HK1163093A

HK1163093A - Quinoxaline derivatives and their use for treating benign and malignant tumour disorders

Info

Publication number: HK1163093A
Application number: HK12103812.6A
Authority: HK
Inventors: M.格拉赫; I．塞佩尔特; E．京特; T.舒斯特; E．波利梅罗波洛斯; M．切赫; E.克劳斯
Original assignee: 阿特纳赞塔里斯有限公司
Priority date: 2009-04-02
Filing date: 2010-03-25
Publication date: 2012-09-07

Description

Quinoxaline derivatives and their use for the treatment of benign and malignant tumor disorders

Technical Field

The present invention relates to quinoxaline derivatives, their preparation and their use as medicaments, in particular for the treatment of benign and malignant tumors in humans and other mammals.

Background

In the next few years, tumors and tumor-related deaths are expected to increase dramatically worldwide. In 2001, about ten million people worldwide have cancer, and over six million people die from the disease. The development of tumors is a fundamental disease of higher organisms in the plant field, the animal field and humans. The well-established multi-stage model of carcinogenesis postulates that due to the accumulation of a large number of variations in individual cells, their proliferation and differentiation behavior is so modified that, ultimately, through benign intermediate stages, metastatic malignant states are reached. After the term cancer or tumor, the clinical situation of more than 200 different individual diseases is hidden. Tumors can develop in either a benign or malignant manner. The most important tumors are those of the lung, breast, stomach, cervix, prostate, head and neck, large and small intestine, liver and blood system. There are great differences with respect to the course, prognosis and response to treatment. More than 90% of the identified cases are associated with solid tumors, particularly those at advanced or metastatic stages, which are currently refractory or untreatable. The 3 bases of cancer control remain surgical removal, radiation therapy and chemotherapy. Despite the great advances, there is still no development of drugs that can significantly prolong survival time or even completely cure a wide distribution of solid tumors. It is therefore of interest to develop new drugs for the control of cancer.

Quinoxaline derivatives are present in many applications in the pharmaceutical industry as pharmacokinetic active compounds and as building blocks for synthesis.

Quinoxaline derivatives are described as PI3K inhibitors in document WO08/141065a1, angiogenesis inhibitors in patent US2007/0254894, CHK inhibitors in patent WO08/015423, PDGF and Lck-tyrosine kinase inhibitors in patents WO9854156, WO9854157, WO9854158, WO2000031049, WO2000031050 and WO2000031051, and glutamate receptor antagonists in patents WO9962887 and WO 9732858. Reference j.med chem.2001, 44, 1758 describes the synthesis of XK469 derivatives having a quinoxaline structure and their use as antitumor agents, reference Cancer Research 1996, 3540 describes quinoxalines as Flk-1 inhibitors, j.med chem.1981, 24, 93 describes the preparation of CNS-active quinoxalines.

Summary of The Invention

The present invention relates to quinoxaline derivatives of formula I, their preparation and their use as medicaments, in particular for the treatment of benign and malignant tumours in humans and other mammals.

It has now surprisingly been found that quinoxaline derivatives, in particular having a urea or thiourea group, have a significant cytotoxic activity against a variety of human tumor cell lines. They inhibit the differentiation of intestinal cancer cells, ovarian cancer cells, prostate cancer cells, uterine cancer cells, glioblastoma cells, lung cancer cells, leukemia cells and breast cancer cells, among others, at nanomolar concentrations. The quinoxalines having urea or thiourea groups according to the invention are highly active, in particular also for cell lines resistant to cisplatin, doxorubicin and vincristine. The quinoxaline of the general formula I is shown to be highly effective in biological action and therefore may be used as an active compound in a medicament for the control of cancer disorders.

The object of the present invention is to provide cytotoxic substances which are suitable for the treatment of a large number of tumors, in particular in the case of resistance to other drugs and metastatic cancer.

This object is achieved by quinoxaline derivatives of the general formula I

Formula I

Wherein

X is: oxygen or sulfur;

R₁the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) the cyano group(s),

(iv) the halogen(s) are selected from the group consisting of,

R₂/R₃the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

R₄the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted cycloalkyl group,

(iv) an unsubstituted or substituted heterocyclic group,

(v) an unsubstituted or substituted aryl group, or a substituted aryl group,

(vi) an unsubstituted or substituted heteroaryl group,

(vii) an unsubstituted or substituted alkylaryl group,

(viii) unsubstituted or substituted alkylheterocycloaryl,

and

R₅-R₈the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted aryl group, or a substituted aryl group,

(iv) an unsubstituted or substituted heteroaryl group,

(v) the halogen(s) are selected from the group consisting of,

(vi) the cyano group(s),

(vii) a hydroxyl group(s),

(viii)(C₁-C₁₂) -an alkoxy group,

(ix) an amino group, a carboxyl group,

(x) Carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl,

(xi) Alkoxycarbonylamino, alkoxycarbonylaminoalkyl, and

wherein the substituent R₅-R₈At least 1 of which is an unsubstituted or substituted aryl or heteroaryl residue.

Certain terms used in the specification and patent claims are as defined below.

The term "alkyl" according to the invention includes, for the purposes of the present invention, acyclic saturated or unsaturated hydrocarbon residues, which may be branched or straight-chain having from 1 to 12C atoms, i.e. C_1-12Alkyl radical, C_2-12-alkenyl and C_2-12-alkynyl. In this regard, alkenyl groups have at least 1C-C double bond and alkynyl groups have at least 1C-C triple bond. Alkyl is preferably selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl, ethenyl (ethenyl), ethynyl, propenyl (-CH), propenyl (-CH₂CH＝CH₂；-CH＝CH-CH₃，-C(＝CH₂)-CH₃) Propynyl (-CH)₂-C≡CH、-C≡C-CH₃) Butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl and octynyl.

The term "cycloalkyl" means, for the purposes of the present invention, a cyclic hydrocarbon having from 3 to 12 carbon atoms, which may be saturated or unsaturated. It is possible to attach to the compounds of general structure I via any possible ring member of the cycloalkyl residue. Cycloalkyl residues may also be part of a di-or polycyclic ring system.

The term "heterocyclyl" denotes an organic residue of a 3-, 4-, 5-, 6-, 7-or 8-membered ring which contains at least 1, when appropriate 2, 3, 4 or 5 heteroatoms, which are identical or different, the ring residue being saturated or unsaturated, but not aromatic. It is possible to attach to the compounds of general structure I through any possible ring member of the heterocyclyl residue. Heterocycles can also be part of a di-or polycyclic ring system. Preferred heteroatoms are nitrogen, oxygen and sulfur. The heterocyclyl residue is preferably selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

The term "aryl" means, for the purposes of the present invention, aromatic hydrocarbons having from 6 to 14 carbon atoms, in particular phenyl, naphthyl and anthracenyl. The residues may also be fused to other saturated, (partially) unsaturated or aromatic ring systems. It is possible to attach to the compounds of the general structure I via any possible ring member of the aryl residue.

The term "heteroaryl" denotes a 5-, 6-or 7-membered ring aromatic residue comprising at least 1 and, where appropriate, also 2, 3, 4 or 5 heteroatoms, which are identical or different. It is possible to attach to the compounds of the general structure I via any possible ring member of the heteroaryl residue. Heterocycles can also be part of a di-or polycyclic ring system. Preferred heteroatoms are nitrogen, oxygen and sulfur. The heteroaryl residue is preferably selected from pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.

The term "alkylaryl" or "alkylheteroaryl" means, for the purposes of the present invention, alkyl, aryl and heteroaryl groups as defined above, the aryl or heteroaryl residue passing through C_1-8-an alkyl group is attached to the compound of formula I.

In the context of "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", "alkylaryl" and "alkylheteroaryl", the term "substituted", in the context of the present invention, unless explicitly defined as above in the description or in the claims, will be understood to mean the substitution of 1 or more hydrogen residues for F, Cl, Br, I, CN, CF₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂NH-CO-alkyl, NH-CO-aryl, NH-CO-heteroaryl, NH-SO₂-alkyl, NH-SO₂Aryl, NH-SO₂Heteroaryl, NH-CO-NH-alkyl, NH-CO-NH-aryl, NH-CO-NH-heteroaryl, NH-C (O) O-alkyl, NH-C (O) O-aryl, NH-C (O) O-heteroaryl, NO₂SH, S-alkyl, OH, OCF₃O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, O-CO-heteroaryl, O-C (O) O-alkyl, O-C (O) O-aryl, O-C (O) O-heteroaryl, O-CO-NH-alkyl, O-CO-N (alkyl)₂O-CO-NH-aryl, O-CO-NH-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Aryl, OSO₂Heteroaryl, OP (O) (OH)₂alkyl-P (O) (OH)₂、CHO、CO₂H. C (O) O-alkyl, C (O) O-aryl, C (O) O-heteroaryl, CO-alkyl, CO-aryl, CO-heteroaryl, SO₃H、SO₂-NH₂、SO₂-NH-alkyl, SO₂-NH-aryl, SO₂-NH-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the residue "alkyl", "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl" may also be substituted. The substituents may be the same or different and may be substituted at any possible position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl residues.

Polysubstituted residues are to be understood as meaningResidues substituted (e.g. di-or tri-substituted) multiple times on different or the same atoms, e.g. in CF₃、-CH₂CF₃In the case of (A) is trisubstituted on the same carbon atom or in-CH (OH) -CH-CHCl₂In the case of (a) trisubstituted at different positions.

The poly-substitution may be by the same or different substitution groups.

If the compounds of the general formula I according to the invention have at least 1 asymmetric center, they can be present as racemates, pure enantiomers and/or diastereomers, or as mixtures of these enantiomers and/or diastereomers. The mixture may be present in any desired mixture ratio of stereoisomers.

Thus, for example, the compounds of the general formula I according to the invention, which have 1 or more chiral centers and which are present as racemates, can be separated into their optical isomers, i.e. enantiomers or diastereomers, by methods known per se. The separation can be carried out by column separation on a chiral phase, or by recrystallization from an optically active solvent, or using an optically active acid or base, or by derivatization with an optically active agent such as an optically active alcohol and subsequent removal of the residue.

