medium supplemented with 10% FBS

Breast MDA-MB-361 ATCC Leibovitz's L-15 medium supplemented with 20%

FBS

Breast MDA-MB-415 ATCC Leibovitz's L-15 medium supplemented with 15%

FBS, 2mM of L-glutamine, 0.01 mg/ml bovine insulin, and 0.01 mg/ml of glutathione

Breast MDA-MB-436 ATCC Leibovitz's L-15 medium supplemented with 10%

FBS, 0.01 mg/ml bovine insulin, and 0.016 mg/ml glutathione

Breast MDA-MB-453 ATCC Leibovitz's L-15 medium supplemented with 10%

FBS

Breast SK-BR-3 ATCC McCoy's 5A medium modified supplemented with

10% FBS

Breast T-47D ATCC RPMI-1640 medium supplemented with 10% FBS and 0.2 Units/ml bovine insulin

Breast ZR-75-1 ATCC RPMI-1640 medium supplemented with 10% FBS

Breast ZR-75-30 ATCC RPMI-1640 medium supplemented with 10% FBS Breast HMEC Lonza MEGM Bulletkit (CC-3150)

Liver SNU-182 ATCC RPMI-1640 medium supplemented with 10% FBS and 1 mM sodium pyruvate

Liver SNU-387 ATCC RPMI-1640 medium supplemented with 10% FBS,

1 mM sodium pyruvate, and 2 mM L-glutamine

Liver SNU-398 ATCC RPMI-1640 medium supplemented with 10% FBS,

1 mM sodium pyruvate, and 2 mM L-glutamine

Liver SNU-423 ATCC RPMI-1640 medium supplemented with 10% FBS,

1 mM sodium pyruvate, and 2 mM L-glutamine

Liver SNU-475 ATCC RPMI-1640 medium supplemented with 10% FBS,

1 mM sodium pyruvate, and 2 mM L-glutamine

Ovary A2780 J ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary A2780 CIR ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary IGROV-1 RPMI-1640 medium supplemented with 10% FBS

Ovary OVCAR3 ATCC RPMI-1640 medium supplemented with 20% FBS and 0.01 mg/ml insulin

Ovary PEO-1 ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary PEO-1 CRT ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary PEO-4 CRT ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary PEO-6 CRT ECACC RPMI-1640 medium supplemented with 10% FBS

Ovary SK-OV-3 ATCC McCoy's 5A medium modified supplemented with

10% FBS

Ovary SKOV-8 Minimum Essential Media supplemented with 10%

FBS

Pancreas BxPC-3 ATCC RPMI-1640 medium supplemented with 10% FBS

Pancreas CAPAN-2 ATCC RPMI-1640 medium supplemented with 10% FBS

Pancreas MIA PaCa-2 ATCC Dulbecco's Modified Eagle's medium supplemented with 10% FBS and 2 mM L- glutamine

Pancreas PANC-1 ATCC Dulbecco's Modified Eagle's medium supplemented with 10% FBS and 2 mM L- glutamine

Bone K562 ATCC Iscove's Modified Dulbecco's Medium Marrow supplemented with 20% FBS and 4 mM L- glutamine

Peripheral LAMA-84 DSMZ RPMI-1640 medium supplemented with 20% FBS Blood

Peripheral KU812 ATCC RPMI-1640 medium supplemented with 10% FBS Blood

Peripheral KYO-1 DSMZ RPMI-1640 medium supplemented with 20% FBS Blood

Culture Cells were cultured at 37°C in 5% C0₂.

Kinase profiling Various compounds were delivered to DiscoveRX (Fermont, CA) Kinase assay was performed at 1 μΜ concentration in a scanTK^™ and scanMAX^™ Kinase Assay Panel. The scanTK^™ panel includes 130 receptor and non-receptor tyrosine kinases and important mutant forms. The scanMAX^™ panel includes 456 protein and lipid kinases.

Cell Viability Assay Cancer cell lines or HMEC cells were seeded onto 96-well plates in 100 μΙ medium. After 24 hours, various concentrations (0-10 μΜ) of inhibitor compounds were added to cells. Three days later, cell viability assay was carried out according to manufacturer's instructions using Cell Titer-Glo reagent (Promega, Madison, Wl), and luminescent signal was determined. Data were expressed as percentage of viability vs vehicle-treated controls.

