EP2646438A1 - 3-hetaryl-substituted pyrrolo[2,3-b]pyridine derivatives as pdk1 inhibitors - Google Patents

Abstract

Compounds of the formula I in which Q, R¹, R², R³ and R⁴ are each as defined in claim 1 are PDK1 inhibitors and can be used for treatment of tumors.

Description

 3-hetaryl-substituted pyrrolo [2,3-b] pyridine derivative as

 PDK1 inhibitors The invention relates to compounds of the formula I.

wherein

 Q Het-diyl,

R ¹ Br, Het ¹ or phenyl which is monosubstituted by CH ₂ OH,

R ² , R ^{3 are} each independently H, Hai, A, Ar, [C (R ⁵ ) ₂ ] _n OH,

[C (R ⁵ ) ₂ ] _n OA or [C (R ⁵ ) ₂ ] _n N (R ⁵ ) _2>

R ² , R ³ together also = 0, = CH ₂ or an alkylene chain with 2-5 C

atoms,

R ^{4 is} H, Ar or Het ² ,

R ^{5 is} H or A ',

Het ¹ pyrazolyl, which is easily replaced by A, CH ₂ OH, (CH ₂ ) ₂ OH, COOH,

COOA, CH ₂ COHet ³ or CONH ₂ may be substituted,

 Ar unsubstituted or one, two or three times by shark, A,

(CH ₂ ) _n OR ⁵ , (CH ₂ ) _n N (R ⁵ ) ₂ , SR ⁵ , NO ₂ , COOR ⁵ , CON (R ⁵ ) ₂ ,

NR ⁵ COA, NR ⁵ SO ₂ A, SO ₂ N (R ⁵ ) ₂ , COR ⁵ , (CH ₂ ) _n CN and / or S (O) mA substituted phenyl, naphthyl or biphenyl,

 Het an unsubstituted or one or two times by shark, A,

[C (R ⁵ ) ₂ ] _n OR ⁵ , [C (R ⁵ ) ₂ ] _n N (R ⁵ ) ₂₎ NO _2> CN, COOR ⁵ , CON (R ⁵ ) ₂ , NR ⁵ COA, NR ⁵ SO ₂ A, COR ⁵ , SO ₂ NR ⁵ , S (0) mA, = S, = NH, = NA and or = O (carbonyl oxygen) substituted on or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N and / or O and / or S atoms,

Het ^{2 is} an unsubstituted one or two times by Hai, A, OR ⁵ ,

N (R ⁵⁾ _2, N0 _2> CN, COOR ^5, CON (R ⁵⁾ _2, NR ⁵ COA, NR ⁵ S0 ₂ A, COR ^5, SO ₂ NR ^5, S (0) mA, = S, = NH, = NA and or = O

 (Carbonyl oxygen) substituted mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and / or the O and / or S atoms,

Het ^{3 is} an unsubstituted monocyclic saturated heterocycle having 1 to 4 N, and / or O and / or S atoms,

 A unbranched or branched alkyl having 1-10 C atoms,

wherein 1-7 H atoms may be replaced by F, Cl and / or Br, and / or wherein one or two non-adjacent CH and / or CH ₂ groups are represented by NR ⁵ , O, S, SO, SO ₂ , C = c and / or CH = CH groups can be replaced,

 or

 cyclic alkyl with 3-7 C atoms,

A 'is unbranched or branched alkyl having 1-6 C atoms,

 or

 cyclic alkyl with 3-7 C atoms,

 Hai F, Cl, Br or I,

 m 0, 1 or 2,

 n 0, 1, 2, 3 or 4,

 mean,

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

The invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts, tautomers and stereoisomers possess very valuable pharmacological properties while being well tolerated.

In particular, they show an inhibitory effect of cell proliferation / cell vitality as antagonists or agonists. The invention

Compounds can therefore be used to control and / or treat tumors, tumor growth and / or tumor metastases. The antiproliferative effect can be tested in a proliferation assay / vitality assay.

Pyrimidinyl-2-amine derivatives are described in WO 2008/155000.

Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are also available from P.M. Fresneda et al. in Tetrahedron 57 (2001) 2355-2363.

Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are also described by A. Karpov in his dissertation, University of Heidelberg, April 2005.

Other amino-pyridine derivatives bearing a 2,2,6,6-tetramethyl-piperidin-4-yl radical are described for the treatment of inflammatory and autoimmune diseases in WO 2004/089913.

Accordingly, the compounds of the invention or a pharmaceutically acceptable salt thereof are administered for the treatment of cancer including solid carcinomas such as carcinomas (eg, the lungs, pancreas, thyroid, bladder, or colon), myeloid diseases ( eg myeloid leukemia) or

 Adenomas (eg villous colon adenoma).

The tumors further include monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma, pancreatic and / or breast carcinoma. The compounds are also useful in the treatment of HIV-1 (human immunodeficiency virus type 1) induced immunodeficiency.

Cancerous hyperproliferative disorders include brain, lung, squamous, bladder, stomach, pancreatic, liver, kidney, colorectal, breast, head, neck, esophageal, gynecological, thyroid, lymphoma, chronic leukemia and acute leukemia. In particular, cancerous cell growth is a disease that is an object of the present invention. The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said

 Diseases comprising the administration of one or more

Compounds according to the invention to a patient in need of such administration.

It can be shown that the compounds according to the invention have an antiproliferative action. The compounds of the invention are administered to a patient with a hyperproliferative disorder, e.g. To inhibit tumor growth, to reduce inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection or neurological damage due to tissue repair, etc. The present compounds are useful for prophylactic or therapeutic purposes. As used herein, the term "treating" is used to refer to both the prevention of disease and the treatment of pre-existing conditions Prevention of proliferation / vitality is achieved by administration of the compounds of the invention prior to the development of the apparent disease, e.g. Prevention of tumor growth. Alternatively, the compounds for treatment become more persistent

Diseases used by stabilization or improvement of the clinical symptoms of the patient.

The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.

The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is incubated with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or to inhibit cell proliferation, cell vitality or migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The amount of cells remaining after treatment are then determined. The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the undesirable cell population in the target tissue while increasing the viability of the patient

 Patient is maintained. Treatment is generally continued until there is a significant reduction, e.g. At least about 50%

 Reduction of cell load and can be continued until essentially no more unwanted cells are detected in the body.

There are many diseases associated with deregulation of cell proliferation and cell death (apoptosis). The ailments of interest include, but are not limited to, the following conditions. The invention Compounds of this type are useful in the treatment of a variety of conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells into the intimal layer of a vessel is present, resulting in restricted perfusion of this vessel, e.g. In neointimal occlusive lesions. Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.

The compounds of the formula I also act as regulators, modulators or inhibitors of protein kinases, in particular of the serine / threonine kinase type, which include, among others, phosphoinositide-dependent kinase 1 (PDK 1). Some effect of the compounds of the invention in the inhibition of serine / threonine kinase PDK1.

PDK1 phosphorylates and activates a subset of the AGC protein kinase family, including PKB, SGK, S6K and PKC isoforms. These kinases are involved in the PI3K signaling pathway and control basic cellular functions such as survival, growth, and differentiation. PDK1 is thus an important regulator of diverse metabolic, proliferative and life-sustaining effects.

Protein kinase-mediated diseases are characterized by abnormal activity or hyperactivity of such protein kinases. Abnormal activity involves either: (1) expression in cells that usually do not express these protein kinases; (2) increased kinase expression leading to unwanted cell proliferation such as cancer; (3) increased kinase activity resulting in undesired cell proliferation, such as cancer, and / or hyperactivity of the corresponding protein kinases. Hyperactivity refers to either amplification of the gene encoding a particular protein kinase or the generation of an activity level associated with a cell proliferation activity. disease (as the level of kinase increases, the severity of one or more symptoms of cell proliferative disease increases) the bioavailability of a protein kinase may also be affected by the presence or absence of a set of binding proteins of that kinase.

The major cancers that can be treated using a compound of the invention include colorectal cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, and renal cell carcinoma and endometrial carcinoma, but especially cancers in which PTEN is mutated, and the like. a. Breast cancer, prostate cancer and glioblastoma.

In addition, the compounds of the invention may be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiation and / or to restore the efficacy of certain existing cancer chemotherapies and radiation.

The invention also relates to the optically active forms (stereoisomers), salts, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Among solvates of the compounds are additions of inert solvent molecules to the

 Understand connections that develop because of their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.

 Pharmaceutically usable derivatives are understood, for example, as the salts of the compounds of the invention as well as so-called prodrug compounds.

Of course, the invention also encompasses the solvates of the salts of the compounds according to the invention. Under prodrug derivatives is understood with z. As alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved in the organism to the active compounds of the invention.

 These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).

The term "effective amount" means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.

 Moreover, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in:

improved curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a condition, a disorder or side effects or even a reduction in the progression of a disease, a condition or a disorder.

 The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

The invention also provides the use of mixtures of

Compounds of the formula I, e.g. Mixtures of two diastereomers, e.g. in the

Ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000.

 Particularly preferred are mixtures of stereoisomeric

Links.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ and Q have the meanings given for the formula I, unless expressly stated otherwise. A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,

2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2 or 1, 2, 2-trimethylpropyl, more preferably, for example Trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluorethyl or 1,1,1-trifluoroethyl, wherein preferably also one or two CH and / or CH ₂ groups may be replaced by O and / or NR ³ . Therefore, A also means, for example, CH ₂ OCH ₃ or CH ₂ OCH ₂ CH ₂ NH ₂ .

 A further preferably denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F, or cyclic alkyl having 3-7 C atoms.

A 'is preferably alkyl having 1, 2, 3, 4, 5 or 6 C atoms,

 preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl, furthermore cyclopentyl or cyclohexyl.

 Cyclic alkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.

R ¹ is preferably Het.

R ² , R ^{3 are} preferably each independently H, Hai, A, Ar, OH or OA.

R ² particularly preferably denotes H, A or Ar.

R ³ particularly preferably denotes H, Hal, OH or OA. R ⁵ is preferably H or methyl.

Het ¹ is preferably pyrazolyl, which may be monosubstituted by A, CH ₂ COHet ³ or COOA.

Het ¹ particularly preferably means pyrazolyl which is monosubstituted by A.

Ar is, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-amino-phenyl, o-, m- or p- (N-methylamino ) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) - phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m - or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, o-, m- or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-Aminosulfonylphenyl, more preferably 2,3-, 2, 4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3 , 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2 , 5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5 -chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl , 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6 methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl. In a further embodiment, Ar is preferably phenyl which is unsubstituted or monosubstituted or disubstituted by Hal, COOR ⁵ and / or CON (R ⁵ ) 2.

Het, irrespective of further substitutions, e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl , 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl , 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-triazole-l, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1,2,4-oxadiazol-3 or -5-yl, 1, 3, 4-thiadiazol-2 or -5-yl, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or 5-yl, 3- or 4-pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1- , 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,

3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4- , 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,

4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl, 2 , 1, 3-Benzoxadiazol-5-yl or dibenzofuranyl.

 The heterocyclic radicals may also be partially or completely hydrogenated.

