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(21)Application Number: KE/P/2004/000294   
   
(22) Filing Date: 05/08/2003
   
(30) Priority da~a: 10237722.7  17/08/2002  DE
   
(86)  PCT data     PCT/EP03/008629    05/08/2003 W02004/022553    18/03/2004

(86) PCT data     PCT/EP03/008629    05/08/2003 W02004/022553    18/03/2004           
               
(54) Title: INDOLE OR BENZIMIDAZOLE DERIVATIVES FOR MODULATING hill KINASE

(57) Abstract: The invention relates to compounds of formula (I). Said compounds are suitable for producing medicaments for the prophylaxis and treatment of diseases, the progression of which involves increased activity ofiKB kinase.
 
Description

Indole derivatives or benzimidazole derivatives for modulating hcB kinase

5    The invention relates to indole derivatives or benzimidazole derivatives which inhibit IKB kinase, to processes for preparing them and to their use as pharmaceuticals.

Patent application WO 94/12478 describes, inter alia,  indole derivatives

10    which inhibit blood platelet aggregation. Patent applications WO 01/00610 and WO 01/30774 describe indole derivatives and benzimidazole derivatives which are able to modulate NFKB.

NFKB is a heterodimeric transcription factor which is able to activate a large number of genes which encode, inter alia, proinflammatory cytokines such

15    as IL-1, IL-2, TNFa or IL-6. NFKB is present in the cytosol of cells, where it is complexed with its naturally occurring inhibitor IKB. Stimulation of the
cells, for example by cytokines, leads to the IKB being phosphorylated and

subsequently broken down proteolytically. This proteolytic breakdown leads

to the activation of NFKB, which then migrates into the nucleus of the cell,

20    where it activates a large number of proinflammatory genes.

In diseases such as rheumatoid arthritis (in connection with inflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer'sdiseases, diabetes Type II, "inflammatory bowel disease" or atherosclerosis, NFKB is activated to beyond the normal extent. The inhibition of NFKB is also of value in the

25    treatment of cancer since it is used in such treatment on its own or to augment the cytostatic therapy. It has been demonstrated that pharmaceuticals such as glucocorticoids, salicylates or gold salts, which are used in the therapy of rheumatism, inhibit the NFKB-activating signal

chain at various points or interfere directly with the transcription of the

30    genes.

The first step in the abovementioned signal cascade is the breakdown of IKB. This phosphorylation is regulated by the specific IKB kinase. Thus far, no inhibitors are known which inhibit IKB kinase specifically.

35    The known inhibitors of IKB kinase frequently suffer from the disadvantage of lacking the specificity of inhibiting only one class of kinases. For example, most inhibitors of IKB kinase inhibit several different kinases at the same time because the structures of the catalytic domains of these
 

kinases are similar. Consequently,  the  inhibitors act,  in  an  undesirable

manner,  on  many  enzymes,  including  those  which  possess  the  vital

function.

5    Patent application WO 01/30774 has already described indole derivatives which are able to modulate NFKB and which exhibit a strong inhibitory effect on IKB kinase. However, the compounds which are disclosed in WO 01/30774, and are described in the examples, also exhibit a powerful inhibitory effect on other kinases, such as cAMP-dependent protein kinase,

10    protein kinase C and casein kinase II. However, when their specificity is improved, some of these indole derivatives then exhibit a decrease in their ability to inhibit IKB kinase. Furthermore, the blood plasma level which can be achieved with the compounds disclosed in WO 01/30774 is insufficient for administering these derivatives orally.
15

In the endeavor to obtain effective compounds for treating rheumatoid arthritis (in association with inflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer's diseases, cancer diseases (potentiation of treatments with cytotoxic agents) or atherosclerosis, it has now been found

20    that the indole derivatives and benzimidazole derivatives according to the invention do not suffer from the abovementioned disadvantages. The indole derivatives and benzimidazole derivatives according to the invention are

powerful inhibitors of IKB kinase, in this connection inhibiting kinases very selectively, and have a high blood plasma level following oral

25    administration.

The invention therefore relates to the compound of formula I

~R1
~R4
_......N
~N\):X:-,. ;=::;>('_R11
R2    I    7---\\ - //N    (I)
A    f'\    M~
H    _......N-H

R3
 

and/or a stereoisomeric form of the compound of the formula I and/or a 30 physiologically tolerated salt of the compound of the formula I, where

X and M are identical or different and are, independently of each other, N atom or CH,

R 1 and R 11 are identical or different and are, independently of each other,

5    1. hydrogen atom,

2.    F, Cl, I or Br,

3.    -(C1-C4)-alkyl,

4.    -CN,

5.    -CF3,
10    6. -OR5, in which R5 is hydrogen atom or -(C1-C4)-alkyl,

7.    -N(R\R6 , in which R5 and R6 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,

8.    -C(O)-R5, in which R5 is hydrogen atom or -(C1-C4)-alkyl, or

9.    -S(O)x-R5 , in which x is the integer zero, 1 or 2, and R5  is
15    hydrogen atom or -(C1-C4)-alkyl,

R2 is 1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine,

20    isoxazolone, morpholine, oxazole, 1,3,4-oxadiazole, oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine,

pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or

25    triazolone, and

the heteroaryl radical is unsubstituted or is substituted, once,

twice or three times, independently of each other, by
1.1    -C(O)-Rs, in which R5 is hydrogen atom or -(C1-C4)-

alkyl,

30    1.2   -(C1-C4)-alkyl,
1.3    -O-R5 , in which R5 is hydrogen atom or -(C1-C4)-alkyl,

1.4    -N(R\R6 , in which R5 and R6 are, independently of each other, hydrogen atom or -(C1-C4-alkyl),

1.5    halogen, or

35    1.6    keto radical,
2.    -C(O)-OR5, in which R5 is hydrogen atom or -(C1-C4-alkyl},

3.    -C(O)-OR5, in which R5 is hydrogen atom or -(C1-C4-alkyl), or


4.    -C(O)-N(R\R8 , in which R7 and R8 are, independently of each other, hydrogen atom, -(C1-C4)-alkyi-OH, -O-(C1-C4)-alkyl or -(C1-C4-alkyl},

5    R3 is hydrogen atom or -(C1-C4-alkyl},
 

R4 is 1. a heteroaryl radical from the group pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1 ,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole, 3-hydroxypyrro-2,4-diones, 5-oxo-1 ,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, J3-carboline and benzofused, cyclopenta derivatives or cyclohexa derivatives of these heteroaryl radicals

where the heteroaryl radical is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-Cs)-alkyl, -(C1-Cs)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4}-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4)-alkoxycarbonyl, or
2.    an aryl radical from the group phenyl, naphthyl, 1-naphthyl,

2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, and
the aryl radical is unsubstituted or is substituted, once, twice or three times, independently of each other, by -(C1-Cs}-alkyl, -(C1-Cs)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4}-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4)-alkoxycarbonyl.
 

The invention furthermore relates to compounds of the formula I, where

X and M are identical or different and are, independently of each other, N

35    atom or CH,                   
R1 and R11 are defined as above under 1. to 9.,       
R2 is    1.    a heteroaryl    radical  from    the  group    imidazole,    isothiazole,
    isoxazole,    2-isoxazolidine,    isoxazolidine,    isoxazolone,
    1 ,3,4-oxadiazole,    oxadiazolidinedione,    1,2,3,5-oxadiazolone,

oxazole, 5-oxo-4,5-dihydro-[1 ,3,4]oxadiazole, tetrazole, thiadiazole, thiazole, triazole or triazolone, and the heteroaryl radical is unsubstituted or is substituted, once, twice or three times,
independently of each other, by 5 1.1 keto radical,
1.2    halogen, or

1.3    -(C1-C2)-alkyl, or

2.    -C(O)-N(R\R8, in which R7 and R8 are, independently of each other, hydrogen atom, -(C1-C4)-alkyi-OH, -O-(C1-C4)-

10    alkyl or -(C1-C4)-alkyl,

R 3   is hydrogen atom, methyl or ethyl,
 

R4 is 1. a heteroaryl radical from the group of the unsaturated, partially saturated or completely saturated rings which are derived from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole or isothiazole,

where the heteroaryl radical is unsubstituted or substituted, once, twice or three times, independently of each other, by -(C1-C4)-alkyl, -(C1-C4)-alkoxy, F, Cl, I, Br, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4)-alkoxycarbonyl, or

2.    phenyl, and phenyl is unsubstituted or is substituted, once, twice or three times, independently of each other, by F, Cl, I, Br, CF3, -OH, -(C1-C4)-alkyl or -(C1-C4)-alkoxy.
 

30    The invention furthermore relates to the compound

N-[ (S )-2 -diphenylamino-1-( 5-oxo-4 ,5-dihyd ro[ 1 ,3 ,4 ]oxad iazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide, N-{ 1-carbamoyl-2-[( 4-fluorophenyl)pyridi n-2 -yla m ino]ethyl}-2-(2-methyl-

aminopyrim id i n-4-yl)-1 H-indole-5-carboxamide,

35    N-[(S)-1-(5-oxo-4,5-dihydro-1 ,3,4-oxadiazol-2-yl)-2-(phenylpyridin-2-ylamino )ethyl]-2-(2-methyla minopyri midin-4-yl)-1 H-ind ole-5-ca rboxa mide, N-{1-carbamoyl-2-[(4-fluorophenyl)pyridin-2-ylamino]ethyl}-2-(2-amino-pyrimidin-4-yl)-1 H-indole-5-carboxamide,
 


N-[2-[ (4-fl uorophenyl)pyridin-2 -ylam ino}-1-( 4 H-[1 ,2 ,4]triazol-3-yl)ethyl)-

2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide,

N-[ 1-ca rba moyl-2 -(p henylthiazol-2 -yla mine )ethyi)-(S )-2 -(2 -methyl amino-

pyrimidin-4-yl)-1 H-indole-5-carboxamide,

5    N-[ 1-m ethoxycarba moyl-2-(phenyl pyrid in-2-yla mine )ethyi)-(S )-2-(2-methyl-aminopyrimidin-4-yl)-1 H-indole-5-carboxamide,

N-{ 1-ca rba moyl-2 -[ (phenyl)pyridin-2-yla mine )ethyl}-2 -(2 -aminopyri m idin-4-yl)-1 H-indole-5-carboxamide,

N-{1-carbamoyl-2-[(phenyl)pyrimidyl-2-ylamino)ethyl}-2-(2-methylamino-

10    pyrimidin-4-yl)-1 H-indole-5-carboxamide,

N-[ 1-(2-hyd roxyethylca rbamoyl)-2-(phenylpyri mid in-2 -ylamino )ethyl)-2-(2-methyla minopyrimid in-4-yl)-1 H-indole-5-carboxam ide,
(S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl}amino}-

3-[phenyl-(4-trifluoromethylpyrimidin-2-yl)amino]propionic add,

15    N-{ 1-carbamoyl-2-[ (4-fluorophenyl)-(5-methylpyrimidi n-2 -yl)amino)ethyl}-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide, N-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide,

N-{1-carbamoyl-2-[(phenyl)pyrimidin-2-ylamino)ethyl}-2-(2-methylamino-

20    pyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide, or N-{1-carbamoyl-2-[(phenyl)pyridin-2-ylamino]ethyl}-2-(2-methylamino-pyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide.

The term "halogen" is understood as meaning fluorine, chlorine, bromine or

25    iodine. The terms "-(C1-Cs)-alkyl" or "-(C1-C5)-alkoxy''are understood as meaning hydrocarbon radicals whose carbon chain is, straight-chain or

branched and contains from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, n-butyl, pentyl or tertiary-butyl. The expression "heteroaryl radical from the group of the unsaturated, partially saturated or completely

30    saturated rings which are derived from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole and isothiazole" is understood as meaning, for example, compounds such as piperazine, pyrazoline, imidazoline, pyrazolidine,

imidazolidine,  tetrahydropyridine,  isoxazoline,  isoxazolidine,  morpholine,

35    isothiazoline, isothiazolidine, tetrahydro-1 ,4-thiazine or piperidine.

The compounds of the formula I are prepared, for example, as described in patent applications WO 01/00610 and WO 01/30774. Either the starting

compounds for the chemical reactions are known or they can be readily prepared using methods known from the literature.

