HK1093731B

HK1093731B - Sulfoximine-substituted pyrimidines for use as cdk and/or vegf inhibitors, the production thereof and their use as drugs

Info

Publication number: HK1093731B
Application number: HK06114263.5A
Authority: HK
Inventors: 乌尔里希．吕金; 马丁．克吕格尔; 罗尔夫．乔特莱特; 格哈德．西迈斯特
Original assignee: 拜耳知识産权有限责任公司
Priority date: 2003-10-16
Filing date: 2004-10-12
Publication date: 2012-02-10

Description

Aminosulfoxide substituted pyrimidine compounds as CDK and/or VEGF inhibitors, method for the production thereof and use thereof as medicaments

Technical Field

The present invention relates to amino sulfoxide (sulfoximine) substituted pyrimidine derivatives, a process for their preparation and their use as medicaments for the treatment of various diseases.

Background

Cyclin-dependent kinases (CDKs) are a class of enzymes that play an important role in regulating the cell cycle and thus may serve as particularly advantageous targets for the development of small inhibitory molecules. Selective inhibitors of CDKs are useful for treating cancer or other diseases caused by cell proliferative disorders.

Receptor tyrosine kinases and their ligands that specifically regulate endothelial cell function play a crucial role in physiological and pathological angiogenesis. The Vascular Endothelial Growth Factor (VEGF)/VEGF receptor system is of particular importance here. Increased expression of angiogenic growth factors and their receptors has been found in pathological conditions accompanied by increased neovascularization, such as tumor diseases. Inhibitors of the VEGF/VEGF receptor system inhibit the formation of vascular systems in tumors, thereby separating the tumor from oxygen and nutrient supply and thus inhibiting tumor growth.

Pyrimidine compounds and their analogues have been described as active ingredients, for example 2-anilino-pyrimidine compounds as fungicides (DE 4029650) or substituted pyrimidine derivatives are useful for the treatment of neurological or neurodegenerative diseases (WO 99/19305). As CDK inhibitors, various pyrimidine derivatives have been described, such as di (anilino) pyrimidine derivatives (WO 00/12486), 2-amino-4-substituted pyrimidine compounds (WO 01/14375), purine compounds (WO99/02162), 5-cyano-pyrimidine compounds (WO 02/04429), anilino-pyrimidine compounds (WO 00/12486) and 2-hydroxy-3-N, N-dimethylaminopropoxy-pyrimidine compounds (WO 00/39101).

In particular, in WO02/096888 and WO 03/7076437 disclose pyrimidine derivatives that exhibit inhibitory effects on CDKs. Compounds containing a phenylsulfamoyl group are known to act as human carbohydrases (particularly carbohydrase-2) and as diuretics, for example for the treatment of glaucoma. The nitrogen and oxygen atoms in the sulfamoyl group are bonded to Zn in the active center of carbodehydratase-2 through a hydrogen bridge²⁺Ions and the amino acid Thr 199 and thereby blocking their enzymatic action (a.casini, f.abbate, a.scozzafava, c.t.supuran, bioorganic.med.chem l.2003, 1, 2759.3). The clinical utility of CDK inhibitors containing phenylsulfamoyl groups is limited by the possible inhibitory effects on carbon dehydratase and the side effects resulting therefrom.

It is known that amino sulfoxides can be used as active ingredients, for example sulfonimimidoyl modified triazole compounds as fungicides (h.kawanishi, h.morimoto, t.nakano, t.watanabe, k.oda, k.tsujihara, Heterocycles 1998, 49, 181) or arylalkylamino sulfoxides as herbicides and insecticides (Shell International Research, ger.p.2129678).

Disclosure of Invention

The object of the present invention is to provide compounds with better pharmacological properties than known CDK inhibitors, in particular a reduced inhibition of carbodehydratase-2.

It was found that the compounds of the general formula (I) and isomers, diastereomers, enantiomers and/or salts thereof no longer inhibit carbodehydratases, wherein they simultaneously inhibit cyclin-dependent kinases and VEGF receptor tyrosine kinases in the nanomolar range and thus enable the proliferation of known tumor cells and/or tumor angiogenesis,

wherein:

q represents the following group:

D. e, G, L, M and T independently of one another represent carbon, oxygen, nitrogen or sulfur,

R¹represents hydrogen, halogen, C₁-C₆Alkyl, CF₃CN, nitro or represent the group-COR⁸or-O-C₁-C₆An alkyl group, a carboxyl group,

R²represents hydrogen or represents C which is optionally substituted identically or differently in one or more positions by₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₁₀Cycloalkyl, aryl or heteroaryl: hydroxy, halogen, C₁-C₆Alkoxy, amino, cyano, C₁-C₆Alkyl, -NH- (CH)₂)_n-C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl, -NHC₁-C₆Alkyl, -N (C)₁-C₆Alkyl radical)₂、C₁-C₆Alkanoyl, -CONR⁹R¹⁰、-COR⁸、C₁-C₆Alkyl OAc, carboxy, aryl, heteroaryl, - (CH)₂)_n-aryl, - (CH)₂)_n-heteroaryl, phenyl- (CH)₂)_n-R⁸、-(CH₂)_nPO₃(R⁸)₂or-R⁶or-NR⁹R¹⁰And the above-mentioned phenyl group, C₃-C₁₀Cycloalkyl, aryl, heteroaryl, - (CH)₂)_n-aryl and- (CH)₂)_nThe heteroaryl group itself may optionally be substituted, identically or differently, in one or more positions, by: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or a group-CF₃or-OCF₃，C₃-C₁₀Ring of cycloalkyl and C₁-C₁₀Alkyl may optionally be interrupted by one or more nitrogen, oxygen and/or sulphur atoms and/or by one or more-C (O) -groups in the ring and/or optionally comprising one or more possible double bonds in the ring,

x represents oxygen, sulphur or a group-NH-or-N (C)₁-C₃Alkyl) -, or

X and R²Together form C₃-C₁₀A cycloalkyl ring, which ring may optionally contain one or more heteroatoms and is optionally substituted, identically or differently in one or more positions, by hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen or radicals-NR⁹R¹⁰The substitution is carried out by the following steps,

R³represents hydrogen, hydroxy, halogen, CF₃、OCF₃Or represents a group-NR⁹R¹⁰Or represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkoxy or radicals-NR⁹R¹⁰Substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or C₁-C₆An alkoxy group,

m represents a number of 0 to 4,

R⁴represents hydrogen or represents the group-COR⁸、NO₂Trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), Triethylsilyl (TES) or-SO₂R⁷Or represents C substituted by₁-C₁₀Alkyl or C₃-C₁₀Cycloalkyl groups: hydroxy, halogen, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, C₃-C₁₀Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl or a group-CONR⁹R¹⁰、-COR⁸、-CF₃、-OCF₃or-NR⁹R¹⁰，

R⁵Represents optionally in one or more positions identically or differently substituted by hydroxy, C₁-C₆Alkoxy radical, C₃-C₁₀Cycloalkyl, halogen or the radical-NR⁹R¹⁰Substituted C₁-C₁₀Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₃-C₁₀Cycloalkyl radicals, or

R⁴And R⁵Together form C of the formula₅-C₁₀A cycloalkyl group,

v, W and Y each independently represent optionally in one or more positions identically or differently substituted by hydroxy, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy or-NR⁹R¹⁰substituted-CH₂-, in which C₁-C₁₀Alkyl or C₁-C₁₀Alkoxy is optionally substituted in one or more positions identically or differently by hydroxy, -NR⁹R¹⁰Or C₁-C₁₀Alkoxy substitution, and/or insertion in the ring of one or more-C (O) -groups and/or optionally containing in the ring one or more possible double bonds,

R⁶represents heteroaryl or C₃-C₁₀Cycloalkyl ring, which may optionally contain one or more heteroatoms and which is optionally substituted in one or more positions by hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen is substituted by the group consisting of,

R⁷represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkyl radical, C₁-C₆Alkoxy or Trimethylsilyl (TMS) or-NR⁹R¹⁰Substituted C₁-C₁₀An alkyl group or an aryl group, or a salt thereof,

R⁸represents hydrogen, C₁-C₆Alkyl, hydroxy, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, benzyloxy or-NR⁹R¹⁰，

R⁹And R¹⁰Each independently represents hydrogen or C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy-C₁-C₆Alkyl, dihydroxy-C₁-C₆Alkyl, phenyl, heteroaryl or a radical- (CH)₂)_nNR⁹R¹⁰、-CNHNH₂or-NR⁹R¹⁰Or is or

R⁹And R¹⁰Together form C₃-C₁₀A cycloalkyl ring, which ring optionally comprises one or more nitrogen, oxygen and/or sulfur atoms and/or has one or more-C (O) -groups inserted into the ring and/or optionally comprises one or more possible double bonds in the ring, and

n represents 1 to 6.

Alkyl is defined as a straight or branched chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is defined as a straight or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy.

Cycloalkyl is defined as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Heterocycloalkyl represents an alkyl ring containing from 3 to 12 carbon atoms, but may contain, in place of the carbon atoms, one or more identical or different heteroatoms, such as oxygen, sulfur or nitrogen. Heterocycloalkyl groups may be, for example: oxiranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, dioxolanyl, imidazolinyl, pyrazolinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, and the like.

A ring system which may optionally contain one or more possible double bonds in the ring is defined, for example, as cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, where double and single bonds may be attached.

Halogen is defined as fluorine, chlorine, bromine or iodine.

The alkenyl substituents are all straight-chain or branched and may be, for example, the following groups: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, ethynyl, prop-1-yn-1-yl, but-2-yn-1-yl, but-3-en-1-yl and allyl.

Aryl contains 6 to 12 carbon atoms, for example naphthyl, biphenyl and preferably phenyl.

Heteroaryl groups may also be benzo-fused. Examples of the 5-membered heteroaromatic compounds include thiophene, furan, oxazole, thiazole, imidazole, pyrazole, triazole, thia-4H-pyrazole and benzo-fused derivatives thereof; as the 6-membered heteroaromatic compounds, there may be mentioned pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo-fused derivatives thereof.

Isomers are defined as compounds having the same chemical formula but different chemical structures. Usually, a distinction is made between structural isomers (constitutive isomers) and stereoisomers.

The structural isomers have the same chemical formula but differ in the manner in which their atoms or groups of atoms are attached. They include functional, positional, tautomeric or valence isomers.

In principle, stereoisomers have the same structure (constitution) and therefore also the same chemical formula, but they differ by the spatial arrangement of the atoms.

Typically, configurational isomers and conformational isomers are distinct. Configurational isomers are stereoisomers that can be converted to another isomer by mere bond cleavage. They include enantiomers, diastereomers and E/Z (cis/trans) isomers.

Enantiomers are stereoisomers that appear as images and mirror images of each other but do not have any plane of symmetry. Not all stereoisomers of an enantiomer are referred to as diastereomers. The E/Z (cis/trans) isomer of the double bond is a special case.

A conformational isomer is a stereoisomer that can be converted to another isomer by rotation of a single bond.

To distinguish the various types of isomers from each other, see IUPAC rules, Section E (Pure appl. chem.45, 11-30, 1976).

Physiologically compatible salts of organic acids and inorganic bases are suitable salts if they contain acid groups, for example readily soluble alkali metal and alkaline earth metal salts, and also N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trimethylol-amino-methane, aminopropanediol, Sovak base and 1-amino-2, 3, 4-butanetriol.

If basic groups are included, physiologically compatible salts of organic and inorganic acids are suitable, for example hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, and the like.

The following compounds of general formula (I) and isomers, diastereomers, enantiomers and/or salts thereof are particularly effective, wherein:

q represents an aryl group, and Q represents an aryl group,

x represents oxygen, sulphur or a group-NH-or-N (C)₁-C₃Alkyl) -, or

X and R²Together form C₃-C₁₀A cycloalkyl ring, which ring may optionally contain one or more heteroatoms and is optionally substituted identically or differently in one or more positions by hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen or radicals-NR⁹R¹⁰The substitution is carried out by the following steps,

m represents a number of 0 to 4,

R⁴represents hydrogen or represents the group-COR⁸、NO₂Trimethylsilyl group (TMS), tert-butyl-dimethylsilyl group (TBDMS), tert-butyl-diphenylsilyl group (TBDPS), triethylsilyl groupAlkyl (TES) or-SO₂R⁷Or represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl or C₃-C₁₀Cycloalkyl groups: hydroxy, halogen, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, C₃-C₁₀Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl or a group-CONR⁹R¹⁰、-COR⁸、-CF₃、-OCF₃or-NR⁹R¹⁰，

R⁴And R⁵Together form C of the formula₅-C₁₀A cycloalkyl group,

R⁶represents heteroaryl or C₃-C₁₀Cycloalkyl ring, which may optionally contain one or more heteroatoms and which is optionally substituted identically or differently in one or more positions by hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen is substituted by the group consisting of,

n represents 1 to 6.

In addition, the following compounds of general formula (I) and isomers, diastereomers, enantiomers and/or salts thereof are particularly effective, wherein:

q represents a phenyl group, and Q represents a phenyl group,

R²represents hydrogen or represents C which is optionally substituted identically or differently in one or more positions by₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₁₀Cycloalkyl, aryl or heteroaryl: hydroxy, halogen, C₁-C₆Alkoxy, amino, cyano, C₁-C₆Alkyl, -NH- (CH)₂)_n-C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl, -NHC₁-C₆-alkyl, -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkanoyl, -CONR⁹R¹⁰、-COR⁸、C₁-C₆Alkyl OAc, carboxy, aryl, heteroaryl, - (CH)₂)_n-aryl, - (CH)₂)_n-heteroaryl, phenyl- (CH)₂)_n -R⁸、-(CH₂)_nPO₃(R⁸)₂or-R⁶or-NR⁹R¹⁰And the above-mentioned phenyl group, C₃-C₁₀Cycloalkyl, aryl, heteroaryl, - (CH)₂)_n-aryl and- (CH)₂)_nThe heteroaryl group itself may optionally be substituted, identically or differently, in one or more positions, by: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or a group-CF₃or-OCF₃，C₃-C₁₀Ring of cycloalkyl and C₁-C₁₀Alkyl may optionally be interrupted by one or more nitrogen, oxygen and/or sulphur atoms and/or by one or more-C (O) -groups in the ring and/or optionally comprising one or more possible double bonds in the ring,

x represents oxygen, sulphur or a group-NH-or-N (C)₁-C₃Alkyl) -, or

X and R²Together form C₃-C₁₀A cycloalkyl ring, which ring may optionally contain one or more heteroatoms and is optionally substituted at one or more positions by hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen or radicals-NR⁹R¹⁰The substitution is carried out by the following steps,

m represents a number of 0 to 2,

R⁴represents hydrogen or represents the group-COR⁸、NO₂Trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), Triethylsilyl (TES) or-SO₂R⁷Or represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl or C₃-C₁₀Cycloalkyl groups: hydroxy, halogen, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, C₃-C₁₀Cycloalkyl radical, C₁-C₆A hydroxyalkyl group,C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl or a group-CONR⁹R¹⁰、-COR⁸、-CF₃、-OCF₃or-NR⁹R¹⁰，

R⁴And R⁵Together form C of the formula₅-C₁₀A cycloalkyl group,

R⁶represents heteroaryl or C₃-C₁₀A cycloalkyl ring, which may optionally contain one or more heteroatoms and optionally in one or more positionsBy hydroxy groups, C, in the same or different positions₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen is substituted by the group consisting of,

n represents 1 to 6.

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen, halogen, CN, nitro or CF₃，

R²Represent optionally identical in one or more positionsOr C differently substituted by₁-C₁₀Alkyl radical, C₂-C₁₀Alkynyl, aryl or heteroaryl: hydroxy, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkynyl or radical-COR⁸，

X represents oxygen, sulphur or a group-NH-,

R³represents hydrogen, halogen, hydroxy or represents C optionally substituted in one or more positions by halogen or hydroxy₁-C₆Alkyl or C₁-C₆An alkoxy group,

m represents a number of 0 to 2,

R⁴represents hydrogen or represents the group NO₂、-COR⁸or-SO₂R⁷Or represents C optionally substituted in one or more positions, identically or differently, by halogen or hydroxy₁-C₁₀An alkyl group, a carboxyl group,

R⁵represents optionally in one or more positions identically or differently substituted by hydroxy or C₃-C₁₀Cycloalkyl-substituted C₁-C₁₀Alkyl or C₃-C₁₀Cycloalkyl radicals, or

R⁴And R⁵Together form C of the formula₅-C₁₀A cycloalkyl group,

v, W and Y each independently represent optionally in one or more positions identically or differently substituted by hydroxy, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy or-NR⁹R¹⁰substituted-CH₂-, in which C₁-C₁₀Alkyl or C₁-C₁₀Alkoxy groups optionally in one or more positionsBy hydroxy, -NR, or not⁹R¹⁰Or C₁-C₁₀Alkoxy substitution, and/or insertion in the ring of one or more-C (O) -groups and/or optionally containing in the ring one or more possible double bonds,

R⁷represents C optionally substituted in one or more positions, identically or differently, by Trimethylsilyl (TMS)₁-C₁₀An alkyl group or an aryl group, or a salt thereof,

R⁸represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₃-C₆Cycloalkyl, optionally substituted at one or more positions by C₁-C₆Alkyl radicals, and

n represents 1.

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen or a halogen, and is,

R²represents C optionally substituted in one or more positions, identically or differently, by₁- C₁₀Alkyl radical, C₂-C₁₀Alkynyl or aryl: hydroxy, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkynyl or radical-COR⁸，

X represents oxygen, sulphur or a group-NH-,

R³represents hydrogen, halogen or represents C optionally substituted in one or more positions by halogen₁-C₆Alkyl or C₁-C₆An alkoxy group,

m represents a number of 0 to 2,

R⁴represents hydrogen or represents the group NO₂、-COR⁸or-SO₂R⁷Or represents C₁-C₁₀An alkyl group, a carboxyl group,

R⁵represents optionally in one or more positions identically or differently substituted by hydroxy or C₃-C₁₀Cycloalkyl-substituted C₁-C₁₀Alkyl or C₃-C₁₀A cycloalkyl group,

R⁷represents C optionally substituted in one or more positions, identically or differently, by Trimethylsilyl (TMS)₁-C₁₀An alkyl group, a carboxyl group,

R⁸represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₃-C₆Cycloalkyl, optionally substituted at one or more positions by C₁-C₆An alkyl group.