 Regardless of other substitutions Het can thus z. Also represent 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl,

 Tetrahydro-2- or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or 3-thienyl,

2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetra-hydro-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, Tetrahydro-1, 3 or 4-pyrazolyl,

1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or - 6-pyridyl, 1-, 2-, 3- or 4-pipedinyl, 2-, 3- or 4-morpholinyl, Tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1, -3- or -4- pyridazinyl, hexahydro-1, -2, -4 or 5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1, -2-, -3- , -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1 -, -2 -, -3-, -4-, -5- , -6-, -7- or -8-iso-quinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo [1,4] oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) -phenyl, 2,3-dihydrobenzofuran-5 or 6-yl, 2, 3- (2-oxomethylenedioxy) -phenyl or else 3,4-dihydro-2H-1,5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2 -oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl, 1.3 Dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.

In a further embodiment, Het preferably denotes an unsubstituted or mono- or disubstituted by A and / or [C (R ⁵ ) ₂ ] _n OR ⁵ mononuclear aromatic heterocycle having 1 to 4 N-, and / of O and / or S. -atoms.

Het is very particularly preferably thiazolyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyridinyl or pyrimidinyl,

 wherein the heterocycles are also one or two times by A and / or

[C (R ⁵ ) ₂ ] _n OR ⁵ may be substituted.

Het ² means, notwithstanding further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3- , 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2- , 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1 ₍ 2,3-triazole-1, -4- or -5-yl, 1, 2,4-TriazoM -, -3- or 5-yl, 1- or 5-tetrazolyl, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5 -olsoindolyl, indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,

3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4- , 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,

4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-7 - or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8 -2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or -5-yl, 2 , 1,3-benzoxadiazol-5-yl or dibenzofuranyl.

 The heterocyclic radicals may also be partially or completely hydrogenated.

Regardless of other substitutions Het ^{2 can} thus z. Also represent 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl,

Tetrahydro-2- or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1, -2, -3, -4 or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1, -2- or -4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4- Dihydro-1, -2, -3 or 4-pyridyl, 1, 2,3,4-tetrahydro-l, -2, -3, -4, -5 or -6- pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, 3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxane -2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-l, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2, 3,4-tetrahydro-l, -2, 3, 4, 5, 6, 7 or 8 isoquinolyl, 2, 3, 5, 6, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxy-phenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedio ioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or also 3,4-dihydro-2H-1 , 5-benzodioxepin-6 or -7-yl, more preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3 Dihydrobenzoxazolyl, 2- Oxo-2,3-dihydro-benzoxazolyl, 2,3-dihydro-benzimidazolyl, 1, 3-dihydro-indole, 2-oxo-l, 3-dihydro-indole or 2-oxo-2,3-dihydro-benzimidazolyl.

In a further embodiment, Het ² preferably denotes an unsubstituted or mono- or di-A through A, OR ⁵ and / or = O

substituted mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms.

Het ² very particularly preferably denotes thiazolyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl, piperidinyl,

Pyrrolidinyl, morpholinyl, piperazinyl, imidazolidinyl, oxazolidinyl or

Tetrahydropyranyl, where the heterocycles may also be mono- or disubstituted by A, OR ⁵ and / or = O substituted.

Het ³ is preferably piperidinyl, pyrrolidinyl, morpholinyl,

 Piperazinyl, imidazolidinyl, oxazolidinyl or tetrahydropyranyl.

For the entire invention, all residues that occur multiple times may be the same or different, i. are independent of each other. The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms. Formula I encompasses all these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned

Rests has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ig, which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I, but where in la R ^{1 is} Het ¹ ; in Ib Het ¹ pyrazolyl, which may be substituted by A, CH ₂ COHet ³ or COOA,

 means; in lc Ar unsubstituted or one, two or three times by shark,

COOR ⁵ and / or CON (R ⁵ ) ₂ substituted phenyl

 means; in Id Het an unsubstituted one or two times by A

and / or [C (R ⁵ ) 2] _n OR ⁵ substituted mononuclear

 aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms,

 means; in thethol, thiophenyl, furanyl, pyrrolyl, oxazolyl,

 Isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyridinyl or

 pyrimidinyl,

where the heterocycles may also be monosubstituted or disubstituted by A and / or [C (R ⁵ ) ₂ ] _n OR ⁵ ; in If A is unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F,

 or

 cyclic alkyl with 3-7 C atoms

 means; in Ig Q het-diyl,

R Het ¹ , each independently of one another represents H, Hal, A, Ar, [C (R ⁵ ) ₂ ] _n OH, [C (R ⁵ ) ₂ ] _n OA or [C (R ⁵ ) ₂ ] _{n N} (R ⁵ ) ₂ ,

together also = O, = CH ₂ or an alkylene chain with 2-5

C-atoms,

H, Ar or Het ² ,

 H or A \

Pyrazolyl, which may be substituted by A, CH ₂ COHet ³ or COOA,

unsubstituted or mono-, di- or tri-substituted by Hal, COOR ⁵ and / or CON (R ⁵ ) ₂ phenyl, an unsubstituted or mono- or disubstituted by A and / or [C (R ⁵ ) ₂ ] _n OR ⁵ substituted mononuclear

aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms,

an unsubstituted mono- or di-substituted by A, OR ⁵ and / or = O mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, and / or the O and / or S atoms,

an unsubstituted monocyclic saturated heterocycle having 1 to 4 N, and / or O and / or S atoms,

 unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F,

 or

 cyclic alkyl with 3-7 C atoms,

 unbranched or branched alkyl having 1-6 C atoms, or

 cyclic alkyl with 3-7 C atoms,

 F, Cl, Br or I,

 0, 1 or 2,

0, 1, 2, 3 or 4, and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

The compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart) are described, under reaction conditions which are known and suitable for the said reactions. One can also make use of known per se, not mentioned here variants.

Compounds of formula I may preferably be obtained by reacting compounds of formula II and with a guanidine salt, e.g.

 Guanidinium carbonate, reacted.

 The compounds of formula II are known in the rule. If they are new, they can be produced by methods known per se.

The reaction takes place in an inert solvent and is generally carried out in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.

 The addition of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium, may also be beneficial.

The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about -15 ° C and 150 ° C, normally between 40 ° C and 130 ° C, more preferably between 60 ° C and 110 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether,

Tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.

 Particular preference is given to glycol ethers, such as ethylene glycol monomethyl ether, THF, dichloromethane and / or DMF.

The cleavage of an ether is carried out by methods known to those skilled in the art.

 A standard method for ether cleavage, e.g. a methyl ether, is the use of boron tribromide.

 Hydrogenolytically removable groups, e.g. the cleavage of a benzyl ether, z. By cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon). Suitable solvents are those given above, in particular

 z. For example, alcohols such as methanol or ethanol or amides such as DMF. The

 Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° C and pressures between about 1 and 200 bar, preferably at 20-30 ° C and 1- 10 bar.

For example, esters can be saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 00 ° C. Alkylations on the nitrogen are carried out under standard conditions, as known to those skilled in the art.

The compounds of formula I can be further obtained by solubilizing them from their functional derivatives, in particular

Hydrolysis, or set free by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxyl groups corresponding protected amino and / or hydroxy groups, preferably those which instead of an H atom, which is connected to an N atom is to carry an amino protecting group, for. For example, those corresponding to formula I but containing an NHR 'group (where R' represents an amino-protecting group, e.g., BOC or CBZ) instead of an NH 2 group.

Furthermore, starting materials are preferred, which instead of the H atom of a

 Hydroxy group carry a hydroxy protecting group, for. Those corresponding to formula I, but instead of a hydroxyphenyl group contain an R "O-phenyl group (wherein R" represents a hydroxy-protecting group).

There may also be several - same or different - protected amino and / or hydroxy groups present in the molecule of the starting material. If the protecting groups present are different from each other, they can be selectively cleaved in many cases.

The term "amino protecting group" is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction at other sites of the molecule

 has been carried out. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or

Aralkyl groups. Since the amino protecting groups after the desired reaction (or sequence of reactions) are removed, their nature and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8 C atoms. The term "acyl group" is related to the

present procedures in the broadest sense. It encloses aliphatic, araliphatic, aromatic or heterocyclic

Carboxylic acids or sulfonic acid derived acyl groups as well

in particular alkoxycarbonyl, aryloxycarbonyl and especially

Aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr, Pbf or Pmc. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy protecting group" is also well known and refers to groups which are capable of protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction at other sites of the invention

 Molecule has been performed. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or

 Acyl groups, and also alkyl groups. The nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms. Examples of hydroxy protecting groups include i.a. tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg, Asp (OBut)).

The in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the protecting group used - z. B. with strong Acids, useful with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. As inert

Solvents are preferably organic, for example

Carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. The reaction temperatures for the cleavage are suitably between about 0 and about 50 ° C, preferably between 15 and 30 ° C (room temperature).

The groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 ° C, the FMOC group with an about 5- to 50% solution of

 Dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C.

Hydrogenolytically removable protecting groups (eg CBZ or benzyl) may e.g. By cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon). Suitable solvents are those given above, in particular z. For example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° C and pressures between about 1 and 200 bar, preferably at 20-30 ° C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds z. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 ° C. The conversion of a radical R ⁶ = H into a radical R ⁶ = F can be carried out by reaction with Selectfluor® in a solvent such as THF.

Pharmaceutical salts and other forms

 The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of theirs

pharmaceutically acceptable salts which can be derived from various organic and inorganic acids and bases by art-known procedures. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including

 Potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are also included. In certain compounds of formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable

organic and inorganic acids, for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluene sulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, Aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,

Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,

Hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate,

Isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate,

 Persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium , Sodium and zinc salts, but this should not be limiting. Preferred among the above salts are ammonium; the alkali metal salts sodium and

 Kalium.sowie alkaline earth metal salts calcium and magnesium. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline, Ν, Ν'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, Histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) - methylamine (tromethamine), which is not

To represent restriction. Compounds of the present invention containing basic nitrogen-containing groups can be prepared with agents such as (C ₄ ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; di (C 1 -C ₄ ) Alkyl sulfates, for example dimethyl, diethyl and diamylsulfate; (C ₁₀ -C ₈ ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide, and also AryKC C 1-4 alkyl halides, eg Benzyl chloride and phenethyl bromide, quaternization With such salts, both water- and oil-soluble compounds of the invention can be prepared.

Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but no

 To represent restriction.

The acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are Ν, Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of acidic compounds of the invention are prepared by reacting the free acid form with a

sufficient amount of the desired base in contact, whereby the salt is in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.

In view of the above, it can be seen that the term "pharmaceutically acceptable salt" in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Comparison to the free form of the active substance or any other

 Salt form of the drug, which was used earlier improved

 pharmacokinetic properties. The pharmaceutical

In addition, acceptable salt form of the active ingredient may provide this drug with a desired pharmacokinetic property that it has not previously possessed, and may even positively affect the pharmacodynamics of that drug in terms of its therapeutic efficacy in the body. The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.

Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a unit may, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a

Compound according to the invention, depending on the treated

Disease condition, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.

Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intravenous)

 intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical art, such as by including the active ingredient with the carrier (s) or

 Excipient (s) is brought together.

Pharmaceutical formulations adapted for oral administration may be presented as separate entities, such as capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.

Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. A disintegrants or solubilizers, e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,

Sodium acetate, sodium chloride and the like The explosives include, without to be limited to starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, a

Powder mixture prepared, granulated or pressed dry, a

Lubricant and a disintegrant are added and the whole is compressed into tablets. A powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or

Polyvinylpyrrolidone, a dissolution reducer, such as e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed. The powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds of the invention can also be used with a free-flowing inert

 Carrier combined and then pressed directly into tablets without performing the granulation or Trockenverpressungsschritte. A transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. this

 Coatings can be added to dyes to distinguish between different dosage units.

