ZA200401365B - Novel dihydropteridinones, method for producing the same and the use thereof as medicaments. - Google Patents

Description

Case 1/1250-ff Boehringer Ingelheim Pharma KG #, LO TEA TEE CI wm oe ® ® 1 Boe 200407585 789471ft.206

New dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions

The present invention relates to new dihydropteridinones of general formula (1)

R’ R? lh 7 } rR?

RA AS, NT,

R® RS wherein the groups X, R', R%, R® R* R®, R® and R? have the meanings given in the claims and specification, the isomers thereof, processes for preparing these dihydropteridinones and the use thereof as pharmaceutical compositions.

Background to the invention

Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 01/019825 describes the use of pteridinone derivatives for the treatment of neoplastic and viral diseases. The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.

The aim of the present invention is to prepare new compounds with an antiinflammatory and antiproliferative activity. :

Detailed description of the invention

Surprisingly it has been found that compounds of general formula (I) wherein the groups X and R' to R” have the meanings given hereinafter act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example to treat diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.

The present invention therefore relates to compounds of general formula (1)

R' Re

PN NO _X

R- x JR PE

ST ls R

R R

0) wherein

R! denotes a group selected from among hydrogen, NH, XH, halogen and a

C4-Cs-alkyl group optionally substituted by one or more halogen atoms,

R? denotesa group selected from among hydrogen, CHO, XH, -X-C1-Cz-alkyl and an optionally substituted C4-Cs-alkyl group,

R3, R* which may be identical or different denote a group selected from among optionally substituted C4-C1o-alkyl, C2-Cyo-alkenyl, Co-C1o-alkynyl, aryl, heteroaryl,

Cs-Cg-cycloalkyl, Cs-Cs-heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X-heterocycloalkyl, -NR°®-aryl, -NR®-heteroaryl, -NR®-cycloalkyl and -NR®-heterocycloalkyl, or a group selected from among hydrogen, halogen,

COXR®, CON(R?®),, COR? and XR®, or

R®and R* together denote a 2- to S-membered alkyl bridge which may contain 1 to 2 heteroatoms,

R® denotes hydrogen or a group selected from among optionally substituted

C1-Cqo-alkyl, C2-C1o-alkenyl, C2-Cao-alkynyl, aryl, heteroaryl and -Cs-Ce-cycloalkyl , or

R’and R°or R* and R®together denote a saturated or unsaturated Cs-Cq-alkyl bridge which may contain 1 to 2 heteroatoms,

R® denotes optionally substituted ary! or heteroaryl,

R” denotes hydrogen or -CO-X-C4-C4-alkyl, and

X in each case independently of one another denotes O or S,

R® ineach case independently of one another denotes hydrogen or a group selected from among optionally substituted C4-Cs-alkyl, Co-Cs-alkenyl,

C2-C4-alkynyl and phenyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Preferred compounds of formula (I) are those wherein

X and R® have the meaning indicated, and

R' denotes hydrogen,

R?® denotes a group selected from among a CHO, OH, and CHa group,

R%, R* which may be identical or different denote a group selected from among hydrogen, optionally substituted C4-Ce-alkyl, C2-Ce-alkenyl, Co-Ce-alkynyl, C3-C;- cycloalkyl, or

R%and R* together denote a C,-Cs-alkyl bridge ,

R® denotes a group selected from among optionally substituted C1-C1o-alkyl,

C2-Cio-alkenyl, C-Cyo-alkynyl, Cs-Ce-cycloalkyl and C;-Cs-cycloalkenyl, or

R®and R®or R* and R® together denote a saturated or unsaturated C3-Cy-alkyl bridge which may contain 1 to 2 heteroatoms, and

R’ denotes hydrogen,

optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Particularly preferred compounds of formula (1) are those wherein

R'-R® R’, R® and X have the meaning indicated, and

R® denotes a group of general formula or (R"). 9

R wherein n denotes 1, 2, 3 or 4,

R%denotes a group selected from among optionally substituted C+-Cs-alkyl,

C2-Ce-alkenyl, C,-Cg-alkynyl, -CONH-C1-C4o-alkylene, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among -O-C4-Ce-alkyl-Q’, -CONR®-C4-C1o-alkyl-Q", -CONR®-C-Cc-alkenyl-Q', -CONR®-Q?, halogen, OH, -SO;R?, -SO,N(R®), -COR®-COOR® -N(R®)., -NHCOR®, CONR®OC;-Cio alkylQ' and CONR®0Q?,

Q' denotes hydrogen, -NHCOR®, or a group selected from among an optionally substituted -NH-aryl, -NH-heteroaryl, aryl, heteroaryl, C3-Cg-cycloalkyl- and heterocycloalkyl group,

Q? denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, Cs-Cg-heterocycloalkyl, Cs-Cs-cycloalkyl- and C4-C4-alkyl-C3-Cg- cycloalkyl group,

R'® which may be identical or different denotes a group selected from among optionally substituted C4-Cg-alky! , C2-Ces-alkenyl and C,-Cg-alkynyl, -O-C1-Cs-alkyl, -0-C2-Cs-alkenyl, -O-C,-Cs-alkynyl, Cs-Ce-heterocycloalkyl and C3-Ce-cycloalkyl, or a group selected from among hydrogen, -CONHa, -COOR? -OCON(R?),, 5 -N(R%)s, -NHCOR® -NHCON(R®), , -NO, and halogen, or adjacent groups R® and R'® together denote a bridge of general formula 0

En

I N—R" AN BN ._N ! LON 12 : fo be

Y i 0 vY : ; (CC,AKy-Q'),

Y denotes O, S or NR", m denotes 0, 1 or 2

R'" denotes hydrogen or C4-Cy-alkyl, and

R'? denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C4-Cs-alkyl-phenyl, -C4-Cs-alkyl- pyridyl, -C4-Cs-alkyl-pyrazinyl, -C1-Cs-alkyl-pyrimidinyl and -C,-Cs-alkyl-pyridazinyl,

R™ denotes Ci-Ce-alkyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Particularly preferred are compounds of formula () wherein

R’-R® R® and X have the meaning indicated, and

R' denotes hydrogen,

R? denotes CH3, and

R’ denotes hydrogen,

- optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

The invention further relates to compounds of formula (1), wherein X and R'-R’ have the meanings indicated, for use as pharmaceutical compositions.

Of particular importance according to the invention are compounds of formula (1), wherein X and R*-R” have the meaning indicated, for use as pharmaceutical compositions with an antiproliferative activity.

The invention also relates to the use of a compound of formula (I), wherein X and

R'.R’ have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.

The invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I), wherein X and R'-R’ have the meanings indicated.

The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (1), wherein X and R'-R’ have the meanings indicated, or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.

The invention also relates to a process for preparing a compound of general formula (I),

R'" R

I

RY x R’

NEN NT, ls R

R® R (1 wherein

R'-R” and X are as hereinbefore defined, characterised in that a compound of general formula (1H

R' R

N™ N 4

AL

L N N™ “Rr? ls

R

(1) wherein

R'-R® and X are as hereinbefore defined and L is a leaving group, is reacted with an optionally substituted compound of general formula (lil)

R’

HN”

Re (mn wherein

R® and R” are as hereinbefore defined.

The invention also relates to a compound of formula 1,

®

R' R

NT N

4

AL Lr

Cl N N™ “rd

RS [IAN (In wherein

R'-R® and X are as hereinbefore defined. Compounds of formula (11) are important intermediate products for preparing the compounds of formula (I) according to the invention.

The invention also relates to a process for preparing a compound of general formula (1),

R' Re 7 3

R X ML yu R “ST ls R

R R

(1) wherein

R°® denotes a group of general formula, we 9

R

R® denotes an optionally substituted group -CONH-C4-C1o-alkylene or a group selected from among -CONR®-C+-Cp-alkyl-Q"', -CONR®-C2-C o-alkenyl-Q', -CONR®-Q? and -COOR?®, and

R'-R® R’,R"™ n and X are as hereinbefore defined,

® 9 @ characterised in that a compound of general formula (IA)

R' R

Nr Nd

ANS oo"

R® 8} (R),

JL 0A) wherein

R'toR® R” and R' are as hereinbefore defined, and

L denotes a leaving group, is reacted with a primary or secondary amine to form the corresponding amide or is reacted with an alcohol to form the corresponding ester.

The term alkyl groups, including alkyl groups which are a part of other groups, denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1 — 6, most preferably 1-4 carbon atoms, such as, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Unless otherwise stated, the abovementioned terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyi and decyl include all the possible isomeric forms. For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc.

In the abovementioned alkyl groups one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkyl group may optionally also be replaced.

Similarly, in the abovementioned alkyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced for example by an optionally

PA 10 ® substituted group selected from among CN, OCOCHs, aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.

The term alkyl bridge, unless otherwise stated, denotes branched and unbranched alkyl groups with 2 to 5 carbon atoms, for example propylene, isopropylene, n- butylene, iso-butyl, sec. butyl and tert.-butyl etc. bridges. Propylene and butylene bridges are particularly preferred. In the alkyl bridges mentioned 1 to 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.

The term alkenyl groups (including those which are a part of other groups) denotes branched and unbranched alkylene groups with 2 to 10 carbon atoms, preferably 2 - 6 carbon atoms, most preferably 2 - 3 carbon atoms, provided that they have at least one double bond. Examples include: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated, the abovementioned terms propenyl, butenyl, etc also include all the possible isomeric forms. For example, the term butylene includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1.1-dimethylethenyl, 1.2- dimethylethenyi etc.

In the abovementioned alkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkenyl group may optionally also be replaced.

The term alkynyl! groups (including those which are a part of other groups) denotes branched and unbranched alkynyl groups with 2 to 10 carbon atoms, provided that

PY 11 ® they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl.