The invention furthermore relates to a process for preparing the compound

5    of the formula I and/or a stereoisomeric form of the compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I, which comprises
a)    reacting a compound of the formula IV,

~R1

(N'R4
(IV)

R2ANH2
10

in which R1, R2 and R4 are defined as in formula I, with an acid chloride or an activated ester of the compound of the formula Ill,

R11    X~
N~N~    (Ill)
R3-rr-    H    01

15    H   
       

where 01 is -COOH and R11, X, M and R3 are defined as in formula I, in the presence of a base or, where appropriate, of a dehydrating agent in solution, and converting the product into a compound of the formula I,

20    b) separating a compound of the formula I, which has been prepared by method a) and which, on account of its chemical structure, appears in enantiomeric forms, into the pure enantiomers by means of forming salts with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization using

25    chiral enantiomerically pure compounds such as amino acids, separating the resulting diastereomers and eliminating the chiral auxiliary groups, or

c)    either isolating  the  compound  of the formula  I which  has  been

prepared by methods a) or b) in free form or, when acidic or basic

30    groups are present, converting it into physiologically tolerated salts.

The indole carboxylic acid derivatives or benzimidazole carboxylic acid derivatives are prepared using a method described in Houben-Weyl "Methoden der Org. Chemie" [Methods of Org. Chemistry], volume E6-2A or E6-28. Thus, in order to prepare the indole carboxylic acid derivatives or

5 benzimidazole carboxylic acid derivatives of the formula Ill, hydrazinobenzoic acids and aryl ketones or heteraryl ketones are preferably reacted at 145°C in the presence of polyphosphoric acid as solvent. The necessary hydrazjnobenzoic acids are prepared using methods which are familiar to the skilled person, e.g. from the

10    corresponding benzoic acid anilines; aryl ketones or heteroaryl ketones are also prepared using methods with which the skilled person is familiar, e.g. from the corresponding acid chlorides or nitriles, by reacting them with organometallic compounds, for example.

15    Coupling methods of peptide chemistry which are well-known per se to the skilled person (see, e.g., Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974), are advantageously used for condensing

the compounds of the formula IV with those of the formula Ill. Compounds

20    such as carbonyldiimidazole, carbodiimide such as dicyclohexyl-carbodiimide or diisopropylcarbodiimide (DIC), 0-((cyano(ethoxycarbonyl)-methylene )-amino )-N,N ,N',N'-tetramethyluronium tetrafluoroborate (TOTU) or propyl-phosphonic anhydride (PPA) are suitable for use as condensing agents or coupling reagents.

25

The condensations can be carried out under standard conditions. In the condensation, it is as a rule necessary for the nonreacting amino groups which are present to be protected with reversible protecting groups. The same applies to carboxyl groups which are not involved in the reaction, with

30    these groups preferably being present, during the condensation, as -(C1-C5)-alkyl esters, benzyl esters or tert-butyl esters. An amino group

protection is not necessary if the amino groups are still present in the form of precursors such as nitro groups or cyano groups and are only formed by hydrogenation after the condensation. After the condensation, the

35    protecting groups which are present are eliminated in a suitable manner. For example, N02 groups (guanidine protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters can be eliminated by hydrogenation. The protecting groups of the tert-butyl type
 

are eliminated under acidic conditions while the 9-fluorenylmethyloxy-carbonyl radical is removed using secondary amines.

The invention also relates to pharmaceuticals which are characterized by 5   an effective quantity of at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, together with  a  pharmaceutically  suitable  and  physiologically  tolerated  carrier substance,  additive  and/or  other  active  compounds  and  auxiliary

10    substances.

Because of their pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those diseases whose course involves an increased activity of IKB kinase. These

15    diseases include, for example, chronic diseases of the locomotory apparatus, such as inflammatory, immunologically or metabolism-mediated acute and chronic arthritides, arthropathies, rheumatoid arthritis, or degenerative joint diseases such as osteoarthroses, spondyloses, diabetes

Type II, inflammatory bowel disease, loss of cartilage following joint trauma

20    or a relatively long period of joint immobilization following meniscus or patella injuries or ligament ruptures, or diseases of the connective tissue, such as collagenoses and periodontal diseases, myalgias and disturbances of bone metabolism, or diseases which are due to overexpression of tumor necrosis factor alpha (TNFn) or an increased concentration of TNFn, such

25    as cachexia, multiple sclerosis, craniocerebral trauma, Crohn'sdisease and intestinal ulcers, or diseases such as atherosclerosis, stenoses, ulceration,

Alzheimer'sdiseases, muscle breakdown, cancer diseases (potentiation of treatment with cytotoxic agents), cardiac infarction, gout, sepsis, septic shock, endotoxic shock, viral infections such as flu, hepatitis, HIV
30    infections, AIDS, or diseases caused by adenoviruses or herpesviruses, parasitic infections such as malaria or leprosy, fungal or yeast infections, meningites, chronic inflammatory lung diseases such as chronic bronchitis or asthma, acute respiratory distress syndrome, acute synovitis,

tuberculosis,  psoriasis,  diabetes, treatment of acute or chronic rejection

35    reactions on the part of the organ recipient against the transplanted organ, chronic graft-versus-host diseases and inflammatory vascular diseases. The abovementioned diseases can be treated much more specifically, and with a smaller side-effect spectrum, with the compounds which are used in

accordance with the invention because it is essentially only IKB kinase which is inhibited.

The pharmaceuticals according to the invention can be administered by

5    means of oral, inhalative, rectal or transdermal administration or by means of subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred.

The invention also relates to a process for producing a pharmaceutical

10    which comprises bringing at least one compound of the formula I together with a pharmaceutically suitable and physiologically tolerated excipient and, where appropriate, other suitable active compounds, additives or auxiliary substances, into a suitable form for administration.

15    Examples of suitable solid or galenic preparation forms are granules, powders, sugar-coated tablets, tablets, (micro)capsules, suppositories,

syrups, juices, suspensions, emulsions, drops or injectable solutions, and

also  preparations  with  protracted  active  compound  release,  in  the

preparation  of  which  customary  auxiliary  substances,  such  as  carrier

20    substances, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers, are used. Frequently employed auxiliary substances which may be mentioned are

magnesium  carbonate,  titanium  dioxide,  lactose,  mannitol  and  other

sugars,  talc,  milk protein,  gelatin,  starch,  cellulose  and  its  derivatives,

25    animal and vegetable oils, such as cod liver oil, sunflower oil, groundnut oil or sesame oil, polyethylene glycol and solvents, such as sterile water and monohydric or polyhydric alcohols, such as glycerol. The pharmaceutical preparations are preferably produced and administered in dosage units, with each unit containing, as the active constituent, a particular dose of the

30    compound of the formula I according to the invention. In the case of solid dosage units, such as tablets, capsules, sugar-coated tablets or

suppositories, this dose can be up to about 1 000 mg, preferably from about 50 mg to 300 mg, and, in the case of injection solutions in ampoule form, up to about 300 mg, preferably from about 10 mg to 100 mg.

35    Depending on the activity of the compound according to the formula I, daily doses of from about 20 mg to 1 000 mg of active compound, preferably of from 100 mg to 500 mg, are indicated for treating an adult patient of about 70 kg in weight. However, higher or lower daily doses may also possibly be appropriate. The daily dose can be. administered either by means of a

once-only administration in the form of a single dosage unit, or of several smaller dosage units, or by means of the multiple administration of subdivided doses at predetermined intervals.

5    As a rule, mass-spectroscopic methods (FAB-MS, ESI-MS) are used for determining end products. Temperatures are given in degrees centigrade; RT denotes room temperature (from 22•c to 26.C). Abbreviations which are used are either explained or correspond to the customary conventions. The invention is explained in more detail below with the aid of examples.

10

Preparation examples

A) Aniline preparation

A.1.) 2-(p-Fiuoroanilino)pyridine (3)

15

F~NH +    Cl5)    F~  ~   
        ~N.).L_N.,::J   
2        H   
    2    3   
           


A mixture of 29.34 g (0.264 mol) of 4-fluoroaniline (1) and 29.98 g (0.264 mol) of 2-chloropyridine (2) was heated at 15o•c for 2 h. After
20    having been cooled down to RT, it was distributed between 500 ml of 1N NaOH and 500 ml of ethyl acetate. The aqueous phase was extracted twice with in each case 300 ml of ethyl acetate and the combined organic

phases were dried with magnesium sulfate. After the solvent had been

evaporated,  the  residue  was  taken  up  in 500 ml  of ethyl  acetate  and

25    approx. 40 g of active charcoal were added. The mixture was stirred at RT for 10 minutes and filtered through kieselguhr. The active charcoal was rewashed 4 times with in each case 1 I of ethyl acetate. The solvent was

removed in vacuo (i.v.) and the residue was precipitated from 120 ml of

ethyl acetate. The solid was filtered off with suction and dried at 5o•c i.v.

30    41 g of 2-(p-fluoroanilino )pyridine (3) were obtained;

Yield 83%.

Empirical formula C11H9N2; M.W. =188.21; MS (M+H) 189.1.
1 H NMR (CDCI3) 6.68-6.75 (m, 2H), 6.88 (s, 1H), 7.05 (t, 2H), 7.24-7.32 (m, 2H), 7.43-7.49 (m, 1H), 8.18 (d, 1H).
 




12

A.2.) 2-(Anilino)pyrimidine (6)


~

~NH z  +

4


5    9.15 g (31 %) of the anilinopyrimidine 6 were obtained from 16.2 g of aniline (4} by reaction with 2-chloropyrimidine (5) in an analogous manner to that

described under A.1.).
Empirical formula C1oHgN3; M.W. =171.08; MS (M+H) 172.2.

10    B.) Amino acid synthesis by way of the Z-serine lactone 8

8.1.) Methyl (S)-2-amino-3-diphenylaminopropionate (11)

    OEAOffPP,    /        diphenylamine    Q   
        0                    /N~   
                               
    CH3CNffHF,    "rf.'NHZ  100"C    O.~    u0   
                0                   
    -35"C                    ~NHZ   
                8        OH    9   
SOCI2 /MeOH            H2, Pd(OH)C           
            MeOH           

8.1.1.) N-Benzyloxycarbonyi-L-serine-j3-lactone (8)

54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 ml of acetonitrile, and the suspension was cooled down to from -35°C to -45"C

20    while excluding moisture. 36.4 g (0.209 mol) of diethyl azodicarboxylate were added dropwise, at this temperature, within the space of 50 minutes. The mixture was then stirred at -35°C for 15 minutes. A solution consisting of 50 g (0.209 mol) of N-benzyloxycarbonyi-L-serine (7) in 500 ml of acetonitrile was then added slowly dropwise to this mixture such that the
 

temperature did not rise above -35eC. The resulting mixture was then stirred at sec for 12 h. In order to terminate the reaction, the reaction solution was freed from the solvent under reduced pressure and the crude product was purified by medium-pressure chromatography on silica gel.

5    (DCM/AcCN:25/1) 20.8 g of N-benzyloxycarbonyi-L-serine-~-lactone (8) were obtained after the solvent had been removed; yield 45%; (see also

Org. Synth. 1991 (70) 1ff.} in fine needles.
Empirical formula C11 H11 N04; M.W. =221.2; MS (M+H) 222.1.
1 H NMR (DMSO-d5) 4.30 (m, 1 H), 4.45 (m, 1H), 5.10 (s, 2H), 5.22 (m, 2H),

10    7.45 (m, 5H), 8.20 (d, J = 9.8 Hz, 1H).

8.1.2.) (S)-2-8enzyloxycarbonylamino-3-diphenylaminopropionic acid (9) 5.0 g (22.6 mmol) of serine lactone (5) were stirred together with 20 g

(118.2 mmol) of diphenylamine, and the mixture was heated at 1ooec for

15    2 h. The crude product was purified by means of medium-pressure chromatography on silica gel. (DCM/methanol: 9/1, then ethyl acetate/n-heptane: 4/1) 3.65 g (yield 42%) of clean 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (9) were obtained after the solvent had been removed.
20    Empirical formula C23H22N204; M.W. =390.44; MS (M+H) 391.2.
1 H NMR (DMSO-d5) 3.85 (m, 1 H), 4.18 (m, 1H), 4.3 (m, 1H), 4.9 (m, 2H}, 6.9 (m, 5H), 7.25 (m, 10H).

