EP2536686A1

EP2536686A1 - Cyclic keto-enols for therapy

Info

Publication number: EP2536686A1
Application number: EP11702063A
Authority: EP
Inventors: Ningshu Liu; Kai Thede; Philip Lienau; Arne Scholz; Christoph-Stephan Hilger; Ulf Bömer; Maher Najjar; Knut Eis; Reiner Fischer; Wahed Ahmed Moradi
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2010-02-15
Filing date: 2011-02-08
Publication date: 2012-12-26
Also published as: CA2789551A1; DE102010008644A1; UY33219A; TW201130489A; WO2011098433A1; US20130040935A1; JP2013519639A; CN102844300A

Abstract

The invention relates to 5'-biphenyl substituted cyclic keto-enols of formula (I) for therapeutic purposes, to pharmaceutical agents and to the use thereof in therapy, in particular for prophylaxis and therapy for tumor illnesses.

Description

Cyclic ketoenols for therapy

The present invention relates to 5 ^{'-biphenyl-substituted} cyclic ketoenol to

therapeutic purposes, pharmaceutical agents and their use in therapy, in particular for the prophylaxis and / or therapy of tumor diseases.

Acetyl-CoA carboxylases (ACCs) play a key role in cellular fatty acid homeostasis. ACCs are biotin-containing enzymes that catalyze the carboxylation of acetyl-CoA to malonyl-CoA in an ATP-dependent manner (Kim, 1997, Harwood, 2005, Tong, 2005). This reaction, which runs as two half reactions, a biotin carboxylase (BC) reaction and a carboxyl transferase (CT) reaction, is the first preliminary step in fatty acid biosynthesis and is the rate-limiting step for the pathway.

Two human ACC isoforms are known, ACC1 and ACC2, which are encoded by two different genes (LuTFI ABU-ELHEIGA et al, 1995, Jane WIDMER, et al., 1996). ACC1 is expressed in lipogenic tissue (liver, adipose tissue), located in the cytosol, and fills the malonyl-CoA pool, which serves as a C2 unit donor for the de novo synthesis of long-chain fatty acids by FASN and subsequent chain extension. ACC2 is primarily expressed in oxidative tissues (liver, heart, skeletal muscle) (Bianchi et al., 1990, Kim, 1997), associated with the mitochondria, and regulates a second pool of malonyl-CoA. This controls fatty acid oxidation by inhibiting carnitine palmiyltransferase I, the enzyme that facilitates entry of long-chain fatty acids into the mitochondria for β-oxidation (Milgraum LZ, et al., 1997, Widmer J. et al., 1996). Both enzymes show a very large sequence homology and are similarly regulated by a combination of transcriptional, translational and prosttranslational mechanisms. In humans as well as in animals, ACC activity is strictly controlled by a variety of dietary, hormonal, and other physiological mechanisms such as forward allosteric citrate activation, long chain fatty acid feedback inhibition, reversible phosphorylation, and / or

Inactivation or modulation of enzyme production by altered gene expression. ACC1 knockout mice are embryonic lethal (Swinnen, et al., 2006, Abu-Elheiga, et al., 2005). ACC2 knockout mice show reduced malonyl-CoA levels in skeletal and cardiac muscle, increased fatty acid oxidation in muscle, decreased liver fat levels, decreased levels

Total body fat, increased levels of UCP3 in skeletal muscle (as a sign of increased

Energy consumption), decreased body weight, reduced levels of plasma free fatty acids, decreased plasma glucose levels, decreased levels of glycogen in the tissues and are protected from diet-induced diabetes and obesity (Abu-Elheiga et al., 2001, 2003 Oh et al., 2005).

In addition to involvement in fatty acid synthesis in lipogenic tissues and the Fatty acid oxidation in oxidative tissues, up-regulation of ACC and increased lipogenesis has been observed in many tumor cells (Swinnen, et al., 2004, Heemers, et al., 2000, Swinnen, et al., 2002, Rossi, et al., 2003, Milgraum, et al., 1997, Yahagi, et al., 2005). This phenotype most likely contributes to the development and progression of tumors, but the regulatory mechanisms for this have yet to be clarified.