Flow cytometry analysis MDA-MB 436 cells were seeded onto 6-well plates overnight. Cells were treated in duplicate with vehicle control (DMSO) or various drugs for 24 hours. After treatment, cells were harvested and stained with FITC Annexin V Apoptosis Dectection Kit I (BD Pharmingen™) according to manufracturer's instructions.

Trypan blue exclusion assay MDA-MB-453 cells were seeded onto 6-well plates overnight. Cells were treated in duplicate with vehicle control (DMSO) and various drugs (0.02-10 μΜ) for 24 hours, 48 hours, or 72 hours. At the end point of each treatment, viable and dead cells for each concentration were counted on a hemacytometer after cell trypsinization. Results are presented as percentage of cell death (i.e. number of dead cells over total number of cells x 100%).

MDA-MB 361 mouse xenograft studies 6 weeks old female Balb C nude mice were bred and implanted with 0.72 mg, 60-day sustained release 17b-estradiol pellets (Innovative Researcg of Amercia, Saeasota, FL) a day before inoculation of MDA-MB 361. Cells were trypsinized and re-suspended in media at 2X 10⁸ cells/ml and kept on ice. Next equal volume of matrigel ® was added to the cells to produce a cell concentration of 1X10⁸ cells/ml. Animal is mildly anesthetized with Isoflurance and 1X10⁷ cells in volumne of 0.1 mL was injected subcutaneously on the flank of the animal. Animals were observed regularly for tumor appearance. When majority of the tumors are in the range of 100-200 mm³, animals were randomised to 6 per group and treatment commenced. Dosing of animal is perform via intraperitoneal injection (I. P.) with with vehicle (10% Ν,Ν-dimethylacetamide (DMA), 50% Glycerol and 40% water) or 100, 30 and 10 mg/kg of V3-030 dissolved in the vehicle. Animals were given the treatment once every other day for 3 weeks. Tumor measurement and body weight were taken twice per week. Animals were closely monitored for the post dosing duration of the study. Study is terminated when the tumor condition exceed IACUC limit. Tumor's dimensions (length and width) were measured and tumor volume was calculated by the formula (LxW²)/2.

Example 3.2 - Results V3-030

In vitro efficacy

Bosutinib is an ATP competitive dual inhibitor of Bcr-AbI and Src kinases. The Ack1 inhibitory activity is known in the case of Bosutinib, but in the present disclosure, it is shown that the phthalimide protected compound ("fc-Bosutinib") demonstrates significantly higher activity.

fc-Bosutinib was examined on 5 invasive and 9 non-invasive breast cancer cell lines and normal mammary epithelial cells, compared to Bosutinib as the reference.

viability [uM]

cell line Bosutinib fc -Bosutinib

BT-549 3.8 6.3

HS578T 4.4 5.5

invasive

MDA-MB-231 4.8 >10

breast cancer

MDA-MB-415 8.3

MDA-MB-436 4.8

BT-474 6.2

BT-483 >10 7

MCF7 >i0 >10

MDA-MB-361 3.8

noil- invasive

MDA-MB-453 5.4

breast cancer

SK-BR-3 2.1 >10

T47D >i0 >10

ZR-75-1 >10 >10

ZR-75-30 9.3

normal

mammary MM EC 7.6 >10

epithelial ceil

As shown, fc-Bosutinib shows one to two magnitudes higher effect compared to Bosutinib, and does not show effect on the normal cell line.

Further, a panel of breast (15), pancreatic (4), ovarian (10) and hepatocellular (5) carcinoma cell lines was treated with varying doses of fc-Bosutinib (V3-030). The compound demonstrated superior anti-viability effect on majority of the cell lines tested (Table 2).