In the abovementioned alkynyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkynyl group may optionally also be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise stated, may carry one or more of the following substituents, for example: OH, NO,

CN, -OCHF;, -OCFj, -NH_, halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, C1-C1o-alkyl, preferably C4-Cs-alkyl, preferably C4-Cs-alkyl, most preferably methyl or ethyl, -O-C4-Cs-alkyl, preferably -O-methyl or —O-ethyl, - N-methyl -tetrahydro-oxazinyl, -COOH, -COO-C4-Cg4-alkyl, preferably -COOCH,CHjz, -COO-C(CHs)s or -COOCH3, -CONH,, -CONH-C+-C1o-alkyl, while this alkyl may optionally be further substituted, optionally substituted -CONH-C3-Cs-cycloalkyl, preferably optionally substituted -CONH-cyclopentyl, optionally substituted -CONH-heterocycloalkyl, preferably piperidinyl, pyrrolidinyl or piperazinyl, optionally substituted -CONH-heteroaryl, preferably optionally substituted -CONH-pyridyl, optionally substituted -CONH- aryl, preferably optionally substituted -CONH-phenyl, -CONMeC; -Cs-alkyl, while 2s this alkyl may optionally be further substituted, preferably -CONMeCH,-pyridyl, benzimidazole or a group of formula

PY 12 ®

O

A

S N j= ¢ o

Xs

Examples of 5-10-membered mono- or bicyclic heteroaryl rings wherein up to three C-atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur include furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole and oxadiazole, while each of the abovementioned heterocycles may optionally also be annellated onto a benzene ring, preferably benzimidazole, and unless otherwise stated these heterocycles may for example carry one or more of the following substituents: OH, NO,, CN, -OCHF,, -OCFs, -NH;, halogen, preferably fluorine or chlorine, C4-C1o-alkyl, preferably C4-Cs-alkyl, preferably C4-Cs-alkyl, most preferably methyl or ethyl, -O-C4-Cs-alkyl, preferably -

O-methyl or —~O-ethyl, -methyl-N-tetrahydro-oxazinyl, -COOH, -COO-C;-Cg-alkyl,- preferably ~COO-C(CHas)s or -COOCH3, -CONHs, optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl or pyrazinyl, -CONH-C4-Co-alkyl, while this alkyl may itself optionally be substituted, optionally substituted -CONH-C3-Ce-cycloalkyl, preferably optionally substituted -

CONH-cyclopentyl, optionally substituted -CONH:-heteroaryl, preferably optionally substituted -CONH-pyridyl, optionally substituted -CONHe-aryl, preferably optionally substituted -CONH-phenyl, -CONMeC;-Cs-alkyl, while this alkyl may itself optionally be substituted, preferably —CONMeCH_-pyridyl, benzimidazole or a group of formula

® ’

X

S N

4 O

Xs

The term cycloalkyl groups denotes, for examnle, saturated or unsaturated cycloalkyl groups with 3 - 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the abovementioned cycloalkyl groups may optionally also carry one or more substituents, preferably =O, or may be annellated to a benzene ring. "=O" denotes an oxygen atom linked via a double bond.

The term heterocycloalkyl groups, unless otherwise described in the definitions, may denote 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which may contain nitrogen, oxygen or sulphur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranon, y-butyrolactone, o-pyran, y-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, while the heterocycle may optionally be substituted.

Generally, the term halogen denotes fluorine, chlorine, bromine or iodine.

The leaving group L denotes either identical or different leaving groups such as for example chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyi or p-toluenesulphonyl, preferably chlorine.

The compounds according to the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or

® 14 @ racemates, in the form of the tautomers and also in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

The substituent R' may denote a group selected from among hydrogen, NH,, XH, preferably OH, halogen, preferably fluorine or chlorine and a C1-Cs-alkyl group optionally substituted by one or more, preferably one, two or three halogen atoms, preferably fluorine or chlorine, preferably methyl or ethyl. Most preferably, the substituent R' is hydrogen .

The substituent R> may denote a group selected from among hydrogen, CHO,

XH, preferably OH, -X-C4-Cp-alkyl, preferably —O-CH; or —-O-CH,CHg, and an optionally substituted C4-Cs-alky! group, while the alkyl group preferably consists of 1 to 2 carbon atoms, particularly preferably a carbon atom and may optionally be substituted, preferably by halogen atoms, most preferably by fluorine atoms. In particular, the substituent R? denotes methyl.

The substituents R® and R* may be identical or different and may represent a group selected from among optionally substituted C1-Cyo-alkyl, preferably C4-Ce- alkyl, preferably C4-C4-alkyl, most preferably methyl, ethyl or propyl, particularly preferably methyl or ethyl, C,-Cio-alkenyl, preferably ethenyl or propenyl, preferably ethenyl, C,-Cio-alkynyl, preferably ethynyl or propynyl, aryl, preferably optionally substituted phenyl, heteroary, Cs-Cs-cycloalkyl, preferably cyclopropyl and cyclobutyl, Cs-Cs-heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X- heterocycloalkyl, -NR®-aryl, -NR%-heteroaryl, -NR®-cycloalkyl and -NR®-heterocycloalkyl, or a group selected from among hydrogen, halogen, COXRS, CON(R®),, COR® and

XR® preferably hydrogen, or the groups R®and R* may together denote a 2- to 5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge , while the propylene or

Ps 15 @® butylene bridge may contain 1 to 2 heteroatoms, preferably oxygen , nitrogen or sulphur, most preferably an ethylene bridge .

Most preferably, the substituent R® denotes methyl or ethyl. The substituent R* most preferably denotes hydrogen or methyl. Particularly preferred are compounds wherein R® and R* represent methyl.

All the groups mentioned in the definition of R® and R* may optionally be substituted.

The group R® may contain hydrogen or a group selected from among optionally substituted C4-C1o-alkyl, for example C+-Ce-alkyl-aryl or C1-Ce-alkyl-heteroaryl, preferably C4-Ce-alkyl, most preferably C4-Cs-alkyl, particularly preferably propyl, butyl, pentyl, hexyl, -CHz-cyclohexyl, (CH2)1.ocyclopropyl or (CH2)s-OCOCHS,

C2-Cio-alkenyl, preferably propeny, butenyl, pentenyl or hexenyl, preferably propenyl or hexenyl, C>-C1o-alkynyl, preferably propynyl, butynyl or pentynyl, preferably propynyl, aryl, preferably phenyl, heteroaryl, -Cs-Cg-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and -Ca-Cs- cycioaikenyi, preferably cyciohexenyl or cyclopentenyl, or the substituents

R*and R®or R* and R® together denote a saturated or unsaturated C3-Cy-alkyl bridge which may contain 1 to 2 heteroatoms, preferably oxygen, sulphur or nitrogen.

All the groups mentioned in the definition of R® may optionally be substituted.

The substituent R® may denote optionally substituted aryl, or heteroaryl, preferably aryl, preferably phenyl.

Most preferably, the substituent R® denotes a phenyl group, which may be substituted by one of the groups R® and R'® described hereinafter, while the phenyl ring may carry one of the groups R®, preferably in the para position, and one, two, three or four, preferably one or two, of the groups R", preferably in the ortho or meta position.

The substituent R’ may denote hydrogen or -CO-X-C4-Cs-alkyl, preferably hydrogen.

PA 16 @®

X denotes, in each case independently of one another, O or S, preferably O.

The groups R® mentioned in the definitions of the substituents R® and R* represent, independently of one another in each case, hydrogen or a group selected from among optionally substituted C4-Cs-alkyl, Co-Cy-alkenyl, Co-Cy- alkynyl and phenyl, preferably hydrogen or C1-Co-alkyl

The substituent R® may represent a group selected from among optionally substituted C+-Ce-alkyl, preferably C4-Ca-alkyl, preferably methyl, ethyl or propyl, most preferably methyl, C,-Cs-alkenyl, C2-Ce-alkynyl, -CONH-C4-C1o-alkylene, preferably -CONH-C4-Cs-alkylene, preferably -CONH-C4-C.-alkylene, -O-aryl, preferably O-Ce-C1o-aryl, most preferably O-phenyl, -O-heteroaryl, -O-cycloalkyl, preferably O-Cs-Cs-cycloalkyl, most preferably O-cyclopropyl, -O-heterocycloalkyl, aryl, preferably Ce-Cq-aryl, most preferably phenyl, heteroaryl, cycloalkyl, preferably Cs-Ce-cycloalkyl, most preferably cyclopropyl, and heterocycloalkyl, or a group selected from among -O-C-Cs-alkyl-Q', -CONR®-C;-C1o-alkyl-Q’, -CONR®-C+-C1o-alkenyl-Q', -CONR®-Q?, halogen, for example fluorine, chlorine, bromine or iodine, OH, -SO2R®, -SO,N(R?),, -COR®, -COOR? -N(R?),, -NHCOR®,

CONR®OC+-Cro-alkylQ' and CONR®OQ?, where Q' and Q2 are as hereinbefore defined.

Preferably, R® denotes one of the following groups -CONH-C4-Cyg-alkyl, preferably -CONH-C4-Cs-alkyl, most preferably -CONH-C4-Cz-alkyl, while this alkyl may itself optionally be substituted, by CN, optionally substituted aryl, preferably optionally substituted phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyi or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl.

Moreover R® preferably denotes -CONH-heteroaryl, preferably -CONH-pyridyl, -CONH-C3-C1o-cycloalkyl, preferably -CONH-cyclopropyl -CONH-cyclobutyl or

PS 17 @ -CONH-cyclopentyl, most preferably -CONH-cyclopropyl; -~CONH-C3-C1o- heterocycloalkyl -CONH-Cg-C1o-aryl, preferably -CONH-phenyl, COO-C4-Ca- alkyl, most preferably COOCHs, COOH, halogen, preferably F or chlorine, OH or a group of formula 0

Op 4 0 } Xs

All the groups mentioned in the definition of R® may optionally be substituted, preferably by one or more of the groups selected from among OH, OCHjs, CI, F,

CHa, COOH, CONHCH_Ph and CONHCHz-pyrazinyl-CHs.

The substituent R" may be identical or different in each case and may denote a group selected from among optionally substituted C4-Ce-alkyl , preferably

C4-Cs-alkyl, Co-Ce-alkenyl, preferably C2-Cs-alkenyl and Co-Ce-alkynyl, preferably

C2-Cs-alkynyl, -O-C4-Cs-alkyl, preferably —O-C4-Cs-alkyl, -O-C-Ce-alkenyl, -O-C,-Ce-alkynyl, Cs-Ce-heterocycloalkyl and Cs-Ce-cycloalkyl, or a group selected from among hydrogen, -CONH, -COOR®, -OCON(R®),, -N(R®),, -NHCOR® -NHCON(R?), , -NO, and halogen, for example fluorine, chlorine, bromine or iodine.