8.1.3.) Methyl (S)-2-benzyloxycarbonylamino-3-diphenylaminopropionate

25    (10}

6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at -sec, to

75 ml  of  methanol,  and  the  mixture  was  stirred  for  15  min.  3.6 g

(9.22 mmol)  of 2-benzyloxycarbonylamino-3-diphenylaminopropionic  acid

(9), dissolved in 75 ml of methanol, were then added and the mixture was

30    stirred at room temperature for a further 3 hours (h). After the solvents had been evaporated, the residue was taken up in ethyl acetate and the whole was extracted with sodium carbonate solution. Purification by means of

flash  chromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g (50%

yield}    of   methyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate

35    (10).
Empirical formula C24H24N204; M.W. =404.47; MS (M+H) 405.2.
1 H NMR (DMSO-d5) 3.58 (s, 3H), 3.95 (m, 1H), 4.18 (m, 1 H), 4.4 (m, 1H), 4.95 (m, 2H), 6.9 (m, 6H), 7.3 (m, 9H), 7.85 (d, J = 9.8 Hz, 1H).

8.1.4.) Methyl (S)-2-amino-3-diphenylaminopropionate (11)

In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected derivative (1 0) were dissolved in 500 ml of methanol, and 100 mg of catalyst (1 0% Pd(OH)2-C) were supplied under a protective

5    atmosphere of nitrogen. The inert gas was then displaced with a large excess of hydrogen and the mixture was shaken for 2 h in the hydrogen atmosphere. In order to terminate the reaction, the catalyst was filtered off and the filtrate was concentrated. 1.65 g (yield: 91 %) of methyl 2-amino-3-

diphenylaminopropionate (11) were obtained.

10    Empirical formula C15H1aN202; M.W. = 270.32; MS (M+H) 271.2.

1 H NMR (DMSO-d5) 3.45 (s, 3H), 3.58 (m, 1H), 3.8 (m, 1H), 3.95 (m, 1H), 6.9 (m, 6H), 7.3 (m, 4H).

8.2.) Amino acid synthesis by way of the acrylic acid 13

15    8.2.1.) Separation of the enantiomers

The racemic amino acids which were prepared by way of the acrylic acid

were resolved into the enantiomers by means of preparative HPLC using chiral phases such as Chiralpak AD (Daicel) 100 x 380, RT, flow rate 300 ml/min. The purity of the enantiomers was determined by means of

20    analytical HPLC such as Chiralpak-AD-H (Daicel) 4.6 x 250, 30"C, flow rate 1 ml/min, room temperature).

8 .2.2. Methyl (3-(N-4-fluorophenyi-N-2 -pyridyl)amino )-2-( di-tert-butyloxy-

carbonyl)aminopropionate (14)

8.2.2.1.) Methyl 2-(di-tert-butyloxycarbonyl)aminoacrylate (13)

50 g (0.228 mol) of Soc-serine (12) were dissolved in 300 ml of acetonitrile. 107 g (0.493 mol) of Boc anhydride and 2.64 g (22 mmol) of DMAP were added. The mixture was stirred at RT overnight, after which the solvent was

5    removed i.v. and the residue was taken up in 500 ml of ethyl acetate. The organic phase was washed with 500 ml of 1N HCI and dried using magnesium sulfate. 23 g of the acrylic acid 13 were obtained by crystallizing from 200 ml of heptane at -30°C and then filtering with suction.

The  mother liquor was concentrated  and the  residue was dissolved  in

10    140 ml of acetonitrile. 31 g (0.142 mol) of Boc anhydride and 1.26 g (1 0 mmol) of DMAP were added. After the mixture had been heated at 50°C for 8 h, the solvent was removed i.v. and the residue was taken up in 500 ml of ethyl acetate. The organic phase was washed with 400 ml of 1N HCI and dried over magnesium sulfate. After the solvent had beervemoved
15    i.v., a further 31.5 g of the acrylate 13 were obtained by crystallizing from

heptane. Yield 54.5 g (0.181 mol) 79%. Empirical formula C14H23NOs; M.W. =301.34; MS ((M*2)+Na+) 625.7.

1H NMR (DMSO-ds) 1.40 (s, 18H), 3.74 (s, 3H), 5.85 (s, 1H), 6.28 (s, 1H).

8 .2.2.2.) Methyl (3-(N-4-fluorophenyi-N-2-pyridyl)amino )-2-( di-tert-butyloxy-

20    carbonyl)aminopropionate (14)

11.5    g (38.2 mmol) of acrylate 13 were mixed with 7.2 g (38.2 mmol) of aniline 3 and 37.3 g (114 mmol) of cesium carbonate. 100 ml of acetonitrile

were added and the mixture was stirred at 55°C for 2 days. After that, it

was stirred at RT for a further 2 days. The solids were filtered off with

25    suction through kieselguhr and washed 3 times with in each case 100 ml of acetonitrile. The solvent was removed from the combined organic phases i.v. and the residue was chromatographed on silica gel using heptane/ethyl acetate 4:1. Yield: 14 g (75%) of 14.

Empirical formula C2sH32FN305; M.W. = 489.55; MS (M+H) 490.6.
30    1 H NMR (CDCI3) 1.28 (s, 18H), 3.72 (s, 3H), 4.25 (dd, 1H), 4.75 (dd, 1 H),

5.83    (dd, 1H), 6.22 (d, 1H), 6.56-6.61 (m, 1H), 7.05-7.12 (m, 2H), 7.19-7.26 (m, 3H), 8.18 (d, 1H).
 




16

8.2.3.) Methyl (3-(N-phenyi-N-2-pyrimidyl)amino )-2-( di-tert-butyloxy-

carbonyl)aminopropionate (15)




6, cs.co •.

acetonitrile





5

3 g (7%) of the amino acid 15 were obtained from 35 g of 6 when carrying out the reaction in an analogous manner to that described under 8.2.2.2.). Empirical formula C24H32N405; M.W. =472.23; MS (M+H) 473.1.

10    C.) Synthesizing the heterocyclic parent substance

....._    ,                melhyl~uanidine    I    I   
            ~        hydrochloride    0~   
    1        '    I    NaOEVEIOH,           
        1200C            6.5h, reflux           
'o    + 'o  f" -    'o~ N....._        ~    ~   
16 O    17            018    'N)l~   
4-hydrazino-                        H    19   
benzoic acid                               
                               

50% H2S04
130"C
20

C.1.) Indole parent substance synthesis:

15    2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid (20)

C.1.1.) 1-Dimethylamino-4,4-dimethoxypent-1-en-3-one (18)

100 g (0.76 mol) of 3,3-dimethoxy-2-butanone (16) were stirred together with 90.2 g of N,N-dimethylformamide dimethyl acetal (17) (0.76 mol) at

20    120oc for 48 h. The methanol which was formed in the reaction was removed continuously from the reaction solution by means of distillation. Crystallization occurred spontaneously when the solution was cooled, with the crystallization being brought to completion by adding a little heptane.

This resulted  in  128.24 g of crude  product 18  (yield  90%), which  was

25    reacted without any further purification.

Empirical formula CgH17N03; M.W. = 187.24; MS (M+H) 188.2.

1 H NMR (DMSO-d5) 1.22 (s, 3H), 2.80 (s, 3H), 3.10 (s, 9H), 5.39 (d, J = 15Hz, 1H), 7.59 (d, J =15Hz, 1H).

5    C.1.2.) [4-(1, 1-Dimethoxyethyl)pyrimidin-2-yl]methylamine (19)

1.22    g (53 mmol) of sodium were dissolved in 100 ml of absolute ethanol.

5.8    g (53 mmol) of methylguanidine hydrochloride and 10 g (53 mmol) of 1-dimethylamino-4,4-dimethoxypent-1-en-3-one (18) were added to this
solution, while stirring, and the whole was heated at boiling heat for 4 h. In

10    order to terminate the reaction, the ethanol was evaporated. The resulting product 19 was used for the subsequent reaction without any further purification. Yield 11.5 g (58 mmol, quantitative)

Empirical formula CgH1sN302; M.W. = 197.24; MS (M+H) 198.2.

1 H NMR (DMSO-d5) 1.45 (s, 3H), 2.78 (s, 3H), 3.10 (s, 6H), 6.75 (d, J =

15    3Hz, 1H), 7.0-7.1 (s(b), 1H), 8.30 (d, J =3Hz, 1H).

C.1.3.) 2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid (20)

5 g (25 mmol) of [4-(1, 1-dimethoxyethyl)pyrimidin-2-yl]methylamine (19) and 3.85 g of 4-hydrazinobenzoic acid were added, at room temperature and while stirring, to 150 ml of 50% sulfuric acid, and the mixture was

20    heated at 130CC for 4 h. The methanol which was formed in the reaction was removed continuously from the reaction solution by means of distillation. After it had been cooled down to 10°C, the reaction mixture was

poured  onto  200 ml  of  ice  and  adjusted  to  a  pH  of  about  5.5  with

concentrated sodium hydroxide solution. The precipitate of sodium sulfate

25    and product mixture which was formed in the course of this was filtered off and the filter residue was extracted several times with methanol. The combined methanol extracts were concentrated and the product 20 was purified by means of flash chromatography (DCM/methanol 9:1 ). Yield:

0.76 g (11%)

30    Empirical formula C14H13N402; M.W. = 268.28; MS (M+H) 269.1.

1H NMR (DMSO-d5) 2.95 (s, 3H), 6.90-7.10 (s(b), 1H), 7.18 (d, J =3Hz, 1H), 7.4 (s, 1H), 7.58 (d, J =4.5 Hz, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8.30 (s, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8.38 (d, J =3Hz, 1H), 11.85 (s, 1H), 12.40-12.60 (s(b ), 1H).

35

C.2.) Benzimidazole parent substance synthesis:

2-(2-Methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (25)
 



....._
0

'-o

21    0
 


'l    ....._                methyiQuanidine    I    I   
                    hydrochloride    0    0   
•c        0    ~ J    I   NaOEVEtOH,        ~   
11 o    ) __        3h, reflux    ~ '<:::   
+'-o  r"'•--....0.    If    ~N....._-----       
17            0    22    'NAN"   
 
                    H    23   
                           
    3,4-diamino-                       
2N H2so •.    benzoic acid                F\       
    Nitrobenzene    H02C'CrN~           
BO'C, 3h    _1_so_•c___    1        ~ _fl       
            8           
                N    N\       
                           
                H    NH   
                25    1       

5

C.2.1.) 4-Dimethylamino-1, 1-dimethoxybut-3-en-2-one (22)

300 g (307 ml, 2.54 mol) of methylglyoxal dimethyl acetal (21) were stirred, at 11 o•c for 4 hours (h), together with 303 g (337 ml, 2.54 mol) of N,N-dimethylformamide dimethyl acetal (17). The methanol which was

10    formed during the reaction was removed continuously from the reaction solution by distillation. After the reaction solution had cooled down, it was extracted with heptane and the solvent was evaporated. This resulted in 303 g of crude product 22 (yield 70%), which was reacted without any

further purification.

15    Empirical formula CeH15N03; M.W. = 173.21; MS (M+H) 174.1.

1 H NMR (DMSO-d5) 2.10 (s, 1H), 2.80 (s, 3H), 3.10 (s, 3H), 3.25 (s, 3H), 3.3 (s, 3H), 4.42 (s, 1H), 5.19 (d (b), J = 12.8 Hz, 1H), 7.60 (d, J =15Hz,

1H).

C.2.2.) (4-Dimethoxymethylpyrimidin-2-yl)methylamine (23)

20    0.33 g (14.4 mmol) of sodium was dissolved in 50 ml of absolute ethanol.

1.57    g (14.4 mmol) of methylguanidine hydrochloride and 2.48 g (14.4 mmol) of 4-dimethylamino-1, 1-dimethoxy-but-3-en-2-one (22) were added to this solution while stirring and the whole was heated at boiling

heat for 3 h. The reaction was terminated by evaporating the ethanol. The

25    resulting product 23 was used without any further purification. Yield 2.6 g (quantitative).
Empirical formula CeH13N302; M.W. = 183.21; MS (M+H) 184.1.

1 H NMR (DMSO-d5) 2.78 (s, 6H), 3.10 (s, 3H), 5.02 (s, 1H), 6.62 (d, J =

3 Hz, 1H), 8.30 (d, J = 3 Hz, 1H).

C.2.3.) 2-Methylaminopyrimidine-4-carbaldehyde (24)

10 g (54 mmol) of (4-dimethoxymethylpyrimidin-2-yl)methylamine (23) were dissolved in 54 ml of 2N sulfuric acid and the solution was heated at 8o•c for 3 h while stirring. After the reaction had cooled, the reaction solution

5    was carefully brought to a pH of about 9 using solid Na2C03 and extracted 3 times with ethanol. The combined dried extracts yielded the title aldehyde 24 in 60% yield (4.47 g) after the solvent had been evaporated.