EP0454782 and US5759837 protect the use of fatty acid synthesis inhibitors to inhibit tumor cell growth. Cyclic ketoenols are not revealed. A number of substances have been discovered that are capable of inhibiting plants and / or insect ACC.

PCT patent application PCT / EPP99 / 01787, published as WO 99/48869 corresponding to European patent EP 1 066 258 B1, relates to novel arylphenyl-substituted cyclic ketoenols, to a majority of the processes for their preparation and their use as Pesticides and herbicides.

Pharmaceutical properties of 3-acyl-pyrrolidine-2,4-diones are described above (S. Suzuki et al., Chem. Pharm. Bull., 1120 (1967)). Furthermore, N-phenylpyrrolidine-2,4-diones were synthesized by R. Schmierer and H. Mildenberger (Liebigs Ann. Chem. 1985, 1095). Biological activity of these compounds has not been described.

EP-A-0 262 399 and GB-A-2 266 888 disclose similarly structured compounds (3-aryl-pyrrolidine-2,4-diones), of which, however, no herbicidal, insecticidal or acaricidal activity has become known , Unsubstituted, bicyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-355 599, EP-A-415 211 and EP-A-415 211) are known to have herbicidal, insecticidal or acaricidal activity

JP-A-12-053 670) and substituted monocyclic 3-aryl-pyrrolidine-2,4-dione derivatives (EP-A-377 893 and EP-A-442 077).

Also known are polycyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-442 073) and 1H-arylpyrrolidine-dione derivatives (EP-A-456 063, EP-A-521 334, EP-A- 596,298, EP-A-613,884, EP-A-613,885, WO 95/01 971, WO 95/26954, WO 95/20 572, EP-A-0 668 267, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36 868, WO 97/43275, WO 98/05638, WO 98/06721, WO 98/25928, WO 99/24437, WO 99 / 43649, WO 99/48869, WO 99/55673,

WO 01/17972, WO 01/23354, WO 01/74770, WO 03/013249, WO 03/062244, WO 2004/007448, WO 2004/024 688, WO 04/065366, WO 04/080962, WO 04/111042 , WO 05/044791,

WO 05/044796, WO 05/048710, WO 05/049569, WO 05/066125, WO 05/092897,

WO 06/000355, WO 06/029799, WO 06/056281, WO 06/056282, WO 06/089633,

WO 07/048545, DEA 102 00505 9892, WO 07/073856, WO 07/096058, WO 07/121868, WO 07/140881, WO 08/067873, WO 08/067910, WO 08/067911, WO 08/138551,

WO 09/015801, WO 09/039975, WO 09/049851, WO 09/115262, WO10 / 16161, WO 10/063378,

WO 10/063670, WO10 / 063380, WO10 / 066780 and WO10 / 102758. In addition, ketal-substituted 1H-arylpyrrolidine-2,4-diones from WO 99/16748 and (spiro) - ketalsubstituted N-alkoxy-alkoxy-substituted aryl-pyrrolidinedione from JP-A-14 205 984 and Ito M. et al. Bioscience, Biotechnology and Biochemistry 67, 1230-1238, (2003). In addition, WO 06/024411 discloses herbicidal compositions containing ketoenols. It is known that certain substituted have herbicidal properties (see DE-A-4 014 420). The synthesis of the tetronic acid derivatives used as starting compounds (such as, for example, 3- (2-methylphenyl) -4-hydroxy-5- (4-fluorophenyl) -Al-dideydrooftiranone- (2)) is likewise described in DE-A- 4 014 420. Similarly structured compounds without indication of an insecticidal and / or acaricidal activity are known from the publication Campbell et al., J.Chem.Soc, Perkin Trans. 1, 1985, (8) 1567-76. Furthermore, 3-aryl-A ^ -dihydrofuranone derivatives having herbicidal, acaricidal and insecticidal properties are known from EP-A-528 156, EP-A-647 637, WO 95/26 954, WO 96/20 196, WO 96 No. 25/395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36868, WO 98/05638, WO 98/06 721, WO 99/16748, WO 98/25 928, WO 99/43 649, WO 99/48 869, WO 99/55 673, WO 01/23354, WO 01/74 770, WO 01/17972, WO 04/024 688, WO 04/080 962, WO 04/111 042, WO 05/092 897, WO 06/000 355, WO 06/029 799, WO 07/048545, WO 07/073856, WO 07/096058, WO 07/121868, WO 07/140881, WO 08 / 067911, WO 08/083950, WO 09/015801, WO09 / 039975 and PCT / EP2010 / 003020. Also 3-aryl-A ³ -dihydrothiphen-on derivatives are known from (WO 95/26 345, 96/25 395,