Table 2. Cell viability (IC₅₀) of V3-030 on cancer cell lines

Tissue Cell Line Cell Viability IC₅₀ [μΜ]

Breast BT-474 0.7

Breast MDA-MB-361 0.06

Breast MDA-MB-415 0.052

Breast MDA-MB-436 0.036

Breast MDA-MB-453 0.02

Breast ZR-75-30 0.28

Breast BT-549 6.3

Breast BT-483 > 10

Breast Hs 578T > 10

Breast MCF7 > 10

Breast MDA-MB-231 > 10 Breast SK-BR-3 > 10

Breast T-47D > 10

Breast ZR-75-1 > 10

Breast HMEC > 10

Liver SNU-398 0.046

Liver SNU-182 5.0

Liver SNU-423 5.7

Liver SNU-387 > 10

Liver SNU-475 > 10

Ovary A2780 CIR 1.25

Ovary PEO-1 4.3

Ovary IGROV-1 4.6

Ovary SK-OV-3 4.6

Ovary PEO-4 CRT 7.8

Ovary PEO-1 CRT 8.2

Ovary A2780 J > 10

Ovary OVCAR3 > 10

Ovary PEO-6 CRT > 10

Ovary SKOV-8 > 10

Pancreas PANC-1 0.14

Pancreas CAPAN-2 2.2

Pancreas MIA PaCa-2 3.9

Pancreas BxPC-3 5.4

Importantly, V3-030 has minimum effect on primary mammary epithelial cells (IC₅₀ > 10 μΜ). Kinase profiling was performed with DiscoveRX to test the inhibitory activities of V3-030 on a panel of 130 (scanTK, DiscoveRX) Kinase assay panel and 456 (scanMAX, DiscoveRX) kinases (Table 3).