Oral fluids such as solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared, by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, or the like. can also be added.

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation may also be prepared to prolong or retard the release, such as by coating or embedding particulate material in polymers, wax, and the like.

The compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers can polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidphenol, or Polyhydroxyethylaspartamidphenol

 Polyethylene oxide polylysine substituted with palmitoyl radicals. Furthermore, the compounds can be attached to a class of biodegradable

Polymers used to achieve a controlled release of a For example, polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels may be coupled.

Pharmaceutical adapted to transdermal administration

Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient may be either paraffinic or water-miscible

 Cream base can be used. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

To the topical application in the mouth adapted pharmaceutical

Formulations include lozenges, lozenges and mouthwashes. Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for

Administration as a nasal spray or nasal drops with a liquid as a carrier substance comprise solutions of active substance in water or oil.

For administration by inhalation adapted pharmaceutical

 Formulations include fine particulate dusts or mists, which may be supplied by various types of pressurized dosing dispensers

Aerosols, nebulizers or insufflators can be generated.

Pharmaceutical formulations adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes, foams or

 Spray formulations are presented.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes by which the

 Formulation is made isotonic with the blood of the recipient to be treated included; as well as aqueous and non-aqueous sterile

 Suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed ampoules and vials, presented and in

freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, eg water for injection, is required immediately before use. Prescribed Injection solutions and suspensions may be sterile powders,

Granules and tablets are produced.

It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.

A therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, its severity, the nature of the formulation, and

Route of administration, and will ultimately be determined by the doctor or veterinarian. However, an effective amount is one

 compound of the invention for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount being given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages for the

 Treatment of the other disease states mentioned above are suitable.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable salts thereof, Tautomers and stereoisomers, including mixtures thereof in all proportions, and at least one other drug.

The invention is also a set (kit), consisting of separate packages of

 (a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all proportions,

 and

 (b) an effective amount of another drug.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. containing separate ampoules in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.

USE

The instant compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment and control of cancers.

The invention thus relates to the compounds of the formula I and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, for use in the treatment of tumors, tumor growth, tumor metastases and / or AIDS. The present invention comprises the use of the compounds of formula I and / or their physiologically acceptable salts, tautomers and stereoisomers for the manufacture of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment are from the brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma colorectal cancer. Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.

Also included is the use of the compounds of formula I and / or their physiologically acceptable salts, tautomers and stereoisomers for the manufacture of a medicament for the treatment and / or control of a tumorous disease in a mammal, which method is given to a diseased mammal carrying a requires such treatment, a therapeutically effective amount of a compound of the invention is administered. The therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.

Especially preferred is the use for treating a disease wherein the disease is a solid tumor.

The solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, Urogenital tract, lymphatic system, stomach, larynx and / or lungs.

The solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma. Further preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, the

chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.

The invention furthermore relates to the use of the compounds according to the invention for the treatment of bone pathologies, the bone pathology originating from the group osteosarcoma, osteoarthritis and rickets.

The compounds of formula I may also be coadministered with other well-known therapeutics selected for their particular suitability for the condition being treated.

 The present compounds are also useful for combination with known anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. The present compounds are particularly useful for co-administration with radiotherapy. "Estrogen Receptor Modulators" refers to compounds which inhibit the binding of estrogen to the

 Disrupt or block the receptor, regardless of how this happens. For example, estrogen receptor modulators include

 Tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] -phenyl-2,2-dimethyl-propanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and

 SH646, which should not be a limitation.

"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor regardless of how this happens. The androgen receptor modulators include, for example, finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

 "Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and Ν-4-carboxyphenylretinamide.

 "Cytotoxic agents" refers to compounds that cause cell death or interfere with cell myosis, primarily through direct action on cell function, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

 The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine. pidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane -1, 6-diamine) -mu- [diamine-platinum (II)] bis [diamine (chloro) -platinum (II)] - tetrachloride, diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafid, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide,

 MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting.

The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 \ 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl -L-valyl-L-prolyl-L-proline t-butylamide, TDX258 and BMS188797. Topoisomerase inhibitors are for example topotecan, hycaptamine,

Irinotecan, Rubitecan, 6-ethoxypropionyl-L3 ', 4'-O-exo-benzylidene-chartreusine ₍ 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5-kl] acridine-2- (6H) -propanamine , 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] -pyrano [3 ', 4': b, 7] indolizino [1, 2b] quinoline-10,13 (9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide-phosphate, Teniposide, Sobuzoxan, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazole 1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-3, 5-dimethoxyphenyl] -5,5a, 6,8 _> 8a, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5 (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4- carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one and dimesna.

 Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,

Doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabic sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2 '-deoxycytidine, N- [5- (2,3-dihydrobenzofluoryl) sulfonyl] -N' - (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E) , 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-manno-heptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro- 3H-pyrimidino [5,4-b] [1,4] thiazine-6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, Aminopterin, 5-fluorouracil, alanosine, 1-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-1-oxa-1,11-diazatetracyclo (7.4.1.0.0) -tetradeca-2,4,6 triene-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include other monoclonal antibodies against growth factors than those already mentioned among the "angiogenesis inhibitors", such as Trastuzu-mab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Pat 6,069,134).

Proof of action of pharmacological inhibitors on the

 Proliferation / vitality of tumor cells in vitro

1. Background

In the present experimental description, the inhibition of

Tumor cell proliferation / tumor cell vitality described by drugs.

 The cells are seeded in suitable cell density in microtiter plates (96-well format) and the test substances are added in the form of a concentration series. After four more days of culture in serum-containing medium, tumor cell proliferation / tumor cell vitality can be determined by means of an Alamarblue test system.

2. Experimental procedure 2.1 cell culture

 For example, commercially available colon carcinoma cell lines, cell lines of the ovary, cell lines of the prostate, or breast cell lines.

The cells are cultured in medium. At intervals of several days, the cells are detached from the culture dishes with the aid of trypsin solution and seeded in fresh medium at a suitable dilution. The cells are cultured at 37 ° C and 10% CO ₂ . 2.2. Sowing the cells

 A defined number of cells (for example 2000 cells) are incubated per culture / well in a volume of 180 μM culture medium in microtiter plates (96 well

Cell culture plates) seeded with a multi-channel pipette. The cells are then cultured in a C0 ₂ incubator (37 ° C and 10% C0 ₂ ).

2.3. Addition of the test substances The test substances are dissolved, for example, in DMSO and then used in the cell culture medium in appropriate concentration (if appropriate a dilution series). The dilution levels may vary depending on

Efficiency of the active ingredients and desired spreading of concentrations can be adjusted. The test substances are in corresponding

Concentrations with cell culture medium. The addition of the test substances to the cells can take place on the same day as the sowing out of the cells. In each case, 20 μΙ substance solution is added to the cultures / wells from the predilution plate. The cells are cultured for a further 4 days at 37 ° C and 10% CO ₂ .

2.4. Measurement of the color reaction

20μΙ AlamarBlue reagent are added to each well and the

For example, microtiter plates are incubated for a further seven hours in a CO ₂ incubator (at 37 ° C. and 10% CO ₂ ). The plates are measured on a reader with a fluorescence filter at a wavelength of 540 nm. The plates can be easily shaken just before the measurement.

3. Evaluation The absorbance value of the medium control (no use of cells and test substances) is subtracted from all other extinction values. The controls (cells without test substance) are set equal to 100 percent and all other absorbance values related thereto (expressed as% of control, for example):

 Bill:

 00 * (value with cells and test substance - value of medium control)

 (Value with cells - value of the medium control)

The determination of IC ₅₀ values (50% inhibition) is carried out with the help of statistical programs such as RS1.

 IC 50 data of compounds according to the invention are given in Table 1.

4. Test for Inhibition of PDK1

 The experimental approaches are in a flashplate system with 384

Wells / microtitration performed.

The PDK1 sample His ₆ -PDK1 (A1-50) (3.4 nM), the PDK1 substrate biotin-bA-bA-KTFCGTPEYLAPEVRREP- RILSEEEQEMFRDFDYIADWC (400 nM), 4 μM ATP (with 0.2 pCi ³³ P ATP / well) and the test substance are incubated in 50 μΙ standard test solution for 60 min at 30 ° C. The test substances are used in appropriate concentrations (if appropriate in a dilution series). The control is carried out without test substance. The reaction is stopped by conventional methods and washed. The activity of the kinase is measured by the built-in radioactivity in the topcount. To determine the unspecific kinase reaction (blank), the experimental approaches are carried out in the presence of 100 nM staurosporine.

5. Evaluation

 The radioactivity (decays per minute) of the blank (no use of test substance in the presence of staurosporine) is different from all others

Radiation subtracted. The controls (kinase activity without Test substance) are set equal to 100 percent and all others

 Radioactivity values (after deduction of the blank) are expressed in relation to them (expressed as% of control, for example).

 Bill:

 100 * (value of kinase activity with test substance - blank value)

 (Value of control - blank)

 =% of control

The determination of IC ₅₀ values (50% inhibition) is carried out with the help of statistical programs such as RS1. IC ₅₀ data according to the invention

 Compounds are given in Table 1.

APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) ⁺ .

Method for cellular testing of PDK1 kinase inhibitors in PC3 cells

The cellular assay for determining PDK1 kinase activity is performed as a 96-well Luminex assay. PC3 cells are seeded at 20,000 cells per well in 100 μM medium (45% RPMI1460 / 45% Ham's F12 / 10% FCS) and serum-free the following day for 30 min with a serial dilution of the test substance (7 concentrations)

 Conditions incubated. The cells are then treated with 90 μl lysis buffer (20 mM Tris / HCl pH 8.0, 150 mM NaCl, 1% NP40, 10% glycerol, 1%

Phosphatase inhibitor I, 1% phosphatase inhibitor II, 0.1% protease inhibitor cocktail III, 0.01% benzonase) per well, and the lysates are centrifuged through a 96-well filter plate (0.65 μm). separated from insoluble cell components. The lysates are incubated overnight at 4 ° C with Luminex beads, to which an anti-total PKB antibody is coupled, with shaking. The next day, the detection is carried out by adding a phospho-T308-PKB antibody and a species-specific peroxidase-labeled secondary antibody. Phospho - T308 - PKB is detected by measurement in the Luminex100 device by determination of 100 events per cavity in 60 sec measurement time. As a pharmacological blank, the signals obtained from cells treated with 10 μΜ staurosporine are subtracted from all other mixtures. As a control value of maximum phosphorylation of PKB on T308, the signals from cells treated with the solvent alone (0.3% DMSO) are used. Values of the test substance treated batches are calculated as percent of control and IC50 values are determined by RS1. Above and below, all temperatures are given in ° C. In the following examples, "usual work-up" means adding water if necessary, if necessary, adjusting to pH values between 2 and 10, depending on the constitution of the final product, extracted with

Ethyl acetate or dichloromethane, separates, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺ ESI (Electrospray Ionization) (M + H) ⁺

 APCI-MS (atmospheric pressure chemical ionization - mass spectrometry)

(M + H) ⁺ .