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen or a halogen, and is,

R²represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl radical, C₂-C₁₀Alkynyl or aryl: hydroxy, halogen, methyl, methoxy, ethynyl or a group-COH or COCH₃，

X represents oxygen, sulphur or a group-NH-,

R³represents hydrogen, halogen, methyl, methoxy or-CF₃，

m represents a number of 0 to 2,

R⁴represents hydrogen, methyl, NO₂、-COOC₂H₅or-SO₂-C₂H₄-Si(CH₃)₃，

R⁵Representative nailAlkyl, ethyl, cyclopropyl, cyclopentyl, - (CH)₂) -cyclopropyl or hydroxyethyl.

The compounds according to the invention are capable of effectively inhibiting cyclin-dependent kinases, and on the basis of their action can be used, for example, against cancers, such as solid tumors and leukemias; autoimmune diseases such as psoriasis, alopecia, and multiple sclerosis; chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenosis, arteriosclerosis and restenosis; infectious diseases, for example diseases caused by unicellular parasites such as trypanosomes, toxoplasma or plasmodia, or diseases produced by fungi; kidney diseases, such as glomerulonephritis; chronic neurodegenerative diseases such as huntington's disease, amyotrophic lateral sclerosis, parkinson's disease, AIDS dementia and alzheimer's disease; acute neurodegenerative diseases, such as cerebral ischemia and neurotrauma; and viral infections such as giant cell infection, herpes, hepatitis b and c, and HIV disease.

Eukaryotic cell differentiation ensures the replication of the genome and the distribution by passage in daughter cells via a coordinated and regulated sequence of events. The cell cycle is divided into 4 successive phases: the G1 phase represents the time before DNA replication, during which cells grow and are sensitive to external stimuli. In phase S, the cell replicates its DNA, while in phase G2, it is ready to enter mitosis. In mitosis (M phase), replicated DNA segregates and cell differentiation is complete.

Cyclin-dependent kinases (CDKs) are a class of serine/threonine kinases, the members of which require the binding of cyclins (cycs) as regulatory subunits to activate them, driving the cell through the cell cycle. Different CDK/Cyc pairs are active in different phases of the cell cycle. CDK/Cyc pairs important for the basic function of the cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE, CDK2/CycA, CDK1/CycA and CDK 1/CycB. Some members of the CDK enzyme family have regulatory functions by affecting the activity of the cell cycle CKD described above, but no specific function may be associated with other members of the CDK enzyme family. As a member of the CDK enzyme family, CDK5 is characterized by its atypical cyclin-derived regulatory subunit (p35) and its activity is highest in the brain.

Entry into the cell cycle and passage through "checkpoints" mark the cells independently of further growth signals that begin to complete cell differentiation, and are controlled by the activity of the CDK4(6)/CycD and CDK2/CycE complexes. The essential substrate for these CDK complexes is the retinoblastoma protein (Rb), which is the product of the retinoblastoma inhibitor gene. Rb is a transcription co-repressor protein. For other properties, the mechanism is poorly understood. Rb binds to and inactivates a transcription factor of the E2F type and forms a transcription Repressor complex with Histone Deacetylase (HDAC) (Zhang, H.S. et al (2000) Exit from G1 and S Phase of the Cell Cycle is regulated by expression regulators Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.Cell 101, 79-89). Phosphorylation of Rb by CDK releases the bound E2F transcription factor and leads to transcriptional activation of the gene, the product of which is required for DNA synthesis and S phase progression. In addition, Rb phosphorylation breaks down the Rb-HDAC complex, thereby activating additional genes. Phosphorylation of Rb by CDK was treated as equivalent to exceeding the "limit". The activity of the CDK2/CycE and CDK2/CycA complexes is essential for progression from the S phase and its completion, e.g., CDK2/CycA produces phosphorylation once the cell enters the S phase, thereby shutting off the activity of transcription factors of the E2F type. After completion of DNA replication, CDK1 in complex with CycA or CycB controls entry into the cell and passage through G2 and M phases (fig. 1).

Depending on the unusual importance of the cell differentiation cycle, passage through the cell cycle is tightly regulated and controlled. The enzymes necessary for cell cycle progression must be activated at the correct time and switched off again once a corresponding period of time has passed. If DNA damage is detected, or DNA replication or spindle production is not yet complete, the corresponding control point (checkpoint) stops progression through the cell cycle.

The activity of CDKs is directly controlled by various mechanisms, such as cyclin synthesis and breakdown, CDK complexation with corresponding cyclins, phosphorylation and dephosphorylation of regulatory threonine and tyrosine groups, and binding of natural inhibitory proteins. Although the amount of CDK protein in proliferating cells is relatively constant, the amount of each cyclin fluctuates with the progression of the cell cycle. Thus, for example, CycD expression in early G1 phase is stimulated by growth factors, whereas CycE expression is induced beyond the "limit point" by activation of transcription factors of the E2F type. The cyclins themselves can be broken down by ubiquitin-mediated proteolysis. Activation of phosphorylation or inactivation of phosphorylation may modulate the activity of CDKs, for example, phosphorylate the CDK Activating Kinase (CAK) Thr160/161 of CDK1, whereas in contrast, enzymes of the Weel/Mytl family inactivate the kinase CDK1 by phosphorylating Thr14 and Tyr 15. These inactivated phosphorylations can in turn be destroyed by cdc25 phosphatase. The modulating effect of two natural CDK inhibitor proteins (CKIs), namely, the p21 gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19), on CDK/Cyc complex activity is very significant. Members of the p21 family bind to the cyclin complexes of CDKs 1, 2, 4, 6, but only inhibit the complex comprising CDK1 and CDK 2. Members of the p16 family are specific inhibitors of the CDK4 complex and CDK6 complex.

The plane of control point regulation is above the complex direct regulation of CDK activity. The control points allow the cells to follow each phase of the cell cycle that is ordered. The most important control points are at the transition from G1 to S and at the transition from G2 to M. The G1 control point ensures that the cell does not initiate any DNA synthesis unless it has the proper nutrients, properly interacts with other cells or substrates, and leaves the DNA intact. The G2/M control point ensures completion of DNA replication and the production of mitotic spindles before the cell enters mitosis. The G1 control point was activated by the gene product of the p53 tumor suppressor gene. Upon detection of a change in cellular metabolism or genomic integrity, p53 is activated and can trigger the cessation of cell cycle progression or apoptosis. In this case, p53 plays a decisive role in the transcriptional activation of the expression of the CDK inhibitor protein p 21. The second branch of the G1 control site involved activation of ATM and Chk1 kinase after DNA damage by UV light or ionizing radiation and thereby proteolytic cleavage of cdc25A phosphatase (Mailand, N. et al (2000). Rapid breakdown of Human cdc25A in Response to DNAdamage.science 288, 1425-. This results in a cell cycle shutdown because inhibitory phosphorylation of the CDK is not removed. After activation of the G2/M control point due to DNA damage, both mechanisms stop the progression of the cell cycle in a similar manner.

Loss of regulation of the cell cycle and loss of control point function are characteristic of tumor cells. In more than 90% of human tumor cells, the CDK-Rb signaling pathway is affected by mutations. These mutations ultimately lead to inactivation of Rb phosphorylation and include overexpression of D and E cyclins due to gene amplification or chromosomal shifts, inactivation of mutations or deletions of CDK inhibitors of the p16 type, and increased (p27) or decreased (CycD) proteolysis. The second set of genes affected by mutations in tumor cells encodes the composition of control points. Thus, p53, which is essential for the G1 and G2/M control points, is the gene (more than 50%) that most frequently mutates in human tumors. In tumor cells expressing p53 but without mutations, it is usually inactivated because of greatly increased proteolysis. In a similar manner, the genes for other proteins essential for the function of the control point are affected by mutations, such as ATM (inactivating mutation) or cdc25 phosphatase (overexpression).

Convincing experimental data indicate that the CDK2/Cyc complex occupies a critical position during cell cycle progression: (1) the transcriptional repression of CDK2 expression by two dominant negative forms of CDK2, e.g., antisense nucleotides, stops cell cycle progression. (2) Inactivation of the CycA gene is fatal in mice. (3) Disruption of the CDK2/CycA complex function in Cells by cell-penetrating peptides leads to tumor cell-selective apoptosis (Chen, Y.N.P. et al (1999) selected fertilization of Transformed Cells by Cyclin/Cyclina-Dependent Kinase 2antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-one 4329).

Changes in cell cycle control play an important role not only in tumors. Many viruses, by virtue of their viruses as well as non-transformed viruses, activate the cell cycle, making it possible to replicate the virus in a host cell. The false entry of normal post-mitotic cells into the cell cycle is associated with a variety of neurodegenerative diseases. The mechanisms of Cell Cycle regulation, their changes in disease and many methods for developing Inhibitors of Cell Cycle progression, in particular CDKs, have been described in various documents (Sielecki, T.M. et al (2000) Cycle-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle regulation. J.Med.Chem.43, 1-18; Fry, D.W. terret. M.D. (2000) inhibitor of Cycle-Dependent primers for the Treatment of cancer. Current. operating. Oncol. endo.Metab.attention. drugs 2, 40-59; Rosiana, G.R. changing, Y.T. target of therapy [ 10. tissue of protein, plant, 10. expression. K.10. expression. K.32. expression of protein. K.10. expression. K.32. expression of protein.

For use of the compounds of the invention in the form of medicaments, they may be presented in the form of pharmaceutical preparations comprising, in addition to the active ingredient for enteral or parenteral administration, suitable pharmaceutically acceptable organic or inorganic carrier materials, for example, water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyethylene glycols and the like. The pharmaceutical preparations may be in solid form, such as tablets, coated tablets, suppositories or capsules, or in liquid form, such as solutions, suspensions or emulsions. In addition, they may optionally contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, salts for varying the osmotic pressure or buffers. These pharmaceutical preparations are also the subject of the present invention.

For parenteral administration, injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable.

As carrier system, it is also possible to use surfactants such as salts of cholic acids or animal or vegetable phospholipids and mixtures thereof, liposomes or components thereof.

For oral administration, tablets, coated tablets or capsules containing talc and/or a hydrocarbon carrier or binder, such as lactose, corn starch or potato starch, are particularly suitable. Liquid dosage forms may also be used for administration, such as juices optionally supplemented with sweeteners.

Enteral, parenteral and oral administration are also subjects of the present invention.

The dosage of the active ingredient may vary depending on the method of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the like. The daily dose is 0.5-1000mg, preferably 50-200mg, wherein the dose can be administered in a single dose or divided into two or more daily doses.

In contrast, the compounds of the general formula I according to the invention can also inhibit receptor tyrosine kinases which specifically regulate endothelial cell function and their ligands. Receptor tyrosine kinases and their ligands that specifically regulate endothelial cell function play a crucial role in physiological and pathological angiogenesis. The VEGF/VEGF receptor system is of particular importance here. Increased expression of angiogenic growth factors and their receptors has been found in pathological conditions accompanied by increased neovascularization. Most solid tumors thus express large amounts of VEGF, and the expression of VEGF receptors is preferentially increased in large amounts in endothelial cells that pass near or through the tumor (Plate et al, cancer Res.53, 5822-5827, 1993). Inactivation of the VEGF/VEGF receptor system by VEGF neutralizing antibodies (Kim et al, Nature362, 841-844, 1993), retroviral expression of dominant negative VEGF-receptor variants (Millauer et al, Nature 367, 576-579, 1994), recombinant VEGF neutralizing receptor variants (Goldman et al, Proc. Natl. Acad. Sci. USA 95, 8795-8800, 1998), or small molecule inhibitors of VEGF receptor tyrosine kinases (Fong et al, Cancer Res.59, 99-106, 1999; Wedge et al, Cancer Res.60, 970-975, 2000; Wood et al, Cancer Res.60, 2178-2189, 2000) all result in tumor growth and a reduction in tumor angiogenesis. Thus, inhibition of angiogenesis is a possible treatment for neoplastic diseases.

The compounds according to the invention are thus capable of inhibiting cyclin dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as glycogen synthase kinase (GSK-3 β) and VEGF receptor tyrosine kinase or cyclin dependent kinase or VEGF-receptor tyrosine kinase. These effects enable the compounds according to the invention to be used for the treatment of the following diseases: cancer, angiofibroma, arthritis, ocular diseases, autoimmune diseases, chemotherapy-induced alopecia and mucositis, Crohn's disease, endometriosis, fibrotic diseases, hemangiomas, cardiovascular diseases, infectious diseases, kidney diseases, chronic and acute neurodegenerative diseases, as well as nerve tissue damage, viral infections, for inhibiting vascular reocclusion after bulb therapy, after vascular repair or after opening of blood vessels using mechanical devices such as tubular stents, for supporting scarless healing, as immunosuppressive agents in senile keratitis and contact dermatitis, among which

Cancer is defined as solid tumors, tumor or metastatic growth, Kaposi's sarcoma, Hodgkin's disease, and leukemia;

arthritis is defined as rheumatoid arthritis;

ocular diseases are defined as diabetic retinopathy and neovascular glaucoma;

autoimmune diseases are defined as psoriasis, alopecia and multiple sclerosis;

fibrotic diseases are defined as cirrhosis of the liver, mesangial cell proliferative diseases and arteriosclerosis;

infectious diseases are defined as diseases caused by single-celled parasites;

cardiovascular diseases are defined as conditions such as stent-induced stenosis, arteriosclerosis and restenosis;

nephropathy is defined as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, embolic microvascular disease syndrome, graft rejection and glomerulopathy;

chronic neurodegenerative diseases are defined as huntington's disease, amyotrophic lateral sclerosis, parkinson's disease, AIDS dementia and alzheimer's disease;

acute neurodegenerative diseases are defined as cerebral ischemia and neurotrauma; and

viral infections are defined as giant cell infections, herpes, hepatitis b or c, and HIV disease.

The subject of the invention is also pharmaceutical compositions for the treatment of the above-mentioned diseases comprising at least one compound of the general formula (I), and pharmaceutical compositions comprising suitable formulation substances and carriers.

The compounds of general formula (I) according to the invention are excellent inhibitors of cyclin dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, but also of glycogen-synthase-kinase (GSK-3 β).

The subject of the invention is also the intermediate products of the general formula (IIa) or (IIb) which are preferably used for the preparation of the compounds of the general formula I according to the invention, and their isomers, diastereomers, enantiomers and salts,

or

Wherein Z represents-NH₂Or NO₂And m, R³、R⁴And R⁵The same as defined in the general formula (I).

The subject of the invention is also intermediates of the general formula (IIIa), (IIIb) or (IIIc) and isomers, diastereomers, enantiomers and salts thereof, which are also preferably used for the preparation of the compounds of the general formula I according to the invention, as intermediates for the preparation of the compounds of the general formula (I),

orOr

Wherein W represents halogen, hydroxy or X-R²And R is¹、R²、R³、R⁵M and X are as defined for formula (I).

The subject of the invention is also the intermediate products of the general formula (IV) and their isomers, diastereomers, enantiomers and salts, which are also preferably used for the preparation of the compounds of the general formula I according to the invention,

wherein Hal represents halogen, W represents halogen, hydroxy or X-R²And R is¹、R²And X is as defined for formula (I).

If the preparation of the starting compounds is not described, these compounds are known or can be prepared analogously to known compounds or the methods described herein. All the reactions described herein can also be carried out in parallel reactors or by a combination of operating steps.

The isomer mixture can be separated into enantiomers or E/Z isomers according to a commonly used method such as crystallization, chromatography or salt formation.

The preparation of the salts is carried out in a conventional manner: a solution of a compound of formula I is mixed with the same amount or excess of a base or acid, optionally in solution, and the precipitate is then isolated or the solution is treated in a conventional manner.

Preparation of the Compounds of the invention

One of the most important methods for the preparation of amino sulfoxides is to react the sulfoxide with an azido acid, the latter being prepared in situ, for example by reaction of sodium azide with concentrated sulfuric acid (m.reggelin, c.zur, Synthesis2000, 1, 1). The reaction may be carried out in an organic solvent such as chloroform. Other methods of synthesizing the aminosulfoxides are, for example, reacting a sulfoxide compound with:

a)TsN3((a)R.Tanaka，K.Yamabe，J.Chem.Soc.Chem.Commun.1983，329；(b)H.Kwart，A.A.Kahn，J.Am.Chem.Soc.1967，89，1959))

b) n-tosyliminophenyl Iodinane and catalytic amounts of triflate ketone (I) (J.F.K.Muller, P.Vogt, Tetrahedron Lett.1998, 39, 4805)

c) Boc-azide and catalytic amounts of iron (II) chloride (T.Bach, C.Korber, Tetrahedron Lett.1998, 39, 5015) or

d) o-1, 3, 5-trimethylbenzene (Mesitylene) sulfonylhydroxylamine (MSH) (C.R.Johnson, R.A.Kirchhoff, H.G.Corkins, J.org.chem.1974, 39, 2458)

e) [ N- (2- (trimethylsilyl) ethanesulfonyl) imino ] phenylidinane (PhI ═ NSes) (S.Cren, T.C.Kinahan, C.L.Skinner and H.Tye, Tetrahedron Lett.2002, 43, 2749).