The compounds according to the invention may, if possible, be present in tautomeric form.

If they have sufficient basic groups, for example primary, secondary or tertiary amines, inorganic and organic acids can be used to convert the compounds of the formula I according to the invention into their physiologically acceptable salts. Preferably, pharmaceutically acceptable salts of the compounds of general structure I according to the invention can be formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, pamoic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, or aspartic acid. Salts formed are, in particular, the hydrochloride, hydrobromide, sulfate, hydrogen sulfide, phosphate, methanesulfonate, toluenesulfonate, carbonate, bicarbonate, formate, acetate, trifluoromethanesulfonate, sulfoacetic acid, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutamate and aspartate. The stoichiometry of the salts formed by the compounds according to the invention in this case can be an integer or a multiple of a non-integer of 1.

If they contain sufficient acidic groups, for example carboxyl groups, the compounds of the formula I according to the invention can be converted into their physiologically acceptable salts with inorganic and organic bases. Suitable inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, and suitable organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine, and lysine. The stoichiometry of the salts formed by the compounds according to the invention in this case can be an integer or a multiple of a non-integer of 1.

Preference is also given to solvates, in particular hydrates of the compounds according to the invention, which can be obtained, for example, by crystallization from solvents or from aqueous solutions. Here, 1, 2, 3 or any number of solvate or water molecules or integer parts thereof may be bound to the compounds according to the invention to form solvates and hydrates.

Chemical species are known to form solids in different atomic states, which are described as polymorphic forms or variants. Different variants of polymorphic substances may differ significantly in their physical properties. The compounds of formula I according to the invention may exist in a number of polymorphic forms, some of which may be relatively stable.

Most preferred are compounds of formula I selected from the group consisting of:

1-cyclopentyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (1)

1-cyclohexyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (2)

1-cyclohexyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (3)

1- [7- (3, 4-Dimethoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (4)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-phenylurea (5)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (6)

1-benzyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (7)

1-cyclopentyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (8)

1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (9)

1-tert-butyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (10)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (11)

1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (12)

1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (13)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-phenylurea (14)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (15)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-methylurea (16)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylurea (17)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (18)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (19)

1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (20)

1-cyclohexyl-3- [7- (3, 5-dichloro-4-hydroxyphenyl) quinoxalin-2-yl ] thiourea (21)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (22)

1-cyclopropyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (23)

1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (24)

1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (25)

1-dodecyl-3- (7-phenylquinoxalin-2-yl) urea (26)

1- (3-chloro-2-methylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (27)

1- (3, 4-dimethylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (28)

1-allyl-3- (7-phenylquinoxalin-2-yl) urea (29)

1-cyclopentyl-3- (7-phenylquinoxalin-2-yl) urea (30)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylthiourea (31)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (32)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pentylurea (33)

1-cyclobutyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (34)

1-hexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (35)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-propylurea (36)

1-dodecyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (37)

1- (3-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (38)

1- (3-Acetylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (39)

1- (3, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (40)

1-allyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (41)

1-Cyclooctyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (42)

1- (2, 4-dimethylphenyl) -3-7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (43)

1-Cyclooctyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (44)

1-adamantan-1-yl-3- (7-phenylquinoxalin-2-yl) urea (45)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-p-tolylurea (46)

1- (3, 4-dichlorophenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (47)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (4-methoxyphenyl) urea (48)

1-Adamantan-1-yl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (49)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-naphthalen-2-ylurea (50)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (1, 1, 3, 3-tetramethylbutyl) urea (51)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pyridin-3-ylurea (52)

1- ((R) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (53)

1- ((S) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (54)

1- (5-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (55)

1- ((S) -2-phenylcyclopropyl) -3- (7-phenylquinoxalin-2-yl) urea (56)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- ((S) -2-phenylcyclopropyl) urea (57)

1- (2-chloro-6-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (58)

1-allyl-3-7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (D-118068) (59)

1- (3, 5-Dimethylisoxazol-4-yl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (60)

1-sec-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (61)

1-Ethyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (62)

1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (63)

1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (64)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isobutylurea (65)

1- (1-ethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (66)

1- (2, 2-dimethyl-propyl) -3- [7- (4-hydroxy-3, 5-dimethyl-phenyl) -quinoxalin-2-yl ] -urea (67)

1- [7- (4-amino-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (68)

1- [7- (4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (69)

1-isopropyl-3- [7- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-2-yl ] -urea (70)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-urea (71)

1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (72)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-urea (73)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-urea (74)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-heptyl-urea (75)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (76)

1-tert-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (77)

1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (78)

1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (79)

1-cyclobutyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (80)

1-cyclopentyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (81)

1- [7- (3-chloro-4-hydroxy-5-methoxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (82)

1-cyclopropyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (83)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -urea (84)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-urea (85)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenyl-urea (86)

1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (87)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-thiourea (88)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-thiourea (89)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-thiourea (90)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-thiourea (91)

1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (92)

1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (93)

1-benzyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (94)

1- [7- (3-chloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (95)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -thiourea (96)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-thiourea (97)

1- [2- (4-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (98)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-morpholin-4-yl-propyl) -thiourea (99)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -thiourea (100)

1- (2-cyclohex-1-enyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (101)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (2-thiophen-2-yl-ethyl) -urea (102)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-methoxy-phenyl) -ethyl ] -thiourea (103)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-ethyl-phenyl) -ethyl ] -urea (104)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 5-dimethoxy-phenyl) -ethyl ] -urea (105)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dichloro-phenyl) -ethyl ] -urea (106)

1- [2- (3-bromo-4-methoxy-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (107)

1- (2-Biphenyl-4-yl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (108)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 3-dimethoxy-phenyl) -ethyl ] -urea (109)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2-fluoro-phenyl) -ethyl ] -urea (110)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 4-dichloro-phenyl) -ethyl ] -urea (111)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-fluoro-phenyl) -ethyl ] -urea (112)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -urea (113)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-methoxy-phenyl) -ethyl ] -urea (114)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 5-dimethoxy-phenyl) -ethyl ] -urea (115)

1- [2- (4-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (116)

1- [2- (3-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (117)

1- (2-cyclopentyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (118)

1- (2-cyclohexyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (119)

1- (2-cyclohexyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (120)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-hydroxy-phenyl) -ethyl ] -thiourea (121)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (2-pyridin-3-yl-ethyl) -thiourea (122)

The quinoxalines of the general formula I according to the invention are suitable for pharmaceutical use, in particular as antitumor agents, for the treatment of humans and other mammals. The mammal can be a domestic animal such as a horse, cow, dog, cat, rabbit, sheep, and the like.

According to a further aspect of the present invention, there is provided a method for the treatment of tumors in humans and other mammals, said method being characterized in that at least 1 quinoxaline according to formula I is administered to a human or another mammal in a tumor-treating effective dose. The therapeutically effective dose to be administered for the treatment of each quinoxaline according to the invention depends inter alia on the type and stage of the tumor disorder, the age, weight and sex of the patient, the type of administration and the duration of the treatment. The medicament according to the invention can be administered as liquid, semi-solid and solid medicament forms. Which in each case are present in a suitable manner in the following form: aerosols, powders, pellets and dusting powders, tablets including coated tablets, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.

In addition to at least 1 component according to the invention, the pharmaceutical forms contain, where appropriate, auxiliaries, such as, inter alia, solvents, dissolution promoters (solvation enhancers), solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers (salts), drying agents, flow regulators, fillers, preservatives, antioxidants, colorants, mold release agents, lubricants, disintegrants and taste and odor masking agents (masking flavors and odor), depending on the pharmaceutical form employed. The choice of auxiliary agents and the amounts employed depend on the selected pharmaceutical form and are based on formulations known to the skilled worker.

The medicament according to the invention may be administered in a suitable dosage form, as a solution, suspension, emulsion, foam, ointment, paste or plaster, through the skin, intradermally; buccal, lingual or sublingual administration as tablets, pastilles, coated tablets, lozenges or mouthwashes through the buccal and lingual mucosa; enterally administered as tablets, coated tablets, capsules, solutions, suspensions or emulsions through the gastric and intestinal mucosa; rectal administration as a suppository, rectal capsule or ointment through the rectal mucosa; as drops, ointment or spray, administered nasally through the nasal mucosa; as an aerosol or inhalant, administered by the pulmonary route or by inhalation through the bronchial and alveolar epithelium; conjunctival administration as an eye drop, an eye ointment, an eye tablet, a sheet (lamellae), or an eye lotion; as pessaries, ointments and irrigation solutions, administered intravaginally through the mucous membranes of the reproductive organs, administered as pessaries by the intrauterine route; intraurethral administration as a rinse, ointment or suppository through the urethra; as an injection, entering an artery and performing intra-arterial administration; as an injection or infusion solution, into a vein for intravenous administration, or as an injection or infusion solution for paravenous administration; as an injection or implant, into the skin for intradermal administration; subcutaneous administration is performed subcutaneously as an injection or implant; as an injection or implant, into muscle for intramuscular administration; the composition can be administered intraperitoneally as injection or infusion solution.

In view of the practical therapeutic requirements, the pharmaceutical effect of the compounds of general structure I of the present invention can be prolonged by suitable means. This object can be achieved by chemical and/or pharmaceutical methods. Examples of achieving a prolonged effect are the use of implants, liposomes, sustained release forms, nanoparticle suspensions and the formation of so-called prodrugs, low solubility salts and complexes of the compounds according to the invention, or the use of crystal suspensions.

The compounds according to the invention may be employed as the sole material or in combination with other materials, for example asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levo-asparaginase, cyclophosphamide, cytarabine, dacarbazine D (dactinomycin), daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thalidomide, thioguanine, topotecan, vinblastine, vindesine, vincaminoglutethimide, vincristine, vindesine, and others, L-asparaginase, azathioprine, azacitidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine (erythrohydroxynonyladenine), ethinylestradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone hexanoate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, NUBCNU, DTIC, herceptin, avastin, astragenin, valsartan, diethylstilbestrol, ethionine, vinorelbine, and other compounds, Abiraterone, sorafenib, Gleevec, Iressa, Tabexad, rapamycin, Actinomycin D, sunitinib (Satany).