HPLC / SFC conditions:

N: gradient: 5.5 min; Flow .: 2.75ml / min from 90:10 to - 0: 100 H20 / ACN

 Water + TFA (0.01% vol.); Acetonitrile + TFA (0.01% by volume)

 Column: Chromolith SpeedROD RP 18e 50-4.6

 Wavelength: 220nm

 Merck Hitachi La Chrome plant

P: HPLC method:

Gradient: 5.5 min; Flow .: 2.75ml / min from 99: 1 to - 0: 100 H ₂ 0 / ACN

 Water + TFA (0.01% vol.); Acetonitrile +

 TFA (0.01% Vol.)

 Column: Chromolith SpeedROD

 RP 18e 50-4.6

 Wavelength: 220nm

Merck Hitachi La Chrome investment

O: HPLC method:

Gradient: 5.5 min; Flow: 2.75ml / min from 99: 1 to - 0: 100 H ₂ O / ACN

 Water + TFA (0.01% vol.); Acetonitrile + TFA (0.01% by volume)

 Column: Chromolith SpeedROD RP 18e 50-4.6 Wavelength: 220nm

Agilent facility

Q: HPLC method (polar):

Gradient: 0 min: 4% B, 2.8 min: 100% B; 3.3 min 100% B; 3.4 min 4% B

Water + HCOOH (0.05% vol.); Acetonitrile + HCOOH (0.04% vol.)

 Column: Chromolith SpeedROD RP 18e 50-4.6 Wavelength: 220nm

Agilent facility

W: HPLC method:

Gradient: 10 min; Flow: 3ml / min from 99: 1 to - 1: 99 H ₂ O / ACN

Water + TFA (0.1% vol.); Acetonitrile + TFA (0.1% by volume)

 Column: Chromolith SpeedROD RP

 18e 100 ^ 4.6

 Wavelength: 230nm

 Merck Hitachi La chrome plant

M: HPLC method: Gradient: 10 min; Flow: 3ml / min of 99: 1

after - 1: 99 H ₂ 0 / ACN

 Water + TFA (0.1% vol.); Acetonitrile +

 TFA (0.1% vol.)

 Column: Chromolith SpeedROD

RP 18e 100-4.6

Wavelength: 220nm

Merck Hitachi La chrome plant

The compounds are accessible via various synthetic routes, of which are shown here by way of example:

example 1

Preparation of 1- {3- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -isoxazol-5-yl} - 1-phenylene-ethanol ("A1") 1.1 To a solution of 10.0 g of 5-bromo-1H-pyrrolo [2,3-b] pyridine (5-bromo-7-azaindole) and 18.0 g of 1-methyl-4- (4,4,5 , 5, -tetramethyl- [1,2,2] dioxaborolan-2-yl) -1H-pyrazole

 Under nitrogen protection, 2.96 g of tetrakis (triphenylphosphine) palladium (O) and 76 ml of sodium carbonate solution are added in 150 ml of DMF. The mixture is stirred at 100 ° C. for 2 h and at 120 ° C. for 1.5 h. Cool and work as usual. 8.87 g of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine are obtained

1.2 To a solution of 8.87 g of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine in 75 ml of DMF is added 6.08 g of KOH. Subsequently, a solution of 75 ml of DMF and 11, 01 g of iodine is added dropwise. The mixture is stirred for 1.5 h at room temperature (RT). The reaction solution is then poured onto a mixture of 600 g of ice and 500 mg of sodium sulfite. The resulting

 Precipitate is separated, washed with water and dried. This gives 14.0 g of 3-iodo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine.

1.3. To a suspension of 14.0 g of 3-iodo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine in 200 ml of dichloromethane are added 11, 31 ml

Triethylamine and 333 mg of 4- (dimethylamino) pyridine. Then a solution of 6.40 ml of di-tert-butyl dicarbonate is added dropwise in 100 ml of dichloromethane and stirred for 4 ° h at RT. Dilute with dichloromethane and wash with water 3x. The organic phase is dried over sodium sulfate and the Solvent is removed. This gives 14.5 g of tert-butyl 3-iodo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylate

1.4 4.02 g of sodium hydride (in paraffin) is treated with 200 ml of THF under nitrogen and cooled to 0 ° C. Then 9.8 g of 2-phenyl-3-butyn-2-ol are added and the ice bath is removed. It is stirred for 1 h. The mixture is then cooled again to 0 ° C and added under nitrogen 8.61 ml of chloromethyl methyl ether. The mixture is stirred for 14 h at RT. Carefully mix with water and work up as usual. The crude product is subjected to flash column chromatography.

 Conditions:

 Plant: TELEDYNE-ISCO Combi Flash RF

 Column: Silica Sep RF 120 g

 Eluent: gradient petroleum ether: ethyl acetate

 Flow: 85 ml / min

 Detection: UV 254 nm

 11 (1-Methoxymethoxy-1-methyl-prop-2-ynyl) benzene is obtained

 1.5 The starting materials are added together as follows:

3.45 g of cesium carbonate, 67 mg of copper (I) iodide, 80 mg of palladium (II) acetate, 1.18 g of molybdenum hexacarbonyl, 1.5 g of 3-iodo-5- (1-methyl-1H-pyrazole) 4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid tert-butyl ester dissolved in 10 ml of acetonitrile, 1, 21 g (1-methoxymethoxy-1-methyl-prop-2-ynyl) benzene dissolved in 10 ml of toluene and finally 0.45 ml of tri-tert-butylphosphine.

 The mixture is stirred for 5 min at 80 ° C. The reaction mixture is concentrated on a rotary evaporator, mounted on silica gel and on the Combiflash

chormatographiert. This gives 1.59 g of 3- (4-methoxymethoxy-4-phenyl-pent-2-inoyl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3- b] pyridine-1-carboxylic acid tert-but ester

1.6 To a solution of 360 mg of 3- (4-methoxymethoxy-4-phenyl-pent-2-inoyl) -5- (1-methyl-H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester in 7.5 ml of ethanol are added 194 μΙ triethylamine and 122 mg

Hydroxylammonium. The mixture is stirred for 5 days at 80.degree.

 Cool and work as usual. The crude product still contains MOM-protected product. The crude product is dissolved in 10 ml of methanol, treated with 100 .mu.l of 25% HCl and stirred for 30 min at 55.degree.

 Cool to RT and work up as usual. The oily residue is treated with MTB ether and the solvent is removed thereon. 176 mg of 1- {3- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -isoxazol-5-yl are obtained } -1-phenylethanol "A1")

HPLC / SFC condition: W; RT / min. 4.65;

H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 12.30 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.27 (s , 1 H), 8.13 (d, J = 2.9 Hz, 1H), 7.98 (s, 1H), 7.52 (m, 2H), 7.34 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H) , 6.75 (s, 1H), 6.18 (s, 1H), 3.89 (s, 3H), 1.87 (s, 3H).

Analog obtained

5805

 -60-

 Example 2

Preparation of 3- (2-benzyl-thiazol-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine ("A2") 2.1 To 324.8 mg of aluminum chloride in 10 ml of dichloromethane under argon is added 100 mg of 5-bromo-1H-pyrrolo [2,3-b] pyridine (7-bromo-7-azaindole). After stirring for 30 minutes, 0.31 ml of bromoacetyl chloride are added dropwise and the mixture is stirred for a further 2 hours.

The reaction mixture is cooled in ice-bar and it is carefully hydrolyzed with methanol. Subsequently, the solvents are removed. The residue is adjusted to pH 7 with NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried, filtered and the

Solvent is removed. This gives 138 mg of 2-bromo-1- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone.

2.2 To a solution of 59.5 mg of 2-phenylthioacetamide in 1.2 ml of 2-propanol is added 138 mg of 2-bromo-1- (5-bromo-1H-pyrrolo [2,3-b] pyridine). 3-yl) ethanone. The mixture is boiled for 3 minutes.

 It is cooled, adjusted to pH 8 with aqueous ammonia solution and diluted with water. The precipitated crystals are separated, washed with water and dried.

 This gives 134 mg of 3- (2-benzyl-thiazol-4-yl) -5-bromo-1 H-pyrrolo [2,3-b] pyridine

2.3 To a solution of 134 mg of 3- (2-benzyl-thiazol-4-yl) -5-bromo-1H-pyrrolo [2,3-b] pyridine and 121 mg of 1-methyl-4- (4,4 , 5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -1H-pyrazole in 1 mol of DMF is added, under argon, 19.77 mg of tetrakis (triphenylphosphine) palladium (0) and 511, 6 μΙ

Sodium carbonate solution. The mixture is stirred for 1 h at 100 ° C. The usual procedure is followed to obtain 84 mg of 3- (2-benzyl-thiazol-4-yl) -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine ("A2")

 HPLC / SFC condition: N; RT / min. 2.14;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 11.83 (s, 1H), 8.52 (s, 2H), 8.20 (s, 1H), 7.94 (dd, J = 5.4, 1.7 Hz, 2H ), 7.81 (s, 1H), 7.50 - 7.21 (m, 5H), 4.42 (s, 2H), 3.90 (s, 3H).

Analogously, the following compounds are obtained

Example 3

 Preparation of 3- [5- (3-fluoro-benzyl) - [1, 2,4] oxadiazol-3-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine ("A8")

 3.1 With stirring and under argon atmosphere 4.11 g of 3-iodo-5- (1-methyl-1 H-pyrazol-4-yl) -1 H-pyrrolo [2,3-b] pyridine are suspended in 20 ml of pyridine and then added dropwise, 81.1 ml of ethyl chloroformate slowly. During the

Dropwise, the temperature is maintained at 20-25 ° C. 15 ml of dichloromethane are added and the mixture is stirred for a further 1.5 h at RT. You work up as usual and receives 4.8 g of 3-iodo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid ethyl ester

3.2. In a 50 ml rinsed with acetone and then heated

Round flasks are weighed together:

2.0 g of ethyl 3-iodo-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylate, 355.67 mg of zinc cyanide, 209, 01 mg [Pd ₂ (dba) ₃ ] ^* CHCl ₃ ,

231, 65 mg of 1, 1'-bis (diphenylphosphino) ferrocene and 82.5 mg of zinc (coarsely powdered).

Under argon, mixed with 15 ml of Ν, Ν-dimethylacetamide, heated with stirring to 70 ° C and stirred for 1 h after. It is cooled to RT, filtered off with suction through kieselguhr and washed with acetone. The filtrate is concentrated to about 3 ml and then chromatographed on a 540 g RP18 silica gel column of a CombiFlash Companion. Isolate two groups of fractions (with 2 different products). The isolated fractions with product are combined in each case and concentrated on a rotary evaporator to the aqueous residue. This is basified with saturated NaHC0 ₃ solution. The precipitate is separated off and washed with water and diethyl ether.

 You get 2 products:

962 mg of 3-cyano-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid ethyl ester,

and 157 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile

3.3 500 mg of 3-cyano-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-1-carboxylic acid ethyl ester, 3.023 g of hydroxylammonium chloride and 2.37 g KOH are added together then 40 ml of absolute methanol and 8 ml of DMF are added. The resulting suspension is stirred at RT for 60 h. It is added again with 2 ml of DMF and stirred for a further 24 at RT. The reaction mixture is diluted with water, then ethyl acetate is added and shaken. Between the phases a precipitate falls out. This is separated and washed with water and ethyl acetate, then dried at 45 ° C in a vacuum. This gives 222 mg of light brown, powdery

 Substance (Ns).