Table 3. List of kinases and mutants (scanMAX panel) thereof

KINOMEscan Gene Symbol Entrez Gene Symbol

AAK1 AAK1

ABL1 -nonphosphorylated ABL1

ABL1 -phosphorylated ABL1

ABL1 (E255K)-phosphorylated ABL1

ABL1 (F317l)-nonphosphorylated ABL1

ABL1 (F317l)-phosphorylated ABL1

ABL1 (F317L)- nonphosphorylated ABL1

ABL1 (F317L)-phosphorylated ABL1

ABL1 (H396P)- nonphosphorylated ABL1

KINOMEscan Gene Symbol Entrez Gene Symbol

CAMK1 CAMK1

CAMK1D CAMK1D

CAMK1G CAMK1G

CAMK2A CAMK2A

CAMK2B CAMK2B

CAMK2D CAMK2D

CAMK2G CAMK2G

CAMK4 CAMK4

CAMKK1 CAMKK1

CAMKK2 CAMKK2

CASK CASK

CDC2L1 CDK11B

CDC2L2 CDC2L2

CDC2L5 CDK13

CDK11 CDK19

CDK2 CDK2

CDK3 CDK3

CDK4-cyclinD1 CDK4

CDK4-cyclinD3 CDK4

CDK5 CDK5

CDK7 CDK7

CDK8 CDK8

CDK9 CDK9

CDKL1 CDKL1

CDKL2 CDKL2

CDKL3 CDKL3

CDKL5 CDKL5

CHEK1 CHEK1

CHEK2 CHEK2

CIT CIT

CLK1 CLK1

CLK2 CLK2

CLK3 CLK3

CLK4 CLK4

CSF1R CSF1R

CSF1R-autoinhibited CSF1R

CSK CSK

CSNK1A1 CSNK1A1

CSNK1A1L CSNK1A1L

CSNK1D CSNK1D

CSNK1E CSNK1E

CSNK1G1 CSNK1G1

CSNK1G2 CSNK1G2

CSNK1G3 CSNK1G3

CSNK2A1 CSNK2A1

KINOMEscan Gene Symbol Entrez Gene Symbol

STK39 STK39

SYK SYK

TAK1 MAP3K7

TAOK1 TAOK1

TAOK2 TAOK2

TAOK3 TAOK3

TBK1 TBK1

TEC TEC

TESK1 TESK1

TGFBR1 TGFBR1

TGFBR2 TGFBR2

TIE1 TIE1

TIE2 TEK

TLK1 TLK1

TLK2 TLK2

TNIK TNIK

TNK1 TNK1

TNK2 TNK2

TNNI3K TNNI3K

TRKA NTRK1

TRKB NTRK2

TRKC NTRK3

TRPM6 TRPM6

TSSK1 B TSSK1 B

TTK TTK

TXK TXK

TYK2(JH1 domain-catalytic) TYK2

TYK2(JH2domain- pseudokinase) TYK2

TYR03 TYR03

ULK1 ULK1

ULK2 ULK2

ULK3 ULK3

VEGFR2 KDR

VRK2 VRK2

WEE1 WEE1

WEE2 WEE2

WNK1 WNK1

WNK3 WNK3

YANK1 STK32A

YANK2 STK32B

YANK3 STK32C

YES YES1

YSK1 STK25

YSK4 YSK4 KINOMEscan Gene Symbol Entrez Gene Symbol

ZAK ZAK

ZAP70 ZAP70

Table 4 below summarizes the kinases that are inhibited by V3-030 by more than 90% at 1 μΜ concentration (i.e less than 10% activity remaining).

The kinase inhibitory profiles of Bosutinib and fc-Bosutinib were compared on a 130- member kinase panel (DiscoveRx). The kinase inhibitory profiles of Bosutinib and fc- Bosutinib are shown in Fig. 1A and Fig. 1 B. As shown in Fig. 1A and Fig. 1 B, kinase profiling of bosutiinib and fc-bosutinib yield similar tyrosine kinase targets. However surprisingly, although the target list is similar, there is a clear difference in biological assay (anti-cell viability) with fc-bosutinib being more potent compared to bosutinib. The binding affinity difference was higher than 10% in case of 32 kinases. The biggest difference in binding affinity (more than three times) was found at two kinases:

EGFR (T790M): (Bosutinib: 10 %; fc-Bosutinib: 31 %)

TXK: (Bosutinib: 5 %; fc-Bosutinib: 18 %)

Next, flow cytometry was used to analyse the dying population as indicated in Fig. 2. Here the assay showed that fc-Bosutinib-treated cells were either in early or late apoptotic stages as demonstrated with Annexin V and PI positive staining. As shown in Fig. 2, flow cytometry was used to determine the status of the cells after treatment with fc-Bosutinib (V3-030). Using DMSO as vehicle and negative control, -88% of cells were healthy (i.e Annexin V and PI negative, Q1 -UL) while 4.1 % and 4.4% of cells were either at early apoptotic or late apoptotic stage, respectively. Cells treated with staurosporine served as the positive control. Treatment with 0.1 uM of staurosporine resulted in slight increase in apoptotic cells. It is shown that treatment with V3-030 effectively induces apoptosis with 14.8% and 57% of cells at early and late apoptotic stages, respectively.

Table 4. List of kinases inhibited by V3-030 at 1 μΜ

% activity

KINOMEscan Gene Symbol Entrez Gene Symbol

remains

ABL1-nonphosphorylated ABL1 0

ABL1-phosphorylated ABL1 0.55

ABL1 (E255K)-phosphorylated ABL1 1.6

% activity

KINOMEscan Gene Symbol Entrez Gene Symbol

remains

YES YES1 1.9

YSK4 YSK4 1.4

ZAK ZAK 10

Next, V3-030 was investigated for proliferation and survival signalling in the cells. The cell lysate of the two sensitive cells namely MDA-MB 436 and MDA-MB 453 were separated on western blot and probed for ERK and AKT phosphorylation status as shown in Fig. 3. In the presence of V3-030, there is a significant reduction in ERK and AKT phosphorylation. Compared to SKI-606 at the same treatment, the stronger decrease in ERK and AKT phosphorylation by V3-030 indicates the compound is surprisingly more effective in reducing proliferative and survival signalling.

The anti-survival effect of V3-030 was further confirmed using Trypan blue exclusion assay where dying cells lost their membrane integrity and resulting in uptake of Trypan blue dye. In comparison to SKI-606, MDA-MB 453 cells began dying at lower concentration of V3-030 over 1 , 2 and 3 days treatment as shown in Fig. 4. This advantageously indicates that V3- 030 has a potent anti-cancer effect.

In vivo preliminary efficacy studies

V3-030 was tested on a mouse xenograft model to demonstrate preliminary efficacy using three different doses. Tumor formation was induced on 6 weeks old Balb C nude mice by subcutaneous injection of MDA-MB 361 on the animal flank. When the tumor grew to between -200 mm³, treatment commenced through intraperitoneal injection with vehicle or V3-030 at 3 different doses, once every other day (n=6). Treatments were administrated for three weeks. Tumor volume and animal weight were constantly measured throughout the 21 days regime. Animal behaviour was also observed.