Specifically preferred herein are medicaments comprising at least 1 compound of the following quinoxalines:

1-cyclopentyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (1)

1-cyclohexyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (2)

1-cyclohexyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (3)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-phenylurea (5)

1-benzyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (7)

1-cyclopentyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (8)

1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (9)

1-tert-butyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (10)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (11)

1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (12)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-phenylurea (14)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-methylurea (16)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylurea (17)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (18)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (19)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (22)

1-dodecyl-3- (7-phenylquinoxalin-2-yl) urea (26)

1- (3-chloro-2-methylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (27)

1- (3, 4-dimethylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (28)

1-allyl-3- (7-phenylquinoxalin-2-yl) urea (29)

1-cyclopentyl-3- (7-phenylquinoxalin-2-yl) urea (30)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (32)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pentylurea (33)

1-hexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (35)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-propylurea (36)

1-dodecyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (37)

1-allyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (41)

1-Cyclooctyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (42)

1- (2, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (43)

1-Cyclooctyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (44)

1-adamantan-1-yl-3- (7-phenylquinoxalin-2-yl) urea (45)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-p-tolylurea (46)

1- ((S) -2-phenylcyclopropyl) -3- (7-phenylquinoxalin-2-yl) urea (56)

1-allyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (D-118068) (59)

1-sec-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (61)

1-Ethyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (62)

1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (63)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isobutylurea (65)

1- (1-ethylbutyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (66)

1- [7- (4-amino-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (68)

1- [7- (4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (69)

1-isopropyl-3- [7- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-2-yl ] -urea (70)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-urea (71)

1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (72)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-urea (73)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-urea (74)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-heptyl-urea (75)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenyl-urea (86)

1- [7- (3-chloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (95)

These compounds may be present as free bases or as salts of physiologically acceptable acids.

Chemical synthesis

The compounds of general formula I can be obtained according to scheme 1 below:

scheme 1

The starting materials are commercially available or can be prepared by methods known per se. The starting materials B and C are useful intermediates for the preparation of the quinoxalines of the general formula I according to the invention.

For the preparation of the starting materials and the target compounds, reference may be made, for example, to the following original documents, the contents of which are incorporated by reference into the disclosure of the present application:

1) lumma et al, J. Med chem.1991, 24, 93-101;

2) J.P.Horwitz et al, J.Med chem.2001, 44, 1758-.

Any solvents and auxiliaries can be used, if appropriate, the reaction parameters used, such as the temperature and the duration of the reaction, being known to the person skilled in the art by their expert knowledge.

The following compounds, which are apparent from the expression of each chemical name measured below, were synthesized according to a general method based on steps 1, 2 and 3 of synthesis scheme 1. By their melting point and/or by¹H-NMR spectroscopy and/or mass spectroscopy for the analytical characterization of the compounds according to the invention.

The chemicals and solvents used are commercially available or synthesized from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybrid, Merck, Sigma, TCI, etc.).

Examples

The present invention will be explained in more detail by the following examples, but is not limited to the examples.

The chemical name of the substance was generated using AutoNom 2000 software (ISIS TM/Draw 2.5SP 2; MDL).

Example 1 (reaction according to scheme 1, step 1):

example 1.1: 7-chloroquinoxalin-2-ylamine

30.0g (60.0mmol) of 2, 7-dichloroquinoxaline are dissolved in 400ml of NH at 120 ℃ T₃In MeOH (w 22%) was stirred for 16 hours. The mixture is then evaporated to dryness under reduced pressure and the residue is treated in 250ml of dichloromethane and 250ml of water. After phase separation, the organic phase is then washed with 250ml of water, dried over sodium sulfate and the solvent is removed under membrane pump vacuum. The residue obtained is purified by column chromatography on silica gel (ethyl acetate/petroleum ether ═ 1: 5; silica gel: 200-mesh 300) to give 10.5g of 7-chloroquinoxalin-2-ylamine (yield 98%).

Melting point: 219 ℃ and 222 ℃ 2

¹H-NMR(300 MHz，CDCl₃) δ＝8.30(1H，s)，7.83(1H，s)，7.65(1H，m)，7.40(1H，m)ppm

MS(ESI)m/z 180(MH⁺)

Example 2 (reaction according to scheme 1, step 2)

Example 2.1: 4- (3-aminoquinoxalin-6-yl) -2, 6-dimethylphenol

1.66g (6.7mmol) of 3, 5-dimethyl-4-hydroxyphenylboronic acid pinacol ester and 1.42g (13.4mmol) of sodium carbonate are dissolved in 10ml of water under argon, and 0.155g (0.13mmol) of Pd (PPh)₃)₄To a solution of 0.8g (4.5mmol) of 7-chloroquinoxalin-2-ylamine in 40ml of dioxane was added and the mixture was stirred at 100 ℃ for 4 hours.

For workup, 30ml of ethyl acetate and 30ml of water are added to the reaction mixture, the phases are separated, the organic phase is dried over magnesium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue obtained is purified by column chromatography on silica gel (ethyl acetate/n-heptane) to give 0.65g of 4- (3-aminoquinoxalin-6-yl) -2, 6-xylenol.

Yield: 33.1 percent

Melting point: 256 deg.C

¹H-NMR(600MHz，DMSO-d₆) δ＝8.43(1H，br.s)，8.24(1H，s)，7.75(1H，d)，7.62(1H，m)，7.57(1H，m)，7.35(2H，s)，6.90(2H，s)，2.25(6H，s)ppm

MS(ESI)m/z 266(MH⁺)

The synthesis of the intermediate of formula B below is analogous to example 2.1(4- (3-aminoquinoxalin-6-yl) -2, 6-dimethylphenol).

Example 2.2: 7-phenylquinoxaline-2-amines

¹H-NMR(300 MHz，DMSO-d₆) δ＝8.93(1H，m)，8.81(1H，s)，8.00(5H，m)，7.45(3H，s)ppm

MS(ESI)m/z 222(MH⁺)

Example 2.3: 4- (3-aminoquinoxalin-6-yl) -2-methoxyphenol

¹H-NMR(300 MHz，DMSO-d₆) δ＝8.26(1H，s)，7.70(4H，s)，7.30(2H，J＝5.4Hz，m)，6.90(1H，m)，4.00(3H，s)ppm

MS(ESI)269(MH⁺)

Example 2.4: 7- (3, 4-Dimethoxyphenyl) quinoxalin-2-amine

¹H-NMR(300 MHz，DMSO-d₆) δ＝8.26(1H，s)，7.50(4H，s)，7.30(1H，J＝5.4Hz，m)，6.90(2H，m)，3.88(6H，s)ppm；

MS(ESI)282(MH⁺)

Example 2.5: 4- (3-aminoquinoxalin-6-yl) -2, 6-dichlorophenol

Melting point: 263 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.35(1H，s)，8.28(1H，s)，7.78(3H，m)，7.71(1H，m)，7.63(1H，m)，7.02(2H，s)ppm

MS(ESI)m/z 306(MH⁺)

Example 2.6: 7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-ylamine

¹H-NMR(600 MHz，DMSO-d₆) δ＝8.26(1H，s)，7.78(1H，d)，7.67(1H，m)，7.58(1H，m)，7.43(2H，s)，6.95(2H，s)，3.75(3H，s)ppm

MS(ESI)m/z 280 (MH⁺)

Example 3 (according to protocol)1, step 3)

General Process (GP) for the preparation of urea or thiourea derivatives:

0.45mmol of intermediate B (cf. example 2) are added with ice cooling to a mixture of 0.71mmol of sodium hydride (60% strength suspension in mineral oil) in 5ml of dimethylformamide or THF. After stirring at 0 ℃ for 30min, 0.54mmol of the appropriate isocyanate or isothiocyanate dissolved in 2ml of THF is added dropwise, and the ice cooling is removed. After stirring at room temperature for 16 hours, the reaction solution was concentrated to dryness under membrane pump vacuum and the residue was treated in 50ml of water and 50ml of ethyl acetate, resulting in precipitation of the product. The precipitate was filtered off with suction and then dried in a vacuum drying oven to give the title compound.

The synthesis of the following compounds of formula I is analogous to the synthetic route in scheme 1 and follows a general procedure:

example 3.1: 1-cyclopentyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (1)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.99(1H，s)，8.80(1H，m)，8.75(1H，s)，7.95(3H，s)，7.25(2H，s)，6.90(1H，m)，4.01(1H，m)，3.90(3H，s)，1.90(3H，s)，1.6(5H，s)ppm

MS(ESI)m/z 379(MH⁺)

Example 3.2: 1-cyclohexyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (2)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.99(1H，s)，8.80(1H，m)，8.75(1H，s)，7.95(3H，s)，7.25(2H，s)，6.90(1H，m)，3.90(3H，m)，3.68(1H，s)，1.7(4H，s)，1.4(6H，s)ppm

MS(ESI)m/z 392(MH⁺)

Example 3.3: 1-cyclohexyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (3)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.86(1H，m)，8.88(1H，s)，8.77(1H，s)，7.95(3H，s)，7.38(2H，s)，7.11(1H，m)，3.90(3H，s)3.80(3H，s)，3.36(1H，s)，1.75(2H，s)，1.52(6H，m)ppm

MS(ESI)m/z 407(MH⁺)

Example 3.4: 1- [7- (3, 4-Dimethoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (4)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.13(1H，s)，8.89(1H，m)，8.82(1H，s)，8.07(1H，m)，7.96(2H，s)，7.35(2H，s)，7.00(1H，s)，4.22(2H，m)，4.15(1H，m)，3.90(3H，s)，3.82(3H，s)，3.49(1H，s)，3.25(1H，s)，2.04(2H，m)，1.65(2H，m)ppm

MS(ESI)m/z 504(MH⁺)

Example 3.5: 1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-phenylurea (5)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.98(1H，s)，10.40(1H，s)，9.30(1H，m)，8.88(1H，s)，8.20(3H，m)，7.68(2H，s)，7.52(4H，s)，6.90(2H，m)，3.90(3H，s)ppm

MS(ESI)m/z 386(MH⁺)