 The mother liquor (2-phase mixture) is transferred again into the separating funnel, the organic phase is separated off and the aqueous phase is extracted a further 3 times with ethyl acetate. The organic phases are combined, washed once with saturated NaCl solution, dried with sodium sulfate, filtered and concentrated. The residue is triturated with diethyl ether, the diethyl ether is removed and the product is dried.

94 mg of yellow-brown, powdery substance (extr. Ns) are obtained. Ns and Extr. Ns are identical, being N-hydroxy-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxamidine is.

3.4

 Reaction 1:

 31, 1 mg of (3-fluorophenyl) acetic acid, 45.7 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 28.6 mg of benzotriazol-1-ol hydrate are weighed together, treated with 0.7 ml of DMF and Stirred for 5 min at RT. Then, 50 mg of N-hydroxy-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxamidine and 0.3 ml of DMF are added. The mixture is stirred for 20 min at RT. It works as usual and receives 59.3 mg of greenish oil, which crystallizes on standing.

 Reaction 2:

 The product from reaction 1 is used with 1 ml of diethylene glycol dimethyl ether and stirred at 130 ° C. for 15 min. You work up as usual. The residue is purified over a preparative silica gel column RP18e

 Chromatograph.

The isolated fractions are combined and concentrated on a rotary evaporator to the aqueous residue. The aqueous residue is basified with saturated NaHCO ₃ solution and extracted ₃ times with ethyl acetate. The organic phases are combined, washed 1x with saturated NaCl solution and dried with sodium sulfate. Filter and remove the solvent. The residue is dried for a further 14 hours at 45.degree.

This gives 26 mg of 3- [5- (3-fluorobenzyl) [1,2,4] oxadiazol-3-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H -pyrrolo [2,3-b] pyridine ("A8")

 HPLC / SFC condition: O; RT / min. 2.94;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 12.41 (s, 1 H), 8.61 (d, J = 2.1 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.23 (s, 1H), 8.18 (d, J = 1.8 Hz, 1 H), 7.91 (d, J = 0.7 Hz, 1 H), 7.45 (td, J = 7.9, 6.3 Hz, 1 H), 7.39 - 7.24 (m, 2H), 7.23 - 7.11 (m, 1H), 4.49 (s, 2H), 3.90 (s, 3H).

Analogously, the following compounds are obtained

Example 4

 Preparation of 3- [5- (3-fluoro-benzyl) -1H- [1,2,4] triazol-3-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1 H-pyrrolo [2,3-b] pyridine ("A14")

4.1 To a solution of 10.0 g of 5-bromo-7-azaindole are added under argon

33.1 g of aluminum chloride and the suspension is stirred for 10 min at RT. 8.3 ml of trichloroacetyl chloride are added and the mixture is stirred for 14 h. It is poured on ice, stirred until the ice has melted and separates the precipitated solid. You wash with

Dichloromethane and water and dried at 50 ° C.

 This gives 16.36 g of 1- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl) -2,2,2-trichloro-ethanone

4.2 A solution of 2.21 g of 1- (5-bromo-1H-pyrrolo [2,3-b] pyridin-3-yl)-2,2,2-trichloro-ethanone in 40 ml of methanol is added RT 9.16 ml

Hydrazinium. The mixture is stirred for 10 minutes. The solvents are removed to the residue and worked up as usual.

1.25 g of 5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide are obtained

4.3 HCI gas is introduced into a solution of 4.0 ml of 3-fluorophenylacetonitrile in 2.5 ml of ethanol and 25 ml of toluene at 0-5 ° C for 30 min. Thereafter, the reaction solution is warmed to RT, it is stirred for a further 30 min. The solution is poured into 50 ml of diethyl ether and cooled for 14 h. The precipitated crystals are separated and dried.

 6- (3-fluorophenyl) -acetimidate-ethyl ester hydrochloride is obtained

 4.4

 Reaction 1:

93.86 mg of 2- (3-fluorophenyl) -acetimidic acid ethyl ester hydrochloride are mixed with 2 ml of saturated NaHCO ₃ solution and extracted 3 times with 3 ml of dichloromethane. The organic phases are combined, dried with sodium sulfate and then the solvent is removed.

To the residue are added 100 mg of 5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide, 2 ml of absolute ethanol and heated to boiling while stirring. It is refluxed for 2 h. The mixture is cooled to RT and treated with 5 ml of diethyl ether. The precipitate is separated, washed with diethyl ether and dried at 45 ° C.

This gives 96 mg of "intermediate".

Reaction 2:

 The intermediate is transferred to a microwave vessel, with 1 ml

Diethylenglycoldimethylether and heated in the microwave in 5 min up to 200 ° C. The mixture is chromatographed for purification via a preparative RP18e silica gel column of a preparative HPLC. Conventional work-up gives 48 mg of 5-bromo-3- [5- (3-fluorobenzyl) -1H- [1,2,4] triazol-3-yl] -1H-pyrrolo [2,3-b ] pyridine

4.5 To 48 mg of 5-bromo-3- [5- (3-fluoro-benzyl) -1 H- [1,2,4] triazol-3-yl] -1 H -pyrrolo [2,3-b] pyridine , 45.6 mg of 1-methyl-4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -1H-pyrazole and 14.9 mg of tetrakis (triphenylphosphine) - palladium (O) is added 1 ml of DMF and 194 μM sodium carbonate solution (2.0 mol / l). Subsequently, argon is passed through the mixture for 5 min. The

 Suspension is heated to 120 ° C and stirred at 90 ° C for 30 min. Cool and work as usual. The mixture is purified by preparative RP18e silica gel column for preparative HPLC

Chromatograph. After usual work-up, 24.6 mg of 3- [5- (3-fluorobenzyl) -1H- [1,2,4] triazol-3-yl] -5- (1-methyl-1H-pyrazole -4-yl) -1 H -pyrrolo [2,3-b] pyridine ("A14")

HPLC / SFC condition: O; RT / min.2.54;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 13.43 (s, broad, 1H), 11.63 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.43-7.26 (m, 1H), 7.24- 7.14 (m, 2H), 7.10 -6.97 (m, 1H), 4.13 (s, 2H), 3.89 (s, 3H).

Analogously, the following compounds are obtained

Example 5

 Preparation of 3- [5- (3-fluoro-benzyl) - [1, 3,4] oxadiazol-2-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [ 2,3-b] pyridine ("A19")

5.1 100 mg of 5-bromo-1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide and 116.6 mg of 2- (3-fluorophenyl) -acetimidic acid ethyl ester hydrochloride are suspended in 1 ml of ethanol, at 85 ° C heated and stirred for 15 h.

 It is cooled, the solid is separated off, washed with ethanol and water and dried. This gives 99 mg of 5-bromo-3- [5- (3-fluoro-benzyl) - [1, 3,4] oxadiazol-2-yl] -1H-pyrrolo [2, -b] pyridine

 5.2 To 99 mg of 5-bromo-3- [5- (3-fluoro-benzyl) - [1, 3,4] oxadiazol-2-yl] -1 H -pyrrolo [2,3-b] pyridine and 80 mg 1-methyl-4- (4,4,5,5, -tetramethyl-

[1, 3,2] dioxaborolan-2-yl) -1H-pyrazole are added 3 ml of DMF and placed under argon atmosphere. Then a solution of 30 mg of tetrakis (triphenylphosphine) palladium (O) and 80 mg of sodium carbonate in 200 .mu.l of water is added. Argon is passed through the solution for 5 minutes, heated to 120 ° C. and stirred for a further 2.5 hours. Cool and work as usual. This gives 35 mg of 3- [5- (3-fluorobenzyl) - [1,3,4] oxadiazol-2-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H -pyrrolo [2,3-b] pyridine ("ΑΙΘ")

HPLC / SFC condition: N; RT / min. 2.20;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 12.51 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.28 - 8.20 (m, 2H), 7.91 (d, J = 0.6Hz, 1H), 7.51-7.08 (m, 4H), 4.40 (s, 2H), 3.90 (s, 3H).

Analogously, the following compounds are obtained

Example 6

 Preparation of 3- [3- (2-fluoro-benzyl) - [1, 2,4] oxadiazol-5-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine ("A32")

6.1 To a solution of 684 mg of 2,2,2-trichloro-1- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl ] ethanone

in 4 ml of water and 10 ml of THF are added 1.27 ml of triethylamine and stirred for 65 h at RT. Remove the solvents and extract the aqueous

Residue once with ethyl acetate (the organic phase is discarded). The aqueous phase is treated with 10% citric acid and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and then the solvent is removed. There remains a white crystals. In the aqueous phase product is still included. Therefore, it is saturated with NaCl and extracted again with ethyl acetate. After removal of the solvent also gives a white crystals.

 This gives 748 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid

6.2 748 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid, 620 mg of pentafluorophenol and 694 mg of N, N'-dicyclohexyl carbodiimide are added under argon with 10 ml of DMF. The suspension is stirred for 16 h. Then 0.54 g of 1, 1'-carbonyldiimidazole are added and stirred for 45 h. Add 10 ml of dichloromethane and work up as usual. 470 mg of 5- (1-methyl-1H-pyrazol-4-yl) -H-pyrrolo [2,3-b] py din-3-carboxylic acid pentafluorophenyl ester are obtained

6.3 1 ml of 2-fluorophenylacetonitrile and 3.3 ml of triethylamine are added to a suspension of 1.05 g of hydroxylammonium chloride in 16 ml of ethanol. The mixture is stirred at reflux for 2 h. The solution is concentrated and worked up as usual. 1.26 g of 2- (2-fluorophenyl) -N-hydroxyacetamidine are obtained

6.4 To 150 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid pentafluorophenyl ester and 51 mg of 2- (2-fluoro-phenyl ) N-hydroxyacetamidine is added under argon 1.5 ml of DMF, heated to 70 ° C and stirred for 14 h. The mixture is heated to 100 ° C. and stirred for a further 4 h. Cool and work as usual. The crude mixture is purified for purification via a prep-HPLC system.

 This gives 14 mg of 3- [3- (2-fluorobenzyl) - [1, 2,4] oxadiazol-5-yl] -5- (1-methyl-1H-pyrazol-4-yl) -1H -pyrrolo [2,3-b] pyridine ("A32")

HPLC / SFC condition: N; RT / min. 2:43; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 12.76 (s, 1 H), 8.64 (d, J = 2.1 Hz, 1 H), 8.46 (d, J = 3.0 Hz, 1 H), 8.42 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 7.92 (s, 1H), 7.54 - 7.16 (m, 4H), 4.20 (s, 2H), 3.90 (s, 3H) , Analogously, the following compounds are obtained

 Example 7

Preparation of 1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2H- [1, 2,4] triazol-3-yl} -1-phenylethanol ("A42 ^M )

7.1 To a suspension of 1.16 g of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile in 10 ml of dichloromethane is added 0, 91 ml of triethylamine and 60.48 mg of 4- (dimethylamino) -pyridine, followed by 0.63 ml of benzenesulfonyl chloride. The mixture is stirred for 30 min at RT and worked up as usual. 673 mg of 1-benzenesulfonyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile are obtained

7.2 To a solution of 673 mg of 1-benzenesulfonyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carbonitrile in 15 ml of methanol and 20 ml of dichloromethane is introduced at 0 ° C for 30 min HCl gas. The suspension is then stirred at RT for 60 h. The solvents are removed and it is worked up as usual. This gives 471 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboximinic acid methyl ester

7.3 To 50.0 mg of methyl 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboximinate and 33.67 mg of 2-hydroxy- 2-phenyl-propionic acid hydrazide are added 1, 5 ml of ethanol and heated with stirring to 85 ° C (bath temperature). The mixture is stirred for 18 hours at this temperature. It is cooled and the solvent removed. The residue is taken up in 1.5 ml of acetonitrile and chromatographed over a preparative RP18 silica gel column for purification. After working up, 24.9 mg of 1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2H are obtained - [1, 2 _I 4] triazol-3-yl} -1-phenylethanol ("A42")

HPLC / SFC condition: P; RT / min. 2.77; M + H ⁺ 386.