The preliminary animal work shows that V3-030 reduces tumor size of MDA-MB 361 BalbC nude mouse xenograft model in a dose-dependent manner with the strongest anti-growth effect observed on the 100 mg/kg group. As shown in Fig. 5, at day 20, tumor/vehicle is -0.59 for animal treated with 30 mg/kg. The non-toxic effect is also observed in this experiment. There is no significant change to animal body weight and behaviour as demonstrated in Fig. 5. Preclinical development

With the promising preliminary in vivo data, lead optimisation was performed. 50 structural analogues of V3-030 were synthesised in two iterative cycles. Efficacy of the new compounds was tested on the same panel of breast cancer cell lines and their toxicity was evaluated on primary mammary epithelial cells (Table 5).

Table 5. Cell viability (IC50) of V3-030 derivatives on breast cancer cell lines and primary mammary epithelial cells.

Cell Viability IC50 (uM)

As a result of this development, three V3-030 analogues (V1 1-003, V1 1-008 and V11- 010) were selected for further pharmacological and in vivo efficacy studies.

V11-003, V1 1-008 and V1 1-010 were tested for their effect on CML cell viability. The data shows that all compounds demonstrated effective anti-cell viability effect at nanomolar IC₅₀ with exception to V11-003 and V11-010 on K562 cells.

Table 6. Cell viabilit (IC50) of V3-030 and derivatives on CML cell lines.

Further comparison of the compounds to bosutinib in neuroblastoma cell lines showed superior effect of V3-030 and its derivatives on inhibiting these cells at nanomolar range with exception to SK-N-AS (Table 7).

Table 7. Cell viability (IC50) of V3-030 and derivatives on neuroblastoma cell lines

Example 3.3 - Comparison of daily dosage of 100 mg/kg Bosutinib with varying every other day dosages of V3-030, V11-008 and V11-010

MDA-MB 361 mouse xenograft studies 6 weeks old female Balb C nude mice were bred and implanted with 0.72 mg, 60-day sustained release 17b-estradiol pellets (Innovative Researcg of Amercia, Saeasota, FL) a day before inoculation of MDA-MB 361. Cells were trypsinized and re-suspended in media at 2 X 10⁸ cells/ml and kept on ice. Next equal volume of matrigel® was added to the cells to produce a cell concentration of 1X10 cells/ml. The animal was mildly anesthetized with Isoflurance and 1X10⁷ cells in volumn of 0.1 ml_ was injected subcutaneously on the flank of the animal. Animals were observed regularly for tumor appearance. When the majority of the tumors were in the range of 100-200 mm³, animals were randomised to 5 per group and treatment commenced. The dosing of the animals were performed via intraperitoneal injection (IP.) with vehicle (10% DMSO, 30% PEG400, 15% Cremaphor EL and 45% water) or 60 mg/kg of V3-030 or V1 1-008 or V1 1-010 dissolved in the vehicle. Animals were given the treatment every other day for a total of 12 doses. In addition, a group of animals were given bosutinib via oral guage daily at 100 mg/kg dose (15 doses). Tumor measurement and body weight were taken twice per week. Animals were closely monitored for the post dosing duration of the study. The study was terminated when the tumor condition exceed IACUC limit. The dimensions of the tumours (length and width) were measured and tumor volume was calculated by the formula (LxW²)/2.

In vivo efficacy

The animal work showed that in comparison with daily dosing of Bosutinib, V3-030, V11-008 and V11-010 significantly reduced tumor size of MDA-MB 361 BalbC nude mouse xenograft model with the strongest anti-growth effect observed when treated with V1 1-010. At day 21 , tumor/vehicle is approximately 0.45, 0.53, 0.64 and 0.68 for V11-010, V11-008, V3-030 and Bosutinib respectively. A non-toxic effect was also observed in this experiment. There was no significant change to animal body weight and behaviour with exception to day 18 and day 21 where -7% reduction was seen for V11-010 group from Fig. 6. This may be due to the weakening of one specific animal (#2) in the group. In this experiment, one animal dropped out for each treatment group.