Empirical formula C5H7N30; M.W. = 137.12; MS (M+H) 138.2.
1H NMR (DMSO-d5) 2.60-2.80 (s(b), 3H), 6.95 (d, J =3Hz, 1H), 7.40-

10    7.60 (s(b ), 1H), 8.55 (d, J = 3 Hz, 1H).

C .2.4.) 2-(2-Methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (25)
4.3    g (31.3 mmol) of methylaminopyrimidine-4-carbaldehyde (24) and 4.8 g 15   (31.1 mmol) of 3,4-diaminobenzoic acid were heated at 15o•c for 2 h in 300 ml of nitrobenzene. After the mixture had been cooled down too•c,the precipitate of the benzimidazole was separated off from the nitrobenzene by  filtration  and  the  product  25  was  purified  by  means  of  flash

chromatography (DCM/methanol4:1). Yield: 2.66 g (32%)

20    Empirical formula C13H11N502; M.W. = 269.28; MS (M+H) 270.2.
1H NMR (DMSO-d5) 2.95 (s, 3H), 7.50 (d, J = 3 Hz,  1H), 7.75 (d, J =

4.5 Hz, 1H), 7.90 (d, J = 4.5 Hz, 1H), 8.35 (s, 1 H), 8.55 (d, J = 3 Hz, 1 H), 8. 70- 9.05 (s(b ), 1H).

D.) Indole end products

25    0.1.) N-[(S)-2-diphenylamino-1-(5-oxo-4 ,5-dihydro[1 ,3 ,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide @)

        TOTU. OlEA,Q0        hydrazine hydrate       
        DMF, RT    ('N~A;J/    MeOH, RT;2d       
                       
            0 y-'N   "' ~    -           
                           
            OMeI A     N    ~~N           
            26    '           
                           
0.1.1.) Methyl 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyi]-(S)-amino}propionate (26)

5.0 g  (18.64 mmol)  of  2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-car-

5    boxylic acid (20) were dissolved in 1.2 I of OMF, and 7.9 g (24.08 mmol) of

TOTU and 7.9 ml (46.45 mmol) of ethyldiisopropylamine were then added consecutively. The solution was stirred at soc for 20 min, after which 0.73 g

(3.28 mmol)  of methyl  (S)-2-amino-3-diphenylaminopropionate  (11)  was

added to it. After the mixture had been stirred for 15 h, it was concentrated

10    under reduced pressure and the residue was taken up in n-butanol; the organic phase was then extracted with a saturated solution of sodium hydrogen carbonate in order to separate off byproducts. After the organic phase had been dried with MgS04 and concentrated, the methyl ester of

the title compound 26 was isolated by flash chromatography on silica gel

15    (OCM:MeOH = 19:1). Yield: 4.3 g (98%)

Empirical formula C3oH2aN503; M.W. = 520.22; MS (M+H) 521.3.
1H NMR (OMSO-d5) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4:58 (m, 2H), 4.85 (q, 1H), 6.90-7.10 (m, 7H), 7.18 (d, J =3Hz, 1H), 7.25-7.40 (m, 5H), 7.50

(d, J = 4.5 Hz, 1H), 7.65 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 8.35 (d, J = 3 Hz,

20    1H), 8.70 (d, J = 3.75 Hz, 1H), 11.85 (s, 1 H).

0.1.2.) N-((S)-2-0iphenylamino-1-hydrazinocarbonylethyl)-2-(2-methyl-aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (27)
1.0    g   (1.92 mmol)   of   methyl   3-diphenylamino-2-{[2-(2-methylamino-

25    pyrimidin-4-yl)-1 H-indole-5-carbonyi]-(S)-amino}propionate (26) was dissolved in 10 ml of methanol, after which 0.48 g (9.95 mmol) of hydrazine hydrate was added and the mixture was stirred at RT for 15 h. The precipitate of the product (0.3 g) was separated off from the mother liquor by filtration. Further hydrazone 27 (0.1 g) was isolated from the

30    concentrated mother liquor by means of flash chromatography on silica gel (OCM:MeOH = 19:1). Yield: 0.4 g (40%)
Empirical formula C29H2aNa02; M.W. = 520.6; MS (M+H) 521.4.
1H NMR (OMSO-d5) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.4 (s, 2H), 4.85 (q,

1H), 6.90-7.10 (m, 7H), 7.18 (d, J =3Hz, 1H), 7.20-7.45 (m, 5H), 7.50 (d, J

35    = 4.5 Hz, 1 H), 7.62 (d, J = 4.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J =3Hz, 1H),

8.35    (s(b ), 1H), 9.30 (s, 1H), 11.70 (s, 1H).

0.1.3.) N-[(S)-2-Diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxadiazol-

2-yl)ethyl]-2 -(2-methylam i nopyri mid in-4-yl)-1 H-indole-5-ca rboxam ide (28)


200 mg (0.384 mmol) of N-((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (27) were suspended in 20 ml of methylene chloride, and a 20% solution of phosgene in toluene (0.398 mmol) was added dropwise at ooc and while stirring. The

5    mixture was stirred at room temperature for a further 15 h and the solvent was evaporated. The oxadiazolone 28 was then isolated by flash chromatography on silica gel (DCM:MeOH = 9:1 ). Yield: 160 mg (76%)

Empirical formula C3oH25Na03; M.W. = 546.6; MS (M+H) 547.3.
10    1H NMR (DMSO-d5) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.85 (q, 1H), 6.90-7.10 (m, 7H), 7.15 (d, J =3Hz, 1H), 7.20-7.40 (m, 6H), 7.52 (d, J = 4.5 Hz, 1H), 7.68 (d, J =4.5 Hz, 1H), 8.10 (s, 1H), 8.92 (d, J =3Hz, 1H), 11.78 (s, 1H), 12.15-12.40 (s(b ), 1 H).

15    0.2.) N-{1-Carbamoyl-2-[(4-fluorophenyl)pyridin-2-ylamino]ethyl}-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid (30)
    1)HCIFunNN       
        O(W-a   
    2)20,HATU,DIEA       
        'liN    """"'~-   
        0H    I .,.;:    ~--(   
29    ~    NNH   
    FY"ii .    ~        I   
    ~A,_j.           
NHofMeOH
(NON
H2NI('N~ .t=\.
0    H,   tl)_N~~N 30
~  'H

0.2.1.) Methyl   3-[(4-fluorophenyl)pyridin-2-ylamino]-2-{[2-(2-methylamino-

pyrimidin-4-yl)-1 H-indole-5-carbonyl]amino }propionate (29)

20    0.75 g (1.53 mmol) of 14 was dissolved in 10 I of dioxane and the solution was cooled down to 0°C. 10 ml of 4N HCI in dioxane were added and the mixture was allowed to come to RT within the space of 2 h; It was then subsequently stirred for 12 h. The solvent was removed i.v. The residue

was taken up in 10 ml of DMF (solution A). 617 mg of the acid 20 were
25    dissolved in 20 ml of DMF and the solution was cooled down to ooc. 1.05 g

of HATU and 1.6 ml of OlEA were added. After the mixture had been stirred at ooc for 40 minutes, solution A was added. The mixture was allowed to


come to RT and was then subsequently stirred for 4 h. The solvent was removed i.v. and the residue was partitioned between 100 ml of a saturated (sat.) solution of NaHC03 and 100 ml of ethyl acetate. The aqueous phase was extracted 3 times with in each case 50 inl of ethyl acetate and the
5    combined organic phases were washed with 100 ml of a saturated solution of NaCI. The organic phase was dried using magnesium sulfate. The solvents were removed i.v. and the residue was chromatographed on silica

gel using heptane/ethyl acetate 1:3. 560 mg (68%) of the ester 29 were obtained.
10    Empirical formula C29H26FN703; M.W. =539.57; MS (M+H) 540.2.

D .2 .2.) N-{ 1-Carbamoyl-2-[( 4-fluorophenyl)pyridin-2 -ylami no ]ethyl}-

2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (30)
320 mg (0.593 mmol) of the ester 29 were dissolved, at ooc, in 50 ml of

15    ammonia-saturated methanol. The solution was stirred for 24 h and then left to come to RT. The solvents were removed i.v. and the residue was precipitated from 5 ml of ethyl acetate. The solid was filtered off with

suction and dried at 50°C i.v. 270 mg (87%) of the amide 30 were obtained. Empirical formula C2aH25FNa02; M.W. =524.56; MS (M+H) 525.2.

20 1H NMR (DMSO-d6) 2.45 (s, 3H), 4.10 (d, 1H), 4.52-4.66 (m, 2H), 6.26 (d, 1H), 6.77 (t, 1H), 7.02 (bs, 1H), 7.09-7.17 (m, 2H), 7.22-7.32 (m, 5H), 7.38-7.46 (m, 1H), 7.47-7.58 (m, 3H), 7.92 (s, 1H), 8.27-8.36 (M, 2H), 8.59 (d, 1H), 11.70 (s, 1H).

25    0.3.) N-[(S)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(phenylpyridin-2-ylamino)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (33)


2-anilinopyridine
1} enantiomer separation
13

2) HCI

3) 20, HATU, OlEA



1) hydrazine h)"'rate

2)CDCI2

0.3.1.) Methyl (3-(N-phenyi-N-2-pyridyl)amino)-2-(di-tert-butyloxycarbonyl)-

aminopropionate (31)

4.96 g (16.5 mmol) of acrylate 13 were mixed with 5.6 g (32.9 mmol) of

5    2-anilinopyridine and 32.16 g (98.7 mmol) of cesium carbonate. 50 ml of acetonitrile were added and the mixture was stirred at 45aC for 2 days. The solid was filtered off with suction through kieselguhr and washed 3 times

with in each case 100 ml of acetonitrile. The combined organic phases

were evaporated and the residue was chromatographed on silica gel using

10    heptane/diethyl ether 1:1. 5.66 g (73%) of the ester 31 were obtained. Empirical formula C25H33N305; M.W. =471.56; MS (M+H) 472.2.

0.3.2.) The enantiomers were separated as described under 8.2.1.).

0.3.3.) Methyl 2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl]-

15    amino}-3-(phenylpyridin-2-ylamino )propionate (32)

2.9 g of the S enantiomer of 31 were dissolved in 30 ml of dioxane and the solution was cooled down to oac. 30 ml of 4N HCI in dioxane were added, after which the mixture was allowed to come to RT and was then stirred for 12 h. The solvent was removed i.v. The residue was taken up in 30 ml of

20    DMF (solution A). 2.47 g (9.2 mmol) of the acid 20 were dissolved in 50 ml of DMF and cooled down to oac. 4.21 g of HATU and 6.4 ml of OlEA were added. After the mixture had been stirred at ooc for 45 minutes, it was

allowed to come to RT and solution A was added. The mixture was stirred

at  RT  for  12 h.  The  solvent  was  removed  i.v.  and  the  residue  was

25    partitioned between 300 ml of a sat. solution of NaHC03 and 300 ml of ethyl acetate. The aqueous phase was extracted 3 times with in each case
 

100 ml of ethyl acetate and the combined organic phases were washed with 400 ml of a sat. solution of NaCI. The organic phase was dried with magnesium sulfate. The solvents were removed i.v. and the residue was chromatographed on silica gel using heptane/ethyl acetate 1 :3. 1. 78 g

5    (55%) of the ester 32 were obtained.

Empirical formula CzgHz7N703; M.W. =521.58; MS (M+H) 522.2.

0.3.4.) N-[(S)-1-(5-0xo-4,5-dihydro-1 ,3,4-oxadiazol-2-yl)-2-(phenylpyridin-

2-ylamino )ethyl]-2-(2-methylaminopyrim id in-4-yl)-1 H-indole-5-carboxamide

10    (33)

1.78 g (3.4 mmol) of ester 32 were dissolved in 30 ml of MeOH. 0.83 ml of

hydrazine hydrate was added and the mixture was stirred at 40°C for 5 h. After that, a further 1.6 ml of hydrazine hydrate were added and the mixture was stirred at RT for 15 h. The solvents were removed i.v. and the residue

15    was taken up in 80 ml of dichloromethane. 3.2 ml of a 20% solution of phosgene in toluene were added and the mixture was stirred for 3 days. After that, the solvent was removed i.v. and the residue was partitioned between 80 ml of water and 80 ml of ethyl acetate. When this was done, a

solid precipitated out and was filtered off with suction. The organic phase

20    was evaporated and the residue was combined with the solid and chromatographed on silica gel using heptane/ethyl acetate 1:5. 390 mg
(21 %) of the oxadiazolone 33 were obtained. Empirical formula C2gHzsNg03; M.W. =547.58; MS (M+H) 548.2.

