HK1197408A

HK1197408A - 6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines

Info

Publication number: HK1197408A
Application number: HK14110912.8A
Authority: HK
Inventors: N.施梅斯; J.库恩克; B.亨德勒; P.利瑙; A．E．费尔南德斯-蒙塔尔万; P.勒热纳; S.西格尔; W.斯科特
Original assignee: 拜耳知识产权有限责任公司
Priority date: 2011-09-01
Filing date: 2012-08-27
Publication date: 2015-01-16

Description

6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepine

The invention relates to novel 6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesIn particular 6H-thieno [3,2-f ] for therapeutic purposes][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesMedicaments comprising the compounds of the invention and their use in therapy, in particular their use for the prophylaxis and/or treatment of tumor diseases.

Biological background

The human BET family (bromodomain and C-terminal ectodomain family) has 4 members (BRD2, BRD3, BRD4, and BRDT) that contain two associated bromodomains and an ectodomain (extraterminal) domain (Wu and Chiang, J.biol.chem.,2007,282: 13141-13145). Bromodomains are regions of proteins that recognize acetylated lysine residues. These acetylated lysines are often found at the N-terminus of histones (e.g., histone 3 or histone 4) and are characterized by open chromatin structure and active gene transcription (Kuo and Allis, Bioessays,1998,20: 615-. In addition, bromodomains can recognize other acetylated proteins. For example, BRD4 binds to RelA, which leads to NF-. kappa.B agonism and transcriptional activity of inflammatory genes (Huang et al, mol. cell. biol.,2009,29: 1375-1387). The outer end domains of BRD2, BRD3, and BRD4 interact with several proteins with chromatin-regulating and gene expression-regulating effects (Rahman et al, mol. cell. biol.,2011,31: 2641-.

Mechanistically, BET proteins play an important role in cell growth and cell cycle. They are associated with mitotic chromosomes, suggesting a role in epigenetic memory (Dey et al, mol.biol.cell,2009,20: 4899-vol 4909; Yang et al, mol.cell.biol.,2008,28: 967-vol 976). BRD4 is important for transcriptional elongation and recruitment of the elongation complex P-TEFb (consisting of CDK9 and cyclin T1), which leads to activation of RNA polymerase II (Yang et al, mol. cell,2005,19: 535-545). Thus stimulating the expression of genes involved in cell proliferation (e.g., c-Myc and auroraB) (You et al, mol. cell. biol.,2009,29:5094-5103; Zuber et al, Nature,2011, doi: 10.1038). BRD2 and BRD3 bind to transcribed genes in highly acetylated chromatin regions and promote transcription by RNA polymerase II (LeRoy et al, mol.cell,2008,30: 51-60).

Knock-down (knock-down) BRD4 resulted in G1 blockade in various cell lines (Mochizuki et al, J.biol.chem.,2008,283: 9040-. BRD4 has been shown to bind to the promoter regions of several genes that are activated in G1 phase (e.g., cyclins D1 and D2) (Mochizuki et al, J.biol.chem.,2008,283: 9040-.

BRD2 and BRD4 knockout mice die early in embryonic development (Gyuris et al, Biochim. Biophys. acta,2009,1789:413-421; Houzelstein et al, mol. cell. biol.,2002,22: 3794-3802). Heterozygous BRD4 mice have multiple growth defects that can be attributed to reduced cell proliferation (Houzelstein et al, mol.cell.biol.,2002,22: 3794-.

BET proteins play an important role in a variety of tumors. The fusion between BET proteins (BRD3 or BRD4) and NUT (a protein that is normally expressed only in the testis) results in an aggressive form of squamous cell carcinoma, called NUT midline carcinoma (French, Cancer gene. The fusion protein prevents cell differentiation and promotes proliferation (Yan et al, J.biol.chem.,2011,286: 27663-27675). The growth of the in vivo model thus obtained was inhibited by BRD 4-inhibitors (Filippakopoulos et al, Nature,2010,468: 1067-1073). Screening of therapeutic targets in Acute Myeloid Leukemia (AML) cell lines demonstrated that BRD4 plays an important role in this tumor (Zuber et al, Nature,2011, doi: 10.1038). The decrease in BRD4 expression leads to selective arrest of the cell cycle and to apoptosis. Treatment with BRD 4-inhibitors prevented proliferation of AML xenografts in vivo. Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (Kadota et al, Cancer Res,2009,69: 7357-7365). There is also data on the role of BRD2 in tumors. Transgenic mice that selectively overexpress BRD2 in B cells produce B cell lymphomas and leukemias (Greenwall et al, Blood,2005,103: 1475-1484).

BET proteins are also involved in viral infections. BRD4 binds to the E2 protein of a variety of papillomaviruses and is important for the survival of the virus in latently infected cells (Wu et al, Genes Dev.,2006,20: 2383-2396). The herpesviruses causing Kaposi's sarcoma also interact with a variety of BET proteins, which are important for disease resistance (Viejo-Borbola et al, J.Virol.,2005,79:13618-13629; You et al, J.Virol.,2006,80: 8909-8919). BRD4 also plays an important role in HIV replication by binding to P-TEFb (Bisgrove et al, Proc. Natl Acad. Sci. USA,2007,104: 13690-.

Furthermore, BET proteins are involved in inflammatory processes. BRD 2-suballenic (hypomorphic) mice exhibit reduced inflammation in adipose tissue (Wang et al, biochem. J.,2009,425: 71-83). Macrophage infiltration in white adipose tissue was also reduced in BRD 2-deficient mice (Wang et al, biochem. J.,2009,425: 71-83). BRD4 has also been shown to regulate many genes involved in inflammation. In LPS-stimulated macrophages, BRD 4-inhibitors prevent the expression of inflammatory genes such as IL-1 or IL-6 (Nicodeme et al, Nature,2010,468: 1119-.

These data provide evidence that BET proteins have an important role in a variety of pathologies. Therefore, it is important to find effective and selective inhibitors that prevent the interaction between BET proteins and acetylated proteins. These new inhibitors should also have suitable pharmacokinetic properties that enable them to inhibit these interactions in patients.

The state of the art for this structure is retrieved based on the following numbering of the ring systems.

EP0638560 discloses, inter alia, 6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesCan be used for treating osteoporosis. Substituted esters and amides are also provided at the 6-position of the ring system, and no bridging or spiro element is disclosed as a substituent.

U.S. Pat. No. 3,2,25 discloses 6H-thieno [3,2-f ]][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesCan be used for treating inflammation. Amides substituted with a heterocycle are also provided at the 6-position of the ring system, or cyclized through the amide nitrogen. For example, example 50 discloses the cyclization to morpholine by an amide nitrogen. It does not contain or disclose a bridge element or a spiro element. The inhibitory effect of the structure of US5,712,274 on BRD family proteins or the possible use in cancer is not disclosed.

EP0934940 discloses 6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesCan be used for treating inflammation. Substituted esters and amides are also provided at the 6-position of the ring system, and no bridging or spiro element is disclosed as a substituent.

EP0989131 claims 6H-thieno [3,2-f ] having carboxyalkyl side chains][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesHaving an amide function in position 6 of the ring system, with a hydrogen atom on the nitrogen atom and a radical R³。R³It may also represent an aromatic group or a heteroaromatic group. Not imagine R³Represents a heterocyclic ring, a bridge element or a spiro element through the amide nitrogen. The disclosed compounds are useful in inflammatory or allergic diseases in which cell adhesion has a role.

EP1887008 discloses C having a substitution in the 6 position of the ring system₁-C₆6H-thieno [3,2-f ] alkyl esters][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesWherein the alkyl ester is attached to the ring system through an alkylene group. Heterocycles such as morpholine are also contemplated as substituents for the alkyl esters. Amides not containing or disclosing position 6, ring closure through amide nitrogen, bridge elements or spiro elements. The compounds described find application in the field of inflammatory diseases.

EP2239264 discloses 6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesCan be used for treating cancer. The action mechanism is to inhibit BRD protein family. In the 6-position (R) of the ring system⁴) Only primary amides, i.e. amides with a hydrogen atom on the nitrogen, are envisaged. R⁹Are possible substituents on the amide nitrogen. However, R⁹The definition of bridge elements, spiro elements or ring closure via amide nitrogen is not included.

JQ-1 is described in Nature 2010, vol.468, p1067ff (p. filippokoulos et al), which acts as a strong binder of the BET family of proteins and has antiproliferative properties mediated thereby. In the present application JQ1 is comparative example V1. The present application has JQ1 as the closest prior art because JQ1 is related to the same target and the same indications as the substance of the present invention.

WO2011/054553, WO2011/054843, WO2011/054844 and WO2011/054845 disclose 4H- [1,2,4] as bromodomain inhibitors]Triazolo [4,3-a][1,4]Benzodiazepine

The disclosure of WO2011/054553 relates to unique (indigprodial) benzodiazepinesAnd their use in a variety of diseases. Thieno [3,2-f ] is not disclosed][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives

The disclosure of WO2011/054843 relates to a number of unique substances (also including benzodiazepines)) And their use in inflammatory or autoimmune diseases. Thieno [3,2-f ] is not disclosed][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives

The compounds of the invention differ from the compounds of WO2011/054844 in the essential primary amide group in the 6-position of the ring system and the diazaThe rings are directly connected, not through a methylene group. In WO2011/054844 no bridge element or spiro element is envisaged in the 6-position of the ring system.

The compounds of the invention differ from those of WO2011/054845 in that they are fused to diazaIn which benzene is replaced by thiophene and in diazepineThe 6 position of (a) provides an amide group which contains at most one ring. In WO2011/054845 no bridge element or spiro element is envisaged in the 6-position of the ring system.

The compounds of the present invention are related to the closest prior art (6H-thieno [3,2-f disclosed as BRD4 inhibitors in WO 2009/084693)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives) In that they comprise saturated, optionally substituted, carbocyclic or heterocyclic amides having a spiro element and/or a bridging element.

Starting from this prior art, the problem to be solved by the present invention is to provide a new structure for the treatment of human and animal diseases.

In particular, the structures of the present invention should be suitable for the prevention and treatment of tumor diseases and should have advantages over the structures known in the prior art.