Preferably, the substituent R™ denotes hydrogen, methyl, methoxy, fluorine or chlorine, most preferably hydrogen or methoxy, particularly preferably methoxy.

Adjacent groups R® and R'® may together denote a bridge of general formula

CY l | N-R" ANC, FN

T © (C,-C-Alkyl-Q")_

PN 18 ® wherein

Y denotes O, S or NR", preferably NR", m denotes 0, 1 or 2, preferably 1, sR" denotes hydrogen or C-Cy-alkyl, preferably hydrogen or methyl, most preferably hydrogen,

R™ denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C4-Cs-alkyl-phenyl, -C4-Cs-alkyl- pyridyl, -C4-Cs-alkyl-pyrazinyl, -C4-Cs-alkyl-pyrimidinyl and -C4-Cs-alkyl-pyridazinyl, preferably phenyl, pyridyl and pyrazinyi, and

R™ denotes C4-Ce-alkyl, preferably methyl or ethyl.

The compounds according to the invention may be prepared by synthesis methods

A and B described hereinafter, while the substituents of general formulae (A1) to (A6) have the meanings given hereinbefore. These methods are to be understood as illustrations of the invention without restricting it to their subject matter.

Method A

Step 1A

A compound of formula (A1) is reacted with a compound of formula (A2) to obtain a compound of formula (A3) (Diagram 1A). This reaction may be carried out according to WO 0043369 or WO 0043372. Compound (A1) is commercially obtainable, for example, from City Chemical LLC, 139 Allings Crossing Road,

West Haven, CT, 06516, USA. Compound (A2) may be prepared by procedures known from the literature: (a) F. Effenberger, U. Burkhart, J. Willfahrt Liebigs Ann.

Chem. 1986, 314-333; b) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F.E.

Dutton, B.H. Byung Tetrahedron Lett. 1998, 30, 5313-5316: e) J. M. Ranajuhi, M. 30M. Joullie Synth. Commun. 1996, 26, 1379-1384.)

eo 19 @

Diagram 1A §

NT Ng To Re, NTR Nig

Le wee — 10% cI” ONT al RR 0 cr N° ON

N RIN 0. (A1) (AZ) R4 (A3)

InStep 1A, 1 equivalent of the compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of a base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, calcium carbonate, most preferably potassium carbonate, are stirred in a diluent, for example acetone, aqueous acetone, tetrahydrofuran, diethylether or dioxane, preferably acetone or diethylether, most preferably acetone.

At a temperature of 0 to 15 °C, preferably 5 to 10 °C, 1 equivalent of an amino acid of formula (A2), dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethylether or dioxane, preferably acetone, is added dropwise.

The reaction mixture is heated to a temperature of 18°C to 30 °C, preferably about 1s 22°C, with stirring and then stirred for a further 10 to 24 hours, preferably about 12 hours. Then the diluent is distilled off, the residue is combined with water and the mixture is extracted two to three times with an organic solvent, such as diethylether or ethyl acetate, preferably ethyl acetate. The combined organic extracts are dried and the solvent is distilled off. The residue (compound A3) may be used in Step 2 without any prior purification.

® 20 @®

Step 2A

The compound obtained in Step 1A (A3) is reduced at the nitro group and cyclised to form the compound of formula (A4) (Diagram 2A).

Diagram 2A

R' 2 R' , oP NT Reduction 7 N = ! 5

Ny or R

R* § (Ad) (A3)

In Step 2A, 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably glacial acetic acid, formic acid or hydrochloric acid, preferably glacial acetic acid, and heated to 50 to 70 °C, preferably about 60 °C. Then a reducing agent, for example zinc, tin or iron, preferably iron filings, is added to complete the exothermic reaction and the mixture is stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to 125 °C, preferably at about 117 °C. After cooling to ambient temperature the iron salt is filtered off and the solvent is distilled off. The residue is taken up in a solvent or mixture of solvents, for example ethyl acetate or dichloromethane/ methanol 9/1 and semisaturated NaCl solution, and filtered through kieselgur, for example. The organic phase is dried and evaporated down.

The residue (compound (A4)) may be purified by chromatography or by crystallisation or used as the crude product in Step 3A of the synthesis.

PS 21 ®

Step 3A

The compound obtained in Step 2A (A4) may be reacted by electrophilic substitution as shown in Diagram 3A to obtain the compound of formula (A5).

Diagram 3A 1 1 2

I Hoo por

N° NT

AL Le — OC

Cl Nd N 3 Cl NZ N 3

I. R ls R

R R® (Ad) (AS)

In Step 3A 1 equivalent of the amide of formula (A4) is dissolved in an organic solvent, for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to about -5 to 5 °C, preferably 0°C.

Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of alkyl halide, for example methyl iodide, are added. The reaction mixture is stirred for 0.1 — 3 hours, preferably about 1 hour, at about 0 to 10 °C, preferably at about 5 °C, and may optionally be left to stand for a further 12 hours at this temperature. The reaction mixture is evaporated down and extracted with water and an organic solvent, preferably dichloromethane or ethyl acetate. The organic phases are evaporated down. The residue (compound (A5)) may be purified by chromatography, preferably over silica gel.

Step 4A

The amination of the compound (A5) obtained in Step 3A to yield the compound of formula (A7) (Diagram 4A) may be carried out using the methods known from the literature of variants 4.1 A (a) M.P.V. Boarland, J.F.W. McOmie J. Chem. Soc. 1951, 1218-1221; b) F. H. S. Curd, F. C. Rose J. Chem. Soc. 1946, 343-348, 4.2

A (a) Banks J. Am. Chem. Soc. 1944, 66, 1131 b) Ghosh and Dolly J. Indian

Chem. Soc. 1981, 58, 512-513.

PY 22 ®

Diagram 4A

R' Rr’

Rl Rr? , N Ato i o NHR Pi J Py

YX I . » HN N N° “Re

Py _ R* + R1 > ie oS TN

R y R"

R ha Jn (AS) (A6) an

For example, in variant 4.1 A, 1 equivalent of the compound (A5) and 1 to 3 equivalents, preferably about 2 equivalents of the compound (A6) are heated without a solvent or in an organic solvent such as for example sulpholane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulphoxide or dioxane, preferably sulpholane, for 0.1 to 4 hours, preferably 1 hour, at 100 to 220 °C, preferably at about 160 °C. After cooling, the 16 product (A7) is crystaliised by the addition of organic solvents or mixtures of solvents, e.g. diethylether/methanol, ethyl acetate, methylene chloride, or diethylether, preferably diethylether/methanol 9/1, or purified by chromatography.

For example, in variant 4.2 A , 1 equivalent of the compound (A5)and 1 to 3 equivalents of the compound (A6) are stirred with acid, for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol, for example ethanol, propanol, butanol, preferably ethanol, at reflux temperature for 1 to 48 hours, preferably about 5 hours.

The product precipitated (A7) is filtered off and optionally washed with water, dried and crystallised from a suitable organic solvent.

If R® denotes an optionally substituted benzimidazole, the preparation of the compounds (A6) using methods known from the literature may be carried out as shown in the following diagram, for example:

PS 23 ®

NH, R'2 0 AN N 12

SS GR AE 5

NH, OH N (£3) 21) (22) x MN 12 a

H

(24)

Accordingly, for example, 33 mmol of the compound (Z1), 49 mmol of the compound (Z2) and 49 mmol of 1 -ethoxycarbonyl-2-ethoxydihydroquinoline (EEDQ) are stirred into 50 ml of an organic solvent, preferably dimethylformamide, at about 100 to 130 °C, preferably at about 115 °C, 1 to 4 hours, preferably about 3 hours. Then the cooled reaction solution is added to 50 to 400 ml, preferably about 200 ml of a water/ethyl acetate mixture (mixing ratic about 1:1). The crystals formed (Z3) are suction filtered and washed.

Then 4.2 mmol of the compound (Z3) are stirred with 12.5 mmol of tin(ll)chloride and 30 mmol of potassium carbonate in about 50 ml of an organic diluent, preferably ethyl acetate, at about 22 °C for 4 to 48 hours, preferably about 24 hours. After the addition of 22 g of kieselgur the mixture is extracted with an organic diluent or mixture of diluents, preferably with a mixture of dichloromethane / methanol (9:1), the combined extracts are evaporated down and the precipitate formed (Z4) or the crystals produced (Z4) is or are isolated.

Step 5A

If R® denotes -CONR®-C;-C1o-alkyl-Q', -CONH-C1-Cs-alkylene or -CONR-QZ wherein the substituents have the meanings given hereinbefore, the compounds according to the invention may be prepared using methods known from the literature, for example as shown in Diagram 5A.

_ “

The compound (A7") obtained in Step 4A may be reacted either by saponification and subsequent amination to obtain the amide of general formula (A10) (Diagram (5A) variant 5.1A), or by saponification, with subsequent conversion into the acid chloride (AQ) and subsequent amination (Diagram (BA) variant 5.2A).

Diagram 5A 1 5

R : 5 rR! R’

HON NR? HN" SNE Ss

R —_— LE

RY R" Variant 5.2A (AT) © RR (Tx i R

Variant sa) AN Ns

AR

ZN

1 5

HN" SN SN Ss -

Az

Rr (A10) -C,-C,,-Alkyl-Q! or

Sid a -C,-Cg-Alkylene or 8 (A10) RJ -Q2

R®

Variant 5.1 A: in variant 5.1 A, for example, 20 mmol of the ester (A7°) are heated in about 100 ml of a base, preferably 1N sodium hydroxide solution or lithium hydroxide solution and about 500 ml of an alcohol, for example with ethanol, dioxane or methanol, 1s preferably methanol, until the ester is completely reacted. Then the alcohol is distilled off. The residue is taken up in about 200 ml of water and acidified while cooling with acid, for example hydrochloric acid, preferably with 2 N hydrochloric acid. The product (A8) is filtered off and dried.