Example 3.6: 1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (6)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.12(1H，s)，9.30(1H，m)，8.88(1H，s)，8.80(1H，m)，8.78(3H，s)，7.35(2H，s)，6.90(1H，m)，4.15(2H，m)，3.90(3H，s)，3.33(2H，m)，2.15(2H，m)，1.75(2H，m)ppm

MS(ESI)m/z 489(MH⁺)

Example 3.7: 1-benzyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (7)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.50(1H，s)，9.30(1H，m)，8.88(1H，s)，8.00(3H，s)，7.41(5H，s)，7.25(2H，m)，6.90(1H，m)，4.53(2H，m)，3.90(3H，s)ppm

MS(ESI)m/z 400(MH⁺)

Example 3.8: 1-cyclopentyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (8)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.86(1H，m)，8.88(1H，s)，8.77(1H，s)，7.95(3H，s)，7.38(2H，s)，7.11(1H，m)，4.12(1H，s)，3.90(3H，s)3.80(3H，s)，1.75(2H，s)，1.52(6H，m)ppm

MS(ESI)m/z 393(MH⁺)

Example 3.9: 1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (9)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.84(1H，s)，9.88(1H，s)，8.76(1H，m)，8.58(1H，s)，7.89(3H，s)，7.45(2H，s)，2.28(6H，s)，1.40(9H、m)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.10: 1-tert-butyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (10)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.50(1H，s)，9.30(1H，m)，8.88(1H，s)，8.20(1H，m)，8.81(1H，s)，7.91(3H，s)，7.32(2H，s)，6.90(1H，m)，3.90(3H，s)，1.42(9H、m)ppm

MS(ESI)m/z 367(MH⁺)

Example 3.11: 1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (11)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.50(1H，s)，9.30(1H，m)，8.88(1H，s)，8.20(1H，m)，8.00(2H，s)，7.35(2H，s)，7.00(2H，s)，6.90(2H，m)，3.90(3H，s)ppm

MS(ESI)m/z 393(MH⁺)

Example 3.12: 1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (12)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.98(1H，s)，8.86(1H，m)，8.58(1H，s)，7.98(1H，m)，7.89(2H，s)，7.45(2H，s)，3.34(1H，s)，2.28(6H，s)，1.88(2H，s)，1.70(3H，m)，1.35(5H，m)ppm

MS(ESI)m/z 391(MH⁺)

Example 3.13: 1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (13)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.98(1H，s)，8.86(1H，m)，8.58(1H，s)，7.98(1H，m)，7.89(2H，s)，7.45(2H，s)，4.11(1H，s)，2.28(6H，s)，1.96(2H，s)，1.70(6H，m)ppm

MS(ESI)m/z 377(MH⁺)

Example 3.14: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-phenylurea (14)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.98(1H，s)，8.88(1H，s)，8.00(3H，m)，7.86(2H，s)，7.42(4H，s)，7.00(1H，s)，2.25(6H，m)ppm

MS(ESI)m/z 385(MH⁺)

Example 3.15: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (15)

¹H-NMR(300 MHz，DMSO-d₆) δ＝11.85(1H，s)，10.56(1H，s)，9.98(1H，s)，8.96(1H，m)，8.58(1H，s)，8.22(1H，s)，7.98(2H，m)，7.52(2H，s)，7.00(2H，s)，6.95(1H，s)，2.28(6H，s)ppm

MS(ESI)m/z 391(MH⁺)

Example 3.16: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-methylurea (16)

Melting point: 251 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.1(1H，s)，8.82(1H，m)，8.69(1H，s)，8.52(1H，s)，8.08(1H，s)，7.92(1H，m)，7.85(1H，s)，7.44(2H，s)，2.85(3H，s)，2.25(6H，s)ppm

MS(ESI)m/z 323(MH⁺)

Example 3.17: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylurea (17)

Melting point: 280 plus 283 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝9.92(1H，s)，8.82(1H，s)，8.54(1H，s)，7.95-7.85(3H，m)，7.42(2H，s)，3.85(1H，m)，2.25(6H，s)，1.22(6H，d)ppm

MS(ESI)m/z 351(MH⁺)

Example 3.18: 1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (18)

Melting point: 276 ℃ and 280 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.02(1H，s)，8.85(1H，s)，8.73(1H，s)，8.53(1H，s)，7.96-7.83(3H，m)，7.42(2H，s)，3.28(2H，m)，2.48(6H，s)，1.52(2H，m)，1.38(2H，m)，0.95(3H，m)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.19: 1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (19)

Melting point: 257 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.0(1H，s)，8.82(1H，m)，8.74(1H，s)，8.22(1H，m)，7.94-7.84(2H，m)，7.43(2H，s)，3.28(2H，m)，2.23(6H，s)，1.18(3H，m)ppm

MS(ESI)m/z 337(MH⁺)

Example 3.20: 1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (20)

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.78(1H，s)，11.16(1H，s)，8.75(1H，s)，8.55(1H，m)，7.96-7.85(3H，m)，7.41(2H，s)，4.35(1H，m)，3.28(2H，m)，2.28(6H，s)，1.95(2H，m)，1.77(2H，m)，1.62(3H，m)，1.45(3H，m)ppm

MS(ESI)m/z 407(MH⁺)

Example 3.21: 1-cyclohexyl-3- [7- (3, 5-dichloro-4-hydroxyphenyl) quinoxalin-2-yl ] thiourea (21)

Melting point: 284 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.64(1H，s)，11.2(1H，s)，10.48(1H，s)，8.79(1H，s)，8.03-7.96(3H，m)，7.87(2H，s)，4.22(1H，m)，2.02(2H，m)，1.85(2H，m)，1.62(3H，m)，1.4(3H，m)ppm

Example 3.22: 1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (22)

Melting point: 243 ℃ and 244 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.65(1H，s)，11.14(1H，s)，8.74(1H，s)，8.55(1H，m)，8.15(1H，m)，7.97-7.7.91(2H，m)，7.41(2H，s)，3.78(2H，m)，2.24(6H，s)，1.28(3H，m)ppm

MS(ESI)m/z 353(MH⁺)

Example 3.23: 1-cyclopropyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (23)

Melting point: 274 ℃ and 276 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.61(1H，s)，11.23(1H，s)，8.73(1H，s)，8.53(1H，m)，7.99-7.7.91(3H，m)，7.46(2H，s)，3.22(1H，m)，0.91-0.78(4H，m)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.24: 1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (24)

Melting point: 271, 272 ℃ plus

MS(ESI)m/z 393(MH⁺)

Example 3.25: 1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (25)

Melting point: 238 deg.C and 240 deg.C

MS(ESI)m/z 381(MH⁺)

Example 3.26: 1-dodecyl-3- (7-phenylquinoxalin-2-yl) urea (26)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(1H，m)，8.81(1H，s)，8.00(5H，m)，7.45(3H，s)，3.31(2H，s)，1.57(2H，s)，1.24(20H，m)，0.83(3H，s)ppm

MS(ESI)m/z 433(MH⁺)

Example 3.27: 1- (3-chloro-2-methylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (27)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.77(1H，s)，10.14(1H，s)，8.93(1H，m)，8.00(5H，m)，7.45(5H，s)，7.22(1H，s)，2.21(3H，s)ppm

MS(ESI)m/z 389(MH⁺)

Example 3.28: 1- (3, 4-dimethylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (28)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.77(1H，s)，10.14(1H，s)，8.93(1H，m)，8.00(5H，m)，7.45(5H，s)，7.22(1H，s)，2.21(6H，s)ppm

MS(ESI)m/z 369(MH⁺)

Example 3.29: 1-allyl-3- (7-phenylquinoxalin-2-yl) urea (29)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.88(2H，m)，8.00(5H，m)，7.45(3H，s)，6.00(1H，s)，5.21(2H，s)，3.95(2H，m)ppm

MS(ESI)m/z 305(MH⁺)

Example 3.30: 1-cyclopentyl-3- (7-phenylquinoxalin-2-yl) urea (30)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(2H，m)，8.00(5H，m)，7.45(3H，s)，3.61(1H，s)，1.57(8H、s)ppm

MS(ESI)m/z 333(MH⁺)

Example 3.31: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylthiourea (31)

Melting point: 269, 271 deg.C

MS(ESI)m/z 367(MH⁺)

Example 3.32: 1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (32)

Melting point: 278 heat 280 deg.C

MS(ESI)m/z 381(MH⁺)

Example 3.33: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pentylurea (33)

Melting point: 274 plus 275 deg.C

MS(ESI)m/z 379(MH⁺)

Example 3.34: 1-cyclobutyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (34)

Melting point: 285 ℃ 286 DEG C

MS(ESI)m/z 379(MH⁺)

Example 3.35: 1-hexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (35)

Melting point: 272 plus 273 deg.C

MS(ESI)m/z 393(MH⁺)

Example 3.36: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-propylurea (36)

Melting point: 276 ℃ 277 DEG C

MS(ESI)m/z 351(MH⁺)

Example 3.37: 1-dodecyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (37)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(1H，m)，8.71(1H，s)，8.51(1H，s)，7.95(3H，m)，7.45(2H，s)，2.26(6H，s)，1.57(2H，s)，1.24(20H，m)ppm

MS(ESI)m/z 477(MH⁺)

Example 3.38: 1- (3-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (38)

¹H-NMR(300 MHz，DMSO-d₆) δ＝11.14(1H，s)，10.14(1H，s)，8.93(1H，m)，8.51(1H，s)，7.95(4H，m)，7.45(4H，s)，7.15(1H，s)，2.26(6H，s)，2.15(3H，s)ppm

MS(ESI)m/z 433(MH⁺)

Example 3.39: 1- (3-Acetylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (39)

¹H-NMR(300 MHz，DMSO-d₆) δ＝11.14(1H，s)，10.14(1H，s)，8.93(1H，m)，8.51(1H，s)，7.95(4H，m)，7.45(2H，s)，7.15(2H，s)，2.56(3H，s)，2.15(3H，s)ppm

MS(ESI)m/z 427(MH⁺)

Example 3.40: 1- (3, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (40)