In particular, the structures of the present invention should have suitable pharmacokinetics for the prevention and treatment of neoplastic diseases and should have pharmacokinetic advantages over structures known in the prior art. It has surprisingly been found that the compounds of formula (I) according to the invention can have advantageous pharmacokinetic properties.

Preferably, the structure should be made available for the treatment of diseases and have one, preferably several or most preferably even all of the following properties:

in vivo, they are more tolerant than the structures of the prior art, in particular in the mouse models described;

they inhibit more than one or more cancer cell lines more effectively than the structures of the prior art;

they have a higher dose-normalized unbound exposure than the structures of the prior art, in particular in the described mouse model.

It has now surprisingly been found that the compounds of the formula (I) and the diastereomers, racemates and physiologically compatible salts thereof are particularly suitable for the treatment of diseases and solve the problems of the present invention,

wherein

Or

X represents a bond, and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group, and

R¹and R²Independently of one another, represents a hydrogen atom or C₁-C₆Alkyl radical, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

As defined for the compounds of formula (I), if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S1and R^S1Independently of one another, represents a hydrogen atom or C₁-C₆Alkyl, or

R^S2And R^S1Together form keto-C (O) -,

or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated 3-to 8-membered carbocyclic or heterocyclic ring, which is optionally substituted

(i) May be substituted by halogen, hydroxy, cyano, nitro and/or by C₁-C₃Alkyl, halo-C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halo-C₁-C₆Alkoxy radical, C₁-C₆-alkoxy-C₁-C₆Alkyl and/or C₁-C₆Alkylcarbonyl being substituted identically or differently, one or more times, and/or

(ii) May contain a keto group-C (O) -, and

R^b1and R^b2Represents hydrogen, or

R^b1And R^b2Form a mixture of-O-, -C (O) -, -NR³-、-NR⁴-CHR⁵-or-CHR⁶-CHR⁷-a bridge of one of the groups,

wherein R is³、R⁴、R⁵、R⁶And/or R⁷Each otherIndependently represent hydrogen, C₁-C₆Alkyl or C₁-C₆Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₆Alkyl or C₁-C₆An alkoxy group,

with the proviso that,

or

As defined for the compounds of formula (I), R^b1And R^b2A bridge is formed, and the bridge is formed,

or

R^S2And R^S1And R^S1And R^S2The attached carbon atoms taken together form a saturated 3-to 8-membered carbocyclic or heterocyclic ring,

or

and is

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a saturated 3-to 8-membered carbocyclic or heterocyclic ring.

To the best of the applicant's knowledge, the structures of the prior art do not have a bridge element or a spiro element in the side chain at position 6 of the ring system.

Starting from the above prior art, there is no reason to modify the structures in the prior art, since no bridge element or spiro element in the side chain at position 6 of the ring system is disclosed for such structures, let alone structures with inhibitory effect on BRD family proteins.

Surprisingly, the compounds of the present invention prevent the interaction between BRD4 and acetylated histone 4 peptide and inhibit the growth of cancer cells. They therefore represent a novel structure for the treatment of human and animal diseases, in particular cancer.

The invention is based on the following definitions:

alkyl groups:

alkyl represents a linear or branched, saturated, monovalent hydrocarbon radical, generally having from 1 to 6 carbon atoms (C)₁-C₆Alkyl), preferably 1 to 4 carbon atoms (C)₁-C₄Alkyl group), and particularly preferably 1 to 3 carbon atoms (C)₁-C₃Alkyl groups).

For example and preferably, we may mention:

methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 2-dimethylbutyl

Particularly preferred are methyl, ethyl, propyl or isopropyl.

Alkoxy groups:

alkoxy denotes a linear or branched, saturated alkyl ether radical of the formula-O-alkyl, generally having 1 to 6 carbon atoms (C)₁-C₆Alkoxy), preferably 1 to 4 carbon atoms (C)₁-C₄Alkoxy) and particularly preferably 1 to 3 carbon atoms (C)₁-C₃Alkoxy groups).

For example and preferably, we may mention:

methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkoxyalkyl groups:

alkoxyalkyl denotes an alkyl group substituted by an alkoxy group.

C_n-alkoxy-C_mAlkyl means alkoxy havingn carbon atoms, and the alkyl group to which the group is attached has m carbon atoms.

For example and preferably, we may mention:

methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

An alkylcarbonyl group:

alkylcarbonyl represents-c (o) -alkyl, having in general 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and particularly preferably 1 to 3 carbon atoms in the alkyl moiety.

As examples we may mention:

acetyl and propionyl.

Heteroatom:

heteroatoms are to be understood as oxygen atoms, nitrogen atoms or sulfur atoms.

Carbocyclic ring:

carbocycle refers to a monocyclic saturated hydrocarbon ring generally having 3 to 8 carbon atoms, preferably 4 to 6 carbon atoms.

Heterocyclic ring:

heterocycle means a non-aromatic monocyclic ring having 3 to 8 ring atoms, wherein at least one ring atom is a heteroatom or a hetero group (heterogroup). The nitrogen, oxygen and/or sulfur atoms may be present as heteroatoms. -S (O) -, -S (O)₂-or-N⁺(O^-) -may be present as a hetero group.

Preferably 4 to 6 ring atoms.

Halogen:

specified halogens include fluorine, chlorine, bromine and iodine.

Fluorine and chlorine are preferred.

Halogenated alkyl groups:

haloalkyl represents an alkyl group having at least one halogen substituent.

For example and preferably, we may mention:

difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 5,5,5,4, 4-pentafluoropentyl or 5,5,5,4,4,3, 3-heptafluoropentyl.

Perfluorinated alkyl groups are preferred, such as trifluoromethyl or pentafluoroethyl.

Haloalkoxy groups:

haloalkoxy represents an alkoxy group having at least one halogen substituent.

Fluoroalkoxy groups are preferred.

For example and preferably, we may mention:

difluoroethoxy, trifluoromethoxy or 2,2, 2-trifluoroethoxy.

And (3) ring:

rings include carbocyclic and heterocyclic rings.

A preferred subgroup is formed by the compounds of the formula (I) and diastereomers, racemates and physiologically compatible salts thereof,

wherein

Or

X represents a bond, and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group, and

R¹and R²Independently of one another, represents a hydrogen atom or C₁-C₃Alkyl radical, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

As defined for a preferred subgroup of compounds of formula (I), if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S1and R^S1Independently of one another, represents a hydrogen atom or C₁-C₃Alkyl, or

R^S2And R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated 4-to 6-membered carbocyclic or heterocyclic ring, which is optionally substituted

(i) May be substituted by halogen, hydroxy and/or by C₁-C₃Alkyl, halo-C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo-C₁-C₃Alkoxy radical, C₁-C₃-alkoxy-C₁-C₃Alkyl and/or C₁-C₃Alkylcarbonyl being substituted identically or differently, one or more times, and/or

(ii) May contain a keto group-C (O) -, and

R^b1and R^b2Represents hydrogen, or

wherein R is³、R⁴、R⁵、R⁶And/or R⁷Independently of each other, hydrogen and C₁-C₃Alkyl or C₁-C₃Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₄Alkyl or C₁-C₄An alkoxy group,

with the proviso that,

or

As defined for a preferred subgroup of compounds of formula (I), R^b1And R^b2A bridge is formed, and the bridge is formed,

or

R^S2And R^S1And R^S1And R^S2The attached carbon atoms taken together form a saturated 4-to 6-membered carbocyclic or heterocyclic ring,

or

and is

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a saturated 4-to 6-membered carbocyclic or heterocyclic ring.

A more preferred subgroup is formed by the compounds of formula (I) and diastereomers, racemates and physiologically compatible salts thereof,

wherein

Or

X represents a bond, and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group, and

R¹and R²Is represented by C₁-C₃Alkyl radical, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

As for a more preferred subgroup of the compounds of formula (I)Definition if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S1and R^S1Represents hydrogen, or

R^S2And R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated 4-to 6-membered carbocyclic ring or a heterocyclic ring with oxygen as heteroatom, which may optionally be substituted by halogen, hydroxy and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy radicals being substituted identically or differently, one or more times, and

R^b1and R^b2Represents hydrogen, or

R^b1And R^b2Form a group consisting of-O-, -NR³-or-CHR⁶-CHR⁷-a bridge of one of the groups,

wherein R is³、R⁶And/or R⁷Represents hydrogen or C₁-C₃Alkyl or C₁-C₃Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₄Alkyl or C₁-C₄An alkoxy group,

with the proviso that,

or

As defined for a more preferred subgroup of compounds of formula (I), R^b1And R^b2A bridge is formed, and the bridge is formed,

or

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a saturated 4-to 6-membered carbocyclic ring or a heterocyclic ring with an oxygen atom as heteroatom,

or

As defined for a more preferred subgroup of compounds of formula (I)Meaning, R^b1And R^b2A bridge is formed, and the bridge is formed,

and is

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a saturated 4-to 6-membered carbocyclic ring or a heterocyclic ring with an oxygen atom as a heteroatom.

wherein

X represents a bond, and Y represents a nitrogen atom, an

R¹And R²Represents a methyl group, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

As defined for a more preferred subgroup of compounds of formula (I), if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S2and R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated heterocyclic ring containing 4-to 6-membered oxygen as a heteroatom, optionally substituted by halogen, hydroxyl and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy radicals being substituted identically or differently, one or more times, and

R^b1and R^b2Represents hydrogen, or

R^b1And R^b2Formation of bridge-CHR⁶-CHR⁷-，

Wherein R is⁶And/or R⁷Represents hydrogen or C₁-C₃Alkyl or C₁-C₃An alkoxy group,

with the proviso that,

or

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a saturated heterocyclic ring having 4-to 6-membered oxygen as a heteroatom,

or

and is

R^S2And R^S1And R^S1And R^S2The attached carbon atoms together form a heterocyclic ring with a saturated 4-to 6-membered oxygen atom as heteroatom.