In terms of structure and configuration, aminosulfoxide compounds generally have high stability (c.bolm, j.p.hildebrand, j.org.chem.2000, 65, 169). These properties of the functional groups often also allow for drastic reaction conditions and make possible simple derivatization of the aminosulfoxide compounds at the imine nitrogen and the α -carbon. Enantiomerically pure aminosulfoxide compounds can also be used as adjuvants in diastereoselective syntheses ((a) S.G.Pyne, sulfurr Reports 1992, 12, 57; (b) C.R.Johnson, Aldrich chimica Acta 1985, 18, 3). Enantiomerically pure aminosulfoxide compounds are prepared, for example, by cleaving the racemate with enantiomerically pure camphor-10-sulfonic acid ((a) c.r.johnson, c.w.schroeck, j.am.chem.soc.1973, 95, 7418; (b) c.s.shiner, a.h.berks, j.org.chem.1988, 53, 5543). Another method for preparing optically active Another method for producing optically active aminosulfoxide compounds is to use MSH to stereoselectively imidize optically active sulfoxides ((a) C. Bolm, P. Muller, K. Harms, actaChem. Scand.1996, 50, 305; (b) Y. Tamura, J. Minamikawa, K. Sumoto, S. Fujii, M.Ikeda, J.org. Chem.1973, 38, 1239).

The following examples will explain the preparation of the compounds of the present invention, but the scope of the present invention is by no means limited to these examples.

Method example 1

Substituent Q, R¹、R²、R³、R⁴、R⁵And m is as defined for formula (I).

Example 1.0

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1-methylethyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

Method A

40mg (0.23mmol) of (RS) -S- (4-aminophenyl) -S-methylaminosulfoxide and 62mg (0.23mmol) of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino]Propane-1-ol was reacted with 0.5ml of 1-butyl-3-methyl-imidazolium tetrafluoroborate (review article for ionic liquids: a) T.Welton, chem.Rev.1999, 99, 2071; b) zhao, aldrich Acta2002, 35, 75; c) m.j.earle, k.r.seddon, ACS Symposium Series 2002, 819, 10) and stirred at room temperature for 10 minutes. The reaction mixture was heated to 60 ℃ and stirred at this temperature for a further 3 hours. Mixed with 0.08ml of 4M dioxane hydrochloride solution and stirred at 60 ℃ for 60 hours. After cooling, the reaction mixture was mixed with 10ml of ethyl acetate and stirred for 10 minutes. The organic solvent was decanted off and the residue was dissolved in 10ml of methanol. It is mixed with 200ml of ethyl acetate and then washed with 50ml of saturated sodium chloride solution. Organic phase drying (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/ethanol, 8: 2). 23mg (0.06mmol, corresponding to 26% of theory) of product are obtained.

Method B

A solution of 267mg (1.0mmol) of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] propan-1-ol in 2ml of acetonitrile is added at room temperature to a solution of 171mg (1.0mmol) of (RS) -S- (4-aminophenyl) -S-methylaminosulfoxide in 1ml of acetonitrile. The mixture was mixed with 0.25ml of 4M dioxane hydrochloride solution and stirred under reflux overnight. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 8: 2). The crude product obtained was finally purified by HPLC:

column: luna C18(2)5 mu

Length × ID: 150X 21.2mm

Eluent: a ═ H₂O, B ═ CAN, A/0.5g NH₄Ac/l

Flow rate: 10.0ml/min

Gradient: 5 → 100% B (5 ') -5 → 100% B (30 ') + 100% B (5 ')

A detector: PDA 214nm

Temperature: 21 deg.C

RT(min)：20.3

53mg (0.13mmol, corresponding to 13% of theory) of product are obtained.

¹H-NMR(DMSO)：9.71(s，1H)，8.11(s，1H)，7.91(d，2H)，7.78(d，2H)，6.41(d，1H)，4.89(t，1H)，4.25(m，1H)，3.96(br，1H)，3.53(m，2H)，3.03(s，3H)，1.21(d，3H).

MS：400(ES).

Example 1.1

Preparation of (RS) -S- [3- ({ 5-bromo-4- [ (R) - (2-hydroxy-1-methylethyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methyl-N-nitroaminosulfoxide

A solution of 37mg (0.17mmol) of (RS) -S- (3-aminophenyl) -S-methyl-N-nitroaminosulfoxide in 3ml of acetonitrile is admixed with 91mg (0.34mmol) of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino]Propane-1-ol and 0.06ml of 4M dioxane hydrochloride solution were mixed and stirred under reflux overnight. An additional 0.05ml of 4M dioxane hydrochloric acid solution was added and refluxed for an additional 6 hours. After TLC monitoring, 92mg (0.34mmol) of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino are added]Propane-1-ol was mixed and refluxed overnight. After cooling, the reaction was made basic with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue obtained is purified by chromatography (DCM/EtOH 95: 5). 24mg (0.05mmol, corresponding to 32% of theory) of the product are obtained (diastereomer A/B1: 1).

¹H-NMR(DMSO)：9.85(s，2H，A+B)，8.73(m，1H，A)，8.69(m，1H，B)，8.11(s，1H，A)，8.10(s，1H，B)，7.92(m，2H，A+B)，7.58(m，4H，A+B)，6.40(m，2H，A+B)，4.86(t，2H，A+B)，4.32(m，2H，A+B)，3.68(s，3H，A)，3.66(s，3H，B)，3.55(m，4H，A+B)，1.23(d，3H，A)，1.21(d，3H，B).

MS：445(ES).

The following compounds were prepared according to a similar procedure:

example 1.2

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.73(s，1H)，8.12(s，1H)，7.91(d，2H)，7.86(d，2H)，6.14(d，1H)，5.02(br，1H)，4.09(m，1H)，3.97(s，1H)，3.78(m，1H)，3.02(s，3H)，1.25(d，3H)，1.09(d，3H).

MS：414(ES).

Example 1.3

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.72(s，1H)，8.11(s，1H)，7.90(d，2H)，7.78(d，2H)，6.10(d，1H)，4.87(s，1H)，4.07(m，1H)，3.98(s，1H)，3.01(s，3H)，1.19(m，9H).

MS：428(ES).

Example 1.4

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropoxy ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.12(s，1H)，8.45(s，1H)，7.92(d，2H)，7.84(d，2H)，5.21(m，1H)，4.91(d，1H)，4.04(s，1H)，3.87(m，1H)，3.03(s，3H)，1.28(d，3H)，1.13(d，3H).

MS：415(ES).

Example 1.5

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-cyclopropyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

95mg (0.32mmol) of (R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] -2-methyl-butan-2-ol are dissolved in 2ml of acetonitrile and admixed with 116mg (0.32mmol) of (RS) -S- (4-aminophenyl) -S-cyclopropyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide. After addition of 0.08ml of an approximately 4N dioxane hydrochloride solution and 0.08ml of water, the mixture was heated in a sealed vessel for 16 hours to 75 ℃. The suspension was filtered and the filtrate was separated by flash chromatography (dichloromethane-dichloromethane/ethanol 95: 5, 15 ml/min). The 43-51min fraction contains 50mg (25% of theory) of the desired product.

¹H-NMR(DMSO)：9.91(s，1H)，8.16(s，1H)，8.01(d，2H)，7.83(d，2H)，6.14(d，1H)，4.87(s，1H)，4.10(m，1H)，3.18(m，1H)，2.92(m，2H)，1.37-1.00(m，4H)，1.21(s，3H)，1.20(d，3H)，1.14(s，3H)，0.93(m，2H)，0.01(s，9H).

MS：618/620(100％，ES).

Example 1.6

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-cyclopropylamino sulfoxide

Method C

50mg of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) -amino ] -pyrimidin-2-yl } amino) phenyl ] -S-cyclopropyl-N- [2- (trimethylsilyl) ethylsulfonyl ] -aminosulfoxide were dissolved in 1ml of tetrahydrofuran and then mixed with 0.3ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture was stirred at 50 ℃ for 3 days and then purified by flash chromatography (dichloromethane-dichloromethane/ethanol 9: 1). 10mg (28% of theory) of product are obtained.

¹H-NMR(DMSO)：9.72(s，1H)，8.13(s，1H)，7.90(d，2H)，7.74(d，2H)，6.10(d，1H)，4.86(s，1H)，4.10(m，1H)，3.95(s，1H)，3.16(m，1H)，1.40-1.00(m，4H)，1.20(s，3H)，1.19(d，3H)，1.15(s，3H).

MS：454/456(20％，ES).

The following compounds were prepared according to a similar method.

Example 1.7

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1-methylethyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (cyclopropylmethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO)：10.33(s，1H)，8.23(s，1H)，8.01(d，2H)，7.88(d，2H)，7.02(d，1H)，5.58(s br，1H)，4.28(m，1H)，3.67(d，2H)，3.55(m，2H)，2.98(m，2H)，1.21(d，3H)，0.97(m，2H)，0.86(m，1H)，0.44(m，2H)，0.12(m，2H)，0.01(s，9H)

MS：604/606(100％，ES).

Melting point: 195 deg.C (decomposition).

Example 1.8

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (cyclopropylmethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO)：9.93(s，1H)，8.16(s，1H)，8.02(d，2H)，7.83(d，2H)， 6.14(d，1H)，4.87(s，1H)，4.10(m，1H)，3.64(d，2H)，2.96(m，2H)，1.21(s，3H)，1.20(d，3H)，1.15(s，3H)，0.98(m，2H)，0.87(m，1H)，0.46(m，2H)，0.13(m，2H)，0.02(s，9H).

MS：632/634(40％，ES).

Example 1.9

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (cyclopropylmethyl) aminosulfoxide

¹H-NMR(DMSO)：9.73(s，1H)，8.13(s，1H)，7.92(d，2H)，7.75(d，2H)，6.10(d，1H)，4.85(s，1H)，4.10(m，1H)，3.92(s，1H)，3.02(m，2H)，1.20(s，3H)，1.19(d，3H)，1.14(s，3H)，0.87(m，1H)，0.37(m，2H)，0.00(m，2H).

Example 1.10

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-cyclopentyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

Melting point: 200 ℃ and 201 DEG C

Example 1.11

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-cyclopentylamino sulfoxide

Melting point: 194 ℃ and 196 DEG C

1.12) preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

A solution of 200mg (0.55mmol) of (RS) -S- (4-aminophenyl) -S- (2-hydroxyethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide in 2ml acetonitrile and 0.5ml water was mixed with 0.17ml 4N dioxane hydrochloride solution. A solution of 198mg (0.67mmol) of (R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] -2-methyl-butan-2-ol in 1.5ml of acetonitrile was added and the reaction was stirred at 80 ℃ for 20 h. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 9: 1). 148mg (0.24mmol, corresponding to 44% of theory) of product are obtained.

¹H-NMR(DMSO)：10.21(s，1H)，8.21(s，1H)，7.97(m，2H)，7.85(m，2H)，6.42(d，1H)，4.10(m，1H)，3.80(m，2H)，3.70(m，2H)，2.95(m，2H)，1.20(m，9H)，0.96(m，2H)，0.03(s，9H).

Example 1.13

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) -aminosulfoxide

¹H-NMR(DMSO)：9.75(s，1H)，8.13(s，1H)，7.91(m，2H)，7.75(m，2H)6.12(d，1H)，4.85(m，2H)，4.11(m，2H)，3.65(m，2H)，3.23(m，2H)，1.17(m9H).

The diastereomer mixture was separated by preparative HPLC as pure diastereomer:

column: chiralpak AD 20 mu

Length × ID: 250 x 60mm

Eluent: hexane/ethanol 70: 30

Flow rate: 80ml/min

A detector: UV 300nm

Temperature: at room temperature

RT (min): 23.41; diastereomer 1 (example 1.14)

54.16, respectively; diastereomer 2 (example 1.15)

1.16) preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methyl-propyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO)：10.53(s，1H)，8.28(s，1H)，7.95(m，2H)，7.88(m，2H)，6.86(d，1H)，4.13(m，1H)，3.76(m，5H)，2.90(m，2H)，1.25(d，3H)，1.11(d，3H)，0.93(m，2H)，0.03(s，9H).

1.17) preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methyl-propyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) aminosulfoxide

¹H-NMR(DMSO)：9.75(s，1H)，8.11(s，1H)，7.92(m，2H)，7.72(m，2H)，6.14(d，1H)，5.02(d，1H)，4.85(tr，1H)，4.10(m，2H)，3.78(m，1H)，3.62(m， 2H)，3.22(m，2H)，1.23(d，3H)，1.08(d，3H).

MS：444(ES).

column: chiralpak AD-H5 mu

Length × ID: 250 x 20mm

Eluent: a: hexane, C: ethanol

Flow rate: 10ml/min

Gradient: isocyatic 50% C

A detector: UV 300nm

Temperature: at room temperature

RT (min): 13.1; diastereomer 1 (example 1.18)

18.9 of the total weight of the powder; diastereomer 2 (example 1.19)

1.20) preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methyl-propoxy ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) -N- [2- (trimethylsilyl) -ethylsulfonyl ] aminosulfoxide

A solution of 205mg (0.56mmol) of (RS) -S- (4-aminophenyl) -S- (2-hydroxyethyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide in 2ml of acetonitrile was mixed with 0.15ml of 4N dioxane hydrochloride solution. A solution of 175mg (0.62mmol) of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) oxy ] -butan-2-ol in 2ml of acetonitrile is added and the reaction is stirred at 70 ℃ for 24 h. Followed by stirring at 80 ℃ for a further 24 hours. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 9: 1). 110mg (0.18mmol, corresponding to 32% of theory) of product are obtained.

¹H-NMR(DMSO)：10.31(s，1H)，8.45(s，1H)，7.99(m，2H)，7.83(m，2H)，5.25(m，1H)，4.93(m，2H)，3.75(m，5H)，2.90(m，2H)，1.32(d，3H)，1.13(d，3H)，0.93(m，2H)，0.05(s，9H).

MS：609(ES).

1.21) preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methyl-propoxy ] pyrimidin-2-yl } amino) phenyl ] -S- (2-hydroxyethyl) aminosulfoxide

Column: kromasil C85 μ

Length × ID: 125X 20mm

Eluent: a: h₂O+0.1％NH3，B：ACN

Flow rate: 15ml/min

Gradient: 24 → 38% B (10 ') → 95 (1')

A detector: UV 300nm

Temperature: at room temperature

RT(min)：10.9

¹H-NMR(DMSO)：10.10(s，1H)，8.42(s，1H)，7.88(m，2H)，7.77(m，2H)，5.23(m，1H)，4.88(d，1H)，4.85(tr，1H)，4.18(s，1H)，3.84(m，1H)，3.63(m，2H)，3.22(m，2H)，1.28(d，3H)，1.14(d，3H).

MS：445(ES).

Example 1.22

Preparation of (RS) -S- [3- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

127mg (0.43mmol) of (R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] -2-methyl-butan-2-ol in 1ml of acetonitrile are added to a solution of 74mg (0.43mmol) of (RS) -S- (3-aminophenyl) -S-methylaminosulfoxide in 0.5ml of acetonitrile. Mixed with 0.1ml of 4N dioxane hydrochloride solution and the reaction refluxed overnight. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 9: 1). 37mg (0.09mmol, corresponding to 20% of theory) of product are obtained.

¹H-NMR(DMSO)：9.65(s，1H)，8.75(m，1H)，8.08(s，1H)，7.64(m，1H)，7.42(m，2H)，6.04(m，1H)，4.82(br，1H)，4.20(m，1H)，4.06(m，1H)，3.03(s，3H)，1.18(m，9H).

MS：428(ES).

Example 1.23

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) -2-methoxyphenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.32(s，1H)，8.49(m，1H)，8.02(s，1H)，7.64(m，1H)，7.15(m，1H)，5.97(d，1H)，4.81(s，1H)，4.19(m，1H)，4.06(m，1H)，3.87(s，3H)，3.15(s，3H)，1.15(m，9H).

MS：458(ES).

Example 1.24

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropoxy ] pyrimidin-2-yl } amino) -2-methoxyphenyl ] -S-methylaminosulfoxide

220mg (1.1mmol) of (RS) -S- (4-amino-2-methoxyphenyl) -S-methylaminosulfoxide and 280mg (1.0mmol) of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) oxy ] -butan-2-ol are mixed in 10ml of acetonitrile with 0.28ml of 4N dioxane hydrochloride solution and stirred at reflux overnight. Mixed with 1ml of n-butanol/methanol (9: 1) and stirred under reflux for a further 5 days. The reaction was concentrated by evaporation and the residue was chromatographed (DCM/ethanol 8: 2). 36mg (0.1mmol, corresponding to 8% of theory) of product are obtained.

¹H-NMR(DMSO)：9.81(s，1H)，8.32(m，2H)，7.71(m，1H)，7.18(m，1H)，5.25(m，1H)，4.95(br，1H)，4.18(m，1H)，3.91(s，3H)，3.83(m，1H)，3.15(s，3H)，1.25(m，3H)，1.10(m，3H).

MS：445(ES).

Example 1.25

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) -2-methoxyphenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.37(s，1H)，8.43(m，1H)，8.02(s，1H)，7.70(m，1H)，7.14(m，1H)，5.98(d，1H)，5.01(d，1H)，4.20(m，1H)，4.07(s，1H)，3.87(s，3H)，3.75(m，1H)，3.14(s，3H)，1.15(d，3H)，1.07(d，3H).

MS：444(ES).

column: ChiralpakAD 20 mu

Length × ID: 250 x 60mm

Eluent: a is hexane, B is ethanol

Flow rate: 80ml/min

Gradient: isocyatic 50% B

A detector: UV 280nm

Temperature: at room temperature

RT (min): 20.3; diastereomer 1 (example 1.26)

34.8 of the total weight of the powder; diastereomer 2 (example 1.27)

Example 1.28

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -NS-dimethyl-aminosulfoxide

¹H-NMR(DMSO)：9.73(s，1H)，8.11(s，1H)，7.96(m，2H)，7.65(m，2H)，6.14(d，1H)，5.01(d，1H)，4.10(m，1H)，3.79(m，1H)，3.05(s，3H)，2.46(s，3H)，1.25(d，3H)，1.12(d，3H).