WO 97/01 535, WO 97/02 243, WO 97/36868, WO 98/05638, WO 98/25928, WO 99/16748, WO 99/43649, WO 99/48869, WO 99/55673, WO 01 / 17972, WO 01/23354, WO 01/74770, WO 03/013249, WO 04/080 962, WO 04/111 042, WO 05/092897, WO 06/029799 and

WO 07/096058.

Certain phenyl-pyrone derivatives unsubstituted in the phenyl ring have already been disclosed (compare AM Chirazi, T. Kappe and E. Ziegler, Arch. Pharm. 309, 558 (1976) and K.H. Boitze and K. Heidenbluth, Chem. Ber. 9J, 2849). Phenyl-pyrone derivatives having herbicidal, acaricidal and insecticidal properties which are substituted in the phenyl ring are described in EP-A-588 137, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97 / 16,436, WO 97/19941, WO 97/36868, WO 98/05638, WO 99/43649, WO 99/48869, WO 99/55673, WO 01/17972, WO 01/74770, WO 03/013249 , WO 04/080 962, WO 04/111 042, WO 05/092897, WO 06/029799 and

WO 07/096058. Certain 5-phenyl-1,3-thiazine derivatives unsubstituted in phenyl have already been disclosed (see E. Ziegler and E. Steiner, Monatsh., 95, 147 (1964), R. Ketcham, T. Kappe and E. Ziegler, J. Heterocycl Chem 10, 223 (1973)). In the phenyl ring substituted 5-phenyl-l, 3-thiazine derivatives having herbicidal, acaricidal and insecticidal activity are described in WO 94/14785,

WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/02 243, WO 97/36868, WO 99/43649, WO 99/48869, WO 99/55673 WO 01/17972, WO 01/74770, WO 03/013249, WO 04/080 962, WO 04/1 11 042, WO 05/092897, WO 06/029799 and WO 07/096058.

It is known that certain substituted 2-arylcyclopentanediones possess herbicidal, insecticidal and acanzidal properties (cf., for example, US Pat. Nos. 4,283,348, 4,338,122, 4,436,666, 4,526,723, 4,551,547, 4,632,698, WO WO 96/03366, WO 97/14667 and WO 98/39281, WO 99/43649, WO99 / 48869, WO 99/55673, WO 01/17972, WO 01/74770, WO 03/062244 , WO 04/080962, WO04 / 11042, WO05 / 092897, WO06 / 029799, WO07 / 080066, WO07 / 096058, WO09 / 019005, WO09 / 019015, WO09 / 049851, WO10 / 069834, WO10 / 000773, WO10 / 057880, WO 10/081894, WO 10/089210, WO 10/102848 and WO 10/133232 Furthermore, similarly substituted compounds are known; 3-hydroxy-5,5-dimethyl-2-phenylcyclopent-2-en-1-one from the publication Micklefield et al., Tetrahedron, (1992), 7519-26 and the natural product Involutin (-) - cis- 5- (3,4-dihydroxyphenyl) -3,4-dihydroxy-2- (4-hydroxyphenyl) cyclopent-2-en-one from Edwards et al., J. Chem. Soc., S, (1967), 405-9. No insecticidal or akanzide effect is described em is 2- (2,4,6-trimethylphenyl) -l, 3-indanedione from J. Economic Entomology, 66, (1973), 584 and DE-A

2 361 084, with indication of herbicidal and acaricidal effects.