The following compounds are particularly preferred:

-8- {2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetyl } -8-azabicyclo [3.2.1]The content of the octan-3-ketone,

-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) ethan-1-one,

- (1R,5S) -3- ({2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetyl } amino) -9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl ester,

-N- [ (1R,5S) -9-azabicyclo [3.3.1]Non-3-yl]-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]An acetamide compound and a water-soluble compound thereof,

-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) ethan-1-one,

-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-6-azaspiro [ 3.4)]Oct-6-yl) ethan-1-one,

-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-7-azaspiro [3.5 ]]Non-6-yl) ethan-1-one.

In the general formula (I)

X may represent a bond and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group.

In the general formula (I)

X preferably represents a bond, and Y represents a nitrogen atom.

In the general formula (I)

R¹And R²May independently represent hydrogen or C₁-C₆An alkyl group.

In the general formula (I)

R¹And R²Preferably independently of one another, hydrogen or C₁-C₃An alkyl group.

In the general formula (I)

R¹And R²More preferably represents C₁-C₃An alkyl group.

In the general formula (I)

R¹And R²Very preferably represents a methyl group.

In the general formula (I)

m, n, o and p may be 0 or 1,

wherein as defined for the compounds of formula (I), if R^b1And R^b2A bridge is formed, the sum of m, n, o and p is at least 2.

In the general formula (I)

R^S1And R^S1May independently represent hydrogen or C₁-C₆Alkyl, or

R^S2And R^S1Together form keto-C (O) -,

or

(ii) May contain a keto group-C (O) -.

In the general formula (I)

R^S1And R^S1Preferably independently of one another, a hydrogen atom or C₁-C₃Alkyl, or

R^S2And R^S1Together form keto-C (O) -, or

(ii) May contain a keto group-C (O) -.

In the general formula (I)

R^S1And R^S1More preferably represents hydrogen, or

R^S2And R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated 4-to 6-membered carbocyclic ring or a heterocyclic ring with oxygen as heteroatom, which may optionally be substituted by halogen, hydroxy and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy is the same orSubstituted one or more times differently.

In the general formula (I)

R^S2And R^S1Together very preferably form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms linked together very preferably form a saturated heterocyclic ring with 4-to 6-membered oxygen atoms as heteroatoms, which may optionally be substituted by halogen, hydroxyl and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy groups are substituted, identically or differently, one or more times.

In the general formula (I)

R^b1And R^b2May represent hydrogen, or

R^b1And R^b2Can form a compound of-O-, -C (O) -, -NR³-、-NR⁴-CHR⁵-or-CHR⁶-CHR⁷-a bridge of one of the groups,

wherein R is³、R⁴、R⁵、R⁶And/or R⁷Independently of each other, hydrogen and C₁-C₆Alkyl or C₁-C₆Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₆Alkyl or C₁-C₆An alkoxy group.

In the general formula (I)

R^b1And R^b2Preferably represents hydrogen, or

wherein R is³、R⁴、R⁵、R⁶And/or R⁷Independently of each other, hydrogen and C₁-C₃Alkyl or C₁-C₃Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₄Alkyl or C₁-C₄An alkoxy group.

In the general formula (I)

R^b1And R^b2More preferably represents hydrogen, or

wherein R is³、R⁶And/or R⁷Represents hydrogen or C₁-C₃Alkyl or C₁-C₃Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₄Alkyl or C₁-C₄An alkoxy group.

In the general formula (I)

R^b1And R^b2Very preferably represents hydrogen, or

R^b1And R^b2Formation of bridge-CHR⁶-CHR⁷-，

Wherein R is⁶And/or R⁷Represents hydrogen or C₁-C₃Alkyl or C₁-C₃An alkoxy group.

The definitions of the radicals specified in each combination or preferred combination of radicals are also optionally replaced by definitions of radicals which are independent of some other combination of the respective stated combinations of radicals.

Combinations of two or more of the above preferred ranges are particularly preferred.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of salts thereof, compounds of the following formulae encompassed by formula (I) and salts, solvates and solvates of salts thereof, and compounds encompassed by formula (I) and described below as examples and salts, solvates and solvates of salts thereof, with the proviso that the compounds encompassed by formula (I) and described below are not solvates of salts, solvates and salts yet.

The invention is also considered to encompass the use of salts of the compounds of the invention.

Salts in the context of the present invention are preferably physiologically harmless salts of the compounds of the invention. However, salts which are not suitable per se for pharmaceutical use but which can be used, for example, for isolating or purifying the compounds of the invention are also included.

Physiologically harmless salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfuric acid (sulfonic acid), for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

The invention also relates to pharmaceutical products comprising a compound according to the invention and at least one or more further active substances, in particular active substances for the prophylaxis and/or treatment of tumor diseases.

Solvates are defined in the context of the present invention as the form of the compounds of the present invention which form a complex in the solid or liquid state by complexation with solvent molecules. Hydrates are a special form of solvates in which complexation takes place with water. Within the context of the present invention, hydrates are preferred solvates.

Depending on the structure of the compounds of the invention, they may exist in various stereoisomeric forms, i.e. in the form of configurational isomers or optionally also in the form of conformational isomers. The asymmetric centers have the same configuration at position 6 of the compounds of the invention. Thus, when one or more of the substituents depicted in formula (I) comprise an additional asymmetric element (e.g. a chiral carbon atom), they may be in the form of pure diastereomers or mixtures thereof. Accordingly, the present invention also includes diastereomers and their respective mixtures. The pure diastereoisomers can be separated stereoisomerically from such mixtures in a known manner; preference is given to using chromatographic techniques for this, in particular HPLC chromatography in the achiral or chiral phase.

If the compounds of the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.

The invention also includes all suitable isotopic variations of the compounds of the invention. Isotopic variations of a compound of the present invention are intended to mean compounds wherein at least one atom in the compound of the present invention is exchanged with another atom of the same atomic number, but having a different atomic mass than that normally or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. particular isotopic variations of the compounds of the present invention, for example those into which one or more radioactive isotopes are incorporated, are useful, for example, in studying the mechanism of action or distribution of an active substance in vivo³H-or¹⁴The C-isotopically labelled compounds are relatively easy to prepare or detect and are particularly suitable for the above applications. Furthermore, due to the higher metabolic stability of the compounds, the introduction of isotopes (e.g., deuterium) may result in specific therapeutic benefits, such as a longer half-life in vivo or a reduction in the effective dosage required; thus, said modification of the compounds of the invention may also optionally represent a preferred embodiment of the invention. Isotopic variations of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods described below and according to the instructions provided in the examples, using isotopic modifications of the corresponding representative reagents and/or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" includes compounds that may themselves be biologically active or inactive, however, during their residence time in the body they are converted (e.g., by metabolism or hydrolysis) to the compounds of the invention.

The compounds of the invention may have systemic and/or local effects. For this purpose, they can be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, or in the form of implants or stents.

For these routes of administration, the compounds of the present invention may be administered in suitable dosage forms.

Dosage forms suitable for oral administration are those which act according to the prior art for rapid and/or modified release of the compounds of the invention, comprising the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example enteric coatings or coatings delaying dissolution or insoluble coatings which control the release of the compounds of the invention), tablets or films/wafers (ferwa) which disintegrate rapidly in the oral cavity, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out avoiding the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar spinal administration), or including the absorption step (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Dosage forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, sterile powders.

Suitable dosage forms for other routes of administration are, for example, pharmaceutical dosage forms for inhalation (including dry powder inhalation devices, nebulizers), nasal drops, solutions, sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (milk), pastes, foams, dusting powders, implants or stents.

The compounds of the present invention may be converted into the above-described dosage forms. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such excipients include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifying and dispersing agents or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) and flavouring and/or flavoring agents (odour correctants).

The invention also relates to pharmaceutical products comprising the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the above purposes.

The formulation of the compounds according to the invention for the preparation of pharmaceutical preparations is carried out in a manner known per se, in which the active substance or substances and the excipients customary in pharmaceutical manufacture are converted into the desired dosage form.

Excipients which can be used are, for example, carriers, fillers, disintegrants, binders, wetting agents, lubricants, absorbents and adsorbents, diluents, solvents, co-solvents (cosolvent), emulsifiers, co-solvents, flavoring agents (flavor correctants), colorants, preservatives, stabilizers, wetting agents, salts for varying the osmotic pressure or buffers.

Reference may be made to Remington's Pharmaceutical Science,15th ed. Mack publishing company, East Pennsylvania (1980).

The pharmaceutical formulation may be:

solid form: such as tablets, sugar-coated pills, suppositories, capsules, transdermal systems, or

Semi-solid form: such as ointments, creams, gels, suppositories, emulsions, or

Liquid forms, such as solutions, tinctures, suspensions or emulsions.

In the sense of the present invention, excipients can be, for example, salts, sugars (mono-, di-, tri-, oligo-and/or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, wherein the excipients can be of natural origin or can be obtained synthetically or partially synthetically.

For oral or peroral administration, tablets, sugar-coated pills, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions are particularly contemplated.

Suspensions, emulsions and in particular solutions come into consideration for parenteral administration.

The present invention relates to compounds of the present invention.

They are useful for the prophylaxis and treatment of diseases, in particular tumour diseases, in humans.

The compounds of the invention are particularly useful for inhibiting or reducing cell proliferation and/or cell division and/or inducing apoptosis.

The compounds of the invention are particularly suitable for the prophylaxis and/or treatment of hyperproliferative diseases, for example

-a treatment of psoriasis by applying a composition comprising a mixture of at least one of the following components,

keloid and other hyperplasias which attack the skin,

benign Prostatic Hyperplasia (BPH),

-a solid tumor, and

-hematological tumours.

Solid tumors treatable according to the invention are tumors such as the following: breast, respiratory tract, brain, reproductive organs, gastrointestinal tract, urogenital tract, eye, liver, skin, head and neck, thyroid, parathyroid, bone and connective tissue, and metastases of these tumors.

As hematological tumors, for example, the following are treatable:

-a plurality of myeloma cells,

-lymphoma, or

-leukemia.