Analogously, the following compounds are obtained

 Example 8

 Preparation of (4-fluoro-phenyl) - {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-ylH1, 3, 4] oxadiazol-2-yl} -methanol ("A57")

8.1 To a solution of 2.0 g of 2,2,2-trichloro-1- [5- (1-methyl-1H-pyrazol-4-yl) -iH-pyrrolo [2,3-b] pyridine 3-yl] -ethanone in 40 ml of methanol are added 7.87 ml of hydrazinium hydroxide and stirred for 30 min at RT. The resulting precipitate is separated, washed with 2-propanol and diethyl ether and dried. This gives 1.26 g of gray matter (Ns.). The mother liquor is until the

 Residue is concentrated. The residue is taken up in 10 ml of water and chromatographed for purification over a 540 g RP18 silica gel column.

After working up, 140 mg of substance are obtained, which is identical to Ns. This gives 1, 4 g of 5- (1-methyl-1 H-pyrazol-4-yl) -1 H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide

8 _. 2 A suspension of 100 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide and 113.9 mg of 2- (4 Fluorophenyl) - 2-hydroxy-acetimidic acid ethyl ester hydrochloride in 1.5 ml of ethanol is stirred at 90 ° C for 14 h. Cool and work as usual. The residue is chromatographed for purification over a 12 g Si50 silica gel column. After working up, 61 mg of (4-fluoro-phenyl) - {5- [5- (1-methyl-1 H- pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] - [1,3,4] oxadiazol-2-yl} -methanol ( ^M A57 ")

HPLC / SFC condition: N; RT / min.2.12; M + H ⁺ 391;

1H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.55 (s, broad, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.25 ( s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.64-7.57 (m, 2H), 7.29-7.20 (m, 2H), 6.86 (d, J = 5.1 Hz, 1H), 6.11 (d, J = 4.9 Hz, 1H), 3.91 (s, 3H).

Analogously, the following compounds are obtained

Example 9

 Preparation of 1- (3-fluoro-phenyl) -1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-one yl] -2H-pyrazol-3-yl} -ethanol ("A37")

9.1 To a solution of 115 mg of 3- [4- (3-fluoro-phenyl) -4-methoxymethoxypent-2-ynoyl] -5- (1-methyl-1H-pyrazol-4-yl) -pyrrolo [ 2,3-b] pyridine-1-carboxylic acid tert-butyl ester [preparation analogous to Example 1]

in 2.5 ml of ethanol is added 60 μΙ triethylamine and 26.2 μΙ hydrazinium hydroxide and stirred for 50 h at RT. You work up as usual and get 98 mg

3- 5- [1- (3-Fluoro-phenyl) -1-methoxymethoxy-ethyl] -1H-pyrazol-3-yl} -5- (1-methyl-1H-pyrazol-4-yl) -1 H-pyrrolo [2,3-b] pyridine

9.2 97 mg of 3- {5- [1- (3-fluoro-phenyl) -1-methoxymethoxy-ethyl] -1H-pyrazol-3-yl} -5- (1-methyl-1H-pyrazol-4-yl ) -1 H-pyrrolo [2,3-b] pyridine and 3.0 ml HCl in dioxane (4M) are stirred at RT for 14 h. The solvents are removed and purified by preparative HPLC. 38 mg of 1- (3-fluorophenyl) -1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine are obtained. 3-yl] -2H-pyrazol-3-yl} -ethanol ("A37")

HPLC / SFC condition: W; RT / min. 3.89; M + H ⁺ 403;

1H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 11.88 (s, 1H), 8:52 (d, J = 2.0 Hz, 1H) 8.45 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.41 - 7.25 (m, 3H), 7.04 (dd, J = 7.8, 1.5 Hz, 1 H), 6.61 (s , 1 H), 4.5 (s, broad, 1H), 3.90 (s, 3H), 1.87 (s, 3H).

Example 10

 Preparation of 5- (1-methyl-1H-pyrazol-4-yl) -3- {5- [1- (2-methylpyridin-4-yl) -cyclopropyl] - [1, 3,4] oxadiazole -2-yl} -1 H -pyrrolo [2,3-b] pyridine ("A85")

10.1 5.31 ml of trimethylaluminum (2M in toluene) and 454.4 mg of tetrakis (triphenylphosphine) palladium are added under nitrogen to a solution of (2-chloro-pyridin-4-yl) -acetonitrile in 30 ml of 1,4-dioxane (0) and stirred for 2 h at 100 °. The mixture is cooled, the solvent is removed, worked up as usual and receives 2.17 g (2-methyl-pyridin-4-yl) -acetonitrile.

10.2 To a mixture of 670 mg of (2-methyl-pyridin-4-yl) -acetonitrile, 23.1 mg of benzyltriethylammonium chloride and 0.88 ml of 1-bromo-2-chloroethane is added 5.0 ml of 50% sodium hydroxide solution and stirred 3 h at 45 °. It is cooled, neutralized with HCl solution and worked up as usual. The residue will be on

Companion chromatographed. 600 mg of 1- (2-methylpyridin-4-yl) -cyclopropane-carbonitrile are obtained

10.3 A mixture of 300 mg of 1- (2-methyl-pyridin-4-yl) -cyclopropanecarbonitrile, 0.95 ml of ethylene glycol and 5.0 ml of 50% sodium hydroxide solution is stirred at 100 ° for 14 h. It is cooled, slightly acidic with HCl and worked up as usual. The product is in the aqueous phase. The water is removed and the residue is chromatographed on the companion. 300 mg of 1- (2-methyl-pyridin-4-yl) -cyclopropane-carboxylic acid are obtained.

10.4 A suspension of 350 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide, 300 mg of 1- (2-methyl- pyridin-4-yl) -cyclopropane-carboxylic acid, 306 μΙ 4-methylmorpholine, 529 mg N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) and 90.2 mg 1-hydroxybenzotriazole (HOBt) in 5 ml DMF is stirred for 5 h at RT. It is poured into 50 ml of water and extracted with 1-butanol. Of the combined organic phases, the solvent is removed. The residue is taken up in methanol and the precipitate is separated off. From the mother liquor, the solvent is removed and the residue is chromatographed on Companion with ethyl acetate / methanol. Together, 250 mg of 1- (2-methylpyridin-4-yl) -cyclopropanecarboxylic acid N '- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2 , 3-b] pyridine-3-carbonyl-hydrazide

10.5 A mixture of 120 mg of 1- (2-methylpyridin-4-yl) -cyclopropanecarboxylic acid N '- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [ 2,3-b] pyridine-3-carbonyl-hydrazide, 165.2 mg of methyl N- (triethylammonium sulfonyl) -carbamate [Burgess reagent] in 4 ml of tetrahydrofuran is heated for 35 minutes at 100 ° in the microwave. The solvent is removed and chromatographed on preparative HPLC. This gives 45.7 mg of 5- (1-methyl-1H-pyrazol-4-yl) -3- {5- [1- (2-methyl-pyridin-4-yl) -cyclopropyl] - [1, 3 , 4] oxadiazol-2-yl} -1 H -pyrrolo [2,3-b] pyridine ("A85")

HPLC / SFC condition: G; RT / min. 1:49; M + H ⁺ 398;

Analogously, the following compounds are obtained

 Example 11

 Preparation of (2-chloro-phenyl) - {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2H - [1,2,4] triazol-3-yl) -methanol ("A87")

11.1 Release of 2- (2-chlorophenyl) -2-hydroxy-acetimic acid ethyl ester from its HCl salt

To a suspension of 280 mg of 2- (2-chlorophenyl) -2-hydroxy-acetimic acid ethyl ester hydrochloride in 5 ml of ethyl acetate is added, with stirring, 1 ml of saturated NaHCO ₃ solution. After stirring for 2 minutes, the aqueous phase is removed, the organic phase is dried with sodium sulfate. The solvent is then removed and obtained

1 .2 A mixture of 279.1 mg of 2- (2-chlorophenyl) -2-hydroxy-acetimic acid ethyl ester and 260 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2 , 3-b] pyridine-3-carboxylic acid hydrazide in 5 ml of ethanol is heated to boiling with stirring and heated under reflux for 16 h. It is cooled and removed the solvent. 10 ml of diethyl ether are added and treated in an ultrasonic bath. The solid is separated off and dried, giving 410 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid N '- [2 - (2-chlorophenyl) -2-hydroxy-1-imino-ethyl] hydrazide

 11.3 A suspension of 297 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid N '- [2- (2-chlorophenyl ) -2-Hydroxy-1-imino-ethyl] -hydrazide in 3.5 g of pyridine is heated at 110 ° for 28 h. It is cooled and the solvent removed.

The residue is dissolved in 2.5 ml DMSO and purified by preparative HPLC (Chromolith prepRod 100-25). This gives 27.1 mg (2-chlorophenyl) - {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3- yl] -2H- [1,2,4] triazol-3-yl} -methanol ("A87")

HPLC / SFC condition: P; RT / min.2.92; M + H ⁺ 406;

Example 11a

The preparation of 1- {3- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -isoxazol-5-yl} -1 -pyridazin-4-yl-ethanol "A98")

takes place analogously to Example 1 (stages 1-4);

HPLC / SFC condition: M; RT / min (HPLC or SFC): 3.29; [M + H] ⁺ 388; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.34 (d, J = 3.0 Hz, 1H), 9.40 (m, 1H), 9.22 (dd, J = 5.4, 1.2 Hz, 1H), 8.59 (d, J = 2.1Hz, 1H), 8.38 (d, J = 2.2Hz, 1H), 8.27 (d, J = 0.9Hz, 1H), 8.16 (d, J = 2.9Hz, H), 7.99 (i.e. , J = 0.9 Hz, 1H), 7.76 (dd, J = 5.4, 2.5 Hz, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 3.98 (s, 3H), 1.93 (s, 3H) ,

The preparation of 6- (1-hydroxy-1- {3- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] isoxazole -5-yl} -ethyl) -2-methyl-2H-pyridazin-3-one

( "A99")

takes place analogously to Example 1 (stages 1-4); [M + H] ⁺ 418;

HPLC / SFC condition: W; RT / min (HPLC or SFC): 3.36;

1 H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.34 (d, J = 3.2 Hz, 1 H), 8.60 (d, J = 2.2 Hz, 1 H), 8.40 (d, J = 2.2 Hz, 1H), 8.28 (s, 1H), 8.16 (d, J = 2.9Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 9.7Hz, 1H), 6.97 (m, 2H), 6.49 (s, 1H), 3.90 (s, 3H), 3.63 (s, 3H), 1.88 (s, 3H).