¹H-NMR(300 MHz，DMSO-d₆) δ＝11.14(1H，s)，10.14(1H，s)，8.93(1H，m)，8.51(1H，s)，7.95(4H，m)，7.45(4H，s)，7.15(1H，s)，2.26(6H，s)，2.15(6H，s)ppm

MS(ESI)m/z 413(MH⁺)

Example 3.41: 1-allyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (41)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(1H，m)，8.71(1H，s)，8.54(1H，s)，7.45(3H，s)，5.97(1H，s)，5.22(2H，s)，3.95(2H，m)，1.99(6H，s)ppm

MS(ESI)m/z 349(MH⁺)

Example 3.42: 1-Cyclooctyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (42)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(2H，m)，8.81(1H，s)，7.85(3H，m)，7.45(2H，s)，4.08(1H，m)，2.28(6H，m)，1.95(12H，m)，1.85(2H，s)ppm

MS(ESI)m/z 419(MH⁺)

Example 3.43: 1- (2, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (43)

MS(ESI)m/z 413(MH⁺)

Example 3.44: 1-Cyclooctyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (44)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，9.03(1H，m)，8.81(2H，s)，8.00(3H，m)，7.45(2H，s)，6.93(1H，s)，4.08(1H，s)，3.88(3H，s)，2.00(2H，s)，1.75(12H，s)ppm

MS(ESI)m/z 421(MH⁺)

Example 3.45: 1-adamantan-1-yl-3- (7-phenylquinoxalin-2-yl) urea (45)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(2H，m)，8.00(5H，m)，7.45(3H，s)，2.00(12H，s)，1.68(3H，s)ppm

MS(ESI)m/z 399(MH⁺)

Example 3.46: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-p-methylphenyl urea (46)

Melting point: more than 300 DEG C

MS(ESI)m/z 399(MH⁺)

Example 3.47: 1- (3, 4-dichlorophenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (47)

Melting point: more than 300 DEG C

MS(ESI)m/z 454(MH⁺)

Example 3.48: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (4-methoxyphenyl) urea (48)

Melting point: more than 300 DEG C

MS(ESI)m/z 415(MH⁺)

Example 3.49: 1-Adamantan-1-yl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (49)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(2H，m)，8.81(1H，s)，7.85(3H，m)，7.45(2H，s)，2.28(6H，m)，1.85(12H，m)，1.56(3H，s)ppm

MS(ESI)m/z 443(MH⁺)

Example 3.50: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-naphthalen-2-ylurea (50)

Melting point: more than 300 DEG C

MS(ESI)m/z 435(MH⁺)

Example 3.51: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (1, 1, 3, 3-tetramethylbutyl) urea (51)

Melting point: more than 300 DEG C

MS(ESI)m/z 421(MH⁺)

Example 3.52: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pyridin-3-ylurea (52)

Melting point: 298 ℃ C. 300 ℃ C

MS(ESI)m/z 386(MH⁺)

Example 3.53: 1- ((R) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (53)

Melting point: 265 deg.C

MS(ESI)m/z 379(MH⁺)

Example 3.54: 1- ((S) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (54)

Melting point: 267 deg.C

MS(ESI)m/z 379(MH⁺)

Example 3.55: 1- (5-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (55)

MS(ESI)m/z 433(MH⁺)

Example 3.56: 1- ((S) -2-phenylcyclopropyl) -3- (7-phenylquinoxalin-2-yl) urea (56)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(1H，m)，8.81(1H，s)，8.00(5H，m)，7.45(3H，s)，7.32(5H，s)，2.95(1H，s)，2.05(2H，m)，0.83(1H，s)ppm

MS(ESI)m/z 381(MH⁺)

Example 3.57: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- ((S) -2-phenyl-cyclopropyl) urea (57)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，8.93(2H，m)，8.81(1H，s)，8.00(3H，m)，7.45(2H，s)，7.28(5H，s)，2.93(1H，s)，2.28(6H，m)，1.46(2H，m)，0.83(1H，s)ppm

MS(ESI)m/z 425(MH⁺)

Example 3.58: 1- (2-chloro-6-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (58)

MS(ESI)m/z 433(MH⁺)

Example 3.59: 1-allyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (59)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.14(1H，s)，9.03(1H，m)，8.81(2H，s)，8.00(3H，m)，7.45(2H，s)，6.93(1H，s)，5.96(1H，s)，5.21(2H，m)，3.94(2H，s)，3.88(3H，s)ppm

MS(ESI)m/z 351(MH⁺)

Example 3.60: 1- (3, 5-Dimethylisoxazol-4-yl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (60)

¹H-NMR(300 MHz，DMSO-d₆) δ＝12.48(1H，s)，8.42(1H，s)，8.05(1H，s)，7.84(2H，s)，7.41(1H，s)，2.47(3H，s)，2.24(6H，s)，2.18(3H，s)ppm

MS(ESI)m/z 404(MH⁺)

Example 3.61: 1-sec-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (61)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.85(1H，s)，8.84(1H，s)，8.53-8.51(2H，m)，7.93(1H，d)，7.84(2H，m)，7.41(2H，s)，3.76(1H，m)，2.24(6H，s)，1.54(2H，m)，1.21(3H，d)，0.88(3H，t)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.62: 1-Ethyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (62)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.03(1H，s)，8.79(2H，s)，8.08(1H，d)，7.96(1H，d)，7.88(1H，m)，7.52(2H，s)，3.71(3H，s)，3.31(2H，s)，2.33(6H，s)，1.19(3H，t)ppm

MS(ESI)m/z 351(MH⁺)

Example 3.63: 1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (63)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.94(1H，s)，8.87(1H，s)，8.53-8.52(1H，d)，7.98-7.95(2H，m)，7.88-7.86(2H，m)，7.51(2H，s)，3.94-3.91(1H，m)，3.71(3H，s)，2.33(6H，s)，1.25-1.24(6H，d)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.64: 1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (64)

¹H-NMR(300 MHz，DMSO-d₆) δ＝11.63(1H，d)，11.17(1H，s)，8.77(1H，s)，7.99(2H，m)，7.92(1H，m)，7.52(2H，s)，4.49-4.46(1H，m)，3.71(3H，s)，2.34(6H，s)，1.38(6H，d)ppm

MS(ESI)m/z 381(MH⁺)

Example 3.65: 1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isobutylurea (65)

¹H-NMR(300 MHz，DMSO-d₆) δ＝10.02(1H，s)，8.85(1H，m)，8.79(1H，s)，8.53(1H，s)，7.94-7.85(3H，m)，7.41(2H，s)，3.15-3.13(2H，t)，2.27(6H，s)，1.88-1.84(1H，m)，0.95(6H，d)ppm

MS(ESI)m/z 365(MH⁺)

Example 3.66: 1- (1-ethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (66)

¹H-NMR(300 MHz，DMSO-d₆) δ＝9.92(1H，s)，8.85(1H，s)，8.52(2H，s)，7.95(1H，d)，7.85(2H，m)，7.40(2H，s)，3.67-3.64(1H ，m)，2.27(6H ，s)，1.63-1.52(4H ，m)，0.94-0.92(6H，t)ppm

MS(ESI)m/z 379(MH⁺)

Example 3.67: 1- (2, 2-dimethyl-propyl) -3- [7- (4-hydroxy-3, 5-dimethyl-phenyl) -quinoxalin-2-yl ] -urea (67)

Melting point: 275 ℃ C-276 ℃ C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.05(1H，s)，8.91(1H，s)，8.80(1H，s)，8.54(1H，s)，7.96(1H，s)，7.87(1H，s)，7.85(1H，m)，7.38(2H，s)，3.13(2H，d)，2.26(6H，s)，0.97(9H，s)ppm

MS(ESI)：m/z＝379.3(MH⁺)

Example 3.68: 1- [7- (4-amino-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (68)

Melting point: more than 300 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝9.87(1H，s)，8.77(1H，s)，8.62(1H，d)，7.91-7.84(3H，m)，7.58-7.57(2H，m)，6.71-6.69(2H，m)，5.41(2H，m)，3.94-3.90(1H，m)，1.25-1.24(6H，d)ppm

MS(ESI)：m/z＝322.0(MH⁺)

Example 3.69: 1- [7- (4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (69)

¹H-NMR(600 MHz，DMSO-d₆) δ＝9.94(1H，s)，9.71(1H，s)，8.82(1H，s)，8.60(1H，d)，7.96-7.86(3H，m)，7.71-7.7(2H，m)，6.92-6.91(2H，m)，3.94-3.90(1H，m)，1.25-1.24(6H，d)ppm

MS(ESI)：m/z＝322.9(MH⁺)

Example 3.70: 1-isopropyl-3- [7- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-2-yl ] -urea (70)

Melting point: 260 deg.C 263 deg.C

¹H-NMR(600MHz，DMSO-d₆) δ＝9.91(1H，s)，8.78(1H，s)，8.60(1H，d)，8.39(1H，s)，8.10(1H，s)，7.91-7.89(2H，m)，7.85-7.83(1H，m)，3.91(4H，m)，1.26-1.25(6H，d)ppm

MS(ESI)：m/z＝311.2(MH⁺)

Example 3.71: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-urea (71)

Melting point: 297 + 298 deg.C

¹H-NMR(600MHz，DMSO-d₆) δ＝10.41(1H，s)，10.08(1H，s)，8.91(1H，s)，8.78(1H，s)，8.10(1H，m)，7.98-7.87(4H，m)，3.29(2H，m)，1.61-1.56(2H，m)，1.38-1.35(4H，m)，0.93-0.94(3H，t)ppm

MS(ESI)：m/z＝421.1(MH⁺)

Example 3.72: 1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (72)

Melting point: 297 + 298 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.42(1H，s)，10.06(1H，s)，8.80(2H，m)，8.10(1H，m)，7.98-7.88(4H，m)，3.29(2H，s)，1.58-1.56(2H，m)，1.41-1.37(2H，m)，0.96-0.93(3H，m)ppm

MS(ESI)：m/z＝405.1，407.8(MH⁺)

Example 3.73: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-urea (73)