As breast tumors, for example, the following are treatable:

breast tumors of positive hormone receptor status

Breast tumors of negative hormone receptor status

-Her-2 positive breast cancer

Hormone receptor and Her-2 negative breast cancer

-BRCA-associated Breast cancer

Inflammatory breast cancer

As digestive tract tumors, for example, the following are treatable:

-non-small cell bronchial carcinomas, and

small cell bronchial carcinoma

As brain tumors, for example, the following are treatable:

-a glioma tumor cell, a human glioma tumor cell,

-a cell-mediated,

-an astrocytoma and a tumor cell, wherein,

meningiomas, and

-medulloblastoma.

As male reproductive organ tumors, for example, the following are treatable:

-a prostate cancer cell,

-a malignant tumor of the epididymis,

malignant testicular tumors and

-penile cancer.

As female reproductive organ tumors, for example, the following are treatable:

-endometrial cancer

Cervical cancer

Ovarian cancer

Vaginal cancer

-cancer of the vulva

As gastrointestinal tumors, for example, the following are treatable:

-a cancer of the colon and rectum,

anal cancer

-gastric cancer

Pancreatic cancer

-cancer of the esophagus

Gallbladder cancer

Small bowel cancer

Salivary gland cancer

Neuroendocrine tumors

Gastrointestinal stromal tumors

As urogenital tumors, for example, the following are treatable:

-bladder cancer

Renal cell carcinoma

Cancer of the renal pelvis and lower urinary tract

As tumors of the eye, for example, the following are treatable:

retinoblastoma

Intraocular melanoma

As tumors of the liver, for example, the following are treatable:

-hepatocellular carcinoma

Cholangiocellular carcinoma

As skin tumors, for example, the following are treatable:

malignant melanoma

Basal cell carcinoma

-spine cell (primary-cell) carcinoma

Kaposi's sarcoma

Merkel cell carcinoma

As tumors of the head and neck, for example, the following are treatable:

-laryngeal carcinoma

Pharyngeal and oral cancer

As sarcoma, for example, the following are treatable:

-soft tissue sarcoma

-osteosarcoma

As lymphomas, for example, the following are treatable:

-non-hodgkin's lymphoma

Hodgkin's lymphoma

Cutaneous lymphomas

-lymphoma of the central nervous system

AIDS-related lymphoma

As leukemia, for example, the following are treatable:

acute myeloid leukemia

Chronic myelogenous leukemia

Acute lymphatic leukemia

-chronic lymphatic leukemia

-hairy cell leukemia

The compounds of the invention can be advantageously used for the prevention and/or treatment of leukaemia, in particular acute myeloid leukaemia, prostate cancer, in particular androgen receptor positive prostate cancer, cervical cancer, breast cancer, in particular hormone receptor negative breast cancer, hormone receptor positive breast cancer or BRCA-associated breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell bronchial carcinomas, endometrial cancer and colorectal cancer.

The compounds of the invention can be used with particular advantage for the prophylaxis and/or treatment of acute myeloid leukaemia, prostate cancer (in particular androgen receptor positive prostate cancer), cervical cancer, breast cancer (in particular estrogen- α -positive breast cancer and estrogen- α -negative breast cancer), multiple myeloma or melanoma.

The compounds of the invention are also suitable for the prophylaxis and/or treatment of benign hyperproliferative diseases, such as endometriosis, leiomyoma and benign prostatic hyperplasia.

The compounds of the invention are also suitable for the prophylaxis and/or treatment of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and/or bacterially induced sepsis.

The compounds of the invention are also suitable for the prophylaxis and/or treatment of inflammatory or autoimmune diseases, for example:

-pulmonary diseases accompanied by inflammatory, allergic and/or proliferative processes: chronic obstructive pulmonary disease of any origin, particularly bronchial asthma; bronchitis of various origins; all forms of restrictive lung disease, particularly allergic alveolitis; all forms of pulmonary edema, particularly toxic pulmonary edema; sarcoidosis and granulomatosis, in particular Burkholderia.

Rheumatic diseases/autoimmune diseases/joint diseases accompanied by inflammatory, allergic and/or proliferative processes: all forms of rheumatic diseases, especially rheumatismSexual arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; inflammatory soft tissue diseases of other origin; arthritic symptoms of degenerative joint disease (arthropathy); traumatic arthritis rash; collagen diseases of any origin, e.g. systemic lupus erythematosus (systemic lupus erythematosis), scleroderma, polymyositis, dermatomyositis, Sjogren: () Syndrome, Still (Still) syndrome, Felty (Felty) syndrome.

-allergies accompanied by inflammatory and/or proliferative processes: all forms of allergy, such as Quincke (Quincke) edema, pollinosis, poisonous insect sting, allergy to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis.

-vascular inflammation (vasculitis): systemic lymphangitis, temporal arteritis, erythema nodosum.

-dermatological diseases accompanied by inflammatory, allergic and/or proliferative processes: atopic dermatitis; psoriasis; pityriasis rubra pilaris; erythematous diseases triggered by various etiologies (e.g., radiation, chemicals, burns, etc.); bullous skin diseases; licheniform (lichenoid type) disease; itching; seborrheic eczema; rosacea; pemphigus vulgaris; exudative erythema multiforme; balanitis; vulvitis, hair loss such as alopecia areata; cutaneous T cell lymphoma.

-renal diseases accompanied by inflammatory, allergic and/or proliferative processes: nephrotic syndrome; all nephritis.

Liver diseases accompanied by inflammatory, allergic and/or proliferative processes: acute hepatocyte disintegration (dissociation); acute hepatitis of various origins (e.g., viral, toxic, drug-induced); chronic aggressive and/or chronic intermittent hepatitis.

Gastrointestinal disorders accompanied by inflammatory, allergic and/or proliferative processes: regional enteritis (crohn's disease); ulcerative colitis; gastritis; reflux esophagitis; gastroenteritis of other origin (e.g. coeliac disease).

Rectal diseases accompanied by inflammatory, allergic and/or proliferative processes: anal eczema; anal fissure; hemorrhoids; primary proctitis.

Ocular diseases accompanied by inflammatory, allergic and/or proliferative processes: allergic keratitis, uveitis, iritis, conjunctivitis; blepharitis; optic neuritis; choroiditis; sympathetic ophthalmia.

ENT diseases accompanied by inflammatory, allergic and/or proliferative processes: allergic rhinitis, pollinosis, otitis externa, e.g. due to contact eczema, infection; otitis media.

-neurological diseases accompanied by inflammatory, allergic and/or proliferative processes: cerebral edema, particularly tumor-induced cerebral edema; multiple sclerosis; acute encephalomyelitis, meningitis; various forms of seizures, such as the salaam seizure.

-hematological diseases accompanied by inflammatory, allergic and/or proliferative processes: acquired hemolytic anemia; idiopathic thrombocytopenia.

-neoplastic diseases accompanied by inflammatory, allergic and/or proliferative processes: acute lymphatic leukemia; malignant lymphoma; lymphogranulomatosis; lymphosarcoma; particularly in the extensive metastasis of breast, bronchial and prostate cancer.

Endocrine diseases accompanied by inflammatory, allergic and/or proliferative processes: endocrine orbital disease; thyroid toxicity crisis; de Quervain thyroiditis; hashimoto thyroiditis; barcelado disease.

Organ and tissue transplants, graft versus host disease

Severe shock, such as anaphylactic shock, Systemic Inflammatory Response Syndrome (SIRS).

-substitution therapy in: congenital primary adrenal insufficiency, such as congenital aporenal genital syndrome; acquired primary adrenocortical insufficiency, such as addison's disease, autoimmune adrenalitis, post-infection (postinfection), tumors, metastases, etc.; congenital secondary adrenal insufficiency, such as congenital hypopituitarism; acquired secondary adrenocortical insufficiency, such as after infection, tumor, etc.

Emesis accompanied by inflammatory, allergic and/or proliferative processes, for example in combination with a 5-HT3 antagonist in cytostatic-induced emesis.

Pain of inflammatory origin, such as lumbago.

The compounds of the invention are also suitable for the treatment of viral diseases, such as infections caused by papilloma virus, herpes virus, Epstein-Barr virus, hepatitis B virus or hepatitis C virus and human immunodeficiency virus.

The compounds of the invention are also suitable for the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disease, cardiovascular disease, angina pectoris, ischemia, stroke, myocardial infarction, restenosis following angioplasty (angioplastic), hypertension, thrombosis, obesity, endotoxemia.

The compounds of the invention are also suitable for the treatment of neurodegenerative diseases, such as multiple sclerosis, alzheimer's disease and parkinson's disease.

These diseases are well characterized in humans, but occur in other mammals as well.

The present invention relates to compounds of formula (I) according to the invention, in particular the following compounds:

-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-7-azaspiro [3.5 ]]Non-6-yl) ethan-1-one,

- (S) -1- (7-azabicyclo [ 2.2.1)]Hept-7-yl) -2- [ (6S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]The ethyl ketone is added into the mixture of the ethyl ketone,

- (S) -1- (2-azabicyclo [2, 2)]Oct-7-yl) -2- [ (6S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]An ethanone.

The invention also relates to compounds of the invention for use as a medicament, in particular for use as a medicament for the prophylaxis and/or treatment of tumor diseases.

The invention also relates to compounds of the invention for use in the prevention and/or treatment of leukemia, in particular acute myeloid leukemia, prostate cancer, in particular androgen receptor positive prostate cancer, cervical cancer, breast cancer, in particular hormone receptor negative breast cancer, hormone receptor positive breast cancer or BRCA-associated breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell bronchial carcinomas, endometrial cancer and colorectal cancer.

The invention also relates to a compound of the invention for use in the prevention and/or treatment of acute myeloid leukemia, prostate cancer (in particular androgen receptor positive prostate cancer), cervical cancer, breast cancer (in particular estrogen- α -positive breast cancer and estrogen- α -negative breast cancer), multiple myeloma or melanoma.

The invention also relates to the use of the compounds of the invention for the preparation of a medicament.

The invention also relates to the use of the compounds according to the invention for producing medicaments for the prophylaxis and/or treatment of tumor diseases.

The invention also relates to the use of the compounds according to the invention for the preparation of a medicament for the prophylaxis and/or treatment of leukaemia, in particular acute myeloid leukaemia, prostate cancer, in particular androgen receptor positive prostate cancer, cervical cancer, breast cancer, in particular hormone receptor negative breast cancer, hormone receptor positive breast cancer or BRCA-associated breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell bronchial carcinomas, endometrial carcinomas and colorectal cancers.