MS：428(ES)

column: chiralpak AD-H5 mu

Length × ID: 250 is prepared from

4.6mm eluent: hexane, ethanol a/0.1% DEA

Flow rate: 15ml/min

Gradient: isocyatic 15% B

A detector: UV 300nm

Temperature: at room temperature

RT (min): 25.45 of; diastereomer 1 (example 1.29)

29.32; diastereomer 2 (example 1.30)

Example 1.31

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

600mg (2.48mmol) of (RS) -S- (4-aminophenyl) -N- (ethoxycarbonyl) -S-methylaminosulfoxide and 610mg (2.07mmol) of (R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] -2-methyl-butan-2-ol are mixed in 8ml of acetonitrile with 0.52ml of water and 0.52ml of 4N dioxane hydrochloride solution. The reaction was stirred at 60 ℃ for 24 hours and then concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 8: 2). 649mg (1.30mmol, corresponding to 53% of theory) of product are obtained.

¹H-NMR(DMSO)：10.10(s，1H)，8.20(s，1H)，7.97(m，2H)，7.85(m，2H)，6.39(d，1H)，4.10(m，1H)，3.91(m，2H)，3.30(s，3H)，1.10(m，12H).

Example 1.32

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.88(s，1H)，8.13(s，1H)，7.98(m，2H)，7.79(m，2H)，6.18(d，1H)，5.01(d，1H)，4.10(m，1H)，3.90(q，2H)，3.78(m，1H)，3.41(s，3H)，1.21(d，3H)，1.08(m，6H).

Example 1.33

Preparation of (RS) -S- {4- [ (5-bromo-4- { [ (1R, 2R) -2-hydroxy-1- (methoxymethyl) -propyl ] amino } pyrimidin-2-yl) amino ] phenyl } -N- (ethoxycarbonyl) -S-ethylamino-sulphoxide

¹H-NMR(DMSO)：9.92(s，1H)，8.17(s，1H)，7.99(m，2H)，7.70(m，2H)，6.08(d，1H)，5.12(m，1H)，4.20(m，1H)，4.00(m，1H)，3.89(m，2H)，3.50(m，4H)，3.28(s，3H)，1.08(m，9H).

Example 1.34

Preparation of (RS) -S- {4- [ (5-bromo-4- { [ (1R, 2R) -2-hydroxy-1- (methoxymethyl) -propyl ] amino } pyrimidin-2-yl) amino ] phenyl } -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.91(s，1H)，7.95(s，1H)，7.95(m，2H)，7.78(m，2H)，6.08(d，1H)，5.13(m，1H)，4.20(m，1H)，3.95(m，3H)，3.48(m，2H)，3.40(s，3H)，3.27(s，3H)，1.10(m，6H).

Example 1.35

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-ethylaminosulfoxide

¹H-NMR(DMSO)：9.89(s，1H)，8.14(s，1H)，7.99(m，2H)，7.72(m，2H)，6.13(d，1H)，4.84(s，1H)，4.09(m，1H)，3.90(m，2H)，3.54(q，2H)，1.15(m， 15H).

Example 1.36

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-ethylaminosulfoxide

¹H-NMR(DMSO)：9.92(s，1H)，8.13(s，1H)，7.97(m，2H)，7.72(m，2H)，6.27(d，1H)，4.10(m，1H)，9.92(m，2H)，3.80(m，1H)，3.55(q，2H)，1.23(d；3H)，1.10(m，9H).

Example 1.37

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) -2-methylphenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.98(s，1H)，7.75(m，3H)，6.22(d，1H)，4.05(m，1H)， 3.88(q，2H)，3.39(s，3H)，2.57(s，3H)，1.15(m，12H).

MS：514(ES).

Example 1.38

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) -2-methylphenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.88(s，1H)，8.13(s，1H)，7.79(m，3H)，6.33(d，1H)，4.04(m，1H)，3.90(q，2H)，3.82(m，1H)，3.30(s，3H)，2.62(s，3H)，1.22(d，3H)，1.08(m，6H).

Example 1.39

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropoxy ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-ethylaminosulfoxide

128mg (0.51mmol) of (RS) -S- (4-aminophenyl) -N- (ethoxycarbonyl) -S-ethylaminosulfoxide and 150mg (0.53mmol) of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) oxy ] -butan-2-ol are mixed in 2ml of acetonitrile with 0.12ml of 4N dioxane hydrochloride solution. The reaction was stirred at 60 ℃ for 2 days. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 95: 5). 43mg (0.09mmol, corresponding to 17% of theory) of product are obtained.

¹H-NMR(DMSO)：10.28(s，1H)，8.45(s，1H)，7.99(m，2H)，7.78(m，2H)，5.22(m，1H)，4.91(d，1H)，3.88(m，3H)，3.53(q，2H)，1.30(d，3H)，1.10(m，9H).

Example 1.40

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropoxy ] pyrimidin-2-yl } amino) phenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.24(s，1H)，8.45(s，1H)，7.97(m，2H)，7.85(m，2H)，5.22(m，1H)，4.91(d，1H)，3.90(m，3H)，3.43(s，3H)，1.30(d，3H)，1.11(m，6H).

Method D

Example 1.41/1.42

Preparation and isolation of the diastereomer of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide (example 1.3)

1.65g (3.30mmol) of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino]Pyrimidin-2-yl } amino) phenyl]-N- (ethoxycarbonyl) -S-methylaminosulfoxide was mixed in 6.5ml of ethanol with 19.1ml (6.69mmol) of a 0.35M NaOEt ethanol solution, followed by stirring at reflux for 5 hours. The reaction was stirred at room temperature overnight and then added to a saturated sodium chloride solution. Extraction with ethyl acetate and drying of the combined organic phases (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 9: 1). 0.95g (2.22mmol, corresponding to 67% of theory) of product are obtained.

The analytical data are analogous to those of example 1.3 in method A of method example 1.

column: chiralpak OJ 20 mu

Length × ID: 290X 50.8mm

Eluent: hexane + 0.1% DEA, ethanol

Flow rate: 80ml/min

Gradient: isocyatic 15% B

A detector: UV 300nm

Temperature: at room temperature

RT (min): 29.4; diastereomer 1 (example 1.41)

37.1; diastereomer 2 (example 1.42)

The following compounds were prepared analogously:

example 1.43/1.44

Preparation and isolation of the diastereomer of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide (example 1.2)

The analytical data are analogous to those of example 1.2 in method A of method example 1.

Separation of the diastereomer mixture into diastereomers by preparative HPLC:

column: chiralpak OJ 20 mu

Length × ID: 290X 0.8mm

Eluent: hexane + 0.1% DEA, ethanol

Flow rate: 80ml/min

Gradient: isocyatic 15% B

A detector: UV 280nm

Temperature: at room temperature

RT (min): 44.6; diastereomer 1 (example 1.43)

57.3; diastereomer 2 (example 1.44)

Example 1.45

Preparation of (RS) -S- {4- [ (5-bromo-4- { [ (1R, 2R) -2-hydroxy-1- (methoxymethyl) -propyl ] amino } pyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.77(s，1H)，8.14(s，1H)，7.91(m，2H)，7.76(m，2H)，6.05(d，1H)，5.12(br，1H)，4.20(m，1H)，3.98(m，2H)，3.49(m，2H)，3.29(s，3H)，3.02(s，3H)，1.19(d，3H).

Separation of the diastereomer mixture into diastereomers by preparative HPLC:

column: chiralcel OJ 20 mu

Length × ID: time.50.8mm

Eluent: flow rate of hexane/ethanol 80: 20: 80.0ml/min

A detector: UV 300nm

Temperature: at room temperature

RT (min): 47.55: diastereomer 1 (example 1.46)

61.02: diastereomer 2 (example 1.47)

Example 1.48

Preparation of (RS) -S- {4- [ (5-bromo-4- { [ (1R, 2R) -2-hydroxy-1- (methoxymethyl) -propyl ] amino } pyrimidin-2-yl) amino ] phenyl } -S-ethylaminosulfoxide

¹H-NMR(DMSO)：9.78(s，1H)，8.14(s，1H)，7.94(m，2H)，7.70(m，2H)，6.05(d，1H)，5.11(d，1H)，4.19(m，1H)，3.97(m，2H)，3.50(m，2H)，3.30(s，3H)，3.05(q，2H)，1.07(m，6H).

Separation of the diastereomer mixture into diastereomers by preparative HPLC:

column: chiralcel OJ 20 mu

Length × ID: 290X 50.8mm

Eluent: hexane: ethanol 80: 20

Flow rate: 80ml/min

A detector: UV 300nm

Temperature: at room temperature

RT (min): 45.5: diastereomer 1 (example 1.49)

53.1: diastereomer 2 (example 1.50)

Example 1.51

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-ethylaminosulfoxide

¹H-NMR(DMSO)：9.71(s，1H)，8.11(s，1H)，7.90(m，2H)，7.71(m，2H)，6.13(d，1H)，5.01(d，1H)，4.08(m，1H)，3.93(s，1H)，3.78(m，1H)，3.03(q，2H)，1.22(d，3H)，1.10(m，6H).

Separation of the diastereomer mixture into diastereomers by preparative HPLC:

column: chiracel OJ 20 mu

Length × ID: 250X 50.8mm

Eluent: a: hexane + 0.1% DEA; b: ethanol

Flow rate: 80ml/min

Gradient: isocyatic 15% B

A detector: UV 300nm

Temperature: at room temperature

RT (min): 34.0: diastereomer 1 (example 1.52)

43.7: diastereomer 2 (example 1.53)

Example 1.54

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-ethylamino sulfoxide

¹H-NMR(DMSO)：9.74(s，1H)，8.13(s，1H)，7.92(m，2H)，7.71(m，2H)，6.09(d，1H)，4.84(s，1H)，4.08(m，1H)，3.92(s.1H)，3.06(q，2H)，1.15(m，12H).

Separation of the diastereomer mixture into diastereomers by preparative HPLC:

column: chiralpak AD 20 mu

Length × ID: 250 x 60mm

Eluent: Hexane/2-Propanol 80: 20

Flow rate: 80/100ml/min

A detector: UV 280nm

Temperature: at room temperature

RT (min): 222.2: diastereomer 1 (example 1.55)

249.8: diastereomer 2 (example 1.56)

Example 1.57

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) -2-methylphenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.63(s，1H)，8.11(s，1H)，7.81(m，2H)，7.63(m，1H)，6.08(d，1H)，4.88(s，1H)，4.06(m，2H)，3.03(s，3H)，2.67(s，3H)，1.2(m，9H)

MS：442(ES).

column: ChiralpakAS 20 mu

Length × ID: 250X 50.8mm

Eluent: a is hexane, B is ethanol

Flow rate: 80ml/min

Gradient: isocyatic 15% B

A detector: UV 300nm

Temperature: at room temperature

RT (min): 18.96 parts; diastereomer 1 (example 1.58)

21.56; diastereomer 2 (example 1.59)

Example 1.60

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) -2-methylphenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.62(s，1H)，8.11(s，1H)，7.82(m，2H)，7.66(m，1H)，6.14(d，1H)，5.02(d，1H)，4.04(m，2H)，3.80(m，1H)，3.03(s，3H)，2.65(s，3H)，1.22(d，3H)，1.10(d，3H).

column: chiralpak AD 20 mu

Length × ID: 250X 50.8mm

Eluent: a: hexane + 0.1% DEA, B: ethanol

Flow rate: 80ml/min

Gradient: isocyatic 25% B

A detector: UV 280nm

Temperature: at room temperature

RT (min): 104 diastereomer 1 (example 1.61)

124 diastereomer 2 (example 1.62)

Example 1.63

Preparation of (RS) -S- {4- [ (5-bromo-4-ethoxypyrimidin-2-yl) amino ] phenyl } -S-ethylaminosulfoxide

28mg (0.056mmol) of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropaneOxy radical]Pyrimidin-2-yl } amino) phenyl]-N- (ethoxycarbonyl) -S-methylaminosulfoxide was mixed in 0.11ml ethanol with 0.32ml (0.113mmol) of a 0.35M NaOH ethanol solution and stirred under reflux for 6 hours. The reaction was stirred at room temperature overnight and then added to a saturated sodium chloride solution. Extraction with ethyl acetate and drying of the combined organic phases (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 85: 15). 9mg (0.023mmol, corresponding to 42% of theory) of product are obtained.

¹H-NMR(DMSO)：10.17(s，1H)，8.45(s，1H)，7.94(m，2H)，7.78(m，2H)，4.49(q，2H)，3.98(s，1H)，3.07(q，2H)，1.40(tr，3H)，1.04(tr，3H).

MS：385(ES).

Example 1.64

Preparation of (RS) -N- (ethoxycarbonyl) -S- (4- { [ 5-iodo-4- (prop-2-yn-1-ylamino) pyrimidin-2-yl ] amino } phenyl) -S-methylaminosulfoxide

400mg (1.65mmol) of (2-chloro-5-iodopyrimidin-4-yl) -prop-2-yn-1-yl-amine and 630mg (2.15mmol) of (RS) -S- (4-aminophenyl) -N- (ethoxycarbonyl) -S-methylamino sulfoxide are mixed in 7ml of acetonitrile with 0.6ml of 4N dioxane hydrochloride solution and 1ml of water. The reaction was stirred at 50 ℃ 24. The solvent was removed and the residue was purified by chromatography (DCM/EtOH 9: 1). 279mg (0.56mmol, corresponding to 54% of theory) of product are obtained.

1H-NMR(DMSO)：10.19(s，1H)，8.30(s，11H)，8.05(m，2H)，7.81(m，2H)，7.59(br，1H)，4.17(d，2H)，3.88(q，2H)，3.43(s，3H)，3.18(b r，1H)，1.10(tr，3H).

MS：500(ES).

Example 1.65

Preparation of (RS) -N- (ethoxycarbonyl) -S- {4- [ (4- { (R) - [1- (hydroxymethyl) -2-methylpropyl ] amino } -5-iodopyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.81(s，1H)，8.22(s，1H)，7.98(m，2H)，7.78(m，2H)，5.89(d，1H)，4.85(tr，1H)，4.04(m，1H)，3.92(q，2H)，3.65(m，1H)，3.56(m，1H)，3.41(s，3H)，2.02(m，1H)，1.10(tr，3H)，0.95(dd，6H).

MS：548(ES)

Example 1.66

Preparation of (RS) -S- {4- [ (4- { (R) - [1- (hydroxymethyl) -2-methylpropyl ] amino } -5-iodopyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.68(s，1H)，8.21(s，1H)，7.92(m，2H)，7.75(m，2H)，5.87(d，1H)，4.86(tr，1H)，4.01(m，2H)，3.66(m，1H)，3.55(m，1H)，3.01(s，3H)，2.02(m，1H)，0.94(m，6H).

Example 1.67

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) - (2-hydroxy-1-methylpropyl) amino ] pyrimidin-2-yl } amino) -2-fluorophenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.08(s，1H)，8.18(s，1H)，8.02(m，1H)，7.68(m，2H)，6.27(d，1H)，5.03(br，1H)，4.08(m，1H)，3.88(m，2H)，3.79(m，1H)，3.48(s，3H)，1.21(d，3H)，1.09(m，6H).

MS：504(ES).

Example 1.68

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) -2-fluorophenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.12(s，1H)，8.17(s，1H)，8.02(m，1H)，7.73(m，1H)，7.63(m，1H)，6.26(d，1H)，4.08(m，1H)，3.85(m，2H)，3.42(s，3H)，1.11(m，12H).

MS：518(ES).

Example 1.69

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1, 2-dimethylpropyl) amino ] pyrimidin-2-yl } amino) -2-trifluoromethylphenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.21(s，1H)，8.65(s，1H)，8.19(s，1H)，8.05(s，2H)，6.18(d，1H)，4.90(br，1H)，4.05(m，1H)，3.89(q，2H)，3.40(s，3H)，1.12(m，12H).

MS：568(ES).

Method example 2

Substituent R¹、R²、R³、R⁴、R⁵Q and m are as defined for formula (I).

Method A

Example 2.0

Preparation of (RS) -S- (4- { [ 5-bromo-4- (isopropylamino) pyrimidin-2-yl ] amino } -phenyl) -S-methylaminosulfoxide

185mg (0.50mmol) of (RS) -5-bromo-N-4-isopropyl-N2- [4- (methylsulfinyl) phenyl]Pyrimidine-2, 4-diamine was mixed with 40mg (0.55mmol) of sodium azide in 1ml of DCM. The reaction was slowly mixed with 0.13ml of concentrated sulfuric acid at 0 ℃ and then heated to 45 ℃. After 16 h, the reaction was cooled to room temperature, mixed with 2ml of 1N NaOH solution and then extracted with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 9: 1). 38mg (0.10mmol, corresponding to 20% of theory) of product are obtained.

¹H-NMR(DMSO)：9.70(s，1H)，8.08(s，1H)，7.90(d，2H)，7.77(d，2H)，6.62(d，1H)，4.35(m，1H)，3.99(s，1H)，3.03(s，3H)，1.29(d，6H).

MS：384(ES).

Method B

Example 2.1

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1-methylethyl) amino ] pyrimidin-2-yl } amino) phenyl ] -S-methyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

50mg (0.13mmol) of (R) -2- [ 5-bromo-2- { (RS) -4-methylsulfinyl-phenyl-amino } -pyrimidin-4-ylamino-were reacted at room temperature]-propan-1-ol in 3ml acetonitrile with a spatula tip of CuPF₆[CH₃CN]₄(about 0.05 eq.) were mixed and stirred for 30 minutes. The mixture was cooled in an ice bath and reacted with 55mg (0.13mmol) of [ N- (2- (trimethylsilyl) ethanesulfonyl) imino ] imide]The phenyl iododinanes were mixed and then stirred at room temperature for 4 hours. Cooling in an ice bath, and mixing with CuPF solution₆[CH₃CN]₄And 22mg (0.06mmol) of [ N- (2- (trimethylsilyl) ethanesulfonyl) -imino ] -N]The phenyl iododinanes were mixed and stirred at room temperature for an additional 3 hours. The mixture was evaporated to dryness and the residue was purified by chromatography. This gave 20mg of (RS) -S- [4- ({ 5-bromo-4- [ (R) - (2-hydroxy-1-methylethyl) amino group]Pyrimidin-2-yl } amino) phenyl]-S-methyl-N- [2- (trimethylsilyl) ethylsulfonyl]An aminosulfoxide having a melting point of 194-197 ℃.