Melting point: 295 ℃ and 296 DEG C

¹H-NMR(600MHz，DMSO-d₆) δ＝10.44(1H，s)，10.06(1H，s)，8.85-8.80(2H，m)，8.13(1H，s)，7.97-7.88(4H，m)，3.28-3.24(2H，m)，1.62-1.56(2H，m)，0.95-0.91(3H，t)ppm

MS(ESI)：m/z＝391.2，392.9(MH⁺)

Example 3.74: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-urea (74)

Melting point: 295 ℃ and 296 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.44(1H，s)，10.07(1H，s)，8.86(1H，m)，8.78(1H，s)，8.18(1H，m)，7.97-7.90(4H，m)，3.35-3.30(2H，m)，1.23-1.18(3H，)ppm

MS(ESI)：m/z＝377.1(MH⁺)

Example 3.75: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-heptyl-urea (75)

Melting point: 289 Ampelopsis Grossdentata 291 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.41(1H，s)，10.08(1H，s)，8.93(1H，s)，8.77(1H，s)，8.08(1H，m)，7.96(1H，m)，7.93-7.9(1H，m)，7.86(2H，m)，3.28(2H，m)，1.60-1.55(2H，m)，1.40-1.27(8H、m)，0.83-0.81(3H，t)ppm

MS(ESI)：m/z＝447.1(MH⁺)

Example 3.76: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (76)

Melting point: 298 ℃ C. 300 ℃ C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.44(1H，s)，9.96(1H，s)，8.87(1H，s)，8.54(1H，s)，8.05(1H，m)，7.98(1H，m)，7.93(1H，m)，7.88(2H，m)，3.95-3.91(1H，m)，1.26-1.25(6H，d)ppm

MS(ESI)：m/z＝391.1(MH⁺)

Example 3.77: 1-tert-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (77)

Melting point: 292 plus 295 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.45(1H，s)，9.85(1H，s)，8.86(1H，s)，8.67(1H，s)，7.98-7.96(1H，m)，7.92-7.90(2H，m)，7.86(2H，s)，1.42(9H，m)ppm

MS(ESI)：m/z＝405.1(MH⁺)

Example 3.78: 1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (78)

Melting point: 283 ℃ 286 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.45(1H，s)，9.99(1H，s)，8.87(1H，s)，8.67(1H，m)，7.98-7.97(2H，m)，7.92-7.91(2H，m)，7.86(1H，s)，3.87-3.83(1H，m)，1.92-1.88(2H，m)，1.68-1.50(10H，m)ppm

MS(ESI)：m/z＝445.1(MH⁺)

Example 3.79: 1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (79)

Melting point: 258 ℃ and 260 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.44(1H，s)，9.97(1H，s)，8.88(1H，s)，8.67(1H，m)，7.98-7.91(3H，m)，7.85(2H，s)，3.89-3.87(1H，m)，1.89-1.84(2H，m)，1.73-1.55(12H，m)ppm

MS(ESI)：m/z＝459.4(MH⁺)

Example 3.80: 1-cyclobutyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (80)

Melting point: 277 heat treatment at 280 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.74-11.73(1H，d)，11.25(1H，s)，10.46(1H，s)，8.79(1H，s)，8.17(1H，s)，7.99-7.98(2H，m)，7.92(2H，s)，4.73-4.67(1H，m)，2.44-2.40(2H，m)，2.25-2.20(2H，m)，1.84-1.75(2H，m)ppm

MS(ES I)：m/z＝418.9(MH⁺)

Example 3.81: 1-cyclopentyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (81)

Melting point: 295 ℃ and 296 DEG C

¹H-NMR(600MHz，DMSO-d₆) δ＝10.44(1H，s)，9.96(1H，s)，8.89(1H，s)，8.60(1H，m)，7.99-7.97(2H，m)，7.92-7.91(1H、m)，7.87(2H，s)，4.10-4.07(1H，m)，1.95-1.92(2H，m)，1.74-1.73(2H，m)，1.62-1.56(4H，m)ppm

MS(ESI)：m/z＝417.1(MH⁺)

Example 3.82: 1- [7- (3-chloro-4-hydroxy-5-methoxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (82)

¹H-NMR(600MHz，DMSO-d₆) δ＝9.92(1H，s)，9.68(1H，s)，8.88(1H，s)，8.51(1H，s)，8.01-7.92(3H，m)，7.44(1H，d)，7.38(1H，d)，3.97(3H，s)，3.94-3.91(1H，m)，1.25(6H，d)ppm

MS(ESI)：m/z＝387.3(MH⁺)

Example 3.83: 1-cyclopropyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (83)

Melting point: 260 ℃ to 262 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.59(1H，d)，11.31(1H，s)，10.50(1H，s)，8.78(1H，s)，8.16(1H，s)，7.98(2H，s)，7.93(2H，s)，3.25-3.20(1H，m)，0.91-0.90(4H，m)ppm

MS(ESI)：m/z＝405.2(MH⁺)

Example 3.84: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -urea (84)

Melting point: 271 plus 274 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.42(1H，s)，10.10(1H，s)，8.86(1H，s)，8.79(1H，s)，8.13(1H，s)，7.98(1H，m)，7.94-7.93(1H，m)，7.87(2H，s)，7.28-7.17(5H，m)，3.31(2H，s)，2.70-2.68(2H，t)，1.91-1.89(2H，m)ppm

MS(ESI)：m/z＝467.3(MH⁺)

Example 3.85: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-urea (85)

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.45(1H，s)，10.16(1H，s)，9.00(1H，s)，8.70(1H，s)，7.94-7.91(2H，m)，7.82(2H，s)，7.70(1H，s)，7.32-7.36(4H，m)，7.21(1H，t)，3.63-3.61(2H，m)，2.91-2.89(2H，t)ppm

MS(ESI)：m/z＝453.1，455.9(MH⁺)

Example 3.86: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenyl-urea (86)

Melting point: more than 300 DEG C

¹H-NMR(600MHz，DMSO-d₆) δ＝10.96(1H，s)，10.45(1H，s)，10.37(1H，s)，8.95(1H，s)，8.26(1H，m)，8.03-8.02(2H，m)，7.98-7.95(2H，m)，7.73-7.71(2H，d)，7.4-7.37(2H，t)，7.10-7.09(1H，t)ppm

MS(ESI)：m/z＝425.1，427.2(MH⁺)

Example 3.87: 1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (87)

Melting point: 226 ℃ C. (227 ℃ C.)

¹H-NMR(600MHz，DMSO-d₆) δ＝11.71(1H，t)，11.23(1H，s)，10.49(1H，s)，8.79(1H，s)，8.16(1H，s)，7.99(2H，s)，7.88(2H，s)，3.74-3.71(2H，m)，1.75-1.70(2H，m)，1.47-1.43(2H，m)，0.99-0.97(3H，t)ppm

MS(ES I)：m/z＝421.2，425.3(MH⁺)

Example 3.88: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-thiourea (88)

Melting point: 237 ℃ C. -

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.65-11.63(1H，t)，11.21(1H，s)，10.47(1H，s)，8.78(1H，s)，8.27(1H，s)，7.99(2H，s)，7.90(2H，s)，3.79-3.74(2H，m)，1.32-1.30(3H，t)ppm

MS(ESI)：m/z＝393.1，395.2(MH⁺)

Example 3.89: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-thiourea (89)

Melting point: 237 plus 239 DEG C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.69-11.67(1H，t)，11.23(1H，s)，10.48(1H，s)，8.79(1H，s)，8.2(1H，s)，7.99(2H，m)，7.88(2H，s)，3.71-3.68(2H，m)，1.78-1.74(2H，m)，1.00-0.98(3H，t)ppm

MS(ES I)：m/z＝407.1，409.3(MH⁺)

Example 3.90: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-thiourea (90)

Melting point: 237 ℃ C. -

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.72-11.70(1H，t)，11.24(1H，s)，10.49(1H，s)，8.78(1H，s)，8.13(1H，s)，8.00(2H，m)，7.87(2H，s)，3.73-3.70(2H，m)，1.76-1.72(2H，m)，1.44-1.40(4H，m)，0.95-0.92(3H，t)ppm

MS(ESI)：m/z＝435.2(MH⁺)

Example 3.91: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-thiourea (91)

Melting point: 276 ℃ C

¹H-NMR(600 MHz，DMSO-d₆)δ＝11.60-11.59(1H，d)，11.18(1H，s)，10.46(1H，s)，8.79(1H，s)，8.10(1H，s)，7.98(2H，s)，4.49-4.47(1H，m)，1.39-1.38(6H，d)ppm

MS(ESI)：m/z＝407.1(MH⁺)

Example 3.92: 1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (92)

Melting point: 281 ℃ C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.73-11.71(1H，d)，11.20(1H，s)，10.50(1H，s)，8.79(1H，s)，7.99-7.97(3H，m)，7.85(2H，s)，4.46-4.41(1H，m)，2.04-1.99(2H，m)，1.87-1.81(2H，m)，1.73-1.69(2H，m)，1.65-1.64(4H，m)，1.61-1.57(2H，m)ppm

MS(ESI)：m/z＝461.2(MH⁺])

Example 3.93: 1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (93)

Melting point: 288-289 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.82-11.81(1H，d)，11.2(1H，s)，10.5(1H，s)，8.78(1H，s)，7.99-7.95(3H，m)，7.85(2H，s)，4.52-4.48(1H，m)，2.01-1.95(2H，m)，1.87-1.83(2H，m)，1.77-1.73(2H，m)，1.67-1.61(8H，m)ppm

MS(ESI)：m/z＝475.5(MH⁺)

Example 3.94: 1-benzyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (94)

Melting point: 275 ℃ C. 277 ℃ C

¹H-NMR(600 MHz，DMSO-d₆) δ＝12.19-12.18(1H，t)，11.39(1H，s)，10.50(1H，s)，8.80(1H，s)，8.05(1H，s)，7.99(2H，s)，7.83(2H，s)，7.48-7.47(2H，m)，7.41-7.38(2H，m)，7.32-7.31(1H，m)，4.98-4.97(2H，d)ppm

MS(ES I)：m/z＝455.2(MH⁺)

Example 3.95: 1- [7- (3-chloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (95)