In conclusion, the data shows the efficacy of V3-030, V1 1-010, V11-008 for their anticancer property. Current every other day dosing with 60 mg/kg of compounds of the present disclosure is also superior to daily dosing of 100 mg/kg of bosutinib.

Industrial Applicability

The compound and pharmaceutical composition may be useful in the medical field. In particular, the compound and pharmaceutical composition of the present disclosure may be used as a medicament. Furthermore, the disclosed compound and pharmaceutical composition may be used in the preparation of a medicament for treating cancer. More specifically, disclosed compound and pharmaceutical composition may be used in the preparation of a medicament for treating cancer the selected from lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, neuroblastoma, leukemia or myeloma.

It will be apparent that various other modifications and adaptations of the invention will be apparent to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.

Claims

1. A compound of general formula (I) and/or its solvates, hydrates and

Y

(I) wherein

R¹ represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH₂, -CO-O-alkyl or -CO-alkyl;

R², R³ and R⁴ independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl-CO- cycloalkyl or alkyl-CO-heterocyclyl and R² can also represent hydrogen;

Q represents a heterocyclyl group;

Y represents an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ or - CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

n is a number selected from 1 , 2, 3, 4, 5 or 6;

m is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

p is a number selected from 0 or 1 ;

r is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

s is a number selected from 0, 1 , 2, 3, 4, 5 or 6;

t is a number selected from 0 or 1 ; and

u is a number selected from 0 or 1.

2. The compound of claim 1 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

R¹ represents hydrogen, cyano, Ci-C₄-alkylamino, C C₄-alkoxy, -COOH, -CO-NH₂, - CO-0-Ci-C₄-alkyl or -CO-C C₄-alkyl;

R², R³ and R⁴ independently of each other represent d-C₆-alkyl, thio-CrC₆-alkyl, C C₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo-CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-C C₈-alkyl, Ci-C₄-alkyl-CO-C₃-C₈-cycloalkyl or C C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O) and R² can also represent hydrogen;

Q represents a heterocyclyl group;

W represents an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non- aromatic heterocyclyl group or an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aryl group;

Y represents of an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from CrC₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-CrC₆-alkyl, C C₄-alkyl- thio-C C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, C C₆-alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, thio-C C₆-alkoxy, C₂-C₆-alkenyloxy, halo-C C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-C C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, Ci-C₄-alkylamino-C C₄-alkyl, C C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, CrC₆- acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, CrC₆-acylamino, di-CrC₆-acylamino, C C₆- acyloxy, CrC₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-C C₄-alkyl, five to six ring membered optionally benzofused heterocyclyloxy, five to six ring membered optionally benzofused heterocyclylamino, five to six ring membered optionally benzofused haloheterocycloalkyl, C C₆- alkylsulfenyl, d-C₆-alkylcarbonyloxy, CrC₆-alkylthio, C C₆-acylthio, phosphorus- containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused CrC₆-alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(CrC₆-alkyl), - C(0)N(CrC₆-alkyl)₂ or-CH₂N(Ci-C₆-alkyl)₂.

3. The compound of claim 1 or 2 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t and p are both 0.

4. The compound according to any one of claims 1 to 3 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), m and s are both 0 or 1 and n and r are each selected from 3, 4, 5, and 6.

5. The compound according to any one of claims 1 to 4 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), Y is absent.

6. The compound according to any one of claims 1 to 5 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), u is 0.

7. The compound of claim 1 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

Ri represents hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH , -CO-NH₂, -CO-0-CH₃ or -CO-CH3; R₂, R₃ and R₄ independently of each other represent C C₆-alkyl, thio-C C₆-alkyl, C C₆-alkylcarbonol, halo, -COOH, -CONH₂, halo-CrC₆-alkyl, hydroxyl, C C₆-alkoxy, nitro, amino, CrC₆-alkylamino, di-CrC₆-alkylamino, C C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-C C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO- heterocyclyl(having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O);

Q represents a piperidin, tetrahydropyridin or piperazinyl group;