Py 25 ®

For example, about 0.5 mmol of the compound (A8) are dissolved with about 0.5 mmol of O-benzotriazolyl-N,N,N",N"-tetramethyluronium tetrafluoroborate (TBTU) and about 1.4 mmol of diisopropylethylamine (DIPEA) in about 5 ml of an organic diluent, for example tetrahydrofuran, dimethylformamide, N-methylpyirolidone, dimethylacetamide, preferably dimethylformamide. After the addition of about 0.75 mmol of an amine which forms the substituent R® , the reaction mixture is stirred for 0.1 to 24 hours, preferably about 12 hours at 20°C to 100°C. The product of formula (A10) is obtained for example by crystallisation or chromatographic purification.

Variant 5.2 A:

In variant 5.2 A about 1 mmol of the acid (A8) for example is suspended in about 2.7 ml of thionyl chloride. The mixture is heated to 40°C to 80 °C, preferably about 50 °C, and at constant temperature 2 to 10 drops, preferably about 3 drops of dimethylformamide are added to the reaction mixture with stirring. Then stirring is continued at 90°C until the reaction is complete. Excess thionyl chloride is distilled off. About 1 mmol of the acid chloride formed (A9) are dissolved in about 30 ml of an organic diluent, for example dichloromethane. After the addition of an amine which forms the substituent R® the mixture is stirred at about 22°C. The precipitate formed is filtered off and washed with water. The residue remaining is washed with an organic diluent, for example methanol. The mother liquor is purified, for example by chromatography, and evaporated down. The product (A10) remains.

Method B

Alternatively to the methods described above, after Step 1A first the compound (A3) may be aminated and then the product (B1) may be cyclised to yield the compound (B2), as shown in Diagram B. Further substitution of the compound (B2) to yield the compound (A7) may be carried out for example as in Step 3A.

Diagram B a 3 0 . R

N . le

NL R NT

DEE YL Eg

CN Ne is 1 NN 5

RO cl” ONT ON-R

RS

(A1) (A2) Ré SN fo) (A3)

R'" H 9 4

No _O NX or

NT © 7

RL | Lx RN. rr 5

SP N ) N N= ON-R

Le R [=& = R © = a! ~ hn 82) R"), r® rR’ (B1) rR! R’

NL Ne rR R*

NT ONT ONT Ng?

R®

Oe 9

R (AT)

® :

The new compounds of general formula (I) may be synthesised analogously to the following examples of synthesis. These Examples are, however, intended only as examples of procedures to illustrate the invention further, without restricting the invention to their subject matter.

Example 63 and Example 109 :

In order to synthesise the compounds 63 and 109 , first an intermediate compound 4

NT N Oo

PW

Cl N N is prepared as described hereinafter. 38.9 ml (0.263 mol) of ethyl 2-bromobutyrate and 36.4 g (0.263 mol) of potassium carbonate were placed in 350 ml of ethyl acetate, and then 46.7 ml (0.402 mol) of isoamylamine, dissolved in 70 ml of ethyl acetate, were rapidly added dropwise.

The mixture was refluxed for 20 h. The salt formed was filtered off, the filtrate was concentrated by evaporation, combined with 50 ml of toluene and again evaporated to dryness.

Yield: 54.3 g of a compound 1 (red oil) 54.3 g of compound 1, dissolved in 400 mi acetone, and 30.7 g (0.222 mol) of potassium carbonate were cooled to 8° C with stirring, combined with a solution of 43.1 g (0.222 mol) of 2,4-dichloro-5-nitropyrimidine in 250 ml acetone and then stirred for 24 h at RT.

PS 28 @®

The suspension formed was concentrated by evaporation, the residue was extracted with water and ethyl acetate, the organic phase was washed with water and NaCl solution, dried over MgSO; and evaporated to dryness.

Yield: 87.3 g of a compound 2 (brown oil) 44.1 g of compound 2 were dissolved in 800 mi glacial acetic acid and heated to 65°C and 36 q of iron filings were added bhatchwise. Then the mixture was stirred for 3 h at 70° C, the precipitate was filtered off and the filtrate was concentrated by evaporation.

The residue was applied to silica gel in dichloromethane / methanol 90:10, concentrated by evaporation and purified by column chromatography (eluant: ethyl acetate / cyclohexane 1:1).

The residue was precipitated from ethyl acetate / petroleum ether.

Yield: 16.1 g of a compound 3 (beige powder) 16.1 g of compound 3 were dissolved in 75 ml of dimethylacetamide and cooled to 5°C under a nitrogen atmosphere with stirring. Then 2.51 g (0.063 mol) of NaH, 60% dispersion in mineral oil, was added, whereupon the temperature temporarily rose to 16°C. After 30 minutes 3.94 ml (0.063 mol) of methyl iodide, dissolved in 75 ml dimethylacetamide, were added, and the mixture was stirred for 24 h at 22°C.

The solvent was concentrated by evaporation, combined with 200 ml of water and the precipitate formed was suction filtered, then extracted by stirring with petroleum ether.

Yield: 15.1 g of a compound 4 (yellow powder) "H-NMR (250 MHz): = 7.80 (1H, s), 4.35 (m, 1H), 3.92 (m, 1H), 3.22 (s, 3H), 3.14 (m, 1H), 1.81 (m, 2H), 1.60- 1.40 (m, 3H), 0.90 (m, 6H), 0.70 (t, 3H).

Synthesis of Example 63 2.5 g of compound 4, 1.43 g of 4-amino-3-methoxybenzoic acid, 1.25 mL of conc, hydrochloric acid, 150 mL of dist. water and 37.5 mL of ethanol were refluxed for 10 h. The precipitate was filtered off, washed with water and extracted by stirring

PS 29 @ in methanol. Then the precipitate was recrystallised using petroleum ether and ether.

Yield: 1.6 g of a compound 5 (white powder) 0.29 of compound 5, 5 mL of benzylamine, 0.16 g of TBTU, 0.17 g of DIPEA were dissolved in 2 ml of dimethylformamide (DMF) and stirred for 48 h at ambient temperature. Then the reaction mixture wae taken up in methylene chiuride, washed with water and the organic phase was evaporated down. When petroleum ether/ethyl acetate 9:1 was added the product was precipitated in the form of light beige crystals.

Yield: 0.18 g. Melting point: 178°C

Synthesis of Example 109 : 5g of 2 amino-5-nitroaniline, 6.03 g of 4-pyridylcarboxylic acid, 12.1 g of EEDQ are dissolved in 50 mL of DMF and stirred at 115°C for 1.75 h, then the DMF is distilled off in vacuo and the reaction mixture is then heated to 180°C for 1 h. The residue is taken up in 30 mL of DMF and combined with 200 mL of water and 100 mL of ethyl acetate. The crystal slurry obtained is filtered off and washed with water, ethyl acetate and ether.

Yield: 5.8 g of a compound 6 2 g of the compound 6 is combined with 0.2 g of 5 % Pd/C in 30 mL of ethanol and hydrogenated in the presence of hydrogen. It is then evaporated down and crystallised from ethanol and toluene.

Yield: 1.75 g of white powder of a compound 7. 0.2 g of the compound 5, 0.28 g of the compound 7, 0.001 g of sodium-tert. butoxide, 2.5 mL of ethyleneglycol dimethylether, 0.006 g of palladium(il) acetate and 0.22 gof 2-(di-tert.-butylphospino)biphenyl are dissolved in 1.5 mL of N- methylpyrrolidone (NMP). Then the mixture is heated to 160°C for 0.5 h. The

® ” reaction mixture is then purified over 20 g of silica gel and the product is crystallised from ether, ethyl acetate and petroleum ether.

Yield: 0.04 g of yellow crystals. Melting point: 180°C

Example 218, 58 and 4:

In order to synthesise the compounds 218, 58 and 4, first an intermediate compound 11

Py

Cl N N 11 pS is prepared as described hereinafter. 55.8 g of DL-alanine methyl ester x HCI were dissolved in 500 ml of methanol, then 76.1 ml of 30% sodium methoxide solution was added and the salt was filtered off. 37.8 g of trimethylacetaldehyde were added to the filtrate, then it was left to stand for 22 h. Then 9.5 g of 10% Pd/C was added and the mixture was hydrogenated for 3.1 h at 0.5 bar and 20° C. The reaction mixture was suction filtered through kieselgur and concentrated by evaporation. The residue was taken up in diethylether, the salts were filtered through kieselgur and the filtrate was concentrated by evaporation.

Yield: 55.8 g of a compound 8 (clear liquid) 48.5 g of 2,4-dichloro-5-nitropyrimidine were placed in 400 mi of diethylether, 41.0 g of potassium hydrogen carbonate in 400 ml of water were added, and the mixture was cooled to -5°C. 43.3 g of compound 8 were dissolved in 400 ml of diethylether and added dropwise at —5° C. The mixture was stirred for 1 h at -5°C and for 2 h at 0° C, then heated to ambient temperature and the reaction mixture was left to stand for 24 h.

® 31 ®

The organic phase was separated off, dried over MgSO, and evaporated to dryness.

Yield: 79.2 g of a compound 9 (yellow resin) 79.0 g of compound 9 were dissolved in 1000 ml of glacial acetic acid and heated to 70°C. After the removal of the heat source 52 g of iron was added batchwise.

The temperature rose to about 110° C and the mixture was sired (or | h al iis temperature. The suspension was filtered while hot and the filtrate was concentrated by evaporation.

The residue was taken up in ethyl acetate and combined with 150 ml of conc. HCI, the organic phase was separated off and the aqueous phase extracted several times with dichloromethane. The combined organic phases were concentrated by evaporation, applied to silica gel and purified by column chromatography (eluant: petroleum ether/ethy! acetate 1:1).

As the isolated substance was still highly contaminated, it was again purified over silica gel. The desired compound crystallised out, the crystals were suction filtered.

The mother liquor was concentrated by evaporation and recrystallised from ethyl acetate / diethylether.