1H NMR (DMSO-ds) 2.96 (s, 3H), 4.30 (dd, 1H), 4.67 (dd, 1H), 5.40 (dd,
25    1H), 6.32 (d, 1H), 6.70-6.75 (m, 1H), 6.98 (bs, 1H), 7.16 (d, 1H), 7.22-7~33 (m, 4H), 7.38-7.46 (m, 3H), 7.52 (d, 1H), 7.63 (d, 1H), 8.08 (s, 1H), 8.21 (d, 1H), 8.31-8.35 (m, 1H), 9.00 (d, 1H), 11.72 (s, 1H), 12.15 (s, 1 H).

D .4.) N-{1-Ca rbamoyl-2-[ (4-fluoroph enyl)pyridin-2-yla mino ]ethyl}-

30    2-(2-aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (35)
 




25



1)    HCJ

2)    20, HATU, OlEA




NH3/Me0H


0.4.1.) Methyl 3-[(4-fluorophenyl)pyridin-2-ylamino]-2-{[2-(2-aminopyrimidin-

4-yl)-1 H-indole-5-carbonyl]amino}propionate (34)

5    370 mg (46%) of the methyl ester 34 were obtained from 750 mg of 14 when carrying out the reaction in an analogous manner to that described under 0.2.1.).
Empirical formula C2sH24FN703; M.W. = 525.55; MS (M+H) 526.2.

10    0.4.2.) N-{1-Carbamoyl-2-[(4-fluorophenyl)pyridin-2-ylamino]ethyl}-2-(2-aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (35)

95 mg (65%) of the amide 35 were obtained from 150 mg of 34 when carrying out the reaction in an analogous manner to that described under

0.2.2.).

15    Empirical formula C27H23FNs02; M.W. = 510.54; MS (M+H) 511.2.

1H NMR (OMSO-d6) 4.08-4.17 (m, 1 H), 4.54-4.65 (m, 2H), 6.29 (d, 1H), 6.54 (s, 2H), 6.74-6.80 (m, 1H), 7.10 (s, 1H), 7.18 (d, 1H), 7.22-7.31 (m, 4H), 7:38-7.56 (m, 6H), 7.92 (s, 1H), 8.29-8.35 (m, 2H), 8.74 (d, 1H), 11.80 (s, 1H).


F~ 0

~N.J,,v!l

(    0    DMF dimethyl acetal
H,N)""~~ ;='N 2) h~drazine. hydrate
0    CJ-NT-\~
35    H    fH



130 mg (0.25 mmol) of the amide 35 were dissolved in 10 ml of OMF. 40 1-11 of OMF dimethyl acetal were added and the mixture was heated at gooc for

5    4 h. The solvent was removed i.v. and the residue was taken up in 3.5 ml of acetic acid. After 27 IJI of hydrazine hydrate had been added, the mixture was stirred for 18 h. The solvent was removed i.v. and the residue was

purified by means of preparative HPLC. 84 mg (50%) of the triazole 36

were obtained.

10    Empirical formula CzgHzsFN1oO; M.W.::: 548.59; MS (M+H) 549.2.
1 H NMR (OMSO-d5) 3.04 (s, 3H), 4.36-4.43 (m, 1 H), 4.49-4.59 (m, 1H), 5.60-5.67 (m, 1H), 6.50 (d, 1H), 6.78 (t, 1H), 7.17-7.37 (m, 7H), 7.45-7.65

(m, 4H), 8.02 (s, 1H), 8.19 (d, 1H), 8.35 (d, 1 H), 8.39 (d, 1H), 11.85 (s, 1H). 0 .6.) N-[1-Carbamoyl-2-(phenylthiazol-2-ylamino )ethyi]-S-2-(2-methyl-
15    aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (42)

    s        (    Br    ~  ~J    13   
    NJl.NH    +A               
                       
    H    z    EIO    OEt    ~N..).::,N   
    37        38        H   
                           
~    s~                       
~NAN)        1)enantiomerseparalion           
O(    Jl )( 2)HCI               
/ gJ        3) 20, HATU, DIEA           
0+                       
40
NH3/MeOH

0.6.1.) Phenylthiazol-2-ylamine (39)

10 g (65.7 mmol) of phenylthiourea 37 were dissolved in 100 ml of acetic acid. 9.9 ml of the acetal 38 were added and the mixture was heated at

20    100°C for 2 h. The solvent was removed i.v. and the residue was partitioned between 300 ml of 1N NaOH and 300 ml of ethyl acetate. The

aqueous phase was extracted twice with in each case 100 ml of ethyl acetate and the combined organic phases were dried using magnesium sulfate. The solvent was removed and the residue was precipitated from 50 ml of diisopropyl ether. The solid was filtered off with suction and dried

5    at 50°C i.v. 2.5 g of aniline 39 were obtained. The diisopropyl ether mother liquor was evaporated and the residue was chromatographed on silica gel using heptane/ethyl acetate 2:1. This resulted in a further 3.5 g of 39 being

obtained. Yield: 6.0 g (52%).
Empirical formula CgHsNzS; M.W. =176.24; MS (M+H) 177.1.

10

0.6.2.) Methyl (3-(N-phenyl-N-2-thiazolyl)amino )-2-(di-tert-butyloxy-carbonyl)aminopropionate (40)
4.5 g (75%) of the ester 40 were obtained from 3,8 g (12.5 mmol) of the acrylate 13, 2.2 g (12.5 mmol) of the aniline 39 and 20 g of cesium

15    carbonate when carrying out the reaction in an analogous manner to that

described under 0.3.1.).
Empirical formula Cz3H31N305S; M.W. =477.58; MS (M+H) 478.2.

0.6.3.) The enantiomers were separated as described under 8.2.1.).

20    0.6.4.) Methyl S-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl]-amino}-3-(phenylthiazol-2-ylamino)propionate (41)

640 mg (55%) of 41 were obtained from 1.07 g (2.2 mmol) of the ester 40 and 901 mg (3.3 mmol) of the acid 20 when carrying out the reaction in an

analogous manner to that described under 0.3.3.)
25    Empirical formula Cz7HzsN703S; M.W. =527.61; MS (M+H) 528.1.

0.6 .4.) N-[ 1-Carbamoyl-2-(phenylthiazol-2-yla mino )ethyi]-S-2-(2-methyl-

aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (42)

340 mg (70%) of the amide 42 were obtained from 500 mg (0.95 mmol) of

30    41 when carrying out the reaction in an analogous manner to that described under 0.2.2.)

Empirical formula C25H24Ns02S; M.W. = 512.60; MS (M+H) 513.3.
1 H NMR (OMSO-d5) 2.97 (s, 3H), 4.23-4.30 (M, 1H), 4.39-4.48 (M, 1 H),

4.71-4.78 (m, 1H), 6.78 (d, 1H), 7.16 (d, 1H), 7.28-7.35 (m, 3H), 7.37-7.60

35    (m, 7H), 7.98 (s, 1H), 8.33 (d, 1H), 8.62 (d, 1H), 11.70 (s, 1 H).

0. 7.) N-[1-Methoxycarbamoyl-2-(phenylpyridin-2-ylamino )ethyi]-S-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (43)
 




28

~0           
~NAN )J        0-methy\hydroxylamine
~    o        hydrochloride   
/   00~~r - =-N    -iso-p-ro-py-1m-a-gn-es-iu_m_ch_lo_rid_e_
0 .    ~N~~N_N~;       
    32H    NH   
        I       
        QJ:JNN   
    ~  (~o43
    'o~    I('N    """'    -
        0H    I ..-?     "\:::    "I:..JN
            N    N~
            H    /NH

80 mg (0.95 mmol) of 0-methylhydroxylamine hydrochloride were dissolved in 10 ml ofTHF and cooled down to -40°C. 0.95 ml (1.9 mmol} of a 2M solution of isopropyl magnesium chloride in THF was then added

5    dropwise. The mixture was left to come to -20oc within the space of 1 h. A solution of 100 mg (0 .19 mmol) of the ester 32 in 3 ml of THF was then added dropwise. The mixture was left to come to RT within the space of 4 h and the reaction was ended by adding 5 ml of water. The THF was

removed i.v. and the residue was partitioned between 20 ml of a saturated

10    solution of ammonium chloride and 20 ml of ethyl acetate. The aqueous phase was extracted 3 times with in each case 20 ml of ethyl acetate and the combined organic phases were dried using magnesium sulfate. The solvent was removed i.v. and the residue was purified by means of

preparative  HPLC.  60 mg  (61%)  of the  methyl  hydroxamate  43  were

15    obtained.

Empirical formula CzgHzsNs03; M.W. =536.60; MS (M+H) 537.2.
1H NMR (DMSO-d5) 2.95 (s, 3H), 3.52 (s, 3H}, 4.09-4.18 (m, 1H), 5.51-

4.62    (m, 2H}, 6.33 (d, 1H), 6.78 (t, 1H), 7.00 (bs, 1 H), 7.18 (d, 1H), 7.25-

7.33    (m, 4H}, 7.49-7.61 (m, 5H), 7.98 (s, 1H), 8.29-8.36 (m, 2H}, 8.79 (d,

20    1H), 11.31 (s, 1H}, 11.75 (s, 1H).

0.8.) N-{1-Carbamoyl-2-[(phenyl)pyridin-2-ylamino]ethyl}-2-(2-amino-

pyrimidin-4-yl)-1 H-indole-5-carboxamide (45)

29
QNn        Q~       
,...o    (NH    1)H2,Pd(OH)C,MeOH    0N~::;,..   
'[    2) desmethyl analog    ...-0NH    "<::::~    -N   
0    . ) . __ \) of20,HATU,DIEA    0    I A      N    ~~   
    0                   
    rac-10I:        44    H    NH   
        Q~        2   
                   
    NH3/Me0H"~~~~ ~,    45   
        o    UHJ       
            ~    N\       
NH2

0.8.1.) Methyl 3-[(phenyl)pyridin-2-ylamino]-2-{[2-(2-aminopyrimidin-4-yl)-

1H-indole-5-carbonyl]amino}propionate (44)

816 mg (80%) of the methyl ester 44 were obtained from 540 mg of rac-10

5    when carrying out the reaction in an analogous manner to that described under 8.1.4.) and 0.1.1.).
Empirical formula C29H26N603; M.W. = 506.56; MS (M+H) 507.37.

0.8.2.) N-{1-Carbamoyl-2-[(phenyl)pyridin-2-ylamino]ethyl}-2-(2-amino-

10    pyrimidin-4-yl)-1 H-indole-5-carboxamide (45)

162 mg (67%) of the amide 45 were obtained from 150 mg of 44 when carrying out the reaction in an analogous manner to that described under

0.2.2.).

Empirical formula C2sH25N702; M.W. = 491.56; MS (M+H) 492.32.
15    1H NMR (OMSO-d6) 3.18 (s(b ), 3H), 4.05 - 4.13 (m, 2H), 4.85 (q, 1H), 6.58 (s(b), 2H), 6.88-7.59 (m, 19H), 7.98 (s, 1H), 8.25 (d, J =3Hz, 1H), 8.35 (d, J =2Hz, 1H), 11.78 (s, 1H).

0.9.) N-{1-Carbamoyl-2-[(phenyl)pyrimidyl-2-ylamino]ethyl}-2-(2-methyl-

20    aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (47)

                ~    N~           
                ~A,_j           
1) HCI            N    N           
2) 20, HATU, OlEA    ...-oyCN~~   
                OH    JA    '1-._jjN   
NH 3 /MeOHQ        N~        ~    N----.._   
            46        /H   
        A,_j               
    H,N        (N~N"":       
                   
        [("'~    I    ~    ~-,N    47   
        0        A    N    N~       
                    H    NH       
 
I

0.9.1.) Methyl 3-[(phenyl)pyridimyl-2-ylamino]-2-{[2-(2-methylamino-

pyrimidin-4-yl)-1 H-indole-5-carbonyl]amino}propionate (46)

1.75 mg (67%) of the methyl ester 46 were obtained from 2.36 g of 15 when carrying out the reaction in an analogous manner to that described

5    under 0.2.1.).
Empirical formula C2aH25Na03; M.W. =522.57; MS (M+H) 523.3.

0.9.2.) N-{1-Carbamoyl-2[(phenyl)pyrimidyl-2-ylamino}ethyl}-2-(2-methyl-

aminopyrimidin-4-yl)-1 H-indole-5-carboxamide (47)

440 mg (65%) of the amide 47  were obtained from 700 mg of 46 when

10    carrying out the reaction in an analogous manner to that described under

0.2.2.).
Empirical formula C27H2sNs02; M.W. =507.21; MS (M+H) 508.4.