¹H-NMR(DMSO)：9.92(s，1H)，8.14(s，1H)，8.02(d，2H)，7.87(d，2H)，6.48(d，1H)，4.90(t，1H)，4.27(m，1H)，3.53(s，3H)，3.52(m，2H)，2.95(m，2H)，1.22(d，3H)，0.95(m，2H)，0.01(s，9H).

MS：564/566(100％，ES).

Example 1.0

After removal of the half-protecting groups with tetrabutylammonium fluoride in analogy to example 1.6 (as described in tetrahedron Lett.2002, 43, 2751), 10mg (0.02mmol, corresponding to 70% of theory) of product are obtained.

Following a procedure analogous to procedures a and B in method example 2 above, the following compounds were prepared:

example 2.2

Preparation of (RS) -S- (4- {1[ 5-bromo-4- (phenylamino) pyrimidin-2-yl ] amino } phenyl) -S-methyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO)：9.98(s，1H)，8.83(s，1H)，8.32(s，1H)，7.88(d，2H)，7.71(d，2H)，7.59(d，2H)，7.44(t，2H)，7.23(t，1H)，3.53(s，3H)，2.86-3.03(m，2H)，0.82-1.01(m，2H)，0.00(s，9H).

MS：582/584(100％，ES).

Example 2.3

Preparation of (RS) -S- (4- { [ 5-bromo-4- (phenylamino) pyrimidin-2-yl ] amino } phenyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.82(s，1H)，8.79(s，1H)，8.30(s，1H)，7.78(d，2H)，7.65(d，2H)，7.60(d，2H)，7.42(t，2H)，7.23(t，1H)，3.96(s，1H)，3.00(s，3H).

MS：418/420(20％，ES).

Example 2.4

Preparation of (RS) -S- [4- ({4- [ (2-fluoro-5-methylphenyl) amino ] -pyrimidin-2-yl } amino) phenyl ] -S-methyl-N- [2- (trimethylsilyl) ethylsulfonyl ] -aminosulfoxide

¹H-NMR(DMSO)：9.85(s，1H)，9.22(s，1H)，7.98(d，2H)，7.88(d，1H)，7.76(d，2H)，7.63(d，1H)，7.21(m，1H)，7.02(m，1H)，6.40(m，1H)，3.53(s，3H)，2.81-2.90(m，2H)，0.87-1.00(m，2H)，0.00(s，9H).

MS：536(100％，ES).

Example 2.5

Preparation of (RS) -S- [4- ({4- [ (2-fluoro-5-methylphenyl) amino ] -pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：9.65(s，1H)，9.18(s，1H)，8.09(d，1H)，7.87(d，2H)，7.69(d，2H)，7.65(d，1H)，7.19(m，1H)，7.02(m，1H)，6.37(m，1H)，3.02(s，3H).

MS：372(10％，ES).

Method example 3

Substituent R¹、R²、R³、R⁴、R⁵Q and m are as defined for formula (I). Y is defined as halogen.

Example 3.0

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (1-hydroxymethyl-propyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

362mg of (RS) -S- {4- [ (5-bromo-4-chloropyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide were dissolved in 1.5ml of dimethylformamide, mixed with 0.5ml of triethylamine and 320mg of (RS) -2-mercapto-butan-1-ol at room temperature and stirred for 18 hours. The mixture was evaporated to dryness in vacuo and purified by flash chromatography (dichloromethane/ethanol). 255mg of product are obtained, with a melting point of 175-180 ℃.

¹H-NMR(DMSO)：10.18(s，1H)，8.39(s，1H)，7.91(d，2H)，7.83(d，2H)，5.13(t，1H)，4.05(s，1H)，4.00(m，1H)，3.74(m，1H)，3.63(m，1H)，3.03(s，3H)，1.93(m，1H)，1.69(m，1H)，1.00(t，3H).

MS：431/433(95/100％，ES).

The following examples were prepared in a similar manner:

example 3.1

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (1-methyl-propyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

Melting point: 175 deg.C and 183 deg.C

¹H-NMR(DMSO)：10.19(s，1H)，8.40(s，1H)，7.95(d，2H)，7.85(d，2H)，4.04(s，1H)，3.97(m，1H)，3.03(s，3H)，1.76(m，2H)，1.42(d，2H)，1.01(t，3H).

MS：415/417(90/100％，ES).

Example 3.2

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (1-methyl-2-oxo-propyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.18(s，1H)，8.44(s，1H)，7.87(s，4H)，4.82(q，1H)，3.06(s，3H)，2.26(s，3H)，1.52(d，3H).

MS：429/431(90/100％，ES).

Example 3.3

Preparation of (RS) -S- [4- ({4- [ (RS) - (1-acetylpropyl) sulfanyl ] -5-bromopyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.16(s，1H)，8.44(s，1H)，7.86(s，4H)，4.79(t，1H)，3.04(s，3H)，2.25(s，3H)，2.04(m，1H)，1.89(m，1H)，1.18(t，1.5H)，0.96(t，1.5H).

MS：443/445(90/100％，ES).

Example 3.4

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (2-hydroxy-propyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.17(s，1H)，8.39(s，1H)，7.90(d，2H)，7.84(d，2H)，5.04(d，1H)，4.04(s，1H)，3.93(m，1H)，3.26(d，1H)，3.03(s，3H)，1.21(d，3H).

MS：417/419(90/100％，ES).

Example 3.5

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS, RS) - (2-hydroxy-1-methylpropyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.17(s，1H)，8.38(s，1H)，7.93-7.81(m，4H)，5.13+5.06(d，1H)，4.06(m，1H)，4.04(s，1H)，3.95(m，1H)，3.03(s，3H)，1.42+1.36(d，3H)，1.18(m，3H).

MS：431/433(94/100％，ES).

Example 3.6

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS, RS) - (1-ethyl-2-hydroxypropyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

It is prepared by Reacting (RS) -S- [4- ({4- [ (RS) - (1-acetylpropyl) sulfanyl ] -5-bromopyrimidin-2-yl } amino) phenyl ] -S-methylamino sulfoxide with 1 equivalent of sodium borohydride in tetrahydrofuran/methanol (1: 1).

Melting point: 192 ℃ C

¹H-NMR(DMSO)：10.14(s，1H)，8.38(s，1H)，7.90(d，2H)，7.83(d，2H)，5.06+4.98(d，1H)，4.08(s，1H)，4.00(m，2H)，3.03(s，3H)，1.93(m，1H)，1.66 (m，1H)，1.16(d，3H)，0.99(t，3H).

MS：445/447(96/100％，ES).

Example 3.7

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (2-hydroxy-1, 2-dimethylpropyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

It is prepared by Reacting (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (1-methyl-2-oxo-propyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide with 6 equivalents of methylmagnesium bromide in tetrahydrofuran.

Melting point: 201-

¹H-NMR(DMSO)：10.18(s，1H)，8.38(s，1H)，7.92(d，2H)，7.83(d，2H)，4.89(s，1H)，4.09(m，1H)，4.05(s，1H)，3.03(s，3H)，1.43(d，3H)，1.27(s，6H).

MS：445/447(93/100％，ES).

Example 3.8

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (1-ethyl-2-hydroxy-2-methylpropyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

It is prepared by reacting RS) -S- [4- ({4- [ (RS)7 (1-acetylpropyl) sulfanyl ] -5-bromopyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide with 6 equivalents of methylmagnesium bromide in tetrahydrofuran.

Melting point: 218 deg.C (decomposition)

¹H-NMR(DMSO)：10.17(s，1H)，8.38(s，1H)，7.92(d，2H)，7.83(d，2H)，4.78(s，1H)，4.12(dd，1H)，4.05(s，1H)，3.03(s，3H)，2.10(m，1H)，1.48(m，1H)，1.24(s，6H)，0.95(dd，3H).

MS：459/461(93/100％，ES).

Example 3.9

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (2-hydroxy-2-methyl-propyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

It is prepared by Reacting (RS) -S- [4- ({ 5-bromo-4- [ (4-methoxycarbonylmethyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylamino sulfoxide with 6 equivalents of methylmagnesium bromide in tetrahydrofuran.

¹H-NMR(DMSO)：10.17(s，1H)，8.39(s，1H)，7.92(d，2H)，7.83(d，2H)，4.84(s，1H)，4.05(s，1H)，3.41(s，2H)，3.03(s，3H)，1.26(s，6H).

MS：431/433(94/100％，ES).

Example 3.10

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (RS) - (2-hydroxy-1-methyl-ethyl) sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

Melting point: 218, 220 DEG C

¹H-NMR(DMSO)：10.19(s，1H)，8.40(s，1H)，7.92(d，2H)，7.84(d，2H)，5.18(t，1H)，4.07(m，2H)，3.69(m，1H)，3.61(m，1H)，3.04(s，3H)，1.42(d，3H).

MS：417/419(92/100％，ES).

Example 3.11

Preparation of (RS) -S- [4- ({ 5-bromo-4- [ (4-methoxycarbonylmethyl) -sulfanyl ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide

¹H-NMR(DMSO)：10.22(s，1H)，8.44(s，1H)，7.82(s，4H)，4.22(s，2H)，4.16(s(br)，1H)，3.58(s，3H)，3.05(s，3H).

MS：431/433(91/100％，ES).

Example 3.12/3.13

Preparation and isolation of the diastereomer of (RS) -S- [4- ({ 5-bromo-4- [ (1R, 2R) -2-hydroxy-1-methylpropoxy ] pyrimidin-2-yl } amino) phenyl ] -S-methylaminosulfoxide (example 1.4)

While cooling with water, 674mg (7.5mmol) of a solution of (R, R) - (-) -2, 3-butanedihydride in 6ml of DMSO was mixed in portions with 330mg of sodium hydride (55-60%) and then stirred at room temperature for 45 minutes. The reaction was mixed with 196mg (0.54mmol) of (RS) -S- {4- [ (5-bromo-4-chloropyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide in 0.5ml of DMSO and then stirred overnight. This was mixed with 191mg (0.53mmol) of (RS) -S- {4- [ (5-bromo-4-chloropyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide in 0.5ml of DMSO and stirred for a further 2 hours. Finally 190mg of (RS) -S- {4- [ (5-bromo-4-chloropyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide (0.53mmol) were mixed in 0.5ml of DMSO and stirred for 1 hour. The reaction was added to ice water and extracted with ethyl acetate (4 times). The combined organic phases were washed with sodium chloride solution, filtered through a Whatman filter and then concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 9: 1). 166mg (0.41mmol, corresponding to 25% of theory) of product are obtained.

The analytical data were the same as those of the compound prepared in example 1 according to the method.

column: chiracel OJ 20 mu

Length × ID: 290X 50.8mm

Eluent: a: hexane, B: ethanol

Flow rate: 80ml/mm

Gradient: isocyatic 15% B

A detector: UV 300nm

Temperature: at room temperature

RT (min): 32.8: diastereomer 1 (example 3.12)

39.2: diastereomer 2 (example 3.13)

Preparation of intermediate products

a) Preparation of (RS) -S- (4-aminophenyl) -S-methylaminosulfoxide

2.45g (12.2mmol) of (RS) -S- (4-nitrophenyl) -S-methylaminosulfoxide are dissolved in 150ml of ethanol at room temperature under a hydrogen atmosphere and at atmospheric pressure with 0.80g of Pd/C (10%. times.50% H)₂O) was hydrogenated for 4 hours. The hydrogen uptake was 920 ml. The reaction was filtered and concentrated by evaporation. The resulting residue was treated with diisopropyl ether. Yield 1.90g (11.2mmol, corresponding to 92% of theory).

¹H-NMR(DMSO)：7.53(d，2H)，6.64(d，2H)，5.91(s，2H)，3.68(s，1H)，2.93(s，3H).

ES：171(ES).

b) Preparation of (RS) -S- (4-nitrophenyl) -S-methylaminosulfoxide

1.56g (8.5mmol) of 1- (methylsulfinyl) -4-nitrobenzene are mixed with 0.70g (9.5mmol) of sodium azide in 20ml of DCM. The reaction was slowly mixed with 2.3ml of concentrated sulfuric acid at 0 ℃ and then heated to 45 ℃. After 16 h, the reaction was cooled to room temperature, mixed with water and extracted with DCM. The aqueous phase was adjusted to pH 11 with 15% sodium hydroxide solution and then extracted with DCM. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. 1.08g (5.4mmol, corresponding to 63% of theory) of product are obtained.

¹H-NMR(DMSO)：8.43(d，2H)，8.17(d，2H)，4.62(s，1H)，3.18(s，3H).

ES：201(ES).

c) Preparation of 1- (methylsulfinyl-4-nitrobenzene

16.0g (95mmol) of 1-methylsulfanyl-4-nitro-benzene are placed in 400ml at room temperature

The solution in DCM was mixed with 24.6g (100mmol) of 3-chloroperoxybenzoic acid (ca. 70%). After 1 hour, the reaction was diluted with DCM and washed with saturated sodium bicarbonate solution. Organic phase drying (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 8: 2). 7.6g (41mmol, corresponding to 43% of theory) of product are obtained.

¹H-NMR(DMSO)：8.41(d，2H)，7.97(d，2H)，2.86(s，3H).

ES：186(ES).

d) Preparation of (RS) -S- (3-aminophenyl) -S-methylaminosulfoxide

A solution of 200mg (1.00mmol) of (RS) -S-methyl-S- (3-nitrophenyl) aminosulfoxide in 20ml of THF is mixed at room temperature with 8ml of an approximately 10% solution of Ti (III) Cl in 20-30% hydrochloric acid. After 3 hours, another 2ml of an approximately 10% solution of Ti (III) Cl in 20-30% hydrochloric acid was added and stirred at room temperature overnight. The reaction was made basic with 1N sodium hydroxide solution and then mixed with ethyl acetate. Filtration and the filter cake washed with ethyl acetate/MeOH (3: 2). The organic solvent was removed in a rotary transponder and the residue was extracted with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue obtained is purified by chromatography (DCM/EtOH 95: 5). 0.82mg (0.48mmol, corresponding to 48% of theory) of product are obtained.

¹H-NMR(DMSO)：7.19(m，1H)，7.11(m，1H)，7.00(m，1H)，6.75(m，1H)，5.56(s，2H)，3.96(s，1H)，2.98(s，3H).

ES：171(ES).

e) Preparation of (RS) -S- (3-aminophenyl) -S-methyl-N-nitroaminosulfoxide

A solution of 100mg (0.41mmol) of (RS) -S-methyl-N-nitro-S- (3-nitrophenyl) aminosulfoxide in 8ml of THF is mixed at room temperature with 3.1ml of an approximately 10% solution of Ti (III) Cl in 20-30% hydrochloric acid. After 1 hour, another 1.0ml of an approximately 10% solution of Ti (III) Cl in 20-30% hydrochloric acid was added and stirred at room temperature for an additional 45 minutes. The reaction was made alkaline with 1N sodium hydroxide solution and then extracted with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue obtained is purified by chromatography (DCM/EtOH 95: 5). 40mg (0.19mmol, corresponding to 45% of theory) of product are obtained.

¹H-NMR(DMSO)：7.33(m，1H)，7.13(m，1H)，7.03(m，1H)，6.90(m，1H)，5.88(s，2H)，3.59(s，3H).

ES：216(ES).

f) Preparation of (RS) -S-methyl-N-nitro-S- (3-nitrophenyl) aminosulfoxide (A) and (RS) -S-methyl-S- (3-nitrophenyl) aminosulfoxide (B)

1.0g (6.45mmol) of (RS) -S-phenyl-5-methylaminosulfoxide is carefully mixed with 3ml of concentrated sulfuric acid. The reaction was carefully mixed dropwise with 1ml of fuming nitric acid while stirring at 0 deg.CMix and slowly heat to room temperature overnight. The reaction solution was carefully added to ice-cooled 1n naoh solution. The basic reaction was extracted with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The resulting residue was mixed with 15ml of MeOH. The precipitate formed is filtered off with suction and then washed with diisopropyl ether. After drying, 485mg (1.98mmol, corresponding to 31% of theory) of product are obtained. The filtrate was rotary evaporated and the precipitate formed was chromatographed (DCM/EtOH 97: 3). 200mg (1.00mmol, corresponding to 16% of theory) of product are obtained.

(A)：

¹H-NMR(DMSO)：8.79(m，1H)，8.64(m，1H)，8.49(m，1H)，8.05(m，1H)，3.88(s，3H).

(B)：

¹H-NMR(DMSO)：8.65(1，1H)，8.48(m，1H)，8.35(m，1H)，7.90(m，1H)，4.62(s，1H)，3.17(s，3H).

MS：201(ES).

g) Preparation of 5-bromo-N⁴-isopropyl-N²- [4- (methylsulfinyl) phenyl group]-pyrimidine-2, 4-diamines

1.77g (4.6mmol) of 5-bromo-N⁴-isopropyl-N²- [4- (methylsulfanyl) phenyl group]Pyrimidine-2, 4-diamine hydrochloride was taken in 40ml DCM and mixed with 1.73g (5.5mmol) of 3-chloroperoxybenzoic acid (55%). The reaction was stirred at room temperature for 90 minutes and then diluted with DCM. Washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Organic phase drying (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (DCM/EtOH 9: 1). 553mg (1.5mmol, corresponding to 33% of theory) ofAnd (3) obtaining the product.

¹H-NMR(DMSO)：9.55(s，1H)，8.08(s，1H)，7.90(d，2H)，7.53(d，2H)，6.53(d，1H)，4.35(m，1H)，2.70(s，3H)，1.25(d，6H).