Yield: 17.63 g of a compound 10 7.6 g of the compound 10 and 6.4 ml of methyl iodide were placed in 75 ml of dimethylacetamide (DMA) and cooled to —15°C. 1.25 g of NaH, 60% dispersion in mineral oil, was added batchwise, and stirred for 30 min. at =10° to —5° C. Then 150 mi of ice water were added, the crystals were suction filtered and washed with water and petroleum ether. The crystals were taken up in dichloromethane, filtered through kieselgur and the filtrate was evaporated to dryness. It was recrystallised from petroleum ether.

Yield: 6.3 g of compound 11 (beige crystals) "H-NMR (250 MHz): = 7.73 (1H, s), 4.35 (d, 1H), 4.25 (m, 1H), 3.35 (s, 3H), 2.55 (d, 1H), 1.31 (d, 3H), 0.95 (s, 9H).

® 32 @

Synthesis of Example 218 0.2 g of compound 11, 3,5-diflucro-4-hydroxyaniline and 0.75 mL of sulpholane were heated to 130°C for 15 min, to 140°C for 15 min and to 170°C for 10 min.

Then the mixture was combined with ether, the supernatant solution was decanted off and the residue was crystallised from methanol/ether and recrystallised again from methanol.

Yield: 0.15 g of white crystals. Melting point:>250°C

Synthesis of Example 4 6.3 g of compound 11 were dissolved in 25 mL of sulpholane at 100°C, then combined with 4.0 g of ethyl 4-aminobenzoate and heated to 170°C for 1 h. Then the mixture was combined with 50 mL of ether. After crystallisation started, a further 50 mL of ether and 50 mL of methanol were added. The crystals were recrystallised from methanol.

Yield: 6.6 g of a compound 12 (yellowish crystals), melting point: from 65°C decomposition sets in 3.55 g of compound 12 were suspended in 250 mL of methanol and at 60°C combined with 25 mL of 4N sodium hydroxide solution. After 6 h, 15 mL of glacial acetic acid were added, the resulting crystals were filtered off and washed with methanoi/ether.

Yield: 1.2 g of a compound 13 (white crystals) 1.5 g of compound 13 were dissolved in 7.5 mL of thionyl chloride and heated to 80°C for 1 h. Then the thionyl chloride was eliminated by distillation, the residue was stirred with ether, the crystals were suction filtered and washed with ether.

Yield: 1.7 g of a compound 14 (yellow crystals) 0.18 g of 3-aminopyridine were dissolved in 10 mL of tetrahydrofuran (THF) and combined with 0.4 mL of triethylamine. Then 0.22 g of compound 14 were added and the mixture was stirred for 16h at ambient temperature. The mixture was evaporated to dryness, taken up in ethyl acetate, extracted with water, evaporated down again and the product was crystallised from ethyl acetate.

Yield: 0.07 g (beige crystals), Melting point: 215-216°C

Synthesis of Example 58 0.05 g of compound 13 were suspended in 10 mL of dichloromethane, then combined with 0.15 mL of DIPEA and 0.05 g of TBTU. The solufion was then stirred for 30 min and combined with 0.01 mL of 4-picolylamine. After 18 h the mixture was combined with 20 mL of water, the organic phase was separated off and the product was purified by silica gel chromatography, then recrystallised from ethyl acetate /petroleum ether.

Yield: 0.044 g (white crystals), Melting point: 238-240°C

Examples 65 and 125

In order to synthesise the compounds 65 and 1 25, first an intermediate compound 18

NT N 0]

PW

Cl N N is prepared as described hereinafter. 28.3 g of isobutylamine, 36 g of ethyl R,S-2-bromopropionate and 28 g of potassium carbonate were refluxed in 150 ml of ethyl acetate for 6 h.

After cooling the salt was suction filtered, the mother liquor was concentrated by evaporation.

The residue was combined with 100 ml of toluene and evaporated to dryness.

Yield: 37.2 g of a compound 15 (yellow oil)

® @® 38.4 g of 2,4-dichloro-5-nitropyrimidine were placed in 300 ml of diethylether, 30 g of potassium hydrogen carbonate in 300 m| of water were added and the mixture was cooled to 0° C. 37.0 g of compound 15 were dissolved in 300 ml of diethylether and added dropwise at 0°-3° C. After 3 h the phases were separated, the organic phase was dried and evaporated to dryness.

Yield: 71.6 g of a compound 16 40.0 g of compound 16 were dissolved in 300 m| of glacial acetic acid and heated to 70°C. After removal of the heat source, 30 g of iron was added batchwise. The temperature rose to 110°C. The reaction mixture was cooled to 90°C and stirred for 20 min. at this temperature. Then it was filtered while hot and the filtrate was concentrated by evaporation. The residue was stirred with 300 mi of water and 300 ml of dichloromethane and filtered through kieselgur. The phases were separated. The organic phase was washed with water, dried over MgSO, and evaporated to dryness. It was extracted from petroleum ether.

Yield: 26.7 g of a compound 17 15.0 g of compound 17 were placed in 100 ml of DMA, 4.13 ml of methyl iodide were added and the mixture was cooled to 5° C. 2.60 g of NaH were added batchwise as a 60% dispersion in mineral oil. The temperature rose to 13°C.

After 30 min. 300 ml of ice water were added, the crystals precipitated were suction filtered and washed with petroleum ether.

Yield: 13.9 g of a compound 18 "H-NMR (250 MHz): = 7.95 (1H, s), 4.30 (m, 1H), 3.95 (m, 1H), 3.24 (s, 3H), 2.95 (m, 1H), 2.05 (m, 1H), 1.30 (d, 3H), 0.96 (d, 3H), 0.92 (d, 3H).

Synthesis of Example 65 2.1 g of compound 18 were combined with ethyl 4-aminobenzoate in 10 mL sulpholane and stirred for 2 h at 160°C. Then ether was added and the crystals precipitated were washed with ether:

Yield: 3.0 g of a compound 19

_ @ 3 g of the compound 19 were combined with 200 mL of methanol and 25 mL of 4N

NaOH and stirred for 4 h at 60°C. Then glacial acetic acid was added, the crystals precipitated were filtered off and washed with ether.

Yield: 2.3 g of a compound 20 (white crystals) 0.1 g of compound 20 were suspended in 3 mL of dichloromethane and 3 mL of

DMF, and then combined with 0.13 g of DIPEA, 0.095 g of TBTU and 0.045 g of hydroxybenzotriazole (HOB). Then the solution was stirred for 30 min and combined with 0.035 g of N-methyl-3-picolylamine. After 0.5 h the mixture was combined with water and 1 g of potassium carbonate, the aqueous phase was extracted twice with 50 mL of ethyl acetate and the product was purified by silica gel chromatography and then recrystallised from ethanol/acetone.

Yield: 0.08 g

Synthesis of Example 125 3.7 g of compound 20, 3.8 g of TBTU, 1.6 g of HOB, 5 mL of DIPEA were dissolved in 40 mL of DMF and stirred for 4 h at ambient temperature. The mixture was evaporated down, taken up in 200 mL of ethyl acetate and extracted twice with 5 mL of 5% potassium carbonate solution. The organic phase was evaporated down, the crystals precipitated were filtered off and washed with ethyl acetate and ether.

Yield: 1.65 g of a compound 21 (yellowish crystals) 0.486 g of compound 21 were refluxed with 0.33 g of 1,2- phenylenediamine in 10 mL of toluene for 0.5 h, then the mixture was evaporated down. The residue was combined with 100 mL ethyl acetate, the organic phase was extracted twice with water. The organic phase was evaporated down, the crystals precipitated were suction filtered and washed with a little ethyl acetate.

Yield: 0.25 g of a compound 22 (white crystals)

0.22 g of compound 22 were stirred into 20 g of polyphosphoric acid for 0.5 h at 150°C, then the mixture was poured onto ice and ammonia was added. It was then extracted twice with 100 mL of ethyl acetate, the organic phase was washed with water and evaporated down. The precipitated product (crystals) was suction filtered and washed with ethyl acetate and ether.

Yield: 0.115 g of yellowish crystals, Melting point: 287°C (decomposition)

Example 171

In order to synthesise compound 171 first an intermediate compound 27 [sic]

NX N 0

PW

Ci N L ip 34.4 g of N-isopentyl-benzylamine, 36.2 g of ethyl 2-bromo-propionate and 42.0 g of potassium carbonate were placed in 250 ml of DMF and stirred for 3 h at 110°C.

After cooling the inorganic salts were filtered off, the filtrate was concentrated by evaporation. The residue was extracted with water and diethylether, the organic phase was washed with water, dried and evaporated to dryness.

Yield: 55.5 g of a compound 23 55.5 g of compound 23 were placed in 600 ml of ethanol, and hydrogenated with 20 ml of 32% HCI and 6 g of 10% Pd/C at 20°C under 5 bar for 20 min. Then it was filtered through kieselgur and concentrated by evaporation. The residue was combined with 400 ml of diethylether, the precipitate was suction filtered and washed with diethylether.

® 37 ®

Yield: 23.5 g of a compound 24, melting point 105°C 23.5 g of compound 24 were dissolved in 200 m! of water and combined with 20.0 g (0.103 mol) of 2,4 -dichloro-5-nitropyrimidine in 400 ml of diethylether. After the reaction mixture had been cooled to 10°C, 50.0 g (0.499 mol) of potassium carbonate were added batchwise. The mixture was stirred at —5°C for 1 h and at 0°C for 1 h, then heated to ambient temperature. The aqueous phase was

Separated off, the organic phase was washed with water, dried and evaporated to dryness.

Yield: 36.9 g of a compound 25 20.0 g of the compound 25 were dissolved in 280 ml of glacial acetic acid and heated to 70°C. After removal of the heat source 17 g of iron were added. The temperature rose to 100°C, then the mixture was stirred for 30 min. at this temperature.