Preparation of 2,2-dimethyl-1- {3- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] - isoxazol-5-yl} -1-pyridazin-4-yl-propan-1-ol

( "A100")

takes place analogously to Example 1 (stages 1-4);

HPLC / SFC condition: W; RT / min (HPLC or SFC): 4.16; [M + Hf 430; 1H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 12.16 (d, J = 2.9 Hz, 1 H), 9:46 (m, 1 H), 9.25 (dd, J = 5.5, 1.2 Hz, 1 H) , 8.57 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.2 Hz, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 8.23 (d, J = 0.9 Hz, 1H ), 7.91 (d, J = 0.9 Hz, 1 H), 7.87 (dd, J = 5.5, 2.5 Hz, 1 H), 7.07 (s, 1 H), 6.77 (s, 1 H), 3.90 (s, 3H), 1.00 (s, 9H). Preparation of {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -2H-pyrazol-3-yl} - phenyl- (tetrahydro-pyran-4-yl) -methanol

( "A101")

takes place analogously to Example 1 (stages 1-4); the cyclization is carried out with hydrazine; HPLC / SFC condition: M; RT / min (HPLC or SFC): 3.59; [M + H] ⁺ 455;

¹ H NMR (500 MHz, DMSO-d ₆ , H / D exchange with TFA-d ₁ ) δ [ppm] 9.00 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.31 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.29 (m, 2H), 3.98 (m, 5H), 3.45 (m, 1H), 3.36 (m, 1H), 2.80 (m, 1H), 1.77 (m, 1H), 1.59 (m, 1H), 1.46 (m, 1H ), 1.19 (m, 1H).

Analogously, the following compounds are obtained

Example 12 Preparation of C - ((S) -C- {5- [5- (1-Methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl ] - [1, 3,4-oxadiazol-2-yl} C-phenyl) -methylamine ("A109")

a) A suspension of 200 mg of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide, 296.1 mg Boc-D Phenylglycine, 175.1 μΙ 4-methylmorpholine, 302.2 mg N- (3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (EDCI), 108.7 1-Hydroxybenzotriazolehydrat (HOBt) in 5 ml DMF is under

Argon atmosphere stirred for 14 hours.

 It is poured into 50 ml of water, the precipitate is separated off, dried and 382 mg (2- {N '- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3- b] pyridine-3-carbonyl] hydrazino-2-oxo-1-phenyl-ethyl) -carbamic acid tert-butyl ester

b) A mixture of 228 mg of the ester obtained under a) and 445.3 mg Burgess reagent in 5 ml of THF is heated at 100 ° C for 15 min in the microwave. After cooling, the mixture is purified on preparative HPLC.

 Burgess reagent = methoxycarbonylsulfamoyl) triethylammonium hydroxides, inner salt.

 20.3 mg of "A109" are obtained;

HPLC / SFC condition: Q; RT / min (HPLC or SFC): 1.36; [M + H] ⁺ 372.

Analogously, C - ((R) -C- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl is obtained ] - [1, 3,4] oxadiazol-2-yl} C-phenyl) -methylamine ("A108")

HPLC / SFC condition: Q; RT / min (HPLC or SFC): 1.33; [M + H] ⁺ 372; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.53 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.28-8.20 (m, 2H), 7.94 ( s, 1H), 7.55 (d, 2H), 7.48 - 7.38 (m, 2H), 7.33 (t, J = 7.2 Hz, 1H), 5.47 (s, 1H), 3.92 (s, 3H).

Analogously to Example 10, the following compounds are obtained

The following connections are obtained analogously to "Α109"

Analogously to Example 10, the following compounds are obtained

 Example 13

Preparation of 5- (1-methyl-1H-pyrazol-4-yl) -3- [5- (1-methyl-1-pyridazin-4-yl-ethyl) - [1, 3,4] oxadiazole-2 -yl] -1H-pyrrolo [2,3-b] pyridine ("A121")

13.1 Boil 2- (3,6-dichloropyridazin-4-yl) -2-methyl-propionic acid with thionyl chloride for 10 min. under reflux.

 It is cooled, mixed with toluene and concentrated to the residue.

13.2 To a suspension of 5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2, 3-b] pyridine-3-carboxylic acid hydrazide, N-ethyldiisopropylamine in 2.5 ml of THF is added dropwise a solution of the product from 13.1 in 2.5 ml of THF and stirred for one hour. The procedure is as usual, giving 6-chloro-4- (1-methyl-1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3- b] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -pyridazine-3-ol

 13.3 By reaction of the product from 13.2 in acetonitrile with

Phosphoryl chloride under a protective gas atmosphere at 90 ° is obtained after conventional workup 3- {5- [1- (3,6-dichloro-pyridazin-4-yl) -1-methyl-ethyl] - [1, 3,4] oxadiazol-2 yl} -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine

13.4 The product from 13.3 is hydrogenated in ethanol, THF, triethylamine, palladium-aluminum powder (5% Pd) with hydrogen under pressure.

 After usual work-up, 5- (1-methyl-1H-pyrazol-4-yl) -3- [5- (1-methyl-1-pyridazin-4-yl-ethyl) - [1, 3,4] oxadiazole is obtained -2-yl] -1H-pyrrolo [2,3-b] pyridine ("A121")

HPLC / SFC condition: P; RT / min (HPLC or SFC): 2.85; [M + H] ⁺ 387; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.55 (s, 1H), 9.41 (dd, J = 2.6, 1.2 Hz, 1 H), 9.23 (dd, J = 5.5, 1.1 Hz, 1 H), 8.63 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.71 (dd, J = 5.5, 2.7 Hz, 1H), 3.91 (s, 3H), 1.89 (s, 6H).

Example 14

Preparation of 3- {5- [1- (6-chloro-pyridin-3-yl) -cyclopropyl] -1 H- [1,2,4] triazol-3-yl} -5- (1-methyl-1 H -pyrazol-4-yl) -1 H -pyrrolo [2,3-b] pyridine ( ^M A122 ^M )

 and 3- {5- [1- (6-chloro-pyridin-3-yl) -cyclopropyl] - [1, 3,4] oxadiazol-2-yl} -5- (1-methyl-1H-pyrazole) 4-yl) -1H-pyrrolo [2,3-b] pyridine ("A123")

A mixture of 194 mg of 5- (1-methyl-H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide and 253 mg of 1- (6-chloropyridine). 3-yl) - cyclopropane-carboximinsäure ethyl ester in 5 ml of ethanol is stirred at 90 ° C for 3 days.

 The solvent is removed with 5 ml of pyridine stirred for 2 days at 150 °. After cooling, the solvent is removed. The residue is purified over a 40 g Si50 silica gel column of a CombiFlash

 Companion chromatographed.

The two products are obtained from the fractions; "A122":

HPLC / SFC condition: P; RT / min (HPLC or SFC): 3.03; [M + H] ⁺ 417; H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 13.62 and 13:44 (2s, 1H), 12.12 and 11.86 (2s, 1 H), 8.6-8.45 (m, 3H), 8.13 (s, 1H), 8.05-7.78 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 1.70-1.28 (m, 4H);

"A123":

HPLC / SFC condition: P; RT / min (HPLC or SFC): 3.14; [M + H] ⁺ 418; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.51 (s, 1 H), 8.60 (dd, J = 13.1, 2.2 Hz, 2H), 8.32 (d, J = 2.1 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.01 (dd, J = 8.3, 2.6 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 3.91 (s , 3H), 1.80 (q, J = 4.8 Hz, 2H), 1.63 (q, J = 4.8 Hz, 2H).

From "A123", the compound 5- (1-methyl-1H-pyrazol-4-yl) -3- [5- (1-pyridin-3-yl-cyclopropyl) - [1,3,4] oxadiazole is obtained by hydrogenation. 2-yl] -1 H -pyrrolo [2,3-b] ridine ("A124")

HPLC / SFC condition: N; RT / min (HPLC or SFC): 1.7; [M + H] ⁺ 384; 1H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.57 (d, J = 1.7 Hz, 1H), 8.80 (dd, J = 2.3, 0.6 Hz, 1 H), 8.67 (d, J = 2.1 Hz , 1 H), 8.62 (dd, J = 4.8, 1.6 Hz, 1 H), 8.37 (d, J = 2.1 Hz, 1 H), 8.29 (d, J = 2.8 Hz, 1H), 8.26 (s, 1 H), 7.98 (ddd, J = 7.9, 2.3, .7 Hz, 1 H), 7.94 (d, J = 0.6 Hz, 1 H), 7.50 (ddd, J = 7.9, 4.8, 0.7 Hz, 1 H) , 3.97 (s, 3H), 1.85 (dd, J = 7.2, 4.7 Hz, 2H), 1.67 (dd, J = 7.3, 4.8 Hz, 2H).

From "A122" the compound 5- (1-methyl-1H-pyrazol-4-yl) -3- [5- (1-pyridin-3-yl-cyclopropyl) -1H- [1, 2] is obtained by hydrogenation , 4] triazol-3-yl] -1H-pyrrolo [2,3-b] pyridine ("A125")

HPLC / SFC condition: P; RT / min (HPLC or SFC): 2.63; [M + H] ⁺ 383; ¹ H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 13.60 (s, 1 H), 11.12 and 11.88 (2s, 1H), 8.67 (s, 1 H), 8.61 - 8:42 (m, 3H), 8.14 (s, 1H), 8.07-7.78 (m, 3H), 7.39 (dd, J = 7.7, 4.8Hz, 1H), 3.92 (s, 3H), 1.68 - 1.25 (m, 4H).

From "A122" is obtained by heating in water and conc. HCl (120 ° bath temperature, 3 days) and purification by preparative HPLC the compound 5- (H5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine -3-yl] -2H- [1,2,4] triazole-3-l} -cyclopropyl) -1H-pyridin-2-one ("A126")

HPLC / SFC condition: P; RT / min (HPLC or SFC): 2.73; [M + H] ⁺ 399; 1H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 13:57 and 13:34 (2s, 1 H), 12.12 and 11.86 (2s, 1 H), 11.50 (s, 1 H), 8:53 (s, 2H), 8.11 (s, 1H), 8.06-7.75 (m, 2H), 7.65 - 7.24 (m, 2H), 6.35 (d, J = 9.4 Hz, 1H), 3.92 (s, 3H), 1.56 - 1.11 ( m, 4H).

Analogously to the preparation of "A42", the compound 3- {5- [1- (6-methoxypyridin-3-yl) -cyclopropyl] -1 H- [1,2,4] triazol-3-yl} is obtained. -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine ("A127")

HPLC / SFC condition: P; RT / min (HPLC or SFC): 2.97; [M + H] ⁺ 413;

1H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 13:53 and 13:31 (2s, 1 H), 12.09 and 11.82 (2s, 1H), 8:51 (s, 2H), 8.23 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 8.03-7.68 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.36 (dd, J = 83.7, 47.3 Hz, 4H).

Analogously to the preparation of "A57", the compound 3-chloro-4- (hydoxy {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrorolo is obtained [2, 3-b] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -methyl) -benzoic acid methyl ester ("A128")

HPLC / SFC condition: N; RT / min (HPLC or SFC): 2.26; [M + H] ⁺ 465.