Melting point: 275-277

¹H-NMR(600 MHz，DMSO-d₆) δ＝10.50(1H，s)，9.95(1H，s)，8.84(1H，s)，8.57(1H，m)，7.98-7.95(2H，m)，7.89-7.87(1H，m)，7.85-7.84(1H，m)，7.68-7.66(1H，m)，7.12-7.11(1H，d)，3.94-3.91(1H，m)，1.25-1.24(6H，m)ppm

MS(ESI)：m/z＝357.2(MH⁺)

Example 3.96: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -thiourea (96)

Melting point: 248-250 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.72-11.7(1H，t)，11.26(1H、s)，10.50(1H、s)，8.79(1H，s)，8.17(1H，m)，7.99(2H，m)，7.87(2H，s)，7.28-7.24(4H，m)，7.16-7.14(1H，m)，3.77-3.73(2H，m)，

2.75-2.73(2H，m)，2.09-2.07(2H，m)ppm

MS(ESI)：m/z＝481.2，483.4(MH⁺)

Example 3.97: 1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-thiourea (97)

Melting point: 282 Dill 285 deg.C

¹H-NMR(600 MHz，DMSO-d₆) δ＝11.61-11.58(1H，t)，11.29(1H，s)，10.53(1H，s)，8.76(1H，s)，7.97(2H，m)，7.83(2H，s)，7.68(1H，m)，7.40-7.39(2H，m)，7.33-7.29(2H，m)，7.2-7.17(1H，m)，4.07-4.04(2H，m)，3.06-3.04(2H，t)ppm

MS(ES I)：m/z＝469.1(MH⁺)

Biological Effect of the Compounds according to the invention

Example 4 antiproliferative Effect in different tumor cell lines

Determination of the antiproliferative action of the compounds of general formula I according to the invention Using the proliferation test

a) The Alamalan test (Page et al, int. J. Oncology 1993, 3, 473)

b) XTT test (Scuderio et al, Cancer Res.1988, 48, 4827).

The cell lines used were the KB/HeLa cell line (cervix), the SKOV-3 cell line (ovary), the NCI-H460 cell line (lung), the PC3 cell line (prostate), the HCT-116 (colon), the MDA-MB468 cell line (breast), the A549 cell line (lung), the U87MG cell line (glioma), the L363 cell line (leukemia), the TMM cell line (leukemia), the RKOp27 cell line (colon), the RS4, 11 cell line (leukemia), the HSB-2 cell line (leukemia), the NALM-6 cell line (leukemia), the MOLT-3 cell line (leukemia), the MOLT-16 cell line (leukemia), the MCF-7 cell line (breast), the MDA-MBA435 cell line (breast) and the LnCap cell line (prostate).

The cytotoxic and growth inhibitory activity of the compounds according to the invention is shown in tables 1a and 1 b. The results show that the mentioned substances are highly effective in inhibiting the proliferation of selected tumor cell lines.

TABLE 1a

Proliferation assay, EC50 in [ mu.M ]

TABLE 1b

Proliferation assay, EC50 in [ mu.M ]

Vbb RS4，11 HSB-2 NALM- MOLT- MOLT- KB- MCF-7 MDA- LNCaP

6 3 16 HeLa MB435

17 0.037 0.037 0.054 0.036 0.056 0.037 0.032 0.018 0.040

TABLE 1a/1 b: growth inhibition of tumor cell lines by substances according to the invention in a proliferation assay

Example 5 antiproliferative Effect in drug-resistant tumor cell lines

To further characterize this, the substances according to the invention are determined in drug-resistant tumor cell lines in comparison with non-drug-resistant wild-type tumor cell lines.

The cell lines tested were the a2780 cell line (ovary), the cisplatin-resistant a2780 cell line (ovary), the L1210 cell line (leukemia), the vincristine-resistant L1210 cell line (leukemia), the MESSA cell line (uterus), the doxorubicin-resistant MESSA Dx5 cell line (uterus), the NCIH69 cell line (lung), and the multi-drug resistant NCIH69AR cell line (lung).

The results are summarized in table 3 below:

proliferation assay, EC50 cis-platin in [ mu.M ]

Table 3: inhibition of non-drug resistant and drug resistant tumor cell lines by quinoxaline in XTT proliferation assays.

The quinoxalines of formula I according to the invention show a highly potent inhibitory effect on all cell lines tested.

Claims

1. Quinoxaline derivatives of the general formula I and their physiologically acceptable salts, hydrates, solvates

Formula I

Wherein

X is: oxygen or sulfur;

R₁the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) the cyano group(s),

(iv) the halogen(s) are selected from the group consisting of,

R₂/R₃the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

R₄the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted cycloalkyl group,

(iv) an unsubstituted or substituted heterocyclic group,

(v) an unsubstituted or substituted aryl group, or a substituted aryl group,

(vi) an unsubstituted or substituted heteroaryl group,

(vii) an unsubstituted or substituted alkylaryl group,

(viii) unsubstituted or substituted alkylheteroaryl,

and

R₅-R₈the method comprises the following steps:

(i) the presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted aryl group, or a substituted aryl group,

(iv) an unsubstituted or substituted heteroaryl group,

(v) the halogen(s) are selected from the group consisting of,

(vi) the cyano group(s),

(vii) a hydroxyl group(s),

(viii)(C₁-C₁₂) -an alkoxy group,

(ix) an amino group, a carboxyl group,

(x) Carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl,

(xi) Alkoxycarbonylamino, alkoxycarbonylaminoalkyl, and

with the proviso that the substituent R₅-R₈At least 1 of which is unsubstitutedOr a substituted aryl or heteroaryl residue,

and wherein the substituents are selected from F, Cl, Br, I, CN, CF₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂NH-CO-alkyl, NH-CO-aryl, NH-CO-heteroaryl, NH-SO₂-alkyl, NH-SO₂Aryl, NH-SO₂Heteroaryl, NH-CO-NH-alkyl, NH-CO-NH-aryl, NH-CO-NH-heteroaryl, NH-C (O) O-alkyl, NH-C (O) O-aryl, NH-C (O) O-heteroaryl, NO₂SH, S-alkyl, OH, OCF₃O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, O-CO-heteroaryl, O-C (O) O-alkyl, O-C (O) O-aryl, O-C (O) O-heteroaryl, O-CO-NH-alkyl, O-CO-N (alkyl)₂O-CO-NH-aryl, O-CO-NH-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Aryl, OSO₂Heteroaryl, OP (O) (OH)₂alkyl-P (O) (OH)₂CHO、CO₂H. C (O) O-alkyl, C (O) O-aryl, C (O) O-heteroaryl, CO-alkyl, CO-aryl, CO-heteroaryl, SO₃H、SO₂-NH₂、SO₂-NH-alkyl, SO₂-NH-aryl, SO₂-NH-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the residues "alkyl", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" may also be substituted,

wherein the compounds of general formula (I) and their salts, hydrates or solvates may exist in the form of their racemates, enantiomers and/or diastereomers, or in the form of mixtures of enantiomers and/or diastereomers, or in the form of their tautomers and polymorphs.

2. Quinoxaline derivatives of the general formula I according to claim 1, wherein

The substituents X are independently oxygen or sulfur;

substituent R₁Independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -alkyl radical，

Substituent R₂/R₃Independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

substituent R₄Independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) unsubstituted or substituted (C)₃-C₈) -a cycloalkyl group,

(iv) an unsubstituted or substituted piperidinyl group,

(v) unsubstituted or substituted phenyl, naphthyl,

(vi) unsubstituted or substituted pyridyl, isoxazolyl, thienyl,

(vii) an unsubstituted or substituted benzyl group, or a substituted benzyl group,

substituent R₅、R₇、R₈Independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

and is

Substituent R₆Is that

(i) An unsubstituted or substituted phenyl group, which is substituted,

and wherein the substituents are selected from F, Cl, Br, I, CN, CF₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂NH-CO-alkyl, NH-CO-aryl, NH-CO-heteroaryl, NH-SO₂-alkyl, NH-SO₂Aryl, NH-SO₂Heteroaryl, NH-CO-NH-alkyl, NH-CO-NH-aryl, NH-CO-NH-heteroaryl, NH-C (O) O-alkyl, NH-C (O) O-aryl, NH-C (O) O-heteroaryl, NO₂SH, S-alkyl, OH, OCF₃O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, O-CO-heteroaryl, O-C (O) O-alkyl, O-C (O) O-aryl, O-C (O) O-heteroaryl, O-CO-NH-alkyl, O-CO-N (alkyl)₂O-CO-NH-aryl, O-CO-NH-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂-an aryl group,OSO₂Heteroaryl, OP (O) (OH)₂alkyl-P (O) (OH)₂CHO、CO₂H. C (O) O-alkyl, C (O) O-aryl, C (O) O-heteroaryl, CO-alkyl, CO-aryl, CO-heteroaryl, SO₃H、SO₂-NH₂、SO₂-NH-alkyl, SO₂-NH-aryl, SO₂-NH-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the residues "alkyl", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" may also be substituted.