It was then filtered while hot and the filtrate was concentrated by evaporation. The residue was combined with 300 ml of dichloromethane and 30 ml of 32% HCI, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with water and agueous ammonia solution, dried and evaporated to dryness. The residue was extracted with diethylether. © Yield: 10.5 g of a compound 26, melting point: 182°-185°C ~~ ~~ ~~ = 2.7 g of the compound 26 and 2.5 mi of methyl iodide were placed in 27 ml of

DMA and cooled to —10° C. 0.45 g of NaH, 60% dispersion in mineral oil, was added and stirred for 30 min. at =5°C. Then 10 g of ice and 5 ml of 2N HCI were added and the mixture was concentrated by evaporation. The residue was extracted with ethyl acetate and water, the organic phase was dried, evaporated to dryness and filtered through silica gel.

Yield: 3.0 g of compound 27 (oil) "H-NMR (250 MHz): = 7.67 (1H, s), 4.32-4.07 (m, 2H), 3.32 (s, 3H), 3.08 (m, 1H), 1.70-1.50 (m, 3H), 1.42 (d, 3H), 0.95 (m, 6H).

J

®

Synthesis of Example 171 0.28 g of compound 27, 0.9 mL of sulpholane and 0.22 g of p-aminobenzoic acid- benzylamide were stirred for 0.5 h at 1 70°C, then the mixture was combined with ether and the crystals were filtered off. The product was recrystallised from ethanol.

Yield: 0,15 g, melting point: 228-240°C (yellowish crystals)

The compounds of formula (1) listed in Table 1 are obtained analogously to the process described above.

The abbreviations Xa, Xs, Xs, Xs and Xs used in Table 1 in each case denote a link toa position in the general formula shown under Table 1 instead of the corresponding groups R? R®, R* Rf and RE.

@ 1 (Continued) 39

TR

N 0]

N=

Ho rr Te

NT NT OND, bd rT

By, 122 rR? R* config. |R® 'RE

R¥orR* 1 X CH, % cr, i

H H rac. ho 2 208

He en, % a x N

H rac. NT Xy

He” Son | Lo 241 % N

H rac. 4 H,C C X,

L, |" L, "ou

H rac. é Lot MY ¥ ©

NT

CH | Xo _CH, x X 175 i bY

H rac. H,C CH, Pn

NN

©

Xo [HO HOO |% N 2 7 OLD

X, lo] 7 > HC ~~ %

CH, & A Cl.

H . rac X “0

NT

Qa 1 (Continued) 40 config.

EE

8

I Ren, x 200

H rac. N 0 ° N

AY

© 9 CH, |X; CH % % 168 3 NT ; NO

H rac. —. X

A fh oem, ¥ IN 190 % Y

H rac. |HC on 3 07 TN 7) = 11

P Xan, ; T 2 CH, NTE

H rac. he UL = 12 ® Xs _CH, J AT )

CH, 0

H rac. X N =

Nao 13

OH Pony X P 145 % CH, N

H rac.

CH, ® x

NF oH, Xs ~_-CHs Xs F % No

H rac. CH, [o} N <N ©

@... 1 (Continued) 41

Ex. R® R* config. R®

X HO CL 55

CH, NS | 0)

H | rac. | X | ™

Co A a ~ Na 16 CH |X CH, X % 250 }

LE

H rac. EN X =

MN

17 CH, Xe-CH, % . x 204 ) IAS

H rac. H,C CH, G N =

Ld 1B TCH Xe X Cp

Cl

H j rac. oN 19

CH, o} ge rac. Xs N 2

A

% HC H,C._ CH, x 2 221

Xs 0 21 oH, X~_-CHs X o Xx 172 ) UE, rac. HC CH, o "

ZZ

@... 1 (Continued) 42

Ex. rR2 Rr? R* config.

R® or R* mp.[°C] 22 | CH, Xe-CH, % % 221 a. .

H rac. HC CH, 5 N

CC

ZN

28 eH, |X CH, x a % L NA

H rac. AV; y x SA

Zz 241% [HC] CH, % on | 210 % HC

CH, 3 Ne CT

H rac. Hy FL) % _C 213 % [Hos Ho Cr os ” “OL ge

H R ‘

X, x le} 2 CH, |X CH, . X ¥ 188 1, CK

H rac. H,C CH, lo) “

Q

27 X, ~~ HC Ny OC! X

H rac. CH, o

Xs 28 X x; CH, H,C._ CH, y % ca, J A JT

Xs lo} 29 [oH [Xs CH x . X 178

X

H rac. HC CH, A =

_ 1 (Continued) 43

Ex. config. |R®

R*orR* mp.[°C]

TR EN ~~

CH, Ne A , i | | | x

CH, lo] iN —_— pl N

Ps 32 221

Gta xen, X 0 x N

H rac. rg % = 33 % Yon, H,C.__-CH, oS 124

CH, X N : ve

X, > a 34 x H,C._ i CH, RNG ~~ 136 on > HC | FZ I

H rac. CH,

X [o]

Ben [Xa oy X, x 162 i \.

H rac. He SoH, \ < 7 8

CH, | XK % 0 ! 1, of

H rac.

HC CH, OF %

Ns 37 219

TE S dS x rac. [pc bio PN =

@.. 1 (Continued) 44

Ex. R* config. R®

A orc 38 CH, ¥sn_-CHs %5 . %; 179

X, H

H rac.

HC CH,

Pn, ¥en iad L A 211 % =

H AN > rac. cen,

BY ou

CH; 40 Ten, [Xo X x ah aay rac. CH, A 41

X Cx Cer, 5

CH, HC 0

H rac. X | N

Fo 1 ~F

J

42 CH, 100 eo [Res HOCH, oC

CH, X, = oN

Xs to) 43 % HC CH, % 175

CH, x A Cs

CH, N

H rac. X, CH, aA

Na

CH, 44 203

CH Xn x . % x HC”

HC "CH 07 "NH,

@Q... (Continued) 45

Ex. config. orc)

CFF OF Ree eer 4 Tod, xeon, X, o | 165 % \ N

H rac. y ~ gel

Xs 46 CH, ~~ X Ft i AE

HH Iau. HC “cH, A \& 47 a fos X, h Xn, A TCL

H rac. X. o

BT a I jouw oe Aan l

H rac. | x CH o

F bu ha HC rh or rac. CH, Cl F % 0

CT EN % X, 212 %

HC” “CH, 07 “NH, 51 HC. CH, Xs 3 To

CH, 3 N

A s [ Sf I ¥Z 52 CH, |X 6

BE La

HC™ "CH,

@.. 1 (Continued) a

BT = config.

Ror R* mpl] 53 X [HC | IR *

Xs | Co i o bp

H rac. i X ! ™ ' o _ 54 C I RS

Hy X Tes CL ~0

HC” h I

H rac. Xs FE. . 55 cH, CH, t t ” nL x, [9

H rac. | HG” “CH PN

Ton xa, 5 a i > “QL

X

7 ICH, |X \ I ~ oe pAliPS ae rac. x “ly 58 X, HCx, JA ) o

CH, wo

H rac. % " : oy HC. CH, CH, 125 3 JN Oo

@.. 1 (Continued) 4 config. R® cer TF ee

RE | or NS x0 3 Cl

H H rac. on d ve : 61 CH, |X * BP: ee NO

H rac. halk Ay ~~ x i" 62 CH Xo” CH, t \ 0. : DUS

H rac. HC CH, 0="N a xn J 8 oH Xa Ch t I - ‘ DIAS

H rac. HC CH, cn, t !

X, Ne

H rac. * lo} N e

[1]

Cl

Le pegs! rac.

NZ

X Xi EN “Z

Eee 3 Oy

H a Bedi [eo]

Q.. 1 (Continued) 48

Ex. config. R° 2) A 67 CH, X, % % :

Lr os ol 3

H rac. | oH | Py ro | | | Po eto pe 68 x H.C CH, % XN [

CH, * Ae TL 7° [ CH, N

H rac. |X “2

Ig

CH, |X x 0 <7 ge! % CH, N

CH, 70 fs Kon, X *

Xx, J

H rac. i | 7 SEN i

LY

CH, A [0]

CH,

H rac. X, CH, P z \—/ 72 TH ) Sd CH, % t % No rac. CH, o ”

IE Ph xe y ns:

RCC, 0? nN

@.. 1 (Continued) 49

Ex. |R? config. RC = 74 ; 7 | | \ | Fp | 167

I ah mm 4 ! PNR Ne

J

75 Cu ~~ rE k % Tre, TJ .0 3 He P ~ Y

H rac. X, 3

F

76 CH, |X, X o 246

X Cy pe OL

H rac. or

CH, EN X,

NI

77 X MCs cH, x

Ch Ase 0

H rac. eH ! “NT =o

CH, 78 CH, |X X fo) 172

X or oo OL

H rac. ~

CH, N == Xs \_s 79 C % 170

Ea Xa

X, He rac. CH, o N x7 CH, Xen, x [0] 222

HN rac. x

HC” “CH, 6

HC

1 1 8 cH, Xen, % Ia 87 x, N

Joghe

H,C™ “CH, Ho” WP

@.. 1 (Continued) 50 config.

SC

82 oem, | % 0 215 % | ’ | N rac.

KC” CH, pa *

Ae 83 ih YL LA 199

ES oN Po | CO

WGA,

FH x Xo, N 0 127 8 y

HC” TCH, Hc 0 % _0

HC

85 bo Cu | CO 0]

H rac. (he 3 I}

IAN

86 CH, |X | i LX o 160 x * CH, HOS

H rac.

CH, % 87 Cc fo] 250

Ce Lm

H rac. of

CH, % 8 on Xan, X ah 233

He” \ CH

H rac. oH Zn wk J

HC”

PH, X~_-CHs % % 160 a. rac. |HC” “cH, | N

@.. 1 (Continued) 51

Ex. config. 90 | 154

Fh Xing x 0

X No N

H 3 rac | CH, | A X5

RE o1 % Oy ~

CH, “PN

H rac, Ps

X YO

UN

92 or Xon_-CHs Xs X : ©

H rac. HC CH, A 3 8 % HC Cen, jou

CH, Oo

Se ;

H rac. x : % HO, HC. CH, ots

CH, J gol

H x N. [ ] 0 95 CH, CH, X % 150 x | Ne

H rac. CH,

[0] N or

CH, 1X X—~ % % 300 ) i, CH, rac.