1H NMR (OMSO-d5) 3.0 (s(b), 3H), 4.20-4.32 (m, 1 H), 4.45-4.59 (m, 2H), 4.75-4.90 (m, 1H), 6.75 (m, 1H), 7.10-7.60 (m, 12H), 7.95 (s, 1H), 8.35-

15   8.45 (m, 4H), 11.85 (s(b), ,1 H).

0.1 0.) N-[1-(2-Hydroxyethylcarbamoyl)-2-(phenylpyrimidin-2-ylamino )ethyl]-

2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (49)

0.1 0.1.) 2-{[2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl]amino}-

20    3-(phenylpyrimidin-2-ylamino)propionic acid (48)

4.0 g of the methyl ester 46 were dissolved in 400 ml of methanol. 40 ml of a 2N aqueous solution of NaOH were added and the whole was stirred at room temperature for 12 h. After the solvents had been evaporated, the

residue was dissolved with water and the pH was adjusted to -5 using a

25    saturated solution of NaH2P04. The resulting precipitate was filtered off

and washed with water. This resulted in 1.3 g (yield 93%) of the acid 48. Empirical formula C2sH26N503; M.W. =506.21; MS (M+H) 507.3.
 

0.1 0.2.) N-[1-(2-Hydroxyethylcarbamoyl)-2-(phenylpyrimidin-2-ylamino )-

ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (49)

30    200 mg of the acid 48 were dissolved in 2 ml of absolute OMF. 94 mg of
 
HOAt and 158 ~I of OlEA were added. 56 ~I of ethanolamine were then added dropwise and the mixture was cooled down to ooc; 195 mg of EDC

were then added. After 2 days of stirring at room temperature, the solvent was evaporated and the crude product was purified by means of MPLC

5    (eluent: DCM:MeOH = 9:1 ). Yield: 108 mg (50%) of the title amide 49. Empirical formula C31H31Na02; M.W. =549.64; MS (M+H) 550.4.
1 H NMR (DMSO-d6) 1.2 (t, 2H), 3.0 (s(b ), 3H), 3.35 (t, 1H), 4.00-4.32 (m,

2H), 4.80-4.99 (m, 1H), 6.95 (m, 1H), 7.00-7.65 (m, 7H), 7.90 (m, 1H),

-8.35 - 8.40 (m, 1H), 11.90 (s(b ), 1H).

10    0.11.) (S)-2-{[2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethylpyrimidin-2-yl)amino]propionic acid (54)
FtF
                ~f)            13           
                                       
                ~~)!._N~    :tF               
50            5~                   
                                   
                ~__{)               
                fN    0   N        53       
    2)HCI        .....-0~~   
    3) 20, HATU, OlEA    IIN        I    ~        ~ -~N   
                FCSFF 0    0    N        N-4::   
            QJ..:                    l   
                                   
2 N NaOHaq.,    "'g<~ ..           
                       
    MeOH               
l

0.11.1.) Phenyl-(4-trifluoromethylpyrimidin-2-yl)amine (51)

5.1 g (78%) of the aniline 51 were obtained from 5.1 g of the aniline (4) and

15    5 g of chloropyrimidine 50 when carrying out the reaction in an analogous manner to that described under A.1.).

Empirical formula C11HaF3N3; M.W. = 239.20; MS (M+H) 240.1.

0.11.2.) Methyl (3-(N-phenyi-N-4-trifluoromethylpyrimidin-2-yl)amino)-2-di-

20    tert-butyloxycarbonyl)aminopropionate (52)

3.9    g (86%) of the ester 52 were obtained from 2.5 g (8.4 mmol) of the acrylate 13, 3 g (12.5 mmol) of the aniline 51 and 16 g (50 mmol) of cesium carbonate when carrying out the reaction in an analogous manner to that described under 0.3.1.).
 
25    Empirical formula C25H31F3N405; M.W. =540.54; MS (M+H) 541.2.


0.11.3.) The enantiomers were separated as described under 8.2.1.). 0.11.4.) Methyl S-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl]amino}-3-[phenyl-(4-trifluoromethylpyrimidin-2-yl)amino)-propionate (53)

5    467 mg (58%) of 53 were obtained from 7 43 mg (1.375 mmol) of the S enantiomer of the ester 52 and 550 mg (1.436 mmol) of the acid 20 when carrying out the reaction in an analogous manner to that described under

0.3.3.
Empirical formula C2sH25F3Na03; M.W. =590.57; MS (M+H) 591.7.

10

0.11.5.) (S)-2-{[2-(2-Methylaminopyrimidin-4-yl)-1 H-indole-5-carbonyl)-amino }-3-[phenyl-( 4-trifluoromethylpyrimidin-2-yl)amino ]propionic acid (54) 38 mg (40%) of the acid 54 were obtained from 97 mg (0.164 mmol) of the ester 53 when carrying out the reaction in an analogous manner to that

15    described under 0.10.1.).
Empirical formula C2aH23F3Na03; M.W. =576.54; MS (M+H) 577.7.

1H NMR (OMSO-d5) 2.95 (s, 3H), 4.27-4.34 (m, 1H), 4.54-4.63 (m, 1H), 4.83-4.92 (m, 1H), 6.90 (bs, 1H), 7.15 (d, 2H), 7.19-7.23 (m, 1H), 7.27-7.36

(m, 5H), 7.45-7.55 (m, 2H), 7.96 (s, 1H), 8.32 (s, 1H), 8.41 (bs, 1H), 8.66

20    (d, 1H), 11.70 (s, 1H).

0.12.) N-{1-Carbamoyl-2-[(4-fluorophenyl)-(5-methylpyrimidin-2-yl)amino)-ethyl}-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide (61)

EDC*HCI

20
pentafluorophenol




Zn

HOAc

57    58
NH,tMeOH


0.12.1.) Pentafluorophenyl 2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylate (55)
6.38 g (23.78 mmol) of the acid 20 were suspended in 100 ml of THF.

5    5.25 g (28.54 mmol) of pentafluorophenol and 5.47 g (28.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EOC*HCI) were then added. The mixture was stirred at RT for 15 h, after which the solvent was removed i.v. and the residue was partitioned between 300 ml of a sat. solution of NaHC03 and 300 ml of ethyl acetate. The solids were

10    filtered off through kieselguhr and the residue was washed twice with in each 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases were washed with 200 ml of a sat. solution of NaCI and then dried with MgS04. After the solvents had been removed i.v.,

15    the residue was chromatographed on silica gel using heptane/ethyl acetate

1:1. 4.7 g (46%) of the pentafluorophenyl ester 55 were obtained. Empirical formula CzoH11 FsN402; M.W. =434.33; MS (M+H) 435.4.

0.12.2.) 2-Chloro-5-methylpyrimidine (57)
 




34

10.0 g (61.35 mmol) of 2,4-dichloro-5-methylpyrimidine (56) were dissolved in 50 ml of THF. 12.93 g (184 mmol) of zinc were added and the mixture was heated to reflux. A solution of 3.51 ml (61.35 mmol) of acetic acid in 10 ml of THF was then slowly added dropwise. After the addition had come

5    to an end, the mixture was heated to reflux for a further 1 h. A further 1.5 ml of acetic acid in 5 ml of THF were added dropwise and the mixture was
heated to reflux for 1 h. It was then left to cool down to RT, after which it was filtered through kieselguhr; this was then followed by 2 washings with in each case 20 ml ofTHF. The solvents were removed i.v. and the residue
10    was chromatographed on silica gel. 4.7 g (60%) of the chloropyrimidine 57 were obtained.

Empirical formula CsHsCINz: M.W. = 128.56; MS (M+H) 129.2.

0.12.3.) (4-Fiuorophenyl)-(5-methylpyrimidin-2-yl)amine (58)

15    1.8 g (45%) of the aniline 58 were obtained from 2.5 g (19.45 mmol) of 2-chloro-5-methylpyrimidine (57) and 2.7 g (24.31 mmol) of 4-fluoroaniline

(1)    when  carrying  out  the  reaction  in  an  analogous  manner  to  that

described under A.1.).

Empirical formula C11H1oFN3; M.W. =203.22; MS (M+H) 204.2.

20

0.12.4.) Methyl (3-(N-4-fluorophenyi-N-5-methylpyrimidin-2-yl)amino )-2-di-tert-butyloxycarbonyl)aminopropionate (59)
2.88 g (64%) of the ester 59 were obtained from 2.67 g (8.86 mmol) of the acrylate 10, 1.8 g (8.86 mmol) of the aniline 58 and 8.66 g (26.58 mmol) of

25    cesium carbonate when carrying out the reaction in an analogous manner to that described under 0.3.1.).
Empirical formula CzsH33FN405; M.W. = 504.56; MS (M+H) 505.6. 0.12.5.) Methyl 3-[(4-fluorophenyl)-(5-methylpyrimidin-2-yl)amino]-2-{[2-(2-

methylam inopyrimidin-4-yl)-1 H-ind ole-5-carbonyl]amino }propionate (60)

30    500 mg (0.991 mmol) of the ester 59 were dissolved in 10 ml of dichloromethane and the solution was cooled down to 0°C. 5 ml of TFA
were added and the mixture was then left to come to RT, after which it was stirred for 1 h. The solvents were removed i.v. The residue was taken up 10 ml of DMF, after which 430 mg (0.991 mmol) of 55 and 1.38 ml

35    (7.93 mmol) of OlEA were added. The mixture was left to stir at RT for 15 h, after which the solvents were removed i.v. and the residue was chromatographed on silica gel using heptane/ethyl acetate 1 :3. 423 mg
(77%) of 60 were obtained.

Empirical formula CzgH27FNs03; M.W. = 554.59; MS (M+H) 555.2.


0.12.6.) N-{1-Carbamoyl-2-[(4-fluorophenyl)-(5-methylpyrimidin-

2-yl)a m ino ]ethyl}-2 -(2 -methyla m inopyrimidi n-4-yl)-1 H-ind ole-5-ca rboxa mide

(61)

5    250 mg (99%) of the amide 61 were obtained from 260 mg (0.469 mmol) of the ester 60 when carrying out the reaction in an analogous manner to that

described under 0.2.2.).
Empirical formula C2aH25FNg02; M.W. =539.58; MS (M+H) 540.2.

1 H NMR (OMSO-d5) 2.11  (s, 3H), 2.95 (s, 3H), 4.21  (dd, 1H), 4.48 (dd,

10    1H), 4.75-4.80 (m,1H), 7.01 (bs, 1H), 7.10-7.16 (m, 4H), 7.22-7.30 (m, 3H),

7.43    (s, 1H), 7.47-7.53 (m, 2H), 7.91 (s, 1H), 8.26 (s, 2H), 8.29.8.34 (m, 2H), 11.70 (s, 1 H).

F.) Benzimidazole end products

15    F.1.) N-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylamino-pyrimidin-4-yl)-1 H-benzoimidazole-5-carboxamide (63)


NH 3/Me0H, RT,
TOTU, DIEA,    15 h
DMF, RT

F.1.1.) Methyl 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carbonyl]-( S)-amino }propionate (62)

20    2.6 g (9.6 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid (25) were dissolved in 300 ml of OMF, and 3.17 g
(9.6 mmol) of TOTU and 1.6 ml (11.6 mmol) of ethyldiisopropylamine were added consecutively. The mixture was stirred at soc for 20 min and 2.6 g (9.6 mmol) of methyl (S)-2-amino-3-diphenylaminopropionate (11) were

25    then added to the solution. After the mixture had been stirred for 16 h, it

was evaporated under reduced pressure and the methyl ester 62 was then isolated by means of flash chromatography on silica gel (OCM:MeOH = 9:1 ). Yield: 1.61 g (32%)
 




36

Empirical formula C29H27N703; M.W. = 521.58; MS (M+H) 522.3.

1H NMR (DMSO-d5) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.40 (m, 2H), 4.90 (q, 1H), 6.90-7.10 (m, 6H), 7.25-7.35 (m, 6H), 7.40 (d, J = 4.5 Hz, 1H), 7.60-7.80 (d(b), 1H), 8.05-8.25 (d(b), 1H), 8.45 (d, J =3Hz, 1H), 8.90

5    (s(b), 1 H), 11.85 (s(b), 1H).