The invention also relates to the use of the compounds according to the invention for the preparation of a medicament for the prophylaxis and/or treatment of acute myeloid leukemia, prostate cancer (in particular androgen receptor positive prostate cancer), cervical cancer, breast cancer (in particular estrogen- α -positive breast cancer and estrogen- α -negative breast cancer), multiple myeloma or melanoma.

The invention also relates to the use of said compounds for the prophylaxis and/or treatment of tumor diseases.

The invention also relates to the use of the compounds according to the invention for the prophylaxis and/or treatment of leukaemia, in particular acute myeloid leukaemia, prostate cancer, in particular androgen receptor positive prostate cancer, cervical cancer, breast cancer, in particular hormone receptor negative breast cancer, hormone receptor positive breast cancer or BRCA-associated breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell bronchial carcinomas, endometrial cancers and colorectal cancers.

The invention also relates to the use of a compound of the invention for the prevention and/or treatment of acute myeloid leukemia, prostate cancer (in particular androgen receptor positive prostate cancer), cervical cancer, breast cancer (in particular estrogen- α -positive breast cancer and estrogen- α -negative breast cancer), multiple myeloma or melanoma.

The invention also relates to pharmaceutical formulations in the form of tablets comprising one of the compounds of the invention for the prevention and/or treatment of leukemia, in particular acute myeloid leukemia, prostate cancer, in particular androgen receptor positive prostate cancer, cervical cancer, breast cancer, in particular hormone receptor negative breast cancer, hormone receptor positive breast cancer or BRCA related breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell bronchial carcinoma, endometrial cancer and colorectal cancer.

The invention also relates to a pharmaceutical preparation in the form of a tablet comprising one of the compounds of the invention for use in the prevention and/or treatment of acute myeloid leukemia, prostate cancer (in particular androgen receptor positive prostate cancer), cervical cancer, breast cancer (in particular estrogen- α -positive breast cancer and estrogen- α -negative breast cancer), multiple myeloma or melanoma.

The invention also relates to the use of the compounds according to the invention for the treatment of diseases which are accompanied by proliferative processes.

The invention also relates to the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative diseases.

The compounds of the present invention may be used alone or, if desired, in combination with one or more other pharmacologically active substances, provided that the combination does not cause undesirable and unacceptable side effects. The invention therefore also relates to pharmaceutical products which comprise a compound according to the invention and one or more further active substances, in particular active substances for the prophylaxis and/or treatment of the abovementioned diseases.

For example, the compounds of the present invention may be used in combination with known anti-hyperproliferative, cytostatic, or cytotoxic substances for the treatment of cancer. It is specifically stated that the compounds of the invention are combined with other common substances for cancer therapy, or also with radiotherapy.

As suitable combined active substances we may mention for example:

everolimus (Afinitor), aldesleukin, alendronic acid, alpha-interferon (Alfaferone), alitretinoin, allopurinol, sodium allopurinol for injection (Aloprim), palonosetron hydrochloride (Aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasetron (Anzmet), alfa bepotastine injection (Aranesp), Arglabin, diarsene trioxide, exemestane tablet, 5-azacytidine, azathioprine, BCG or Tice, ubenimex (bestatin), betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, busulfan, calcitonin, alemtuzumab (Campath), capecitabine, carboplatin, bicalutamide, Cetrolene, Cetyline, clindamycin butyrate, melphalan, clindamycin hydrochloride, clindamycin chloride, phosphamide, altretamine, amisole, azalide, BCG, and so, Cytarabine, dacarbazine, actinomycin D, daunorubicin liposome citrate (DaunoXome), dicarbazone, dexamethasone sodium phosphate, estradiol valerate, dinebukin 2(denileukin diftitox), methylprednisolone, deslorelin, dexrazoxane, diethylstilbestrol, fluconazole, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprolide acetate (Eligard), Elitek, epirubicin hydrochloride (Ellence), aprepitant capsule (emide), epirubicin alpha (epoetin alfa), recombinant human erythropoietin (Epogen), platinum, levamisole, estradiol formulation (Estrace), estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, etidronic acid, etoposide injection, etoposide, favuzole, favudine, filgrastimide, finasterine, flutolidine, flutolbutamide, flutolflurocine, flutolbutamol, trolene, flutolbutamol, amitriptoretin, ethide, ethiprolide, ethidium, and other, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestan, Fosteabin, fotemustine, fulvestrant, gamma-globulin (Gamma-globulin), gemcitabine, gemtuzumab, gleevec, carmustine wafer capsule (Gliadel), goserelin, granisetron hydrochloride, histrelin, topotecan (hydroxycamtin), hydrocortisone, erythrohydroxynonyladenine (eyrthro-hydroxyynyladenine), hydroxyurea, temozolomide, idarubicin, ifosfamide, alpha interferon, alpha-2 alpha interferon, alpha-2 beta interferon, alpha-n 1 interferon, alpha-n 3 interferon, beta interferon, gamma-1 alpha interferon, interleukin-2, interferon alpha (Intron A), irfitinib tablet (Iressa), irinotecan, Granisetron injection, lapatinib, lentinan sulfate, letrozole, Leukorganonin, leuprorelin acetate, levamisole, calcium levofolinate (Levofolinic acid-calcium salt), levothyroxine sodium preparation (Levoxyl), lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin acetate, megestrol acetate, melphalan, esterified estrone tablets (Menest), 6-mercaptopurine, mesna, methotrexate, metivc, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trostan, Myocet, nedaplatin, pegylated filgrastim (Neulasta), recombinant human interleukin 11 (Neumegaga), YouUpaujin (Neogen), nimesulide, tamoxifen, NSE 43, OCT-631570, trexone, ORE platinum hydrochloride, Paclitaxel, paediatricred, pemetrexed, pyrosin, pentostatin, pisbanil (pivibanil), pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, bemeili, procarbazine, recombinant human erythropoietin alpha, raltitrexed, RDEA119, recombinant human interferon beta 1a injection (Rebif), regorafenib, rhenium-186-etidronate disodium (rhenium-186-etidronat), rituximab, roscovitine (Roferon-A), romotene, pilocarpine hydrochloride (Salagen), octreotide, sargrastim, semustine, Sizopyran, sobromazone, streptozocin, strontium chloride-89, levothyroxine sodium, tamicin, doxycycline, sotolone, testoterone, taxolone, docetaxel injection (docetaxel), docetaxel, tretinomycin), and paclitaxel, Teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoid, methotrexate (Trexall), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, vilizine, dexrazoxane (Zinecard), neat stastatin, ondansetron (Zofran), ABI-007, acobiprofen, interferon gamma-1 b (actimmune), affiniak, aminopterin, azoxifene, axolitinib, atamestane, atrasentan, BAY43-9006 (sorafenib), Avastin (CCI), avissin-779, valacycloxib, CDC, valacyclovir, doxylamine, dox, Cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, escitalopram, eflornithine, efaprotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166-DOTMP, ibandronic acid, gamma interferon, Intron-PEG, ixabepilone, keyhole limpet hemocyanin (keyhole lipped hemacyanin), L-651582, lanreotide, lasofoxifene, libra, farnesol protein transferase inhibitors (lonafarnib), mirtaoxifene, minodronic acid (minodronate), MS-209, MTP-PE liposomes, MX-6, nafarelin, neviracin, neovastat, nola tretinomycin, orlistat, ondo-TCS, oselta, paclitaxel, disodium pamidronate, PN-401, squam-21, qua-401, leucaspof R-1549, leucaspof, amphetamine, and leupeptin, Ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, erlotinib hydrochloride tablets (Tarceva), taxoprexin, alpha-1 thymosin, thiazolecarboxidine, tipifarnine, tirapazamine, TLK-286, toremifene, TransMID-107R, pentostatin, vapreotide, varenib, verteporfin, vinflunine, Z-100, zoledronic acid, and combinations thereof.

In a preferred embodiment, the composition of the invention may be combined with an anti-hyperproliferative agent, which may be for example (this list is not exhaustive):

aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, doxorubicin (doxorubicin hydrochloride for injection (Adriamycin)), epirubicin, epothilones and derivatives thereof, erythro-hydroxynonyladenine (erythro-hydroxyynyladenosine), ethinylol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil monophosphate, fluoromethyltestosterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, isocyclovir, interferon, moroxydisulfide, mordenin, doxycycline, and doxycycline, Irinotecan, leukorganol, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), plicamycin, prednisolone, prednisone, procarbazine, raloxifene, semustine, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine, and vinorelbine.

Desirably, the compounds of the invention can also be combined with biotherapeutics such as antibodies (e.g., Avastin, B cell monoclonal antibodies (Rituxan), erbitux, herceptin) and recombinant proteins.

The compounds of the invention may also achieve positive effects against angiogenesis in combination with other therapeutic agents (e.g., Avastin, axitinib, regorafenib, Recentin, sorafenib, or sunitinib). Due to its favourable side-effect profile, combination with proteasome inhibitors and inhibitors of mTOR as well as anti-hormonal agents and inhibitors of steroid metabolic enzymes is particularly suitable.

In general, the following objectives are achieved by combining the compounds of the present invention with other agents having a cell proliferation inhibitory or cytotoxic effect:

an increased effectiveness in slowing down tumor growth, reducing tumor size or even eliminating it completely, compared to treatment with a single active substance;

the possibility of using lower doses of chemotherapeutic agents than monotherapy;

the possibility of a better tolerated therapy with fewer side effects than the administration alone;

the possibility of treating a variety of neoplastic diseases;

higher rates of response to therapy are achieved;

longer survival time of patients compared to current standard therapy.

In addition, the compounds of the present invention may also be used in combination with radiation therapy and/or surgery.