MS：369(ES).

h) Preparation of 5-bromo-N4-isopropyl-N2- [4- (methylsulfanyl) phenyl ] -pyrimidine-2, 4-diamine

A solution of 4.08g (16.3mmol) of (5-bromo-2-chloro-pyrimidin-4-y-1) -isopropyl-amine in 20ml of acetonitrile is mixed with a solution of 2ml (16.3mmol) of 4-methylsulfanyl-phenylamine in 10ml of acetonitrile at room temperature. The reaction was mixed with 4.1ml of 4M dioxane hydrochloride solution and 4.1ml water and then stirred under reflux for 16 hours. After cooling, the precipitate formed is filtered off with suction, washed with water and dried. 4.94g (12.7mmol, corresponding to 78% of theory) of the product are obtained in the form of the hydrochloride.

¹H-NMR(DMSO)：10.39(s，1H)，8.18(s，1H)，7.88(br，1H)，7.49(d，2H)，7.29(d，2H)，4.30(m，1H)，2.5(s，3H)，1.21(d，6H).

MS：353(ES).85

Other intermediates

Substituent R¹And R²The same as defined in the general formula (I).

i) Preparation of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] propan-1-ol

A solution of 22.8g (100mmol) of 5-bromo-2, 4-dichloropyrimidine in 100ml of acetonitrile is mixed at 0 ℃ with 17.0ml (125mmol) of triethylamine and then with 9.4g (125mmol) of D-aminopropanol. The reaction was stirred at room temperature overnight. The precipitate formed is filtered off with suction, washed with water and dried completely. 21.5g (81mmol, corresponding to 81% of theory) of product are obtained.

¹H-NMR(DMSO)：8.21(s，1H)，7.05(d，1H)，4.86(t，1H)，4.16(m，1H)，3.41(m，2H)，1.17(d，3H).

j) Preparation of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) oxy ] -butan-2-ol

A solution of 1.35g (15.0mmol) of (R, R) - (-) -2, 3-butanediol in 50ml THF was mixed in portions with 480mg (11.0mmol) of sodium hydride (55% dispersion) at 0 ℃ and then stirred at room temperature for 10 minutes. The resulting solution was added to a solution of 2.27g (10.0mmol) of 5-bromo-2, 4-dichloropyrimidine in 25ml of THF at 0 ℃. The reaction was slowly warmed to room temperature and stirred for 12 h. The solvent was removed and the residue was purified by chromatography (hexane/ethyl acetate 1: 1). 2.29g (8.1mmol, corresponding to 81% of theory) of product are obtained.

¹H-NMR(DMSO)：8.44(s，1H)，5.18(q，1H)，3.96(q，1H)，2.02(d，1H)，1.4(d，3H)，1.28(d，3H).

MS：281(ES).

k) Preparation of (R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] -2-methyl-butan-2-ol

A solution of 2.95g (10.0mmol) of methyl-N- (5-bromo-2-chloropyrimidin-4-yl) -D-aminopropionate in 150ml of THF was mixed dropwise with 30ml (90mmol) of a 3M methylmagnesium bromide in diethyl ether under ice-cooling. After 2.5 hours at room temperature, the reaction was mixed with 30ml of saturated ammonium chloride solution. Diluted with water and then extracted with ethyl acetate (3 times). The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate: 4: 1-1: 1). 2.81g (9.5mmol, corresponding to 95% of theory) of product are obtained.

¹H-NMR(CDCl₃)：8.1(s，1H)，5.9(d，1H)，4.2(m，1H)，1.8(br，1H)，1.2(m，9H).

ka) preparation of methyl-N- (5-bromo-2-chloropyrimidin-4-yl) -D-aminopropionate

22.8g (100mmol) of 5-bromo-2, 4-dichloropyrimidine and 14.0g (100mmol) of methyl D-aminopropionate hydrochloride are dissolved in 300ml of THF and 75ml of DMF. The reaction mixture was mixed with 33.5ml (240mmol) of triethylamine under ice-cooling, and then slowly warmed to room temperature. After 48 hours, the solvent is removed in a rotary evaporator and the residue is purified by chromatography (hexane/ethyl acetate: 4: 1-2: 1). 25.5g (86.1mmol, corresponding to 86% of theory) of product are obtained.

¹H-NMR(CDCl₃)：8.2(s，1H)，6.1(d，1H)，4.8(m，1H)，3.8(s，3H)，1.6(d，3H).

l) preparation of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] butan-2-ol

32.7g (159mmol) of copper (I) bromide dimethyl sulfide complex were introduced under nitrogen into 1000ml of diethyl ether and cooled to-78 ℃. Over a period of about 25 minutes, 200ml of a 1.6M solution of methyllithium in diethyl ether were added dropwise, after which the cooling bath was removed. The reaction was stirred for 40 minutes, then the temperature was raised to-35 ℃. Cooled to-55 ℃ and 18.9g (71.5mmol) of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino are then added over a period of 20 minutes]Propionaldehyde. Stirring was carried out at-55 ℃ for 6 hours, followed by filling the cooling bath with dry ice, covering with aluminum foil, and then stirring the reaction overnight. 200ml of a saturated ammonium chloride solution are added dropwise and the reaction is warmed to room temperature. The organic phase is separated by dilution with 500ml of diethyl ether, and the aqueous phase is extracted with diethyl ether. The combined organic phases were washed with saturated ammonium chloride solution and saturated sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate: 4: 1-1: 1). 8.4g (30.0mmol, corresponding to 42% of theory) of product are obtained.

¹H-NMR(CDCl₃)：8.1(s，1H)，5.8(d，1H)，4.2(m，1H)，3.9(m，1H)，2.0(d，1H)，1.3(d，3H)，1.2(d，3H).

HPLC analysis:

column: chiralpak AD-H5 mu

Length × ID: 150X 4.6mm

Eluent: hexane, and ethanol

Flow rate: 1.0ml/min

Gradient: isocyatic 5% C

A detector: UV 254nm

Temperature: 25 deg.C

RT(min)：6.04

la) preparation of (R) -2- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] propanal

A solution of 40.0g (135.8mmol) of methyl-N- (5-bromo-2-chloropyrimidin-4-yl) -D-aminopropionate in 800ml of toluene was mixed at-78 ℃ with 310ml of a 1.2M solution of diisobutylaluminum hydride. After 30 minutes, the reaction was carefully quenched with methanol. The reaction was warmed to room temperature and diluted with 1000ml of tert-butyl methyl ether. Washing was carried out sequentially with 1N HCl (3X 100ml), saturated sodium bicarbonate solution (3 times) and saturated sodium chloride solution (3 times). Organic phase drying (MgSO)₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate: 4: 1-1: 1). 22.5g (83.9mmol, corresponding to 62% of theory) of product are obtained.

¹H-NMR(CDCl₃)：9.6(s，1H)，8.2(s，1H)，6.3(d，1H)，4.8(m，1H)，1.5(d，3H).

lb) preparation of (2R, 3R) -3- [ (5-bromo-2-chloropyrimidin-4-yl) amino ] 4-methoxybutan-2-ol

311mg (2.6mmol) of (2R, 3R) -3-amino-4-methoxy-butane-2-ol hydrochloride (prepared according to A.I. Meyers, D.Hoyer, Tet.Lett.1985, 26, 4687) are mixed in 2ml of acetonitrile with 0.28ml of triethylamine and shaken. Filtration and washing of the filter cake with 2ml acetonitrile. The filtrate was added dropwise at-30 ℃ to a solution of 455mg (2.0mmol) of 5-bromo-2, 4 dichloro-pyrimidine in 26ml of acetonitrile. The cooling bath was removed and the temperature was slowly raised to room temperature while stirring. After 16 h, the solvent was removed in a rotary evaporator and the residue was purified by chromatography (hexane/ethyl acetate: 4: 1-1: 1). 509mg (1.6mmol, corresponding to 80% of theory) of product are obtained.

¹H-NMR(CDCl₃)：8.1(s，1H)，6.3(d，1H)，4.3(m，1H)，4.2(m，1H)，3.8(d，2H)，3.4(s，3H)，3.1(d，1H)，1.2(d，3H).

lc) preparation of 5-bromo-2-chloropyrimidin-4-ol

50.5g of 5-bromo-2, 4-dichloropyrimidine are mixed with 133ml of 2N sodium hydroxide solution at 45-50 ℃ and stirred for 50 minutes. After cooling, the reaction mixture was acidified with 21ml of concentrated hydrochloric acid while cooling with ice. The precipitate is filtered off with suction, washed with water and a little dichloromethane and then dried at 25-35 ℃. 17.12g (36.9%) of product are obtained, which has a melting point of 136 ℃ and 145 ℃ (decomposition).

The following compounds were prepared in analogy to the process examples described above, respectively:

n) preparation of 5-bromo-2- [4- (methylsulfanyl) phenylamino ] pyrimidin-4-ol

9.8g of 5-bromo-2-chloropyrimidin-4-ol are suspended in 200ml of acetonitrile. After addition of 7.2g of 4-methylsulfanyl-phenylamine, 12ml of 4N dioxane hydrochloride solution were added dropwise with vigorous stirring. After dropwise addition of 5ml of water, the mixture was stirred at 78 ℃ for 3 hours and then at room temperature for 2 days. The mixture was cooled in an ice bath and then filtered with suction. The filter cake was washed 2 times with acetonitrile and then dried. 15.2g (92.7%) of the product are obtained, which has a melting point of 238 deg.C (decomposition).

o) preparation of (RS) -5-bromo-2- [4- (methylsulfinyl) phenylamino ] pyrimidin-4-ol

11g of 5-bromo-2- [4- (methylsulfanyl) phenylamino ] pyrimidin-4-ol are suspended in 110ml of glacial acetic acid. While cooling with ice water, 4.6ml of a 30% hydrogen peroxide solution was added dropwise. The mixture was stirred at room temperature for 18 hours and then filtered with suction. The filter cake was washed 2 times with water and 1 time with ethanol and then dried under vacuum at 60 ℃. 8.75g (75.7%) of product are obtained, which has a melting point of 240 ℃ C (decomposition).

p) preparation of (RS) -S- {4- [ (5-bromo-4-hydroxypyrimidin-2-yl) amino ] phenyl } -S-methylaminosulfoxide

324mg of (RS) -5-bromo-2- [4- (methylsulfinyl) phenylamino ] pyrimidin-4-ol and 128mg of sodium azide are suspended in 6ml of dichloromethane and then mixed dropwise with 0.3ml of concentrated sulfuric acid while cooling with ice. The mixture was stirred at 40 ℃ for 36 hours. The organic phase was poured off and the residue was stirred with ice-water. The solid is filtered off with suction, washed 2 times with water and then 1 time with ethanol and then dried. 266mg (78.2%) of the product are obtained, which has a melting point of 230 ℃ C (decomposition).

q) preparation of (RS) -S- {4- [ (5-bromo-4-chloropyrimidin-2-yl) amino ] phenyl } - -S-methylaminosulfoxide

255mg of (RS) -S- {4- [ (5-bromo-4-hydroxypyrimidin-2-yl) amino ] phenyl } -S-methylamino sulfoxide were suspended in 1.5ml of phosphorus oxychloride and stirred at 106 ℃ for 3 hours, then at room temperature for 16 hours. The mixture was poured into ice water, made basic with 25% aqueous ammonia solution while being cooled vigorously (temperature less than 5 ℃) and stirred in an ice bath for 1 hour. The precipitate is filtered off with suction, washed with water and then dried at 60 ℃. 220mg (81.8%) of the product are obtained, which has a melting point of 170-173 ℃.

r) preparation of (RS) -S- (4-aminophenyl) -S-cyclopropyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

320mg of (RS) -S-cyclopropyl-S- (4-nitrophenyl) -N- [2- (trimethylsilyl) ethyl-sulfonyl ] aminosulfoxide was dissolved in 5ml of tetrahydrofuran. While cooling with ice, 7.2ml of a solution of about 10% by weight of titanium (III) chloride in 20 to 30% by weight of hydrochloric acid were added dropwise. The solution was stirred at room temperature for 16 hours and then poured onto ice. The pH was adjusted to 8-9 with 15% sodium hydroxide solution. After addition of ethyl acetate, the mixture was stirred vigorously. The precipitate is filtered off with suction and washed with 100ml of ethyl acetate. The filtrates were combined, dried and concentrated by evaporation. After purification by flash chromatography, 215mg of (RS) -S- (4-aminophenyl) -S-cyclopropyl-N- [2- (trimethylsilyl) ethylsulfonyl ] -aminosulfoxide are obtained.

Melting point: 137-138 deg.C

It was also prepared in a similar manner: (RS) -S- (4-aminophenyl) -S-cyclopropyl-methyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide (melting point: 138 ℃ C.) and (RS) -S- (4-aminophenyl) -S-cyclopentyl-N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide (melting point: 146 ℃ C.) at 147 ℃ C.).

S) preparation of (RS) -S-cyclopropyl-S- (4-nitrophenyl) -N- [2- (trimethylsilyl) ethyl-sulfonyl ] aminosulfoxide

260mg of (RS) -1- (cyclopropylsulfinyl) -4-nitrobenzene were dissolved in 10ml of acetonitrile, mixed with 100mg of copper (I) tetrakis- (acetonitrile) -hexafluorophosphate and stirred at room temperature for 45 minutes. The solution was cooled in an ice bath and mixed with 613mg of [ N- (2- (trimethylsilyl) ethanesulfonyl) imino ] phenyliododine (PhI ═ NSes: J.Org.Chem., 64(14), 5304-5307 (1999)). After stirring for 30 minutes at 0 ℃, a further 232mg of PhI ═ Nses are added. After stirring for 2 hours at 0 ℃, a further 60mg of PhI ═ Nses and 10mg of tetrakis- (acetonitrile) -copper (I) hexafluorophosphate were added. After stirring for 30 minutes at 0 ℃, the mixture was concentrated by evaporation. The oily residue was mixed with hexane, whereby the product was crystallized. The solution was decanted off and the solid was purified by flash chromatography (hexane/ethyl acetate). 325mg of (RS) -S-cyclopropyl-S- (4-nitrophenyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] -aminosulfoxide are obtained.

Melting point: 111 ℃ C. and 114 ℃ C

t) preparation of (RS) -1- (cyclopropylsulfinyl) 4-nitrobenzene

350mg of 1- (cyclopropylsulfanyl) -4-nitrobenzene are dissolved in 5ml of acetonitrile and admixed with 10mg of iron chloride Hexahydrate (HI). After stirring at room temperature for 10 minutes, 450mg of periodic acid was added thereto while cooling. The mixture was stirred at room temperature for 30 minutes, cooled in an ice bath and then mixed dropwise with a half-saturated sodium bisulfite solution. Diluted with dichloromethane, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, and then concentrated by evaporation. After purification by flash chromatography, 270mg of (RS) -1- (cyclopropylsulfinyl) -4-nitrobenzene were obtained.

Melting point: 104 ℃ C

The following compounds were prepared according to a similar procedure:

ta) preparation of (RS) -1- (ethylsulfinyl) -4-nitrobenzene

¹H-NMR(DMSO)：8.39(m，2H)，7.91(m，2H)，3.18(m，1H)，2.88(m，1H)，1.06(tr，3H).

tb) preparation of (RS) -2- [ (4-nitrophenyl) sulfinyl ] ethanol

¹H-NMR(DMSO)：8.41(m，2H)，7.93(m，2H)，5.13(tr，1H)，3.84(m，1H)，3.78(m，1H)，3.16(m，1H)，2.95(m，1H).

MS：216(ES).

tc) preparation of (RS) -1- (isopropylsulfinyl) -4-nitrobenzene

¹H-NMR(DMSO)：8.39(m，2H)，7.88(m，2H)，3.10(m，1H)，1.25(d，3H)，0.88(d，3H).

td) preparation of (RS) -2-methyl-1- (methylsulfinyl) -4-nitrobenzene

¹H-NMR(DMSO)：8.31(m，1H)，8.19(m，1H)，8.04(m，1H)，2.78(s，3H)，2.45(s，3H).

MS：200(ES).

te) preparation of (RS) -1- (methylsulfinyl) -4-nitro-2- (trifluoromethyl) benzene

¹H-NMR(DMSO)：8.78(m，1H)，8.50(m，2H)，2.83(s，3H).MS：270(ES).

tf) preparation of (RS) -2-fluoro-1- (methylsulfinyl) -4-nitrobenzene

¹H-NMR(DMSO)：8.33(m，2H)，7.99(m，1H)，2.90(s，3H).

MS：204(ES).

u) preparation of 1- (cyclopropylsulfanyl) -4-nitrobenzene

1- (3-chloro-propylsulfanyl) -4-nitro-benzene was cyclized as described in the following references: chem., 33(1), 43-47 (1968).

¹H-NMR(DMSO)：8.18(d，2H)，7.60(d，2H)，2.40(m，1H)，1.21(m，2H)，0.66(m，2H).

MS(CI)：195(M+，12％)，213(M++1+NH3，100％)，230(M++1+2NH3，44％).

v) preparation of 1- [ (3-chloropropyl) sulfanyl ] 4-nitrobenzene

1g of potassium hydroxide is dissolved in 40ml of methanol and admixed with 2.3g of 4-nitrothiophenol. The suspension was stirred at room temperature for 1 hour and then mixed dropwise with 1.48ml of 1-bromo-3-chloropropane. After stirring at room temperature for 4 hours, a further 0.15ml of 1-bromo-3-chloropropane are added dropwise. The mixture was stirred at room temperature for 65 hours, concentrated by evaporation in vacuo and taken up in ethyl acetate. Extracted with water and saturated brine solution, dried over sodium sulfate and then concentrated by evaporation. After purification by flash chromatography, 2.54g of 1- (3-chloro-propylsulfanyl) -4-nitro-benzene are obtained.

¹H-NMR(DMSO)：8.16(d，2H)，7.55(d，2H)，3.77(t，2H)，3.25(t，2H)，2.08(q，2H).

MS(ES)：232(100％)，234(38％).