F.1.2.) N-(S)-1-Carbamoyl-2-diphenylaminoethyl)-2-(2-methylamino-pyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (63)
50 ml of (absolute) methanol were saturated with ammonia at o•c. 0.5 g

10    (0.959 mmol) of methyl 3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carbonyi]-(S)-amino}-propionate (62) was then added and the mixture was stirred at room temperature for 24 h. After the solvent and excess ammonia had been evaporated, the amide 63 was isolated by means of flash chromatography on silica gel (DCM:MeOH =

15    19:1). Yield: 0.43 g (89%)

Empirical formula C29H2aNaOz; M.W. = 506.57; MS (M+H) 507.2.

1H NMR (DMSO-d5) 2.95 (s(b), 3H), 4.02- 4.35 (m, 2H), 4.85 (q, 1H),
6.80-7.10 (m, 6H), 7.15- 7.25 (m, 5H), 7.40 (d, J = 4.5 Hz, 1H), 7.58

(s(b), 1H), 7.68 (s(b), 1H), 8.06- 8.19 (d(b), 1H), 8.40- 8.58 (m, 2H),

20    13.10 (s, 1H).

F .2.) N-{1-Carbamoyl-2-[(phenyl)pyrimidin-2-ylamino]ethyl}-2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (65)

QJ,~

    1)HCI        yCN               
    2)25. HATU, OlEA    ...--0    NJL~ ~N~<.    ;==\   
                0    H        "l.J -h tf   
            N~            ~    N-'<_   
                    64    /H   
NH,JMeOH    2        A.J    '\               
            N    N  '-""                   
    H    NyC~~O        F\       
                       
            o    I h    .r-\'    tf    s5       
                    NN-'<_       
                    H        NH       
                            I       

25    F.2.1.) Methyl 3-[(phenyl)pyridimidin-2-ylamino)-2-{[2-(2-methylamino-pyrimidin-4-yl)-1 H-benzimidazole-5-carbonyl]amino}propionate (64)

210 mg (29%) of the methyl ester 64 were obtained from 657 mg of 15 when carrying out the reaction in an analogous manner to that described under 0.2.1.).


Empirical formula C27H2sNs03; M.W. == 523.56; MS (M+H) 524.2.

F. 2.2.) N-{1-Carbamoyl-2-[(phenyl)pyrimidin-2-ylamino]ethyl}2-(2-methyl-aminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (65)

5    11 0 mg (65%) of the amide 65 were obtained from 200 mg of 64 when carrying out the reaction in an analogous manner to that described under 0.2.2.).
Empirical formula C25H24FN1o02; M.W. == 508.55; MS (M+H) 509.3.
1H NMR (OMSO-d5) 3.0 (s(b), 3H), 4.20-4.32 (m, 1H), 4.41-4.55 (m, 2H),

10    4.80-4.90 (m,1H), 6.75 (m,1H), 7.10-7.50 (m,10H), 7.65 (q, 2H), 8.10 (s, 1H), -8.45 (d, 2H), 8.50 (d, 1H), 8.58 (d, 1H), 12.95 (s(b), 1H).

F .3.) N-{1-Carbamoyl-2-[ (phenyl)pyridyl-2-ylamino ]ethyl}-2-(2-methyla m ino-pyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (67)

NH 3/Me0H
15

F.3.1.) Methyl 3-[(phenyl)pyridyl-2-ylamino]-2-{[2-(2-methylaminopyrimidin-

4-yl)-1 H-benzimidazole-5-carbonyl]amino}propionate (66)

0.85 g (22%) of the methyl ester 66 was obtained from 3.44 g of 31 when carrying out the reaction in an analogous manner to that described under

20    0.2.1.).
Empirical formula C2aH25Na03; M.W. =522.57; MS (M+H) 523.3.

F .3 .2.) N-{1-Carbamoyl-2-[(phenyl)pyridyl-2-ylam ino]ethyl}-2-(2 -methyl-

aminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxamide (67)

160 mg (98%) of the amide 67 were obtained from 200 mg of 66 when

25    carrying out the reaction in an analogous manner to that described under 0.2.2.).
Empirical formula C27H2sNs02; M.W. = 507.56; MS (M+HCOO") 552.3.
1H NMR (DMSO-d5) 3.0 (s(b), 3H), 4.20-4.32 (m, 1H), 4.41-4.55 (m, 2H), 4.70-4.80 (m, 1H), 6.63 (m, 1H), 6.85 (m, 1H), 7.20-7.75 (m, 14H), 8.10
 




38

(s, 1 H),- 8.20 (d, 2H), 8.50 (d, 1H), 8.88 (d, 1H).


Pharmacological examples

5    IKB kinase ELISA:

The activity of the IKB kinase was determined using an ELISA which consisted of a biotinylated substrate peptide, which contained the amino

acid sequence of the IKB protein from serine 32 to serine 36, and a specific

polyclonal  or  monoclonal  antibody  (e.g.  obtained  from  New  England

10    Biolabs, Beverly, MA, USA, cat.: 9240) which only bound to the phosphorylated form of the IKB peptide. This complex was immobilized on an antibody-binding (protein A coated) plate and detected using a conjugate composed of a biotin-binding protein and HRP (e.g. streptavidin-

HRP). The activity was quantified with the aid of a standard curve which

15    was constructed using substrate phosphopeptide.

Implementation:

In order to obtain the kinase complex, 10 ml of Hela S3 cell extract S100

were diluted with 40 ml of 50 mM HEPES, pH 7.5, brought to 40% with

20    respect to ammonium sulfate and incubated on ice for 30 minutes. The precipitated pellet was dissolved in 5 ml of SEC buffer (50 mM HEPES, pH 7.5, 1 mM DlT, 0.5 mM EDTA, 10 mM 2-glycerophosphate), centrifuged at 20 000 g for 15 minutes and filtered through a 0.22 ).lm filter. The sample was loaded onto a 320 ml Superose-6 FPLC column

25    (Amersham Pharmacia Biotech AB, Uppsala, Sweden) which had been equilibrated with SEC buffer and which was operated at 4 "C with a flow rate of 2 ml/min. The fractions which were located at the migration time of the 670 kDa molecular weight standard were combined for the activation.

Activation was achieved by means of a 45-minute incubation with 100 nM

30    MEKK1A, 250 )!M MgATP, 10 mM MgCiz, 5 mM dithiothreitol (DlT), 10 mM 2-glycerophosphate and 2.5 11M microcystin-LR at 3rC. The activated enzyme was stored at -80°C.

The test substances (2 )ll), which were dissolved in DMSO, were preincubated, at 25"C for 30 minutes, with 43 )!I of activated enzyme

35    (diluted 1:25 in reaction buffer 50 mM HEPES pH 7.5, 10 mM MgCiz, 5 mM

DTT, 10 mM ~-glycerophosphate, 2.5 )!M microcystin-LR). 5 )!I of substrate peptide (biotin-(CH2)5-DRHDSGLDSMKD-CONHz) (200 11M) were then added, after which the mixture was incubated for one hour and the reaction was stopped with 150111 of 50 mM HEPES, pH 7.5, 0.1% BSA, 50 mM
 

EDT A, antibody [1 :200]. 100 111 of the stopped reaction mixture or of a standard phosphopeptide dilution series (biotin-(CH2)6-DRHDS[P03]GLDSMKD-CONH2) were then transferred to a protein A plate (Pierce Chemical Co., Rockford, IL, USA), after which the plate was

5    incubated for 2 hours while being shaken. After 3 washing steps with PBS, 100 Ill of 0.5 llg/ml streptavidin-HRP (horseradish peroxidase) {diluted in 50 mM HEPES/0.1% BSA) were added for 30 minutes. After 5 washing steps with PBS, 100 11L of TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD, USA) were added and the color

10    development was stopped by adding 100 11L of 0.18 M sulfuric acid. The absorption was measured at 450 nm. The standard curve was produced by linear regression corresponding to a 4-parameter dose-effect relationship. This standard curve was used to quantify the enzyme activity or its inhibition by the test substances.

15

The  ICso for N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxadiazol-

2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide   was

0.050 11M.

20    Blood plasma level of N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]-oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indol-5-carboxamide

The    compound   N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxa-

25    diazol-2-yl)ethyl)-2-(2-methylaminopyrimidin-4-yl)-1 H-indol-5-carboxamide, termed compound 28 below, was administered to male C57/BL6 mice. For this, in each case about 25 mg of compound 28 per kg of body weight of the mice, were administered, wet-ground in 0.5% hydroxyethyl cellulose

(HEC), orally as a suspension {by way of a probang). Blood samples were

30    taken after 0.25; 0.5; 1; 2; 4; 6 and 8 hours (sacrificial blood was withdrawn from in each case 2 animals at each of the time points mentioned). The blood samples were converted into heparin plasma. The plasma samples were stored at -20°C until analyzed.

Analysis:

35    The plasma samples were thawed. The plasma proteins which interfered with the analysis were then precipitated with acetonitrile.
Processing: 50 111 of plasma + 20 111 of internal standard (5 llg/ml) + 50 Ill of buffer (2 mMol ammonium formate solution, pH 2.6/acetonitrile, 40:60, v/v) were mixed for about 10 sec on a Whirlmixer. 150 111 of acetonitrile were

then added and the whole was mixed once again for about 10 sec. The samples were then centrifuged (Hettich, EBA 12, about 12 000 revolutions per minute). The supernatants (in each case about 200 J.LI) were transferred to glass tubes. 70 J.LI of the supernatant were injected.

5    The respective supernatant was used to determine the plasma level content of compound 13 by means of LC-MS/MS in accordance with the following method:
HPLC system: Agilent 1100

Software: Analyst

10    Column: 125 x 4 mm Nucleosil120 5 C18 (Machery & Nagel) Column length: 125 mm
Detection: LC-MS/MS

MS instrument: PE-Sciex API 365 (Triple Quadrupole mass spectrometer) Software: MacQuan software (PE-Sciex)

15    Detection type: MS/MS (MRM) Flow rate: 0.5 mllmin Injection volume: 70 j.LI

Internal standard: SK-7 in acetonitrile

Mobile  Phase: Acetonitrile/2 mMol  ammonium  formate  solution,  pH 2.6

20    (70:30, v/v) Retention times (Rt):

Internal Standard: 4.4 min Compound 28: 3.9 min
The lower detection limit of the method is 0.01 J.lg/ml.

25

Results:

The plasma level of compound 28 was at most 4.3 J.lg/ml. The exposure, measured as AUC =area under the curve, was 5.4 J.lg/ml x h.

30    Protein tyrosine kinase

As examples of the specificities of the lxB kinase inhibitors which had been discovered, their ICso values were determined in the case of the kinase

enzyme protein tyrosine kinase.

Protein tyrosine kinase activity was determined using the appropriate test

35    kit from Upstate Biotechnologie in accordance with the manufacturer's instructions and at an ATP concentration of 50 J.LM. As a difference from the manufacturer's method, Multi-Screen plates (Millipore; phosphocellulose MS-PH, cat. MAPHNOB10, or Durapore PVDF, cat. MADVNOB 50), were used, together with the appropriate exhaust system, instead of phospho-


cellulose filters. Poly (Giu, Tyr 4:1) (Sigma cat. P0275) was used as the

test kit substrate at a test concentration of 1 mg/ml. The plates were then

measured in a Wallac Micro Beta scintillation counter. 100 J.LM of the test

substance were used in each case.

5    The test substance was tested in a duplicate determination. The ICso calculations were performed using the GraFit 3.0 software package.

The ICso for N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1 ,3,4]oxadiazol-

2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide

10    (compound 28) in the protein tyrosine kinase assay was 82.5 J.LM.

Comparison experiment: The compound

15    was prepared as described in WO 01/30774 and is termed the comparison compound below. The comparison compound was administered to male NMRI mice. For this, in each case about 50 mg of the comparison compound per kg of body weight of the mice were administered orally as a suspension in 0.5% HEC (by way of a probang). Blood samples were taken

20    after 0.25; 0.5; 1; 2; 4; 6 and 8 hours (sacrificial blood was withdrawn from in each case 2 animals at each of the time points mentioned). The blood samples were converted into heparin plasma. The plasma samples were stored at -20°C until analyzed.

Analysis: The analysis was carried out using HPLC/UV.

25

Processing: 50 IJI of plasma + 20 J.LI of internal standard (5 J.lg/ml) + 50 IJI of buffer (1% formic acid/acetonitrile, 40:60, v/v) were mixed for about 10 sec on a Whirlmixer. 150 IJI of acetonitrile were then added and the whole was mixed once again for about 10 sec. The samples were then centrifuged

30    (Hettich, EBA 12, about 12 000 revolutions per min). The supernatants (in each case about 200 IJI) were transferred to glass tubes. 100 IJI of the supernatant were injected.