From "A128", under standard conditions, the compound 3-chloro-N-cyclohexyl-4- (hydroxy- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2 3- b] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -methyl) -benzamide ("A129")

HPLC / SFC condition: N; RT / min (HPLC or SFC): 2.41; [M + H 532; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.59 (s, 1 H), 8.64 (d, J = 2.1 Hz, 1 H), 8.40 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.0-7.9 (m, 4H), 7.13 (d, J = 5.6 Hz , 1H), 6.31 (d, J = 5.5 Hz, 1H), 3.91 (s, 3H), 3.82-3.72 (m, 1H), 1.89-1.68 (m, 4H), 1.66-0.77 (m, 6H) ,

Example 15

Production of

(R) - (2-chloro-phenyl) - {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -methanol ("A131") and (S) - (2-chlorophenyl) - {5- [5- (1-methyl-1H-pyrazole) 4-yl) -1H-pyrrolo [2,3-b] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -methanol ("A130") from the racemate "A58": To 520 mg "A58" and 281, 9 mg imidazole are added to 15 ml DMF. To the

Suspension is added 526.7 μΙ tert-Butyldiphenylchlorsilan and the mixture is stirred for 16 h at RT. It is again mixed with Silylreagenz and stirred again 16. The mixture is worked up as usual and purified on a 205 g RP18ec silica gel column of a Combiflash Companion. After working up, 3- {5 - [(tert-butyl-diphenyl-silanyloxy) - (2-chlorophenyl) -methyl] - [ 1, 3, 4] oxadiazol-2-l} -5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b] pyridine

The analytical separation is carried out on Chiralpak AD-H with CO ₂ + 20%

Methanol. For preparative separation, in each case 50 mg of the compound obtained are dissolved in 10 ml of boiling methanol and separated by means of 3 × 25 cm Chiralpak AD-H column with 80 ml of CO ₂ and 20 ml of methanol.

There are 2 fractions collected.

Fraction 1: enantiomeric ratio 95: 5;

Fraction 2: enantiomeric ratio 2:98.

 The absolute configuration of the two products is not assigned.

To cleave the silyl group, the products obtained from the two fractions are treated with tetrabutylammonium fluoride in THF. After usual work-up you get "A13":

HPLC / SFC condition: N; RT / min (HPLC or SFC): 2.17; [M + H] ⁺ 407; and "A130":

HPLC / SFC condition: N; RT / min (HPLC or SFC): 2.19; [M + H] ⁺ 407; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ [ppm] 12.57 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H ), 8.25 (d, J = 2.9 Hz, 1H), 8.20 (s, 1H), 7.93 - 7.85 (m, 2H), 7.55 - 7.46 (m, 2H), 7.46 - 7.35 (m, 1H) , 6.99 (d, J = 5.5 Hz, 1 H), 6.28 (d, J = 5.5 Hz, 1 H), 3.91 (s, 3H). Analogously to Example 10, the compound 1- (2-chlorophenyl) -1- {5- [5- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-3-yl] - [1, 3,4] oxadiazol-2-yl} -ethanol ("A132")

HPLC / SFC condition: N; RT / min (HPLC or SFC): 2.26; [M + H] ⁺ 421; 1H NMR (500 MHz, DMSO-d ₆₎ δ [ppm] 12:52 (s, 1H), 8.62 (dd, J = 8.9, 2.2 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.18 ( d, J = 2.5 Hz, 1 H), 8.10 (s, 1H), 8.08 - 8.02 (m, 1H), 7.78 (s, 1H), 7.57 - 7.49 (m, 1H), 7.47 - 7.37 (m, 2H), 6.90 (s, 1H), 3.90 (s, 3H), 2.06 (s, 3H).

Inhibition PDK 1

IC ₅₀ of compounds of the invention

The following examples relate to drugs: Example A: Injection jars

 A solution of 100 g of an active compound of the formula I and 5 g disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l bidistilled water with 2 N hydrochloric acid, sterile filtered, filled into injection jars, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

 A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

 A solution of 1 g of an active compound of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water is prepared. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.

Example F: dragees

Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

2 kg of active compound of the formula I are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

claims

1. Compounds of the formula I

wherein

 Q Het-diyl,

R ¹ Br, Het ¹ or phenyl substituted by CH ₂ OH, R ² , R ^{3 are} each independently H, Hal, A, Ar, [C (R ⁵ ) ₂ ] _n OH,

[C (R ⁵ ) ₂ ] n OA or [C (R ⁵ ) ₂ ] _n N (R ⁵ ) ₂ ,

R ² , R ³ together also = 0, = CH ₂ or an alkylene chain with 2-5 C

atoms,

R ^{4 is} H, Ar or Her ² ,

R ^{5 is} H or A ',

Het ¹ pyrazolyl, which is easily replaced by A, CH ₂ OH, (CH ₂ ) ₂ OH, COOH,

CH ₂ COHet ³ , COOA or CONH ₂ may be substituted,

 Ar unsubstituted or one, two or three times by shark, A,

(CH ₂ ) _n OR ⁵ , (CH ₂ ) _n N (R ⁵ ) _{2 l} SR ⁵ , NO ₂ , COOR ⁵ , CON (R ⁵ ) _2>

NR ⁵ SO ₂ A, S0 ₂ N (R ⁵⁾ _2, COR ^5, (CH _{2) n} ⁵ COA, NR CN and / or S (O) mA substituted phenyl, naphthyl or biphenyl,

Het an unsubstituted or mono- or disubstituted by Hal, A, [C (R ⁵ ) ₂ ] _n OR ⁵ , [C (R ⁵ ) ₂ ] _n N (R ⁵ ) ₂ , NO ₂ , CN, COOR ⁵ , CON (R ⁵ ) ₂ , NR ⁵ COA, NR ⁵ SO ₂ A, COR ⁵ , SO ₂ NR ⁵ , S (O) "A = S, = NH, = NA and / or O (carbonyl oxygen) substituted on or

dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms, Het ^{2 is} unsubstituted or mono- or disubstituted by Hal, A, OR ⁵ , N (R ⁵ ) ₂ , NO _2> CN, COOR ⁵ , CON (R ⁵ ) ₂ , NR ⁵ COA, NR ⁵ SO ₂ A, COR ⁵ , SO ₂ NR ⁵ , S (O) n A = S, = NH, = NA and or = O

 (Carbonyl oxygen) substituted mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and / or the O and / or S atoms,

Het ^{3 is} an unsubstituted monocyclic saturated heterocycle having 1 to 4 N, and / or O and / or S atoms,

 A unbranched or branched alkyl having 1-10 C atoms,

wherein 1-7 H atoms may be replaced by F, Cl and / or Br, and / or wherein one or two non-adjacent CH and / or CH ₂ groups are represented by NR ⁵ , O, S, SO, SO ₂ , C = C and / or CH = CH groups can be replaced,

 or

 cyclic alkyl with 3-7 C atoms,

 A 'is unbranched or branched alkyl having 1-6 C atoms,

 or

 cyclic alkyl with 3-7 C atoms,

 Hal F, Cl, Br or I,

 m 0, 1 or 2,

 n 0, 1, 2, 3 or 4,

 mean,

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios. 2. Compounds according to claim 1,

 wherein

R ¹ Het ¹ means

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

3. Compounds according to claim 1 or 2, Wonn

Het ¹ pyrazolyl, which may be substituted by A, CH ₂ COHet ³ or COOA,

 means

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios. 4. Compounds according to one or more of claims 1-3,

 wherein

Ar unsubstituted or mono-, di- or trisubstituted by Hal, COOR ⁵ and / or CON (R ⁵ ) _2- substituted phenyl,

 means

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios. 5. Compounds according to one or more of claims 1-4,

 wherein

Het an unsubstituted or mono- or disubstituted by A and / or [C (R ⁵ ) 2] _n OR ⁵ mononuclear aromatic

 Heterocycle having 1 to 4 N, and / or O and / or S atoms, means

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios. 6. Compounds according to one or more of claims 1-5,

 wherein

 A unbranched or branched alkyl having 1-6 C atoms,

wherein 1-5 H atoms may be replaced by F, or

 cyclic alkyl with 3-7 C atoms

means

and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

Compounds according to one or more of claims 1-6,

wherein

 Q Het-diyl,

R ¹ Het ¹ ,

R ² , R ^{3 are} each independently H, Hai, A, Ar, [C (R ⁵ ) ₂ ] _n OH,

[C (R ⁵ ) ₂ ] _n OA or [C (R ⁵ ) ₂ ] _n N (R ⁵ ) ₂ ,

R ² , R ³ together also = O, = CH ₂ or an alkylene chain with 2-5 C

atoms,

R ^{4 is} H, Ar or Het ² ,

R ⁵ H or A \

Het ¹ pyrazolyl, which is easily replaced by A, CH ₂ COHet ³ or COOA

 may be substituted

Ar unsubstituted or mono-, di- or trisubstituted by Hal, COOR ⁵ and / or CON (R ⁵ ) _2- substituted phenyl,

 Het an unsubstituted or one or two times by A and / or

[C (R ⁵ ) ₂ ] _n OR ⁵ substituted mononuclear aromatic

Heterocycle having 1 to 4 N-, and / or O and / or S atoms, Her ^{2 is} a mononuclear saturated unsubstituted or monosubstituted or disubstituted by A, OR ⁵ and / or = 0,

 unsaturated or aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms,

Het ^{3 is} an unsubstituted monocyclic saturated heterocycle having 1 to 4 N, and / or O and / or S atoms,

 A unbranched or branched alkyl having 1-6 C atoms,

 wherein 1-5 H atoms may be replaced by F,

or cyclic alkyl with 3-7 C atoms

 A 'is unbranched or branched alkyl having 1-6 C atoms,

 or

 cyclic alkyl with 3-7 C atoms,

 Hai F, Cl, Br or l,

 m 0, 1 or 2,

 n 0, 1, 2, 3 or 4,

 mean,

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

8. Compounds according to claim 1

 and their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, 9. Pharmaceuticals containing at least one compound according to claim 1 and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally carriers and / or auxiliaries. 10. Compounds of formula I and / or their pharmaceutically acceptable salts, tautomers and stereoisomers, including their

 Mixtures in all proportions, for use in the treatment of tumors, tumor growth, tumor metastases and / or AIDS. 11. Compounds according to claim 10, wherein the tumor belongs to the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, Prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs. 12. Compounds according to claim 10, wherein the tumor from the group <

 Monocytic leukemia, lung adenocarcinoma, small cell

 Lung carcinoma, pancreatic cancer, colon carcinoma,

Glioblastoma and / or breast carcinoma.

13. Compounds according to claim 10, which is a tumor of the blood and immune system. 14. Compounds according to claim 10, wherein the tumor comes from the group of acute myelotic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia. 15. Compounds according to claim 1 and / or their physiological

 non-hazardous salts, tautomers and stereoisomers for use in the treatment of tumors, wherein a therapeutically effective amount of a compound of formula I in combination with a

 Compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor , 9) reverse transcriptase inhibitors and 10) further angiogenesis inhibitors are administered. 16. Compounds according to claim 1 and / or their physiological

 harmless salts, tautomers and stereoisomers for use in the treatment of tumors wherein a therapeutically effective amount of a compound of formula I in combination with radiotherapy and a compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4)

 Cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors, and 10) other angiogenesis inhibitors.