The following compounds were also prepared in a similar manner: 1-Cyclopropylmethylsulfanyl-4-nitro-benzene (from (chloromethyl) -cyclopropane) and 1-cyclopentylsulfanyl-4-nitro-benzene (from bromocyclopentane).

w) preparation of (RS) -S- (2-hydroxyethyl) -S- (4-nitrophenyl) -N- [2- (trimethylsilyl) ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO)：8.48(m，2H)，8.24(m，2H)，4.97(tr，1H)，3.99(tr，2H)，3.79(m，2H)，3.00(dd，2H)，0.96(m，2H)，0.05(s，9H).

x) preparation of (RS) -S- (4-amino-2-methoxyphenyl) -S-methylaminosulfoxide

1.5g (6.5mmol) of (RS) -S- (2-methoxy-4-nitrophenyl) -S-methylaminosulfoxide are reacted in 100ml of ethanol with 300mg of palladium on charcoal (10%. times.50% H)₂O) mixed and hydrogenated at room temperature and pressure for 45 minutes. The reaction was filtered and concentrated by evaporation. 1.0g (5.1mmol, corresponding to 79% of theory) of product are obtained.

¹H-NMR(DMSO-D6)：7.10(m，1H)，6.92(m，1H)，6.73(m，1H)，4.70(br，3H)，3.76(s，3H)，3.13(s，3H).

MS：201(ES).

y) preparation of (RS) -S- (2-methoxy-4-nitrophenyl) -S-methylaminosulfoxide

7.5g of fuming nitric acid was cooled to-10 ℃ and then slowly mixed with 5.0g (32.4mmol) of 1-methoxy-2-methylsulfanyl-benzene. The reaction was slowly warmed to room temperature while stirring, diluted with 100ml of water, and then neutralized with sodium bicarbonate. Extracted with diethyl ether and ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation.

5.3g of the intermediate obtained were mixed with 1.8g (27.7mmol) of sodium azide and 25ml of CHCl₃And (4) mixing. The reaction was cooled to 0 ℃ and carefully mixed with 6.3ml of concentrated sulfuric acid. First to room temperature and then to 45 ℃. The reaction was stirred at this temperature overnight. After cooling, it was mixed with 75ml ice-water and 20ml CHCl₃And (4) mixing. The organic phase was separated and the aqueous phase was reused with 100ml of CHCl₃And (4) extracting. The aqueous phase is made alkaline with 1N NaOH solution and then with CHCl₃(2X) extraction. The organic phases of the last extraction are combined and dried (Na)₂SO₄) Filtered and concentrated by evaporation. 3.8g (16.5mmol) of product are obtained.

¹H-NMR(DMSO-D₆)：8.66(m，1H)，8.48(m，1H)，7.45(m，1H)，4.70(s，1H)，4.08(s，3H)，3.21(s，3H).

MS：231(ES).

z) preparation of (RS) -S- (2-methyl-4-nitrophenyl) -S-methylaminosulfoxide

1.5g (7.5mmol) of (RS) -2-methyl-1- (methylsulfinyl) -4-nitrobenzene and 1.1g (17.1mmol) of sodium azide were placed in 10.0ml of CHCl at 0 deg.C₃Carefully mixed with 2.2ml of concentrated sulfuric acid. The reaction was first warmed to room temperature and then to 45 ℃ with vigorous stirring. Stirring was carried out at this temperature for 116 hours. After cooling, it was mixed with water and extracted with DCM (2 times). The aqueous phase was made basic with 2N NaOH solution and then extracted with DCM. The combined organic phases were filtered through a Whatman filter and then concentrated by evaporation. The resulting crude product was recrystallized from ethyl acetate. 1.3g (6.1mmol, corresponding to 81% of theory) of product are obtained

¹H-NMR(DMSO)：8.28(m，1H)，8.22(m，2H)，4.67(s，1H)，3.17(s，3H)，2.81(s，3H).

MS：215(ES).

za) preparation of (RS) -S-methyl-S- [ 4-nitro-2- (trifluoromethyl) phenyl ] aminosulfoxide

¹H-NMR(DMSO)：8.73(m，1H)，8.52(m，2H)，5.00(s，1H)，3.17(s，3H)MS：269(ES).

zb) preparation of (RS) -S- (2-fluoro-4-nitrophenyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：8.34(m，1H)，8.24(m，1H)，8.10(m，1H)，5.08(s，1H)，3.21(s，3H).

MS：219(ES).

zc) preparation of (RS) -N, S-dimethyl-S- (4-nitrophenyl) aminosulfoxide

500mg (2.5mmol) of (RS) -S- (4-nitrophenyl) -S-methylaminosulfoxide are stirred in 4ml of formaldehyde (37% in water) and 20ml of formic acid (98-100%) in an open beaker at 100 ℃. After 22 hours, the solvent is evaporated, admixed with 4ml of formaldehyde (37% in water) and 20ml of formic acid (98-100%) and stirred at 100 ℃ for a further 22 hours. The residue of the solvent was removed in a rotary evaporator. The remaining residue was dissolved in 2N HCl and extracted with DCM. NaHCO for aqueous phase₃Made basic and then extracted with DCM. The combined organic phases were dried (Na)₂SO₄) Filtering andand (5) evaporating and concentrating. 448mg (2.1mmol, corresponding to 85% of theory) of product are obtained.

¹H-NMR(DMSO-D₆)：8.43(m，2H)，8.08(m，2H)，3.24(s，3H)，2.48(s，3H)

MS：214(ES).

zd) preparation of (RS) -N- (ethoxycarbonyl) -S-methyl-S- (4-nitrophenyl) aminosulfoxide

8.50g (42.5mmol) of (RS) -S- (4-nitrophenyl) -S-methylaminosulfoxide are mixed dropwise in 400ml of pyridine at room temperature with 18.8ml (197.2mmol) of ethyl chloroformate. The reaction was stirred at room temperature for 4 hours and then added to dilute sodium chloride solution. Extraction was performed with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate 1: 1). 8.94g (32.8mmol, corresponding to 77% of theory) of product are obtained.

¹H-NMR(DMSO-D₆)：8.49(m，2H)，8.22(m，2H)，3.90(m，2H)，3.56(s，3H)，1.10(tr，3H).

ze) preparation of (RS) -S-ethyl-N- ({ [ (1R, 2S, SR) -2-isopropyl-5-methyl-cyclohexyl ] oxy } carbonyl) -S- (4-nitrophenyl) aminosulfoxide

100mg (0.47mmol) of (RS) -S- (4-nitrophenyl) -S-ethylaminosulfoxide are combined dropwise in 4.40ml of pyridine at room temperature with 0.46ml (2.17mmol) of montmor (+) chloroformate. The reaction was stirred at room temperature for 4 hours and then added to diluteSodium chloride solution. Extraction was performed with ethyl acetate. The combined organic phases were dried (Na)₂SO₄) Filtered and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate 1: 1). 161mg (0.41mmol, corresponding to 87% of theory) of product are obtained.

¹H-NMR(DMSO-D₆)：8.49(m，2H)，8.13(m，2H)，4.28(m，1H)，3.67(m，2H)，1.77(m，1H)，1.55(m，2H)，1.25(m，6H)，0.75(m，12H).

zf) preparation of (RS) -N- (ethoxycarbonyl) -S-ethyl-S- (4-nitrophenyl) aminosulfoxide

¹H-NMR(DMSO-D₆)：8.48(m，2H)，8.15(m，2H)，3.92(m，2H)，3.69(m，2H)，1.12(m，6H).

zg) preparation of (RS) -N- (ethoxycarbonyl) -S-methyl-S- (2-methyl-4-nitrophenyl) aminosulfoxide

¹H-NMR(DMSO)：8.33(m，2H)，8.17(m，1H)，3.90(q，2H)，3.55(s，3H)，2.73(s，3H)，1.08(tr，3H).

MS：287(ES).

zh) preparation of (RS) -N- (ethoxycarbonyl) -S- (2-fluoro-4-nitrophenyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：8.45(m，1H)，8.33(m，1H)，8.19(m，1H)，3.40(m，2H)，3.60(s，3H)，1.04(tr，3H).

zi) preparation of (RS) -N- (ethoxycarbonyl) -S-methyl-S- [ 4-nitro-2- (trifluoromethyl) phenyl ] aminosulfoxide

¹H-NMR(DMSO)：8；78(m，1H)，8.65(m，1H)，8.49(m，1H)，3.90(q，2H)，3.58(s，3H)，1.07(tr，3H).

zj) preparation of (RS) -S- (4-aminophenyl) -N- (ethoxycarbonyl) -S-methylaminosulfoxide

8.70g (32.0mmol) of (RS) -N- (ethoxycarbonyl) -S-methyl-S- (4-nitrophenyl) aminosulfoxide in 650ml of THF are slowly mixed at room temperature with 435ml of a 10% Ti (III) Cl solution in about 10% hydrochloric acid (Aldrich). The reaction was stirred at room temperature for 4 hours and then cooled to 0 ℃. 450ml of a 32% NaOH solution are added dropwise. In this case, the reaction mixture was diluted by adding water and ethyl acetate. Mixed with 500ml of ethyl acetate and the organic phase separated. The aqueous phase in the form of a slurry was extracted with ethyl acetate. The combined organic phases were washed with dilute sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated by evaporation. 8.05g (about 32.0mmo1) of product were obtained and used without purification.

¹H-NMR(DMSO-D₆)：7.52(m，2H)，6.66(m，2H)，6.17(m，2H)，3.91(q，2H)，3.30(s，3H)，1.12(tr，3H).

zk) preparation of (RS) -S- (4-aminophenyl) -N- (ethoxycarbonyl) -S-ethylamino sulfoxide

¹H-NMR(DMSO-D₆)：7.47(m，2H)，6.67(m，2H)，6.20(s，2H)，3.90(m，2H)，3.42(q，2H)，1.10(m，6H).

zl) preparation of (RS) -S- (4-aminophenyl) -S- (2-hydroxyethyl) -N- [ 2-trimethylsilyl ] -ethylsulfonyl ] aminosulfoxide

¹H-NMR(DMSO-D₆)：7.54(m，2H)，6.68(m，2H)，6.30(s，2H)，4.90(tr，1H)，3.68(m，4H)，2.95(m，2H)，0.95(m，2H)，0.01(s，9H).

zm) preparation of (RS) -S- (4-amino-2-methylphenyl) -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO-D₆)：7.53(m，1H)，6.48(m，2H)，6.04(s，2H)，3.90(q，2H)，3.30(s，3H)，2.42(s，3H)，1.13(tr，3H).

zn) preparation of (RS) -S- (4-aminophenyl) -N, S-dimethylaminosulfoxide

¹H-NMR(DMSO-D₆)：7.48(d，2H)，6.62(d，2H)，5.95(s，2H)，2.95(s，3H)，2.41(s，3H).

zo) preparation of (RS) -S- (4-amino-2-fluorophenyl) -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：7.45(m，1H)，6.48(m，4H)，3.88(m，2H)，3.30(s，3H)，1.10(tr，3H).

zp) preparation of (RS) -S- [ 4-amino-2- (trifluoromethyl) phenyl ] -N- (ethoxycarbonyl) -S-methylaminosulfoxide

¹H-NMR(DMSO)：7.78(m，1H)，7.12(m，1H)，6.84(m，1H)，6.63(s，2H)，3.89(q，2H)，3.30(s，3H)，1.08(tr，3H).

MS：311(ES).

The following examples will describe the biological effects of the compounds of the present invention, but the scope of the present invention is by no means limited to these examples.

Example 1

CDK1/CycB kinase assay

Recombinant CDK 1-and CycB-GST fusion proteins purified from baculovirus-infected insect cells (Sf9) were obtained from ProQinase GmbH, Freiburg. Histone IIIS used as a kinase substrate was purchased from Sigma.

CDK1/CycB (50 ng/measurement point) in the presence of various concentrations of test substance (0. mu.M, and a range of 0.01-100. mu.M) at 22 ℃ in the presence ofAssay buffer (50mM Tris/HClpH 8.0, 10mM MgCl₂0.1mM sodium orthovanadate, 1.0mM dithiothreitol, 0.5 μm Adenosine Triphosphate (ATP), 10 μ g/measurement point histone IIIS, 0.2 μ Ci/measurement point³³P-gamma ATP, 0.05% NP40, 12.5% dimethyl sulfoxide) for 15 min. The reaction was stopped by adding EDTA solution (250mM, pH8.0, 14. mu.l/measurement point).

For each reaction solution, 10. mu.l were applied to a P30 filter paper strip (Wallac Company) which was washed 3 times for 10 minutes each in 0.5% phosphoric acid, thereby removing unincorporated³³P-ATP. After drying the filter paper strips at 70 ℃ for 1 hour, using scintillator strips (Meltolex)^TMA, Wallac Company) and then baked at 90 ℃ for 1 hour. Determination of incorporated by scintillation measurement in a gamma-radiometer (Wallac)³³Amount of P (substrate phosphorylation).

Example 2

CDK2/CycE kinase assay

Recombinant CDK 2-and CycE-GST fusion proteins purified from baculovirus-infected insect cells (Sf9) were obtained from ProQinase GmbH, Freiburg. Histone IIIS used as a kinase substrate was purchased from Sigma.

CDK2/CycE (50 ng/measurement point) in the presence of various concentrations of test substance (0. mu.M, and a range of 0.01-100. mu.M) in assay buffer (50mM tris/HCl pH8.0, 10mM MgCl) at 22 ℃₂0.1mM sodium orthovanadate, 1.0mM dithiothreitol, 0.5. mu.M Adenosine Triphosphate (ATP), 10. mu.g/measurement point histone IIIS, 0.2. mu. Ci/measurement point³³P-gamma ATP, 0.05% NP40, 12.5% dimethyl sulfoxide) for 15 min. The reaction was stopped by adding EDTA solution (250mM, pH8.0, 14. mu.l/measurement point).

Example 3

VEGF receptor-2 kinase assay

Recombinant VEGF receptor tyrosine kinase-2 was purified as a GST fusion protein from baculovirus-infected insect cells (Sf 9). Poly- (Glu4Tyr) used as a kinase substrate was purchased from Sigma.

VEGF receptor tyrosine kinase (90 ng/measurement point) in the presence of various concentrations of test substance (0. mu.M, and a range of 0.001-30. mu.M) at 22 ℃ in 30. mu.l of assay buffer (40mM Tris/HClpH 5.5, 10mM MgCl)₂1mM MnCl₂3. mu.M sodium orthovanadate, 1.0mM dithiothreitol, 8. mu.M Adenosine Triphosphate (ATP), 27. mu.g poly- (Glu4Tyr) per measurement point, 0.2. mu. Ci per measurement point³³P-gamma ATP, 1% dimethyl sulfoxide) for 15 minutes. An EDTA solution (250mmol, pH7.0, 10. mu.l/measurement point) was added to stop the reaction.

For each reaction solution, 10. mu.l were applied to a P30 filter paper strip (Wallac Company) which was washed 3 times for 10 minutes each in 0.5% phosphoric acid, thereby removing unincorporated³³P-ATP. After drying the filter paper strips at 70 ℃ for 1 hour, using scintillator strips (Meltolex)^TMA, Wallac Company) and then baked at 90 ℃ for 1 hour. Determination of incorporated by scintillation measurement in a gamma-radiometer (Wallac)³³Amount of p (substrate phosphorylation). IC (integrated circuit)₅₀The value is determined by the inhibitor concentration which must be necessary to inhibit the incorporation of phosphoric acid to 50% of the uninhibited incorporation after removal of the blank reading (EDTA-stopped reaction).

Example 4

Proliferation assay

The collected human tumor cells (MCF7, hormone-dependent human breast cancer cells, referred to as ATCC HTB 22; NCI-H460, human non-small cell lung cancer cells, ATCC HTB-177, HCT 116, human contact cancer cells, ATCC CCL-247; DU 145, hormone-dependent prostate cancer cells, ATCCHTB-81; MaTu-MDR, hormone-dependent, multidrug-resistant human breast cancer cells, EPO-GmbH, Berlin) were plated at a concentration of 500 cells/measurement point in 96-well multi-titer plates in 200. mu.l of the corresponding growth medium, depending on the growth rate of the corresponding cells. After 24 hours, the cells of one plate (0 spot plate) were stained with crystal violet (as described below) while the media of the other plate was replaced with fresh medium (200. mu.l) to which various concentrations of the test substance (0. mu.M, and in the range of 0.01-30. mu.M; final concentration of solvent dimethyl sulfoxide was 0.5%) were added. Cells were cultured for 4 days in the presence of the test substance. Cell proliferation was determined by staining the cells with crystal violet: cells were fixed by adding 20. mu.l/measurement point of 11% glutaraldehyde solution at room temperature for 15 minutes. After washing the fixed cells 3 times with water, the plates were dried at room temperature. Cells were stained by adding 100. mu.l/measurement point of a 0.1% crystal violet solution (pH was set to 3 by adding acetic acid). After washing the stained cells 3 times with water, the plates were dried at room temperature. 100. mu.l/measurement point of a 10% acetic acid solution will be added, thereby dissolving the dye. The extinction was determined photometrically at a wavelength of 595 nm. The extinction measurements (═ 0%) for the 0-point plates and those for the untreated (0 μ M) cells (═ 100%) were normalized, and the percentage of growth of the cells was calculated.

Example 5

Carbon dehydratase test

The principle of this experiment is based on the hydrolysis of 4-nitrophenyl acetate by carbodehydratase (Pocker & Stone, Biochemistry, 1967, 6, 668) and subsequent photometric measurement of the dye 4-nitrophenolate produced with a 96-channel spectrophotometer at 400 nm.

Mu.l of test compound dissolved in DMSO (100 times the final concentration) was transferred to wells of a 96-well microtiter plate using a pipette, the concentration of test compound ranged from 0.03-10. mu.M (final), for a total of 4 measurements. Wells containing solvent but no test compound were used as reference values (1, wells containing no carbodehydratase for correct non-enzymatic hydrolysis of the substrate, and 2, wells containing carbodehydratase for determination of the activity of the uninhibited enzyme).