HC” “CH, 0” "NH, 97 Ce CH, x 243

ER A Cs

H, oH, rac. X CH, pe

@.. 1 (Continued) 52

Ex. Rr? config.

R®orR* mp.[°C] a8 9

CH, Xn, % Ae 20

X Ny N

H rac. N een Ng %

CC] | | NF a 19

H rac. He rH, BN 100 X, x Ct J JO

CH, o

H rac. Xs N =

A

101 | x, _ CH, H,C__-CH, 232 = |" ae re

H R N

% lo] 102 JcH 1X X *

X a Ag

H rac. CH, " N 103 | eH |X xX 0 x % re penne!

CH al x 104 OH; | Xn CH x rr 146 : bY rac. |HC” “CH, Pn

N

@... 1 (Continued) 53

CFF OF Rel Fo

R*orR* p[°C] 105 CH, Xing x 0 : 209

Hy . BUNS ge!

H rac. HC” “Ch, ~ %

I | | | NY 0

HG” 1086 CH, | Xe X c 286

HX x SN : PI

H rac. ee Y 07 NH, 107 X % __CH, CH, %

CH, J 0

H rac. | x, N

N= . 108 X % CH, oo H,C__CH, _CH, 202 . ee [ jg

H R x, ! FF " o) 109 oH, X;~_-CHs X % 180 ’

H rac. H,C CH, A 0 —N 110 | CH X, fo] ak ~ X% pallies!

H

Joga 111 % Hex oh 250

CH, A %

H

Xs ° An

@®... 1 (Continued) 54

Ex. config. |RS RS 112 CH, Xen X % ol J,

H | rac.

HC on ° \ N

M3 x CH, CH, x by | g oA d !

H rac. X, [

C4 114 CH, | X—CH, X, X X% 237

J en, bY we

HG Son, won 115 CH, | Xn CH x . X 135 i LY

H rac. H,C™ TCH, NY 116 X. H,C CH, Xs HC ) °

H rac. oy

Xs le} CH, "7 1x HC CH %

Hy % KE je

HC rac. x | oy 118 | cH, CH, Xs i x ) SN Nr oH, s

H rac. CH, oP ‘

@... 1 (Continued) ” = config.

I AG 52 CN, 119 CH; | Xn CH, * | ! x, Ne £

H | rac CH, | Nd . | B

Co | | cs — Ep :

X g

H rac JY Oy

He en, oo 121 r Xn _-CH % %

H rac. N { © |HCT CH, HC = 122 Hy X~_-CH, \ Hy x j RS

H rac. HC” cH, A

Na ll

Cl Xs 123 5 HC, el] CO rac. ©, o] ©

X HC” 124 OC (EC = jews)

H rac. X, ° 287 125 oH, en, t N { No

Holme | ae! %

@.. 1 (Continued) 56 “FFF R-

SN

126 CH, Xn _-CHs | X % [185 ) hl Q

H rac. | HC CH, | \ PA

SE EE ES SE

127 oH, Ix % %

Len Ce A

SY 0

H rac. I Ps 128 x HC Cl X; bu | 2 MO,

H,C

H rac. X, 2 129 [cn [x x X 247

YL. |S

IHC CH, !

H rac. ? CH, a

Ton, 1, oH X x

X, No QL, fo}

H CH, L = 131 oH, X;—CH, x % % 281 ] x br bY

HC eH, . 182 cH Ix X % x "C

H

CH, 0” "NH,

®.. 1 (Continued) 57

Ex. R* config. 133 | oH, on % Es % No

H rac. I” oo ra 134 208 § NG

H rar

Co 135

E, SENN og

CH, 0

H rac. |x N

AN

P

Teo

CH, N

H R

X lo] 137 E x OH CH, whey 212

H rac. a

X [o]

EN FERETN c ® eH, % 2 JO

HC N

H rac. X & he 139 oH, Xe-CH X % x on rac. CH, 07 ™N { or

I 1 (Continued) 58

Ex. config.

A

140 : Xn _-CH X, x, 148 " be!

H (Tac. HC Ten, I N= N )

N— \ 7 141 x Hey Hen, x BS )

Hy oS Z

N

H rac. % 3 cl 142 Tx, [Heo cH, Ix

CH, % a Cl

H rac. CH,

X 0 a 143 Lt cn, 4 A 186 «J

H rac. ne Ge g: me 144 CH, % oh, X 199

X, bY ©

CN HC” CH, 5

Tw, 0} 145 Hy Xen, X Q 214 ” , rac. oN jew “cH, 155

Le Aon, x %

H rac. 4 \ =) fo] ~~

@.. 1 (Continued) 58

Ex. config.

WT] oy Ix CH X x %, po

H rac. CH, A [Hd Ry 8 1x [HCL CH, Xn ow Hon | Om

H . rac 3 MY 149 | x CH, CH, Q 245 xy” I { ) X

CH, N

H rac. J a

Xs 150 CH, Xin X % x, oh “r

H rac. CH, Ny

Cr 151 CH, Xen X 0

J Peas we | OY cr” NT eH, 152 CH, en, N i 0

X, or rac. ho Ho i % 153 X x _ CH, J” JO

CH, 0

H rac. HN AN N x as 154 oH, Xn, X xX

X N rac. oP as

I 1 (Continued) 60

Ex. config. 185 x, HC. CH, I'%

EH, % TC [he

H | rac. |X oH | wo ™

Co Co | pe 158 | cH, |x. CH, X % 265

A JPN

“LX

H rac. CH, . 1 192 7 | cH, Xe, X, %

X, o

H rac. J oD o} N N

CH, 1 H, 222 58 CH, Xen, % Ay x N =

H | rac. | PY x %

HC” “er, § J 9 0 221 5 xen, x 3 Qe! rac. ) x

H,C CH, he

CH, 9 NH, 161 OH, Xen, X s 181

X, Ny

H rac. oP

N, 162 1x Ix HOCH, oot

CH, “ N % : Cl.

X SN

I. 1 (Continued) 61

EX. R* config.

R®or R* mp.[°C] 163 X 172 h | | N I x

AN He ay —A

LT

‘84 L 5 on \ % 227

H rac. |"C ens [eo] N (ce:

In) 165 258

I Kon, % Q

N

H rac. oN

H.C” CH, %

H,C 7 oH 166 CH, X;—CH, x % % 266 : Sal PS { t ] | HC oH | PY ] [o] N he or 167 x. H,C_ CH,

CH, % we °

H rac. X . on, 168 7 Xs CH, Xen, Y io] 159

N rac. he” a, %

Nao HC 0

Hy % cH x 250 ; SU \ ne 0

A, o

@... (Continued) 62

A

R®or R* mp.[°C] 170 Hs Se X, X 213 xX,

H | rac. | N. Q x oN 171 | ¢ x Hy on, t ~ N Ji IR 228

H w= Ae (TKN 72 cH, Xe % x 181

X, Pe

H rac. J N

[0] N NN

AW

73 |e, XNer X ox 182

Tl aR

H rac. 0“ N

To 174 % HOx Choy |X

CH, A 0 rac. HC X, 1) 175 CH, Xn _-CH, Xs x 197

H rac. CH, [o] N 176

L HC, CHow, |X wo 0 rac. X, n

IAN

Ql

@... 1 (Continued) 63

Ex. config. 177 CH, Xn _-CHy % on, | X 216 * Ce

H | rac CH, I )

SAFER I BE

ZN

178 | CH, |X Xs % 200

Cc ve NS

H rac. L Y [e} N 179 CH, cn, Xs %, 197 %

H rac.

S

) 180 GH, % _ CH, Xen, b 8 o] 143 x —— t rac, HC” TCH, | P x I

Cy 17

NN _0

N” HC 181 CH, X oH, X, 234 x bl :

CN HC” oh, ne

He 0

ER Jew

CH,

H,C rac. Xs

NH, 183 CH, “Non, Xs 3 169

X o oO

@ 1 (Continued) 64

Ex. config. 184 % | "oa CH, I %

CH, le CLL

H rac. % H i 185 198

GH, Se SN C x,

H rac. ~~ nN" “QL

Xs 186 CH X oh x 202 k 3 :

A HC” er I

HC o 187 CH, Xan X s 200

X Ns

H rac. Py {

EEE X, S

X N

H rac. iN. 0 189 oth Xeon, x % x o« rac. o NN 190 cn, X fh % 196 : bY

HN” So

@... 1 (Continued) 85

Ex. config. RS =X I 191 CH, X;—CH, X, X % | 253 ; “| 15

Hy CH, 07 oN

WRT

192 % HC ~~ UANFCN z X A je

H rac. X “rr

Ig

CH, 183 CH, Xone Xs X, 201 [

X, CH,

H rac.

LE N—CH, 194 CH, [Xn _CH, X, Ny 250 & AN NP

H rac. \/ li %s 195 CH, Xo Xs x 198 x, CH, rac. o ae

F

196 cH, |x. X, x 245 x, CH,

H rac. oP or 197 X CH, CH, X &n, x” J ATT

H rac. " % iY

® 1 (Continued) 66

Ex. config. I.

CEFF Tee wore x 198 % Cy, Hen, ]

CH, | ho

H rac. | X N . o

B OA

%

IE ay v1

Vox

H rac. Pn “0 200 CH, | X;—CH, X, % . % 198 hig : %

HE” Cr 201 X, Big X eH J oo AT

H H rac. X 4 202 X HCx H,C CH, Xs

CH, J Clow rac. % [0]

X 198 203 CH, Xen, Xs $

X 0

H rac. 0 ae

O—cH, 204 % HO jou

CH, A Lo}

H rac. Xs )

®.. 1 (Continued) 87

Ex. config. orc) a 5 " 205 *% Rex, Is

CH, A 0

H rac. | X ! he " i I | | I p) Z

IS

[1 206 X, H,C ~~ A os

CH, % ) A

H rac. % C-

NN j®! 207 oH, Xen, Xs X 164

X

H rac. NH, ale 208 Cc CH, 0 253 k, x i © NW x,

H | rac. | | i

X

240 209 h X;~_~CH, x oC % x

A a or Cl. oh HC N rac. X; . 211 OH, X;—CH, x X xX 266 x CH, pl

HC eH i

LI 1 (Continued) 68 a 2 a

R’orR mp.[°C] 212 ih Xen CF LX %

F. ! H rac. | Y | 0 een LN

Lo | | a 213 i Xon, N %

C J{ .0

H rac. eu, L 214 CH, Xn, Xs % 2

H rac. 0 “OH 215 GH, *cn, p HO 232 x TL

H rac. X, 216 Le Xen, - ¥ o)

H rac. CH, N 4 aN 217 X, HC Xs

H,C i

H rac. % 0 ne 218

E Hox, | aS % F

CH, CX >250

X !