1. Synthetic routes to compounds of formula (I)

Description of the Synthesis

It has been described that [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ]][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Synthesis of tert-butyl acetate (Nature 2010, Vol.468, p1067ff, P. Filippakoulos et al). The tert-butyl ester can be cleaved using a strong acid, such as trifluoroacetic acid or hydrochloric acid. The example compounds were then obtained by peptide coupling methods known to those skilled in the art. In these cases (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU) was used as a reagent. This is only an example of a reagent known to the person skilled in the art (J.American ChemSoc.1993,115, 4397). In WO1998/11111 it is described that the carboxylic acids used in the preparation of the compounds of the invention in each case R¹、R²And halogen variations. The esters obtained during synthesis are in racemic form and are separated into enantiomers by suitable separation methods. This is carried out using HPLC techniques familiar to the person skilled in the art, using a chiral stationary phase. Preferably, the respective tert-butyl esters are prepared and separated into their enantiomers.

Abbreviations and acronyms:

DMF N, N-dimethylformamide

DMSO-d6 deuterated dimethyl sulfoxide

DMSO dimethyl sulfoxide

HATU (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate

RP-HPLC reversed-phase high performance liquid chromatography

RT Room temperature

tert

NMP N-methylpyrrolidone

ACN acetonitrile

HCl hydrochloric acid

2. Preparation of comparative examples and examples

Starting compounds and intermediates:

precursor:

6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-8-onium hydrochloride

1.6g (3.5mmol) of [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] in 25ml of HCl][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]A solution of tert-butyl acetate in dioxane (4N) was stirred at room temperature overnight. The solvent was completely removed under vacuum to obtain 1.53g of the title compound in the form of a solid.

¹H-NMR(400MHz,RT,DMSO-d6):δ=1.6(s,3H),2.39(s,3H),2.61(s,3H),3.31(dd,1H),3.41(dd,1H),4.46(t,1H),4.56(bs),7.41(d,2H),7.47(d,2H)

Comparative example:

using [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ]][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Tert-butyl acetate (V1) was used as comparative compound.

The preparation of V1 is described in Nature 2010, Vol.468, p1067ff (P.Filippakopoulos et al).

Example (b):

example 1:

8- {2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetyl } -8-azabicyclo [3.2.1]Octan-3-ones

0.65g of 2HATU, 0.4ml of triethylamine and 221.7mg of 3-oxo-8-azoniabicyclo [3.2.1]Octane hydrochloride was added to 0.5g (1.14mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-8-onium hydrochloride in 10ml DMF, stirring at room temperature for 3 hours.Water was added and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The title compound was obtained after separation by silica gel chromatography (eluent: gradient dichloromethane/methanol) and RP-HPLC (XBridge C185 μm100x30mm, eluent: gradient water/acetonitrile, 0.2% saturated ammonia solution as additive). 0.22g of the title compound is obtained.

¹H-NMR(300MHz,RT,CDCl₃):δ=1.67(d,3H),1.70-2.40(m,5H),2.41(s,3H),2.43-2.56(m,1H),2.68(d,3H),2.77(bdd,1H),3.07(dd,1H),3.71(ddd and d,1H+1H),4.77-4.90(m,1.5H),4.90-5.03(m,1.5H),7.28-7.45(m,4H)

And (3) optical rotation: [ alpha ] to_D]=20.9 ° (methanol, c =1g/100ml)

Example 2:

2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) ethan-1-one

0.65g of HATU, 0.47ml of triethylamine and 0.2g of bis (2-oxa-6-azoniabicyclo [ 3.3%]Heptane) oxalate was added to 0.5g (1.14mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-8-onium hydrochloride in 12.5ml DMF, stirring at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. Silica gel chromatography (eluent: gradient dichloromethane/methanol) and RP-HPLC (Xbridge C185 μm100X30mm, eluent): gradient water/acetonitrile, 0.1% formic acid as additive) to yield the title compound. 0.13g of the title compound is obtained.

¹H-NMR(300MHz,RT,CDCl₃):δ=1.65(s,3H),2.39(s,3H),2.66(s,3H),3.24(dd,1H),3.41(dd,1H),4.2(s,2H),4.52(d,1H),4.68(t,1H),4.73-4.93(m,5H),7.32(d,2H),7.36(d,2H)

And (3) optical rotation: [ alpha ] to_D]=26.6 ° (methanol, c =1g/100ml)

Example 3:

(1R,5S) -3- ({2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetyl } amino) -9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl ester

0.39g of HATU, 0.19ml of triethylamine and 0.2g of (1R,5S) -3-amino-9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl ester was added to 0.3g (0.69mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-8-onium hydrochloride in 5ml DMF. The solution was poured into water to crystallize the title compound. Filtration and drying in vacuo then gave 0.35g of the title compound.

¹H-NMR (300MHz, RT, DMSO-d6, selected Signal). delta =1.38(s,9H),1.67(s,3H),1.72-1.94(m,3H),2.37(s,3H),2.55(s,3H),3.06-3.23(m,2H),4.14(bs,1H),4.45(t,1H),4.48-4.62(m,1H),7.38(d,2H),7.47(d,2H)

Example 4:

n- [ (1R,5S) -9-azabicyclo [3.3.1]Non-3-yl]-2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetamide

1ml of trifluoroacetic acid was added to 0.35g (0.56mmol) of 3- ({ [2- (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Acetyl } amino) -9-azabicyclo [3.3.1]A solution of tert-butyl nonane-9-carboxylate in 10ml of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated by evaporation in vacuo, water was added and made basic with saturated sodium carbonate solution. It was extracted with dichloromethane. The solvent was removed in vacuo and the residue was purified by RP-HPLC (XBridge C185 μm100x30mm, eluent: gradient water/acetonitrile, 0.1% formic acid as additive). The crude product was purified by silica gel chromatography (eluent: gradient hexane/ethyl acetate) to yield 12mg of the title compound.

¹H-NMR (300MHz, RT, DMSO-d6, selected Signal) δ =1.67(s,3H),1.60-1.72(m,3H),1.73-1.98(m,3H),2.38(s,3H),2.56(s,3H),3.06-3.35(m,6H),4.40-4.55(m,2H),7.38(d,2H),7.47(d,2H),7.99(d,1/3H),8.05(d,2/3H)

Example 5:

2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-Base of]-1- (8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) eth-1-one

0.199g of HATU, 0.15ml of triethylamine and 0.063g of 8-oxa-3-azabicyclo [3.2.1]Octane hydrochloride was added to 0.14g (0.35mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesA solution of the salt of (E) -8-onium acid in 3ml of DMF was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over sodium sulfate and the solvent was removed under vacuum. The title compound is obtained after separation by silica gel chromatography (eluent: gradient dichloromethane/methanol). 0.088g of the title compound was obtained.

¹H-NMR(300MHz,RT,CDCl₃):δ=1.67(s,3H),1.7-2.1(m,4H),2.39(s,3H),2.67(s,3H),3.01(t,1H),3.58(ddd,1H),3.52-3.63(m,2H),3.88(dd,1H),4.20(d,1H),4.42(bs,2H),4.82(t,1H),7.32(d,2H),7.40(dd,2H)

And (3) optical rotation: [ alpha ] to_D]=46.0°(CHCl₃,c=1g/100ml)

Example 6:

2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-6-azaspiro [ 3.4)]Oct-6-yl) eth-1-one

0.185g of HATU, 0.14ml of triethylamine and 0.044g of 2-oxa-6-azaspiro [3.4]Octane was added to 0.15g (0.35mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesA solution of the salt of (E) -8-onium acid in 5ml of DMF was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over sodium sulfate and the solvent was removed under vacuum. The title compound is obtained after separation by silica gel chromatography (eluent: gradient dichloromethane/methanol). 0.11g of the title compound is obtained.

¹H-NMR(300MHz,RT,DMSO-d6):δ=1.67(s,3H),2.09(t,1H),2.22(t,1H),2.37(s,3H),2.55(d,3H),3.20-3.35(m,2H),3.43(dd,1H),3.51(d,1H),3.65(dt,1H),3.90(dd,1H),4.43-4.54(m,4H),4.59(dd,1H),7.38(dd,2H),7.46(dd,2H)

And (3) optical rotation: [ alpha ] to_D]=30.5°(CHCl₃,c=1g/100ml)

Example 7:

2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-7-azaspiro [3.5 ]]Non-6-yl) ethan-1-one

0.185g of HATU, 0.14ml of triethylamine and 0.049g of 2-oxa-7-azaspiro [3.5]Nonane was added to 0.15g (0.35mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesA solution of the salt of (E) -8-onium acid in 5ml of DMF was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over sodium sulfate and the solvent was removed under vacuum. The title compound is obtained after separation by silica gel chromatography (eluent: gradient dichloromethane/methanol). 0.115g of the title compound is obtained.

¹H-NMR(300MHz,RT,DMSO-d6):δ=1.67(s,3H),1.63-1.71(m,2H),1.81-1.88(m,2H),2.38(t,3H),2.55(s,3H),3.33-3.41(m,3H),3.52(bt,2H),3.58(dd,1H),4.27-4.36(m,4H),4.52(t,1H),7.38(d,2H),7.45(d,2H)

And (3) optical rotation: [ alpha ] to_D]=37.8°(CHCl₃,c=1g/100ml)

Example 8:

(S) -1- (2-azabicyclo [2,2 ] S]Oct-2-yl) -2- [ (6S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Ethanones

0.124g of HATU, 0.12ml of triethylamine and 38.5mg of 2-azabicyclo [2,2 ]]Nonane hydrochloride was added to 100mg (0.22mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesA solution of the (E) -8-onium hydrochloride in 4.4ml of DMF was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over sodium sulfate and the solvent was removed under vacuum. Silica gel chromatography (eluent): gradient dichloromethane/methanol) to yield the title compound. 46mg of the title compound are obtained.

¹H-NMR(300MHz,RT,CDCl₃):δ=1.67(s,3H),1.63-1.78(m,6H),1.80-1.93(m,1H);1.95-2.08(m,2H);2.39(t,3H),2.66(s,3H),3.43-3.63(m,3H),3.81(dd,1H);4.37(d,1H);4.83(t,1H),7.32(dd,2H),7.40(d,2H)

Example 9:

(S) -1- (7-azabicyclo [ 2.2.1)]Hept-7-yl) -2- [ (6S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]Ethanones

0.124g of HATU, 0.12ml of triethylamine and 34.8mg of 7-azabicyclo [2,2,1]Heptane hydrochloride was added to 100mg (0.22mmol) of (S) -6- (carboxymethyl) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivativesA solution of the (E) -8-onium hydrochloride in 4.4ml of DMF was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic phase was washed with water and brine. It was dried over sodium sulfate and the solvent was removed under vacuum. The title compound is obtained after separation by silica gel chromatography (eluent: gradient dichloromethane/methanol). 50mg of the title compound are obtained.