Mu.l of assay buffer (10mM Tris/HCl, pH 7.4, 80mM NaCl) with or without 3 units carbodehydratase I or II per well was transferred to the wells of the microtiter plates using a pipette. The enzymatic reaction was started by adding 10. mu.l of a substrate solution (1mM of 4-nitrophenylacetate (Fluka #4602), dissolved in anhydrous acetonitrile, to a final substrate concentration of 50. mu.M). The plates were incubated at room temperature for 15 minutes. The extinction was measured photometrically at 400 nm. Enzyme inhibition was calculated after numerical normalization of the measurement of the extinction of the reaction in wells containing no enzyme (═ 100% inhibition) and wells containing uninhibited enzyme (═ 0% inhibition).

The results obtained in these examples, as well as comparative data, are shown in tables 1-3 below. To confirm the superiority of the compounds according to the invention compared with known compounds, the compounds according to the invention were compared in an enzyme test with known reference compounds and with known compounds of similar structure as in example 10 of WO 00/096888. The results are shown in tables 1 and 2 below. In table 3, the compounds according to the invention show better data than the compound of example 10 of WO 00/12486 and acetazolamide.

TABLE 1

TABLE 2

Example No. 2

CDK2/CycE IC₅₀[nM]

CDK1/CycB IC₅₀[nM]

VEGF-R2 IC₅₀[nM]

2.0	16	110	70
				1.0	＜10	79	40
1.3	6	10	140
				1.4	10	13	340
1.2	20	130	48
				2.1	390	＞1000	74
2.3	33	160	61
				1.23	6	8	75
1.24	8	5	150
				1.25	3	2	70
1.31	9	27	140
				1.41	2	2	76
1.42	2	5	64
				1.7	＞1000	＞1000	240
1.26	4	2	31
				1.27	4	3	97
1.10	＞1000	＞1000	910
				1.39	19	49	150

Example No. 2	CDK2/CycE IC₅₀[nM]	CDK1/CycB IC₅₀[nM]	VEGF-R2 IC₅₀[nM]
				1.33	51	200	450
1.35	42	96	94
				1.34	28	110	530
1.40	14	21	110
				1.63	63	200	89
1.48	7	16	270
				1.54	5	8	69
1.11	25	44	83
				1.9	4	5	49
1.12	49	160	160
				1.6	8	14	29
1.37	48	63	57
				1.57	4	8	66
1.49	9	15	470
				1.50	9	44	230
1.55	27	45	79
				1.56	24	68	32
1.46	4	11	340
				1.47	6	27	300

Example No. 2	CDK2/CycE IC₅₀[nM]	CDK1/CycB IC₅₀[nM]	VEGF-R2 IC₅₀[nM]
				1.16	130	170	130
1.20	54	160	820
				1.38	78	75	59
1.36	11	43	92
				1.51	4	5	26
1.60	4	4	39
				1.14	4	7	69
1.15	4	25	59
				1.32	12	16	56
1.28	7	14	37

3.4	41	72	250
				3.5	8	17	150
1.58	7	4	45
				1.59	7	9	48
3.0	16	49	170
				3.6	18	22	200
3.7	11	19	110
				3.8	27	91	＞1000
3.1	33	97	120

Example No. 2	CDK2/CycE IC₅₀[nM]	CDK1/CycB IC₅₀[nM]	VEGF-R2 IC₅₀[nM]
				1.29	4	7	16
1.30	6	15	29
				3.10	4	18
3.9	8	55
				1.18	3	3
1.21	6	5
				1.53	4	11
1.19	3	7
				1.44	2	5
Example 10 in WO 02/096888	＜10	90	200

TABLE 3

Example No. 2	Inhibition of human carbon dehydratase-2 IC₅₀[nM]
		Example 1.0	＞10000
Example 2.0	＞10000

Acetazolamide	51
		Example 10 in WO 02/096888	190

Tables 1 and 2 show that the compounds according to the invention inhibit cyclin-dependent kinases and/or VEGF receptor tyrosine kinases in the nanomolar range and thus inhibit the proliferation of tumor cells and/or tumor neovascularization.

Table 3 shows that, in contrast to the compounds of the prior art, such as acetazolamide or the compound of example 10 of WO02/09688 (which represents the closest prior art), the compounds according to the invention do not have any measurable inhibitory effect on carbohydrases and therefore no longer exhibit the possible side effects attributed to the carbohydrase inhibitory effect.

In this respect, the above data confirm that the compounds according to the invention are superior to the compounds of the prior art.

Claims

1. Compounds of the general formula (I) and diastereomers, enantiomers or salts thereof,

wherein:

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen, halogen, C₁-C₆Alkyl, CF₃CN or represents a group-O-C₁-C₆An alkyl group, a carboxyl group,

R²represents hydrogen or represents C which is optionally substituted identically or differently in one or more positions by₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₇Cycloalkyl, or phenyl: hydroxy, halogen, C₁-C₆Alkoxy, amino, cyano, C₁-C₆Alkyl, -NH- (CH)₂)_n-C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl, -NHC₁-C₆Alkyl, -N (C)₁-C₆Alkyl radical)₂、C₁-C₆Alkanoyl, -CONR⁹R¹⁰、-COR⁸、-C₁-C₆Alkyl OAc, carboxyl, phenyl, - (CH)₂)_n-phenyl, -phenyl- (CH)₂)_n-R⁸、-(CH₂)_nPO₃(R⁸)₂or-NR⁹R¹⁰And the above-mentioned phenyl group, C₃-C₇Cycloalkyl and- (CH)₂)_n-the phenyl group itself may be optionally substituted, identically or differently, in one or more positions, by: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or a group-CF₃or-OCF₃，C₃-C₇Ring of cycloalkyl and C₁-C₁₀Alkyl may optionally be interrupted by a nitrogen, oxygen and/or sulfur atom and/or by a-C (O) -group in the ring and/or optionally contain a possible double bond in the ring,

x represents oxygen, sulphur or a group-NH-or-N (C)₁-C₃Alkyl) -,

R³represents hydrogen, hydroxy, halogen, CF₃、OCF₃Or represents a group-NR⁹R¹⁰Or represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkoxy or

group-NR⁹R¹⁰Substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or C₁-C₆Alkoxy, m represents 0 to 4,

R⁴represents hydrogen or represents the group-COR⁸、NO₂Trimethylsilyl group, tert-butyl-dimethylsilyl group, tert-butyl-diphenylsilyl group, triethylsilyl group or-SO₂R⁷Or represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl or C₃-C₇Cycloalkyl groups: hydroxy, halogen, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, C₃-C₇Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl or a group-CONR⁹R¹⁰、-COR⁸、-CF₃、-OCF₃or-NR⁹R¹⁰，

R⁵Represents optionally in one or more positions identically or differently substituted by hydroxy, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl, halogen or the radical-NR⁹R¹⁰Substituted C₁-C₁₀Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₃-C₇A cycloalkyl group,

R⁷represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkyl radical, C₁-C₆Alkoxy or trimethylsilyl groups or-NR⁹R¹⁰Substituted C₁-C₁₀Alkyl or benzeneThe base group is a group of a compound,

R⁹And R¹⁰Each independently represents hydrogen or C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy-C₁-C₆Alkyl, dihydroxy-C₁-C₆Alkyl, phenyl, or

R⁹And R¹⁰Together form C₃-C₇A cycloalkyl ring, which ring optionally comprises a nitrogen, oxygen and/or sulfur atom and/or has a-C (O) -group inserted into the ring and/or optionally comprises a possible double bond in the ring, and

n represents a number of 1 to 6,

wherein said C₃-C₇-cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

2. A compound of general formula (I) according to claim 1, wherein:

q represents a phenyl group, and Q represents a phenyl group,

R²represents hydrogen or represents C which is optionally substituted identically or differently in one or more positions by₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₇Cycloalkyl or phenyl: hydroxy, halogen, C₁-C₆Alkoxy, amino, cyano, C₁-C₆Alkyl, -NH- (CH)₂)_n-C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl, -NHC₁-C₆-alkyl, -N (C)₁-C₆-alkyl groups)₂、C₁-C₆Alkanoyl, -CONR⁹R¹⁰、-COR⁸、-C₁-C₆Alkyl OAc, carboxyl, phenyl, - (CH)₂)_n-phenyl, -phenyl- (CH)₂)_n-R⁸、-(CH₂)_nPO₃(R⁸)₂or-NR⁹R¹⁰And the above-mentioned phenyl group, C₃-C₇Cycloalkyl or- (CH)₂)_n-the phenyl group itself may be optionally substituted, identically or differently, in one or more positions, by: halogen, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or a group-CF₃or-OCF₃，C₃-C₇Ring of cycloalkyl and C₁-C₁₀Alkyl may optionally be interrupted by a nitrogen, oxygen and/or sulfur atom and/or by a-C (O) -group in the ring and/or optionally contain a possible double bond in the ring,

x represents oxygen, sulphur or a group-NH-or-N (C)₁-C₃Alkyl) -,

R³represents hydrogen, hydroxy, halogen, CF₃、OCF₃Or represents a group-NR⁹R¹⁰Or represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkoxy or radicals-NR⁹R¹⁰Substituted C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or C₁-C₆Alkoxy, m represents 0 to 2,

R⁴represents hydrogen or represents the group-COR⁸、NO₂Trimethylsilyl group, tert-butyl-dimethylsilyl group, tert-butyl-diphenylsilyl group, triethylsilyl group or-SO₂R⁷Or represents optionally in one or more positions identically or differently substituted bySubstituted C₁-C₁₀Alkyl or C₃-C₇Cycloalkyl groups: hydroxy, halogen, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, C₃-C₇Cycloalkyl radical, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆alkoxy-C₁-C₆alkoxy-C₁-C₆Alkyl or a group-CONR⁹R¹⁰、-COR⁸、-CF₃、-OCF₃or-NR⁹R¹⁰，

R⁷represents optionally halogen, hydroxy, C in one or more positions, identically or differently₁-C₆Alkyl radical, C₁-C₆Alkoxy or trimethylsilyl groups or-NR⁹R¹⁰Substituted C₁-C₁₀An alkyl group or a phenyl group, or a substituted or unsubstituted alkyl group,

R⁹And R¹⁰Together form C₃-C₇A cycloalkyl ring, which ring optionally contains a nitrogen, oxygen and/or sulfur atom and/or is in the ringInterrupted by a-C (O) -group and/or optionally containing a possible double bond in the ring, and

n represents 1 to 6.

3. A compound of general formula (I) according to claim 1 or 2, wherein:

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen, halogen, CN or CF₃，

R²Represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl radical, C₂-C₁₀Alkynyl or phenyl: hydroxy, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkynyl or radical-COR⁸，

X represents oxygen, sulphur or a group-NH-,

m represents a number of 0 to 2,

R⁵represents optionally in one or more positions identically or differently substituted by hydroxy or C₃-C₇Cycloalkyl-substituted C₁-C₁₀Alkyl or C₃-C₇A cycloalkyl group,

R⁷represents C optionally substituted in one or more positions, identically or differently, by trimethylsilyl₁-C₁₀An alkyl group or a phenyl group, or a substituted or unsubstituted alkyl group,

R⁸represents hydrogen, C₁-C₆Alkyl or C₁-C₆Alkoxy, optionally in one or more positions by C₁-C₆Alkyl substitution, and

n represents 1.

4. A compound of general formula (I) according to claim 1 or 2, wherein:

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen or a halogen, and is,

X represents oxygen, sulphur or a group-NH-,

m represents a number of 0 to 2,

R⁷represents C optionally substituted in one or more positions, identically or differently, by trimethylsilyl₁-C₁₀An alkyl group, a carboxyl group,

R⁸represents hydrogen, C₁-C₆Alkyl or C₁-C₆Alkoxy, optionally in one or more positions by C₁-C₆Alkyl substitution.

5. A compound of general formula (I) according to claim 1 or 2, wherein:

q represents a phenyl group, and Q represents a phenyl group,

R¹represents hydrogen or a halogen, and is,

R²represents C optionally substituted in one or more positions, identically or differently, by₁-C₁₀Alkyl radical, C₂-C₁₀Alkynyl or phenyl: hydroxy, halogen, methyl, methoxy, ethynyl or a group-COH or COCH₃，

X represents oxygen, sulphur or a group-NH-,

R³represents hydrogen, halogen, methyl, methoxy or-CF₃，

m represents a number of 0 to 2,

R⁵Represents methyl, ethyl, cyclopropyl, cyclopentyl, - (CH)₂) -cyclopropyl or hydroxyethyl.

6. Use of compounds of the general formula (IIa) and diastereomers, enantiomers and/or salts thereof as intermediates for the preparation of compounds of the general formula (I) as defined in claim 1,

wherein Z represents-NH₂And Q, m, R³、R⁴And R⁵The same as defined in the general formula (I) as defined in claim 1.

7. Use of a compound of general formula (IIa) according to claim 6, wherein:

m represents a number of 0 to 2,

R³represents halogen, or represents C optionally substituted in one or more positions by halogen₁-C₆Alkyl or C₁-C₆An alkoxy group,

R⁴represents hydrogen or represents the group NO₂、-SO₂-R⁷、-CO-R⁸Or C₁-C₁₀Alkyl radical, wherein R⁷And R⁸Having the definitions as described in general formula (I) as defined in claim 1, and

R⁵represents C optionally substituted in one or more positions by halogen or hydroxy₁-C₁₀Alkyl or C₃-C₆A cycloalkyl group.

8. Use of compounds of the general formula (IIIa) or (IIIc) and diastereomers, enantiomers and/or salts thereof as intermediates for the preparation of compounds of the general formula (I) as defined in claim 1,

wherein W represents X-R²，

Or

Wherein W represents halogen and R¹、R²、R³、R⁴、R⁵M, Q and X are as defined in formula (I) as defined in claim 1.

9. Use of a compound of formula (IIIa) or (IIIc) according to claim 8 wherein:

R¹represents a halogen atom or a halogen atom,

x represents-NH-,

R²represents C optionally substituted in one or more positions by hydroxy₁-C₁₀-an alkyl group,

m represents 0, and

R⁵represents C₁-C₁₀An alkyl group.

10. Use of compounds of the general formula (IV) and diastereomers, enantiomers and/or salts thereof as intermediates for the preparation of compounds of the general formula (I) as defined in claim 1,

wherein Hal represents halogen, W represents halogen, hydroxy or X-R²And R is¹、R²And X is as defined in general formula (I) as defined in claim 1.

11. Use of a compound of general formula (IV) according to claim 10, wherein:

x represents oxygen, sulfur or-NH-,

R¹represents a halogen atom or a halogen atom,

R²represents optionally substituted hydroxy, C₁-C₆Alkoxy or a group-CO-R⁸Substituted C₁-C₁₀Alkyl or C₂-C₁₀Alkynyl, wherein R⁸Has the definition as described in general formula (I) as defined in claim 1.

12. A pharmaceutical composition comprising a compound of general formula (I) according to one of claims 1 to 5.

13. Use of a compound of general formula (I) according to one of claims 1 to 5 for the preparation of a medicament for: for the treatment of cancer, arthritis, ocular diseases, autoimmune diseases, chemotherapy-induced alopecia and mucositis, crohn's disease, endometriosis, fibrotic diseases, hemangiomas, cardiovascular diseases, infectious diseases, renal diseases, chronic and acute neurodegenerative diseases, and nervous tissue injury; used for inhibiting reocclusion of blood vessels after bulb therapy, after vascular repair, or after opening of blood vessels using mechanical devices.

14. Use according to claim 13, wherein the infectious disease is a viral infection.

15. Use according to claim 13, wherein the hemangioma is a angiofibroma.

16. The use according to claim 13, wherein said mechanical device is a tubular stent.

17. Use according to claim 13, wherein:

cancer is defined as solid tumors, hodgkin's disease, and leukemia;

arthritis is defined as rheumatoid arthritis;

ocular diseases are defined as diabetic retinopathy and neovascular glaucoma;

autoimmune diseases are defined as psoriasis, alopecia and multiple sclerosis;

infectious diseases are defined as diseases caused by single-celled parasites;

cardiovascular disease is defined as stenosis;

18. Use according to claim 17, wherein the solid tumour is kaposi's sarcoma.

19. Use according to claim 17, wherein the stenosis is arteriosclerosis and restenosis.

20. Use according to claim 19, wherein the restenosis is stent-induced restenosis.

21. Use according to claim 13, wherein the medicament is in a form for enteral, parenteral and oral administration.

22. The pharmaceutical composition according to claim 12, further comprising suitable formulation and carrier materials.

23. The pharmaceutical composition according to claim 12 or 22, for use in: for the treatment of cancer, arthritis, ocular diseases, autoimmune diseases, chemotherapy-induced alopecia and mucositis, crohn's disease, endometriosis, fibrotic diseases, hemangiomas, cardiovascular diseases, infectious diseases, renal diseases, chronic and acute neurodegenerative diseases, and nervous tissue injury; used for inhibiting reocclusion of blood vessels after bulb therapy, after vascular repair, or after opening of blood vessels using mechanical devices.

24. The pharmaceutical composition according to claim 23, wherein the infectious disease is a viral infection.

25. The pharmaceutical composition according to claim 23, wherein the hemangioma is a angiofibroma.

26. The pharmaceutical composition according to claim 23, wherein the mechanical device is a tubular stent.

27. The pharmaceutical composition according to claim 23, wherein:

cancer is defined as solid tumors, hodgkin's disease, and leukemia;

arthritis is defined as rheumatoid arthritis;

ocular diseases are defined as diabetic retinopathy and neovascular glaucoma;

autoimmune diseases are defined as psoriasis, alopecia and multiple sclerosis;

infectious diseases are defined as diseases caused by single-celled parasites;

cardiovascular disease is defined as stenosis;

28. The pharmaceutical composition according to claim 27, wherein the solid tumor is kaposi's sarcoma.

29. The pharmaceutical composition according to claim 27, wherein the stenosis is arteriosclerosis and restenosis.

30. The pharmaceutical composition according to claim 29, wherein the restenosis is stent-induced restenosis.