@.. 1 (Continued) 69

Ex. |r? config. 219 | Tx, % H rac. | by OA 260

He” eH, Co |(Zers)

FN

220 1x, HC. CH, cH,

HCL T 0”

CH, x;

H R x NN “AAO 221 i 190

H X 0

NH, 555 228

He ONO Xs cl

Ee i

H X

NH, 223 cH, |X _ CH, ? x : bY

H R [HC Don, sill 243 224 CH, |X _ CH, N cH x,

X, [o]

HC” CH, 0

HN TO 258 |x He on,

Cc Xs CH, by | ps x NH, (0 226 |x HC CH, CH,

Cc

I a J % 0 x JO" fo}

e.. 1 (Continued)

TF RE

=F i c 27 x; | HC. H = :

CH, X H | R * | NH,

Co] d a ss x 2% | nel “ha, TT) -

CH, x ] . [ g ¥ lo) xX x

Le Cx, Hoc, § H J 0” NH, %

Xs 0. & H oN, 200 xX x : c 251 Ton, [x cn, " Fo % H R 07 "NH, 232

Xs X cl So 232 oH, XC i” La we & H 07 NH, 149 x I % 234 oH HC AN 1% % H

WNT TO 197 x X% ~

X, x (

HN" TO 226

@®... 1 (Continued) 71

Ex. |r? config. or

CFF FE wor 238 TCH Xx,

I "Ox \ b

H R

I PN oN 182 237 | cH, C x % x, H, “x, A oe 0” "NH, 238 oH, IX CH, A X

H

HN" Yo 239 oH X~_-CH; xX 5 % : Ow 0

H

HN" So 240 CH, —~ i | % % i "YN Cc % Xs o, Hy

HN So 241 % CH, Xx gE 5

H oN 194 % 242 CH, H, Co Xs

X x A s

H

© Ne 200

CH, % 0 ] HC x X DN .

An [ET ne”

Claims (1)

1. ® 91 Patent Claims 1) Compounds of general formula (1), 1 2 Ror RY x R® SYP! ls R R R 0) wherein R’ denotes a group selected from among hydrogen, NH,, XH, halogen and a C+-Cs-alkyl group optionally substituted by one or more halogen atoms, R® denotes a group selected from among hydrogen, CHO, XH, -X-C4-C,-alkyl and an optionally substituted C4-Cs-alkyl group, R®, R* which may be identical or different denote a group selected from among optionally substituted C4-Cye-alkyl, C,-Cyo-alkenyl, C2-Cio-alkynyl, aryl, heteroaryl, Cs- Cg-cycloalkyl, Cs-Cs-heterocycloalkyl, -X-aryl, -X-heteroaryl, -X-cycloalkyl, -X- heterocycloalkyl, -NR®-aryl, -NR®-heteroaryl, -NR®-cycloalkyl, - and -NR®- heterocycloalkyt, or a group selected from among hydrogen, halogen, COXR?, CON(R®),, COR® and XR®, or R’and R* together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms, R® denotes hydrogen or a group selected from among optionally substituted C1-Cio-alkyl, C2-Cio-alkenyl, C2-C1o-alkynyl, aryl, heteroaryl and -Cs-Ce-cycloalkyl , or

   ® ” ® R®and R® or R*and R® together denote a saturated or unsaturated Cs-Cq-alkyl bridge which may contain 1 to 2 heteroatoms, R® denotes optionally substituted aryl or heteroaryl,

   R’ denotes hydrogen or -CO-X-C1-Ca-alkyl, and X in each case independently of one another denotes O or S,

   R® ineach case independently of one another denotes hydrogen or a group selected from among optionally substituted C1-Cy-alkyl, C,-C4-alkenyl, C-Cy-alkynyl and phenyl, optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

   2) Compounds according to claim 1, wherein

   X and R® have the meaning indicated, and R' denotes hydrogen,

   R? denotesa group selected from among a CHO, OH, and CHs group, R®, R* which may be identical or different denote a group selected from among hydrogen, optionally substituted C4-Ce-alkyl, C2-Cs-alkenyl, C,-Cs-alkynyl, C3-C;- cycloalkyl, or

   Rand R* together denote a C,-Cs-alkyl bridge , R® denotes a group selected from among optionally substituted C1-Cyo-alkyl, C2-C1o-alkenyl, C2-C1o-alkynyl, Cs-Ce-cycloalkyl and Cs-Ces-cycloalkenyl, or

   ” ® R®and R® or R* and R® together denote a saturated or unsaturated Ca-Cy-alkyl bridge which may contain 1 to 2 heteroatoms, and R’ denotes hydrogen,

   optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

   3) Compounds according to claim 1 or 2, wherein R'-R%, R”, R® and X have the meaning indicated, and R® denotes a group of general formula Cas 9 R ; wherein n denotes 1, 2, 3 or 4, R® denotes a group selected from among optionally substituted C4-Ce-alkyl, Co-Ce- alkenyl, Co-Ce-alkynyl, -CONH-C4-C1o-alkylene, -O-aryl, -O-heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among -O-C4-Cs-alkyl-Q', -CONR®-C;-Co-alkyl-Q', -CONR®-C-Cro-alkenyl-Q", -CONR®-Q?, halogen, OH, -SO2R®, -SO.N(R®),, -COR® -COOR’® -N(R®)2, -NHCOR?®, CONR®0C+-C1, alkylQ" and CONRP0OQ?,

   Q' denotes hydrogen, -NHCOR®, ora group selected from among an optionally substituted -NH-aryl, -NH-heteroaryl, aryl, heteroaryl, C3-Cs-cycloalkyl- and heterocycloalkyl group, Q? denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, Cs-Cg-heterocycloalkyl, Cs-Cs-cycloalkyl- and C4-Cj4-alkyl-C3-Cs- cycloalkyl group,

   @® ” R'™ which may be identical or different denotes a group selected from among optionally substituted C;-Cs-alkyl! , C2-Ce-alkenyl and Co-Cg-alkynyl, -O-C+-Ce-alkyl, -0-C,-Cg-alkenyl, -0-C,-Ce-alkynyl, Cs-Ce-heterocycloalkyl and Cs-Ce-cycloalkyl, or agroup selected from among hydrogen, -CONH, -COOR® -OCON(R®),, -N(R®);, - NHCOR® -NHCON(R®), , -NO, and halogen, or adjacent groups R® and R" together denote a bridge of general formula 0 R™ ; l a AN HB NR “Oo Pl 4 BD Y \ (C,-Co-Alky-Q")_ Y denotes O, S or NR", m denotes 0, 1 or 2 R'™ denotes hydrogen or C1-C,-alkyl, and R' denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, -C4-Cs-alkyl-phenyl, -C4-Cs-alkyl- pyridyl, -C4-Cs-alkyl-pyrazinyl, -C4-Cs-alkyl-pyrimidinyl and -C1-Cs-alkyl-pyridazinyl, R'™ denotes C4-Ce-alkyl optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

   4) Compounds according to one of claims 1 to 3, wherein R®-R® R® and X have the meaning indicated, and R'! denotes hydrogen, R? denotes CHs, and R’ denotes hydrogen,

   9s optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

   8} Campound of formula | according to one of claims 1 to 4 for use as pharmaceutical compositions.

   8) Compound of formula | acesiding to one of claims 1 10 4 fur use as pharmaceutical compositions with an antiproliferative activity.

   7) Use of a compound of formula 1 for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.

   8) A compound of formula | according to claims 1 to 4 for use in treating and/or preventing cancer, infections, inflammatory and autoimmune diseases. 9) Pharmaceutical preparations, containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 4 or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers. 10)Process for preparing a compound of general formula (1), R' R N IY T.

   RL ~ rR Rh OE Re R® R° 0) wherein R'-R” and X have the meanings given in claims 1 to 4, characterised in that a compound of general formula (11) AMENDED SHEET

   ® 96 ® Lo N™ N 4 P& = R L N N™ “Rr® iE 0) wherein R'-R® and X have the meanings given in claims 1 to 4 and L is a leaving group, Is reacted with an optionally substituted compound of general formula (III)

   RNR H (1) wherein RP® and R’ have the meanings given in ciaims 1 to 4.

   11) Compound of formula (ll), R' R oe 4 A Les Cl N N™ “Re 5 R (1) wherein R'-R® and X have the meanings given in claims 1 to 4.

   @ § ® 12) Process for preparing a compound of general formula (1), =} R? YY 7 3 R Js R SN” N~ N lL ls R R’° R 0) wherein R® denotes a group of general formula, RG) (R™). R® R® denotes an optionally substituted group -CONH-C4-Cp-alkylene or a group selected from among -CONR®-C4-Co-alkyl-Q’, -CONR®-C,-C1o-alkenyl-Q, -CONR®-Q?, and -COOR?, and R'-R%, R, R", nand X are as defined as in claims 1 to 4, characterised in that a compound of general formula (IA)

   1 2 RR C0 Ce 7 R SNE NR ie « (R), 7 ~L © (1A) wherein R'to R%, R’, R" and n are as defined as in claims 1 to 4, and L denotes a leaving group,

   is reacted with a primary or secondary amine to form the corresponding amide or is reacted with an alcohol to form he corresponding ester. 13) Compounds according to claim 1, substantially as herein described and exemplified. 14) The use according to Cai 7, subsianiiaily as Herein described and exempiiiied. 15) Pharmaceutical preparations according to claim 9, substantially as herein described and exemplified. 16) The process according to claim 10 or 12, substantially as herein described and exemplified. 17) The compound according to claim 11, substantially as herein described and exemplified.

   AMENDED SHEET