¹H-NMR(400MHz,RT,CDCl₃):δ=1.42-1.63(s,4H),1.67(s,3H),1.74-1.90(m,2H),1.90-2.06(m,2H);2.39(t,3H),2.66(s,3H),3.56(d,2H);4.57(t,1H);4.68(t,1H);4.78(t,1H),7.31(dd,2H),7.39(d,2H)

3. Assay method

3.1 protein-protein interaction assay

Binding assay for BRD 4/acetylated peptide H4("PRQ

To evaluate the BRD4 binding strength of the substances described in the present application, their ability to dose-dependent inhibition of the interaction between BRD4 and acetylated histone H4 was quantified.

For this purpose, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay is used, which measures the N-terminal His₆-binding of labeled BRD4(1) (amino acids 44-168) and a synthetic acetylated histone H4(Ac-H4) peptide having the sequence grgk (Ac) ggk (Ac) glgk (Ac) ggak (Ac) rhgsk-biotin. Recombinant BRD4 protein (prepared internally) was expressed in e.coli (e.coli) and purified by (Ni-NTA) affinity chromatography and (Sephadex G-75) size exclusion chromatography. The Ac-H4 peptide is available, for example, from Biosyntan (Berlin, Germany)

In this assay, 11 different concentrations of each substance (0.1nM, 0.33nM, 1.1nM, 3.8nM, 13nM, 44nM, 0.15. mu.M, 0.51. mu.M, 1.7. mu.M, 5.9. mu.M and 20. mu.M) were measured in duplicate, usually on the same microplate. For this, 100-fold concentrated solutions in DMSO were prepared in clear 384-well microplates (Greiner Bio-One, Frickenhausen, Germany) by serial dilution (1:3.4) of 2mM stock solutions. From there, 50nl were transferred to a black assay plate (Greiner Bio-One, Frickenhausen, Germany). The assay was initiated by providing 2 μ l of a 2.5-fold concentrated solution of BRD4 (typically 10-50nM final concentration in a 5 μ l reaction volume) in aqueous assay buffer [50mM HEPES pH7.5, 50mM sodium chloride (NaCl), 0.25mM CHAPS, and 0.05% serum albumin (BSA) ] to the material in the assay plate. Then for pre-equilibration of the putative complex between BRD4 and the substance, a step of incubation at 22 ℃ for 10 minutes was performed. Then 3 μ l of a 1.67 fold concentrated solution (in assay buffer) consisting of Ac-H4 peptide (83.5nM) and TR-FRET detection reagent [16.7nM anti-6 His-XL665 and 3.34nM streptavidin cryptate (cryptate) (both from Cisbio Bioassays, Codolet, France) plus 668mM potassium fluoride (KF) ] was added.

The mixture was then incubated in the dark at 22 ℃ for one hour and then at 4 ℃ overnight. Formation of the BRD4/Ac-H4 complex was determined by measuring the resonance energy transfer from the streptavidin-Eu-cryptate to the anti-6 His-XL665 antibody present in the reaction. For this, the fluorescence emission at 620nm and 665nm is measured after excitation at 330-350nm in a TR-FRET meter, for example Rubystar or Pherastar (both from BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622nm is taken as an indication of the amount of BRD4/Ac-H4 complex formation.

The data obtained (ratio) were normalized, with 0% inhibition corresponding to the average of the measurements of a set of controls (typically 32 data points). All reagents were included in the control, using 50nl of DMSO (100%) instead of test substance. 100% inhibition corresponds to the average of the measurements of a set of controls (typically 32 data points) containing all reagents except BRD 4. Using Bayer's own analytical software, based on the 4-parameter equation (min, max, IC50, Hill; Y = max + (min-max)/(1 + (X/IC50)^Hill) IC50 values were determined by regression analysis.

3.2 cellular assay

Cell proliferation assay

According to the invention, the ability of a substance to inhibit the proliferation of a variety of cell lines is determined. By passingReagents (Invitrogen) determine cell viability. Cells were seeded at different densities (MOLM-13, LAPC-4, MDA-MB-231 and MOLP-8: 4000 cells/well; VCaP: 16000 cells/well; LNCaP: 2000 cells/well; MCF-7 and HeLa-MaTu: 1000 cells/well; B16F10:400 cells/well) in 100. mu.l growth medium in 96-well microplates. After overnight incubation at 37 ℃ the fluorescence value (CI value) was determined. The plates were then treated with multiple substance dilutions and incubated at 37 ℃ for 96 hours(MOLM-13, MCF-7, MDA-MB-231, HeLa-MaTu and B16F10 cells), 120 hours (MOLP-8 cells) or 168 hours (LAPC-4, VCaP and LNCaP cells). The fluorescence value (CO value) was then determined. For data processing, CI values were subtracted from CO values and the results of cells treated with dilutions of various substances or treated with buffer solution only were compared. From these results, IC50 values (concentration of the substance required to inhibit cell proliferation by 50%) were calculated.

Substances were studied in table 1, for example in cell lines representing the indications:

TABLE 1

3.3 determination of plasma protein binding by equilibrium dialysis

Binding of the test substance to plasma proteins was determined by equilibrium dialysis using an Ht-dialyzer (96 wells) made of Teflon and a semipermeable membrane (regenerated cellulose, MWCO 12-14K). This separated 150. mu.l of each plasma assay and buffer side (50mM phosphate buffer). The test substance was added to the plasma side at 2 concentrations (typically 3 μ M and 0.3 μ M) and bound to plasma proteins. Unbound fraction of the test substance passes through the membrane and is distributed on each side until equilibrium is reached (after about 6-8h at 37 ℃). The buffer side and plasma measured substance concentrations were determined by LC-MS analysis. For this, the same matrix (10% plasma) was flanked by dilutions of buffer or plasma, followed by precipitation with methanol. The free (unbound) fraction (fu) was calculated from the quotient of the buffer and plasma concentrations (quotient). Stability tests and recovery tests were performed simultaneously as controls. In addition, the material in the buffer was dialyzed against the buffer to check for non-specific binding to the instrument and membrane and to establish equilibrium. Since the osmolarity of the plasma proteins causes a dilution of the plasma (volume change) during the incubation, this possible error is determined by weighing a blank plasma sample and included in the calculation of fu. The establishment of the equilibrium and the plasma stability should have values not lower than 80% and the recovery should be at least 30%. The free fraction <1% was considered high plasma protein binding, 1-10% was considered medium plasma protein binding and >10% was considered low plasma protein binding.

3.4 determination of plasma concentrations from in vivo assays and calculation of PK parameters (by PK calculation software, e.g.)

The ACN + internal standard (1:5(v/v)) was added to the mouse plasma obtained at the appropriate time point after administration of the active substance, shaken and frozen at-20 ℃ for approximately 12 hours (overnight). It was thawed and shaken, and then the sample was centrifuged at 4 ℃ for 20 minutes, and approximately 2000x g. An aliquot of the supernatant (approximately 25 μ L) was measured by LC-MS analysis. If high plasma or tissue levels are expected (>ULOQ, typically 5. mu.M), the pellet sample was additionally treated with ACN/H₂The O (80/20, v/v) + internal standard was diluted 1:100 and the corresponding aliquots were measured by LC-MS. For this, the test substances are added to the control matrix (calibration samples) at 5 to 9 concentrations corresponding to the assay range of the assay method, for example 0nM, 1nM, 10nM, 100nM, 1000nM, 5000 nM. For this, a portion of the solid is weighed and dissolved in DMSO (typically a 1mM stock solution). The stock solution was further diluted 1:10 with DMSO (100. mu.M). Then 1:5(v/v) ACN + internal standard (soln.a) was added to the calibration sample and further processed as with plasma samples. A calibration series in solution was performed similarly to the plasma calibration. In this case, at ACN/H₂Test substances were prepared in O (50/50, v/v) and then 1:5(v/v) ACN + internal standard was added to the samples. This series was used to calibrate the diluted samples. From these obtained concentration-time curves, the following PK parameters were calculated:

AUC_(0-tstart)：

Integrated area under the plasma concentration-time curve from time 0 to the last time point of investigation at which plasma concentrations were measurable (e.g. 24 h).

t last:

plasma concentrations were measurable at the last time point of study (e.g., 24 h).

AUC_{(0-t last), norm}：

The integrated area under the plasma concentration-time curve from time 0 to the last time point in the study (e.g., 24h) at which plasma concentrations were measurable, divided by the dose normalized to body weight (in kg x L/h).

AUC_{(0-t last), norm, u}：

AUC_{(0-t last), norm}Multiplied by the free fraction (fu) of the species studied.

3.5 in vivo tolerability in mice

The material was formulated in NMP/PEG300 (1/9V/V). They were administered orally to female NMRI nude mice (6-8 weeks old; 3 animals per group) in an amount of 10ml/kg, once or twice daily for a period of 5-7 days. The dosages and dosage schedules for the individual substances are shown in the table. Mice were monitored daily for body weight and mortality until the end of the study. Toxicity is defined as follows: greater than or equal to 10% substance-induced death or greater than or equal to 20% weight loss.

3.6 in vivo antiproliferative Activity

3.6.1MOLM-13 acute monocytic leukemia tumor model

On day 0, NMRI nude mice were inoculated subcutaneously on the right side 2x10 in 0.1ml Matrigel⁶MOLM-13 cells. On day 3 post tumor inoculation, treatment with comparative example V1 and example 1 or 2 was started. Comparative example V1 was dissolved in 20% HP β cyclodextrin in saline (0.2% NaCl in water). Example 1 and example 2 were dissolved in 40% PEG400, 5% ethanol, 25% Solutol. The material was administered orally daily for 11 days (days 3-14). Comparative example V1 was administered at a dose of 70mg/kg (maximum tolerated dose) or 40mg/kg per day. Examples 1 and 2 were administered at a dose of 200 (highest dose used), 120 or 70mg/kg per day.