3. Quinoxaline derivatives of the general formula I according to claim 1, wherein

The substituents X are independently oxygen or sulfur;

R₁independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) the cyano group(s),

(iv) the halogen(s) are selected from the group consisting of,

R₂/R₃independently is

(i) Hydrogen, hydrogen,

(ii) Unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

R₄independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted cycloalkyl group,

(iv) an unsubstituted or substituted heterocyclic group,

(v) an unsubstituted or substituted aryl group, or a substituted aryl group,

(vi) an unsubstituted or substituted heteroaryl group,

(vii) an unsubstituted or substituted alkylaryl group,

(viii) unsubstituted or substituted alkylheteroaryl,

R₅、R₇、R₈independently is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted (C)₁-C₁₂) -an alkyl group,

(iii) an unsubstituted or substituted aryl group, or a substituted aryl group,

(iv) an unsubstituted or substituted heteroaryl group,

(v) the halogen(s) are selected from the group consisting of,

(vi) the cyano group(s),

(vii) a hydroxyl group(s),

(viii)(C₁-C₁₂) -an alkoxy group,

(ix) an amino group, a carboxyl group,

(x) Carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl,

(xi) Alkoxycarbonylamino, alkoxycarbonylaminoalkyl,

wherein the substituents are selected from F, Cl, Br, I, CN, CF₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂NH-CO-alkyl, NH-CO-aryl, NH-CO-heteroaryl, NH-SO₂-alkyl, NH-SO₂Aryl, NH-SO₂Heteroaryl, NH-CO-NH-alkyl, NH-CO-NH-aryl, NH-CO-NH-heteroaryl, NH-C (O) O-alkyl, NH-C (O) O-aryl, NH-C (O) O-heteroaryl, NO₂SH, S-alkyl, OH, OCF₃O-alkyl, O-aryl, O-CO-alkyl, O-CO-aryl, O-CO-heteroaryl, O-C (O) O-alkyl, O-C (O) O-aryl, O-C (O) O-heteroaryl, O-CO-NH-alkyl, O-CO-N (alkyl)₂O-CO-NH-aryl, O-CO-NH-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Aryl, OSO₂Heteroaryl, OP (O) (OH)₂alkyl-P (O) (OH)₂CHO、CO₂H. C (O) O-alkyl, C (O) O-aryl, C (O) O-heteroaryl, CO-alkyl, CO-aryl, CO-heteroaryl, SO₃H、SO₂-NH₂、SO₂-NH-alkyl, SO₂-NH-aryl, SO₂-NH-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the residues "alkyl", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" may also be substituted,

and is

R₆Independently is

(i) An unsubstituted or substituted aryl group, or a substituted aryl group,

(ii) an unsubstituted or substituted heteroaryl group,

wherein the substituents are selected from halogen, (C)₁-C₁₂) Alkyl, hydroxy, (C)₁-C₁₂) -alkoxy groups.

4. Quinoxaline derivatives of the general formula I according to any of claims 1 to 3, selected from:

1-cyclopentyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 1)

1-cyclohexyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 2)

1-cyclohexyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (Compound 3)

1- [7- (3, 4-Dimethoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (Compound 4)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-phenylurea (Compound 5)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3- [1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl ] urea (Compound 6)

1-benzyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 7)

1-cyclopentyl-3- [7- (3, 4-dimethoxyphenyl) quinoxalin-2-yl ] urea (Compound 8)

1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 9)

1-tert-butyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 10)

1- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (Compound 11)

1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 12)

1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (compound 13)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-phenylurea (Compound 14)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-thiophen-2-ylurea (Compound 15)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-methylurea (Compound 16)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylurea (Compound 17)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 18)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 19)

1-cyclohexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 20)

1-cyclohexyl-3- [7- (3, 5-dichloro-4-hydroxyphenyl) quinoxalin-2-yl ] thiourea (compound 21)

1-Ethyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (Compound 22)

1-cyclopropyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 23)

1-cyclopentyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 24)

1-tert-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 25)

1-dodecyl-3- (7-phenylquinoxalin-2-yl) urea (Compound 26)

1- (3-chloro-2-methylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (Compound 27)

1- (3, 4-dimethylphenyl) -3- (7-phenylquinoxalin-2-yl) urea (Compound 28)

1-allyl-3- (7-phenylquinoxalin-2-yl) urea (Compound 29)

1-cyclopentyl-3- (7-phenylquinoxalin-2-yl) urea (compound 30)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isopropylthiourea (Compound 31)

1-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 32)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pentylurea (Compound 33)

1-cyclobutyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 34)

1-hexyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 35)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-propylurea (Compound 36)

1-dodecyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 37)

1- (3-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 38)

1- (3-Acetylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 39)

1- (3, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 40)

1-allyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 41)

1-Cyclooctyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 42)

1- (2, 4-dimethylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 43)

1-Cyclooctyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 44)

1-adamantan-1-yl-3- (7-phenylquinoxalin-2-yl) urea (Compound 45)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-p-methylphenyl urea (compound 46)

1- (3, 4-dichlorophenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 47)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (4-methoxyphenyl) urea (compound 48)

1-adamantan-1-yl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 49)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-naphthalen-2-ylurea (Compound 50)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- (1, 1, 3, 3-tetramethylbutyl) urea (Compound 51)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-pyridin-3-ylurea (Compound 52)

1- ((R) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 53)

1- ((S) -1, 2-dimethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 54)

1- (5-chloro-2-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 55)

1- ((S) -2-phenylcyclopropyl) -3- (7-phenylquinoxalin-2-yl) urea (Compound 56)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3- ((S) -2-phenylcyclopropyl) urea (Compound 57)

1- (2-chloro-6-methylphenyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 58)

1-allyl-3- [7- (4-hydroxy-3-methoxyphenyl) quinoxalin-2-yl ] urea (Compound 59)

1- (3, 5-Dimethylisoxazol-4-yl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 60)

1-sec-butyl-3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 61)

1-Ethyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 62)

1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 63)

1-isopropyl-3- [7- (4-methoxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] thiourea (compound 64)

1- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] -3-isobutylurea (Compound 65)

1- (1-ethylpropyl) -3- [7- (4-hydroxy-3, 5-dimethylphenyl) quinoxalin-2-yl ] urea (Compound 66)

1- (2, 2-dimethyl-propyl) -3- [7- (4-hydroxy-3, 5-dimethyl-phenyl) -quinoxalin-2-yl ] -urea (Compound 67)

1- [7- (4-amino-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (Compound 68)

1- [7- (4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (Compound 69)

1-isopropyl-3- [7- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-2-yl ] -urea (Compound 70)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-urea (compound 71)

1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 72)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-propyl-urea (Compound 73)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-urea (compound 74)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-heptyl-urea (Compound 75)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (Compound 76)

1-tert-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (Compound 77)

1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 78)

1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 79)

1-cyclobutyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 80)

1-cyclopentyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 81)

1- [7- (3-chloro-4-hydroxy-5-methoxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (Compound 82)

1-cyclopropyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 83)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -urea (compound 84)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-urea (Compound 85)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenyl-urea (compound 86)

1-butyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 87)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-ethyl-thiourea (compound 88)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl 1-3-propyl-thiourea (Compound 89)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-pentyl-thiourea (compound 90)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-thiourea (compound 91)

1-cycloheptyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 92)

1-Cyclooctyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 93)

1-benzyl-3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 94)

1- [7- (3-chloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-isopropyl-urea (Compound 95)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-phenyl-propyl) -thiourea (compound 96)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3-phenethyl-thiourea (compound 97)

1- [2- (4-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 98)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (3-morpholin-4-yl-propyl) -thiourea (compound 99)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -thiourea (compound 100)

1- (2-cyclohex-1-enyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 101)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (2-thiophen-2-yl-ethyl) -urea (compound 102)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-methoxy-phenyl) -ethyl ] -thiourea (compound 103)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-ethyl-phenyl) -ethyl ] -urea (compound 104)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 5-dimethoxy-phenyl) -ethyl ] -urea (compound 105)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dichloro-phenyl) -ethyl ] -urea (compound 106)

1- [2- (3-bromo-4-methoxy-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 107)

1- (2-Biphenyl-4-yl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (Compound 108)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 3-dimethoxy-phenyl) -ethyl ] -urea (compound 109)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2-fluoro-phenyl) -ethyl ] -urea (compound 110)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 4-dichloro-phenyl) -ethyl ] -urea (compound 111)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-fluoro-phenyl) -ethyl ] -urea (compound 112)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -urea (compound 113)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-methoxy-phenyl) -ethyl ] -urea (compound 114)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (2, 5-dimethoxy-phenyl) -ethyl ] -urea (compound 115)

1- [2- (4-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 116)

1- [2- (3-chloro-phenyl) -ethyl ] -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (Compound 117)

1- (2-cyclopentyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 118)

1- (2-cyclohexyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -urea (compound 119)

1- (2-cyclohexyl-ethyl) -3- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -thiourea (compound 120)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- [2- (4-hydroxy-phenyl) -ethyl ] -thiourea (compound 121)

1- [7- (3, 5-dichloro-4-hydroxy-phenyl) -quinoxalin-2-yl ] -3- (2-pyridin-3-yl-ethyl) -thiourea (compound 122)

5. A pharmaceutical composition comprising a pharmacologically active amount of at least 1 compound according to any one of claims 1 to 4.

6. A pharmaceutical composition according to claim 5, wherein the composition comprises at least 1 additional pharmacologically active substance.

7. The pharmaceutical composition according to claim 5 or 6, wherein the composition further comprises a pharmaceutically acceptable carrier and/or adjuvant.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the additional pharmacologically active substance is selected from the group consisting of:

asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levoasparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, altretamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thalidomide, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, azacitidine, cladribine, busulfan, diethylstilbestrol, 2 '-difluorodeoxyribose, 2' -difluorooxacine, Docetaxel, erythroxinyladenine, ethinyl estradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, flumesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, sahetin, avastin, Ebitesia, sorafenib, glitazone, Icelisan, rapamycin, actinomycin D, sunitinib (sulitinib).

9. A compound according to any one of claims 1 to 4 for use as a medicament.

10. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a neoplastic disorder.

11. Use of a compound according to any one of claims 1 to 4 and 10 for the preparation of a medicament for the treatment of neoplastic disorders resistant to active compounds.

12. Use of a compound according to any one of claims 1 to 4 and 10 in the manufacture of a medicament for the treatment of metastatic cancer.

13. Use according to any one of claims 10 to 12, wherein the medicament additionally comprises at least 1 further pharmacologically active substance.

14. Use according to claim 13, wherein the other pharmacologically active substance is selected from the group consisting of:

15. Medicament for the treatment of tumor disorders, comprising at least 1 quinoxaline derivative according to any one of claims 1 to 4.

16. The medicament according to claim 15, which comprises a quinoxaline derivative in combination with at least 1 further pharmaceutically active compound and/or a pharmaceutically acceptable carrier and/or auxiliary agent.

17. Process for the preparation of a medicament according to claim 15 or 16, characterized in that 1 or more quinoxaline derivatives according to any one of claims 1 to 3 are processed into a pharmaceutical preparation or converted into a therapeutically useful form, which form contains acceptable carriers and/or auxiliaries.