W represents a heterocyclic ring having 5 to 6 ring members and 1 to 3 hetero atoms selected from N, O, or S or represents phenyl;

X represents no further substituent or represents a moiety that is benzofused to the heterocyclic ring or represents a C₃ to C₆ -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-;

Y represents of an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from d-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-CrC₆-alkyl, C C₄-alkyl- thio-C C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, oxo, fluorine, chlorine, bromine, iodine, -COOH, -CONH₂, CrC₆-alkoxycarbonyl, halo-CrC₆- alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, Ci-C₄-alkyl-oxy-C C₄-alkyl, thio-C C₆-alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-CrC₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, C C₆- acyloxy, CrC₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-C C₄-alkyl- and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloxy and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloamino and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused haloheterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, C C₆-alkylsulfenyl, CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, C C₆-acylthio, phosphorus- containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl and 1 to 3 hetero atoms selected from N, O, or S, C C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused CrC₆-alkylheteroaryl and 1 to 3 hetero atoms selected from N , O, or S, cyano, cyanate, isocyanate, -C(0) N H(C C₆- alkyl), and -C(0)N(C C₆-alkyl)₂;

k is a number selected from 0 or 1 ;

I is a number selected from 0, 1 , or 2;

n is a number selected from 1 , 2, 3, or 4;

m is a number selected from 0, 1 , 2, 3, or 4;

p is a number selected from 0 or 1 ;

r is a number selected from 0, 1 , 2 or 3;

s is a number selected from 2, 3, 4 or 5;

t is a number selected from 0 or 1 ; and

u is a number selected from 0 or 1.

8. The compound of claim 1 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

represents hydrogen or a cyano group;

R₂, R3 and R₄ independently of each other represent d-C₆-alkyl, halo, -COOH , halo- CrC₆-alkyl, C C₆-alkoxy, nitro, or cyano;

Q represents a piperidin or piperazinyl group;

W represents a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or represents a phenyl group;

X represents no further substituent or represents a moiety that is benzofused to the heterocycle or represents a C₃ or C₄ bridge formed by two substituents of W in which 1 to 3 C-atoms can be replaced by O, N, S or -CO-;

R₅ represents a substitutent of the W or X-W moiety and is selected from CrC₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-C C₆-alkyl, oxo, halo, -COOH , -CON H₂, C C₆- alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, thio-C C₆-alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-CrC₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆-alkylamino, di-C C₆- alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆- alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, C C₆-acyloxy, CrC₆-alkylsulfonyloxy, CrC₆-alkylsulfenyl, CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, CrC₆-acylthio, nitro , cyano, cyanate, isocyanate, -C(0) N H(CrC₆-alkyl), and -C(0)N(CrC₆-alkyl)₂;

k is a number selected from 0 or 1 ;

I is a number selected from 0, 1 , or 2;

n is a number selected from 1 , 2, or 3; m is a number selected from 0, 1 , 2, or 3;

p is a number selected from 0 or 1 ;

r is a number selected from 0 or 1 ;

s is a number selected from 2, 3, 4, or 5;

t is a number selected from 0 or 1 ; and

u is a number selected from 0 or 1.

9. The compound of claim 7 or 8 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t, r und u are 0, k is 0 or 1 and s is 3, 4 or 5.

10. The compound of claim 1 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

represents hydrogen or a cyano group;

R₂, R3 and R₄ independently of each other represent halo, or C C₆-alkoxy;

Q represents a piperidin-, or piperazinyl group;

W represents a 2,5-dioxo-2,5-dihydro-pyrrol-1-yl group or represents a phenyl group; X represents no further substituent or represents a moiety that is benzofused to the pyrrolyl group or represents a bridge selected from -0-CH₂-CH₂-0-, -S-CH₂-CH₂-S-, - CH₂-CH=CH-CH₂-, -CH=N H-CH₂-CH₂-, -N H=CH-CH₂-CH₂- -CH=CH-S- or -CO-N H- CO-;