3.6.2B16F10 melanoma tumor model

0.5X10 in 0.1ml of medium on day 0⁶Cells were seeded subcutaneously on the right side of C57BL/6 mice. On day 2 post tumor inoculation, treatment with comparative example V1, example 2 was started. Comparative example V1 was dissolved in 20% HP β cyclodextrin in saline (0.2% NaCl in water) and example 2 was dissolved in 40% PEG400, 5% ethanol, 25% Solutol. The material was administered orally for 10 days (days 2-11). Comparative example V1 was administered at a dose of 70mg/kg (maximum tolerated dose) or 55 mg/kg. Example 2 was administered at a dose of 160mg/kg or 120 mg/kg.

4. As a result:

4.1 binding assays

Table 2 shows the results of the binding assay.

TABLE 2

4.2 cellular assay

Tables 3a, 3b and 3c show the results of the cell proliferation assay.

TABLE 3a

TABLE 3b

TABLE 3c

4.3 determination of plasma protein binding by equilibrium dialysis

Table 4 shows the results of the plasma protein binding assay

TABLE 4

Examples	Protein binding, given as% fu
		V1	1.5
1	12
		2	25

4.4. Plasma concentrations determined from in vivo assays and PK parameters (by PK calculation software, e.g.))

Table 5 shows the plasma concentrations determined in the in vivo test (mouse) and table 6 shows the pharmacokinetic parameters determined.

TABLE 5

TABLE 6

		1	2	V1
					Dosage form	(mg/kg)	100	50	60
AUC_{(0-t last).}	(mg*h/kg)	4.9	10	7.1
					t last	(h)	24	6.0	7.0
AUC_{(0-t last), norm}	(kg*h/L)	0.05	0.20	0.12
					fu	(%)	12	25	1.5
AUC_{(0-t last), norm, u}	(kg*h/L)	0.006	0.050	0.002

AUC_{(0-t last), norm, u}It is shown that examples 1 and 2 of the present invention have higher unbound exposure in the effective species mice after a single oral administration compared to comparative example V1. Thus, there is a higher dose-normalized free plasma concentration in mice, such that an increased effectiveness in mice is expected at the same dose.

4.5 in vivo tolerability in mice

Table 7 shows the results of the in vivo tolerability test (mice).

The comparative substance V1 was tolerated at a dose of 100mg/kg per day for 7 days. The highest weight loss (10%) was obtained on day 9 of the treatment. Twice daily dosing of 100mg/kg of substance was not tolerated, since 2 substance-induced deaths were observed on day 6 of the treatment. The maximum tolerated treatment dose (MTD) after 5 days was 50mg/kg twice daily and the maximum weight loss was 7% on day 6.

Examples 1 and 2 were well tolerated at all doses tested administered once or twice daily. The maximum tolerated treatment dose is more than or equal to 200mg/kg per day or more than or equal to 100mg/kg twice per day after treatment for 5 days. The body weight loss was less than 3% in all groups.

In conclusion, examples 1 and 2 showed better tolerability in mice than comparative substance V1. The maximum tolerated therapeutic dose per day for a single treatment was ≥ 200mg/kg for examples 1 and 2 and 100mg/kg for comparative substance V1. The maximum tolerated treatment dose in the twice daily administration was ≥ 100mg/kg for examples 1 and 2 and 50mg/kg for the comparative substance V1.

TABLE 7

MTD = maximum tolerated treatment dose, HDT = maximum tested dose

4.6 in vivo antiproliferative Effect

4.6.1MOLM-13 acute monocytic leukemia tumor model

Increase in animal body weight during the study. There were 1 unexplained deaths in the group treated with example 2.

The highest dose of comparative example V1 was biologically active because 20% T/C was measured on day 14. The low dose was inactive and had a T/C value of 54%. The highest dose of example 1 (200mg/kg) inhibited tumor growth (39% T/C value), the 120mg/kg dose also showed activity (46% T/C value), and the lowest dose was inactive (58% T/C value). The highest dose of example 2 (200mg/kg) was active and had a T/C value of 23%. Lower doses (120mg/kg and 70mg/kg) also showed an effect on tumor growth (T/C value 46%), but these were not statistically significant. Statistical significance was defined as P < 0.05.

4.6.2B16F10 melanoma tumor model

Treatment with comparative example V1 resulted in a weight loss of 6% or 2% at a dose of 160mg/kg or 120mg/kg, respectively. Treatment with example 2 resulted in a weight loss of 5% or 2% at a dose of 160mg/kg or 120mg/kg, respectively. One (12 out) mouse died on day 12 in both groups treated with comparative example V1. In the group treated with 70mg/kg of example 2, one mouse with a weight loss higher than 20% had to be sacrificed on day 10. For the highest dose of both substances, the treatment had to be stopped for some days, since some mice showed a weight loss higher than 10%. The highest tolerated dose (MTD) was 55mg/kg for comparative example V1 and 120mg/kg for example 2. At these doses, both substances were significantly active. Comparative example V1 exhibited a T/C value of 33% and example 2 exhibited a T/C value of 27%.

Claims

1. A compound of formula (I) and diastereomers, racemates and physiologically compatible salts thereof:

wherein

Or

X represents a bond, and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

R^S2And R^S1Together form keto-C (O) -,

or

(ii) May contain a keto group-C (O) -, and

R^b1and R^b2Represents hydrogen, or

wherein R is³、R⁴、R⁵、R⁶And/or R⁷Independently of each other, hydrogen and C₁-C₆Alkyl or C₁-C₆Alkoxy or a group-C (O) -R⁸，R⁸Is represented by C₁-C₆Alkyl radicalOr C₁-C₆An alkoxy group,

with the proviso that,

or

and is

2. A compound of formula (I) according to claim 1, and diastereomers, racemates and physiologically compatible salts thereof, characterized in that:

x represents a bond, and Y represents a nitrogen atom.

3. A compound of formula (I) according to claim 1, and diastereomers, racemates and physiologically compatible salts thereof, characterized in that:

R¹and R²Represents a methyl group.

4. A compound of formula (I) according to claim 1, and diastereomers, racemates and physiologically compatible salts thereof, characterized in that:

R^S2and R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated heterocyclic ring containing 4-to 6-membered oxygen as a heteroatom, optionally substituted by halogen, hydroxyl and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy radicals being substituted identically or differentlyOne or more times.

5. A compound of formula (I) according to claim 1, and diastereomers, racemates and physiologically compatible salts thereof, characterized in that:

R^b1and R^b2Represents hydrogen, or

R^b1And R^b2Formation of bridge-CHR⁶-CHR⁷-，

6. Compounds of formula (I) and diastereomers, racemates and physiologically compatible salts thereof,

wherein

Or

X represents a bond, and Y represents a nitrogen atom, or

X represents an-NH-group and Y represents a-CH-group, and

R¹and R²Is represented by C₁-C₃Alkyl radical, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

As defined for the compounds of formula (I) according to the claims, if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S1and R^S1Represents hydrogen, or

R^S2And R^S1Together form keto-C (O) -, or

R^S2And R^S1And R^S1And R^S2The carbon atoms to which they are attached together form a saturated 4-to 6-membered carbocyclic ring or a heterocyclic ring with oxygen as heteroatom, which may optionally be substituted by halogen, hydroxy and/or by C₁-C₃Alkyl and/or C₁-C₃Alkoxy radicals being substituted identically or differently, once or moreThen, and

R^b1and R^b2Represents hydrogen, or

with the proviso that,

or

R is as defined for the compounds of formula (I) according to the claims^b1And R^b2A bridge is formed, and the bridge is formed,

or

and is

7. Compounds of formula (I) and diastereomers, racemates and physiologically compatible salts thereof,

wherein

X represents a bond, and Y represents a nitrogen atom, an

R¹And R²Represents a methyl group, and

m is 0 or 1, and

n is 0 or 1, and

o is 0 or 1, and

p is 0 or 1, and p is,

wherein

Such as according toThe present claims are defined for compounds of the formula (I) if R^b1And R^b2Form a bridge, the sum of m, n, o and p is at least 2, and

R^S2and R^S1Together form keto-C (O) -, or

R^b1and R^b2Represents hydrogen, or

R^b1And R^b2Formation of bridge-CHR⁶-CHR⁷-，

with the proviso that,

or

and is

8. Compound (I)

2- [ (S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]-1- (2-oxa-6-azaspiro [ 3.4)]Oct-6-yl) ethan-1-one,

- (S) -1- (2-azabicyclo [2, 2)]Oct-2-yl) -2- [ (6S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f][1,2,4]Triazolo [4,3-a][1,4]Diaza derivatives-6-yl]An ethanone.

9. A compound according to any one of claims 1 to 8 for use as a medicament.

10. The compound of claim 9, which is useful for the prophylaxis and/or treatment of tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative diseases.

11. A compound according to claim 10 for use in the prevention and/or treatment of acute myeloid leukaemia, prostate cancer, cervical cancer, breast cancer, multiple myeloma or melanoma.

12. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament.

13. Use of a compound of formula (I) according to claim 12 for the preparation of a medicament for the prophylaxis and/or treatment of tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative diseases.

14. The use according to claim 13 for the preparation of a medicament for the prophylaxis and/or treatment of acute myeloid leukemia, prostate cancer, cervical cancer, breast cancer, multiple myeloma or melanoma.

15. Use of a compound of formula (I) according to any one of claims 1 to 8 for the prophylaxis and/or treatment of diseases in humans or some other mammals.

16. Use according to claim 15 for the prophylaxis and/or treatment of tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative diseases.

17. Use according to claim 16 for the prevention and/or treatment of acute myeloid leukaemia, prostate cancer, cervical cancer, breast cancer, multiple myeloma or melanoma.

18. A compound of formula (I) according to any one of claims 1 to 8 in combination with other active substances.

19. A pharmaceutical formulation comprising a compound of formula (I) according to any one of claims 1 to 8.