The respective supernatant was used to determine the plasma level content of the comparison compound by means of HPLC/UV in accordance with the following method:

5    HPLC System: Gynkoteck P580 HPG pump + Gilson Abimed XL-231 Autosampler
Software: Mass-chrom

Column: 125 x 4 mm Protosil 120 3 ODS AQ 3 (from Bischoff)

Column length: 125 mm

10    Detection: LC-MS/MS

MS instrument: PE-Sciex API 365 (Triple Quadrupole mass spectrometer) Software: MacQuan Software (PE-Sciex)
Detection type: MS/MS (MRM) Flow rate: 0.5 mUmin

15    Injection volume: 100 1-11

Internal Standard: SK-7 (Aventis compound) in acetonitrile

Mobile  Phase: Acetonitrile/2  mMol  ammonium formate  solution,  pH  2.6

(70:30, v/v) Retention times (Rt):
20    Internal standard: 4 min Comparison compound: 1.5 min

At 0.01 IJg/mL, the lower detection limit was identical to that when employing LC-MS/MS in the example using the compound 28.

25

Results: The plasma level of the comparison compound was at most 1.5 IJg/mL. The exposure, measured as the AUC = area under the curve, was 1.7 IJglmL x h.

In comparison with the example using the compound 28, the maximum

30    blood plasma level was about 60% lower in the comparison experiment even though, at 50 mg/kg, the comparison compound was administered at a dose which was twice as high as in the case of compound 28. The AUC values which were determined for the comparison compound also give the same result.

35

In the  above-described  protein tyrosine  kinase  assay,  the  ICso for the

comparison  compound  was  46.35  IJM. The  ICso is therefore  markedly

better than in the case of compound 28.


The improvement in the specificity with regard to the IKB kinase becomes even clearer when the ratios of the ICso values for protein tyrosine kinase relative to IKB kinase are compared. In the case of compound 28, this ratio is 1650 (82.5/0.05) while in the case of the comparison compound it is

5    46.35 (46.35/1.0; in accordance with the data from WO 01/30774).

The specificity ratios and/or plasma levels and exposure of the other examples were determined in an analogous manner.

    Example    Molecular formula    Molecular weight    IKK IC50    Specificity ratio       
    No.    neutral compound        50 1-1M           
                           
                           
    28    C30 H26 N8 03    546.59    0.05    1650       
    30    C28H25FN802    524.56    0.05    > 200       
    33    C29H25N903    547.58    0.012    > 833       
    35    C27H23FN802    510.54    0.01    > 1000       
    36    C29H25FN100    548.59    0.005    > 2000       
                           
    42    C26H24N802S    512.60    0.009    > 1110       
    43    C29H28N803    536.60    0.0008    > 12500       
                           
    45    C28 H25 N7 02    491.55    0.015    > 665       
    47    C27H25N902    507.56    0.006    > 1665       
    49    C31 H31 N7 03    549.63    0.035    > 285       
    54    C28H23F3N803    576.54    0.003    > 3330       
                           
        C28H26FN902    539.58    0.006    > 1650       
    61                       
    63    C28 H26 N8 02    506.57    0.003    > 1000       
    65    C26H24N1002    508.55    0.004    > 2500       
    67    C27H25N902    507.56    0.002    > 5000       

Tuberkulose, Psoriasis, Diabetes, Behandlung von akuten oder chronischen Abstol>ungsreaktionen des Organ-empfangers gegen das verpftanzte Organ, chronische Graft-versus-Host-Erkrankungen und entzOndliche Gefiil>erkrankungen sind.

5

Claims

1.    A compound of the formula I

10



15

(I)


20

and/or a stereoisomeric form of the compound ofthe formula I and/or a physiologically tolerated salt of the compound of the formula I, where
X and Mare identical or different and are, independently of each other, N atom or CH, R1 and R11 are identical or different and are, independently of each other,
25

1.    hydrogen atom,

2.    F, Cl, I or Br,
3.    -(C1-C4)-alkyl,
4.    -CN,
30    5. -CF3,

6.    -QRS, in which R5 is hydrogen atom or -(CrC4 )-alkyl,
7.    -N(R5)-R6, in which R5 and R6 are, independently of each other, hydrogen atom or -(C1-C4)-alkyl,
8.    -C(O)-RS, in which R5 is hydrogen atom or -(C 1-C4)-alkyl, or
9.    -S(O)x-Rs, in which x is the integer zero, 1 or 2, and Rs is hydrogen atom or -(C1-C4)-alkyl,

35

R2 is

1. a heteroaryl radical from the group 3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone, morpholine, oxazole, 1 ,3,4-

40    oxadiazole, oxadiazolidinedione, oxadiazolone, 1 ,2,3,5-oxathiadiazole-2-oxide, 5-oxo-4,5-dihydro[1 ,3,4]-oxa-diazole, 5-oxo-1 ,2,4-thiadiazole, piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and

the heteroaryl radical is unsubstituted oris substituted, once, twice or three times, independently of each other, by

45    1.1 -C(O)-Rs, in which R5 is hydrogen atom or -(C1-C4)-alkyl,
1.2    -(C1-C4)-alkyl,
1.3    -O-R5, in which R5 is hydrogen atom or -(C 1-C4)-alkyl,
1.4    -N(R5)-R6, in which R5 and R6 are, independently of each other, hydrogen atom or-(C1-C4 )-alkyl,
1.5    halogen, or

50    1.6 keto radical,

2.    -C(O)-RS, in which R5 is hydrogen atom or -(CrC 4)-alkyl,
3.    -C(O)-QRS, in which Rs is hydrogen atom or -(C1-C4)-alkyl, or
4.    -C(O)-N(R7)-RB, in which R7 and RB are, independently of each other, hydrogen atom, -(C1-C 4)-alkyi-OH,
55    -0-(C1-C4)-alkyl or -(C1-C4 )-alkyl,

R3 is hydrogen atom or -(C1-C4)-alkyl,

R4 is

ethyl}-amide,

2-(2-methylaminopyrimidin-4-yi)-1H-indole-5-carboxylic acid [(S)-1-(5-oxo-4,5-dihydro-1 ,3,4-oxadiazol-2-yl)-2-(phenylpyridin-2-ylamino)ethyl)-amide,

2-(2-amino pyrimidin-4-yl)-1 H-indole-5-ca rbcxylic  acid  { 1-carbamoyl-2-[(4-fluorophenyl) pyridin-2-yl amino ]ethyl}•
s    amide,

2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid [2•[(4-fluorophenyl)pyridin-2-ylamino]-1-(4H-[1,2,4]tri-

azol-3-yl)ethyl]-amide,

(S)-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-ca rboxylic acid [ 1-carba moyl-2-(phe nylthiazol-2-ylamino) ethyl)-amide,
1o (S )-2-(2-methylamino pyrimidin-4-yl)-1 H-indole-5-carboxylic acid [1-methoxycarbamoyl-2-(phenylpyridin-2-ylami-no}ethyl]-amide,

2-(2-aminopyrimidin-4-yl)-1 H-indole-5-carboxylic acid {1-carbamoyl-2-[(phenyl)pyridin-2-ylamino]ethyl}-amide, 2-(2-m ethyl a minopyrimidin-4-yl)-1 H-indole-5-carboxylic acid {1-carbamoyl-2•[(phenyl)pyrimidyl-2-yl a mine]ethyl}-amide,
15    2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxylic  acid  [1-(2-hydroxyethylcarbamoyl)-2-(phenylpyrimidin-2-

ylamino)ethyl]-amide,

(S)- 2-{ [2-(2- methyla mi no pyri midin-4-yl)-1 H- indole- 5- carbonyl)-amino }-3-[phenyl-(4-trifluoromethylpyrimidin- 2-yl)

amino]propionic acid,

2•(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid {1-carbamoyl-2-[(4-fluorophenyl)-(5-methylpyrimidin-

20    2-yl)amino]ethyl}-amide,

2-(2-methyla mi nopyrim idin-4-yl)-1 H-benzimidazole-5-ca rboxylic   acid   ( (S)-1-carbamoyl-2-d iphenylami noethyl)-

amide,

2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid { 1-carba moyl-2-[ (phenyl) pyrimidyl-2-yla mi no] ethyl}-amide, or

25    2-(2-methylaminopyrimidin-4-yl)-1 H-benzimidazole-5-carboxylic acid {1-carbamoyl-2-[(phenyl)pyridyl-2-ylamino) ethyl}-amide.

4.    A process for preparing the compound of the formula I as claimed in one or more of claims 1 to 3, which comprises

30    a) reacting a compound of the formula IV,

?-R1

35
(N'R4    (IV)

R2/'--.NH,
 

40



45
 

in which R1, R2 and R4 are defined as in formula I, with an acid chloride or an activated ester of the compound of the formula Ill,

;=:xR11"x=Gl
N,, '!M  I    (Ill)
~ M     N
R3 - f    H    D1
 


50    where 01 is -COOH and R11, X, M and R3 are defined as in formula I, in the presence of a base or, where appropriate, of a dehydrating agent in solution, and converting the product into a compound of the formula I,

b) separating a compound of the formula I, which has been prepared by method a) and which, on account of its chemical structure, appears in enantiomeric forms, into the pure enantiomers by means of forming salts with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization using chiral
55    enantiomerically pure compounds such as amino acids, separating the resulting diastereomers and eliminating the chiral auxiliary groups, or

c)    either isolating the compound of the formula I which has been prepared by methods a) or b) in free form or, when acidic or basic groups are present, converting it into physiologically tolerated salts.


5.    A pharmaceutical which comprises an effective content of at least one compound of the formula I as claimed in claim 1, and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, together with a pharmaceutically suitable and physiologically tolerated carrier substance, additive and/or other active compounds and auxiliary substances.

5

6.    The use of the compound of the formula I as claimed in one or more of claims 1 to 3 for producing a pharmaceutical for the prophylaxis and therapy of all of those diseases whose course involves an increased activity of IKB kinase.

7.   The use as claimed in claim 6, wherein the diseases are chronic diseases of the locomotory apparatus, such as 10            inflammatory, immunologically or metabolism-mediated acute and chronic arthritides, arthropathies, rheumatoid arthritis, or degenerative joint diseases such as osteoarthroses, spondyloses, diabetes Type II, inflammatory bowel disease, loss of cartilage following joint trauma or a relatively long period of joint immobilization following meniscus or patella injuries or ligament ruptures, or diseases of the connective tissue, such as collagenoses and periodontal diseases, myalgias and disturbances of bone metabolism, or diseases which are due to overexpression of tumor

15    necrosis factor alpha (TNFct) or an increased concentration of TNFct, such as cachexia, multiple sclerosis, crani-ocerebral trauma, Crohn'sdisease and intestinal ulcers, or diseases such as atherosclerosis, stenoses, ulceration, Alzheimer'sdiseases, muscle breakdown, cancer diseases, cardiac infarction, gout, sepsis, septic shock, endotoxic shock, viral infections such as flu, hepatitis, HIV infections, AIDS, or diseases caused by adenoviruses or herpes-viruses, parasitic infections such as malaria or leprosy, fungal or yeast infections, meningites, chronic inflammatory

20    lung diseases such as chronic bronchitis or asthma, acute respiratory distress syndrome, acute synovitis, tubercu-losis, psoriasis, diabetes, treatment of acute or chronic rejection reactions on the part of the organ recipient against the transplanted organ, chronic graft-versus-host diseases and inflammatory vascular diseases.

25    Revendications

1.   Compose de formule I
 


eVou une forme stereoisomerique du compose de formule I et/ou un sel physiologiquement acceptable du compose de formule I, ou

X et M sent identiques ou differents et son!, independamment l'unde I'autre, un atome d'azoteou CH, R1 et R11 sent identiques ou differents et sent, independamment l'unde l'autre,

45

1.    un atome d'hydrogime,

2.    F, Cl, I ou Br,
3.    un alkyle en C1-C4,
4.    -CN,
50    5. -CF3 ,
6.    -OR5, dans lequel RS est un atome d'hydrogemeou un alkyle en C1-C4,
7.    -N(RS)-RB, dans lequel RS et R6 son!, independamment l'unde !'autre,un atome d'hydrogeneou un alkyle
en C1-C4 ,
8. -C(O)-Rs, dans lequel R5 est un atome d'hydrogeneou un alkyle en C1-C4 , ou
55    9. -S(O)x-Rs, dans lequel x est le nombre entier zero, 1 ou 2, et Rs est un atome d'hydrogimeou un alkyle en C1-C4•

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