R₅ represents a substitutent of the W or X-W moiety and is selected from d-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-C C₆-alkyl, oxo, halo, -COOH , -CON H₂, C C₆- alkoxycarbonyl, halo-CrC₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, C C₆-alkoxy, thio-C C₆-alkoxy, C₂-C₆-alkenyloxy, halo-CrC₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-CrC₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆-alkylamino, di-C C₆- alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, C C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆- alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, C C₆-acyloxy, CrC₆-alkylsulfonyloxy, CrC₆-alkylsulfenyl, CrC₆-alkylcarbonyloxy, CrC₆-alkylthio, CrC₆-acylthio, cyano, cyanate, isocyanate, -C(0) N H(C C₆-alkyl), and -C(0) N(C C₆-alkyl)₂;

k is 0 or 1 ;

I is a number selected from 0, 1 or 2;

n is a number selected from 1 or 2;

m is a number selected from 0, 1 , 2, or 3;

P is O; r is a number selected from 0 or 1 ;

s is a number selected from 2, 3 or 4;

t is 0; and

u is 0.

1 1. The compound of claim 1 and/or its solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

represents hydrogen or cyano;

R₂ represents methoxy;

R₃ represents chlorine;

R₄ represents chlorine;

Q represents a piperazinyl group;

W represents a 2,5-dioxo-2,5-dihydro-dihydro pyrrol-1-yl group or a 2,5-dioxo- pyrrolidin-1-yl group or together with X represents a 1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl group, a 5,7-dioxo-2,3,5,7-tetrahydro-[1 ,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazinyl group;

R₅ represents hydrogen or represents a substitutent of the W or X-W moiety and is selected from d-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, oxo, halogen, C C₆- alkylcarbonyloxy, or nitro;

k is 0 or 1 ;

I is a number selected from 0, 1 or 2;

n is a number selected from 1 or 2;

m is a number selected from 1 , 2 or 3;

P is O;

r is a number selected from 0 or 1 ;

s is a number selected from 2, 3 or 4;

t is 0; and

u is 0

and Y is absent.

12. The compound of claim 1 selected from one of the following formulas and/or its solvates, hydrates and pharmaceutically acceptable salts: 112

13. A process for making a compound of formula (I) according to claim 1 , comprising (a) reacting a compound of formula (II),

(ll)

wherein R¹, R², R³, R⁴, Q, n, m and p are as defined in claim 1 ,

R^s, X, W, Y, I, u, r, t, s and k are as defined in claim 1 and Hal stands for halogen; or (b) reacting a compound of formula (II),

(ll)

wherein R¹, R², R³, R⁴, Q, n, m and p are as defined in claim 1 ,

wherein

R⁵, X, W, Y, I, u, r, t, s and k are as defined in claim 1 ;

wherein R¹, R², R³, R⁴, n, m and p are as defined in claim 1 and

Hal stands for chlorine or bromine,

in an organic solvent in the presence of an alkali or ammonium iodide, preferable

wherein

R⁵, X, W, Y, Q, I, u, r, t, s and k are as defined in claim 1.

14. A compound of formula (I) according to any one of claims 1 to 12 or pharmaceutically acceptable salts, hydrates or solvates thereof for use as a medicament.

15. A compound of formula (I) according to any one of claims 1 to 12 or pharmaceutically acceptable salts, hydrates or solvates thereof for use in the treatment of diseases, disorders and conditions which are caused by cancer cells.

16. The compound according to claim 15 or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the cancer is selected from lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma.

17. The compound according to claim 15 or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the cancer is selected from breast cancer or neuroblastoma.

18. Use of a compound of formula (I) according to any one of claims 1 to 12 or pharmaceutically acceptable salts, hydrates or solvates thereof in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from any cancer form.

19. A method of treating an oncological disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a compound of formula (I) according to any of one of claims 1 to 12 or pharmaceutically acceptable salts, hydrates or solvates thereof.

20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or pharmaceutically acceptable salts, hydrates and solvates thereof and a pharmaceutical acceptable excipient.

21. A pharmaceutical composition according to claim 20 for use in the treatment of cancer.

22. The compound, use, method, or pharmaceutical composition of any one of claims 14-21 , wherein about 30 mg/kg to about 100 mg/kg of the compound of formula (I) is to be administered every 48 hours.

23. The compound, use, method, or pharmaceutical composition of any one of claims 14-21 , wherein 60mg/kg of the compound of formula (I) is to be administered every 48 hours.