It is known that certain substituted 2-arylcyclohexanediones possess herbicidal, insecticidal and acaricidal properties (US 4,175,135, 4,256,657, 4,256,658, 4,256,659, 4,257,858, 4,283,348, 4,303,669, 4,351 666, 4 409 153, 4 436 666, 4 526 723, 4 613 617, 4 659 372, DE-A 2 813 341, and Wheeler, TN, J. Org. Chem. 44, 4906 (1979)), WO 99 / 43649,

WO 99/48869, WO 99/55673, WO 01/17972, WO 01/74770, WO 03/013249, WO 04/080 962, WO 04/1 11 042, WO 05/092897, WO 06/029799, WO 07 / 096058, WO 08/071405,

WO 08/110307, WO 08/110308, WO 09/074314, WO 08/145336, WO 09/015887, WO09 / 074314, WO 10/046194, WO 10/081755, and WO10 / 089211.

It is known that certain substituted 4-aryl-pyrazolidine-3,5-diones have acaricidal, insecticidal and herbicidal properties (see for example WO 92/16510, EP-A-508 126, WO 96/1 1 574,

WO 96/21 652, WO 99/47525, WO 01/17351, WO 01/17352, WO 01/17353, WO 01/17972, WO 01/17973, WO 03/028 466, WO 03 / 062 244, WO 04/080 962, WO 04/1 11 042, WO 05/005428, WO 05/016873, WO 05/092897, WO 06/029799 and WO 07/096058.

It is known that certain tetrahydropyridones have herbicidal properties (JP 0832530). In addition, special 4-hydroxytetrahydropyridones with acaricides, insecticides and herbicidal properties are known (JP 11152273). Also known were 4-hydroxytetrahydropyridones as pesticides and herbicides in WO 01/79204 and

WO 07/096058. 4-hydroxy-quinolones are disclosed in WO 03/01045.

It is known that certain 5,6-dihydropyrone derivatives have antiviral properties as protease inhibitors (WO 95/14012). Furthermore, 4-phenyl-6- (2-phenethyl) -5,6-dihydropyron is known from the synthesis of kawalactone derivatives (Kappe et al., Arch. Pharm. 309, 558-564 (1976) 6-dihydropyron derivatives are known as intermediates (White, JD, Brenner, JB, Deinsdale, MJ, J.Amer.Chem.Soc.93, 281-282 (1971), 3-phenyl-5,6-dihydropyrone derivatives with applications in crop protection are described in WO 01/98288 and WO 07/09658.

4'-biphenyl-substituted tetronic acid derivatives are disclosed in WO 2008/022725 for the therapy of viral diseases. WO 2005/089118 and WO2007 / 039286 disclose genetically nitrogen-containing bicyclic

Structures for the therapy, wherein 5'-biphenyl-substituted cyclic ketoenols are not specifically mentioned.

4-phenyl-substituted [1.2] oxazine-3,5-diones are described as herbicides for the first time in WO 01/17972. Furthermore, 4-acyl-substituted [1.2] oxazine-3,5-diones have been described as pesticides, but especially as herbicides and growth regulators, e.g. in EP-A-394889; WO 92/07837, US 5,728,831 and as herbicides and pesticides in WO 03/048138.

Starting from this prior art, the object of the present invention is to provide new structures for the therapy of diseases. In particular, the structures according to the invention should be suitable for the prophylaxis and therapy of tumor diseases and have advantages over structures known in the prior art. It has now surprisingly been found that a specific subgroup of the aryl-substituted cyclic ketoenols described in the prior art also inhibit human ACC and are suitable for the therapy of diseases. It was unpredictable whether and which of the structures known as insecticides or herbicides would achieve the object according to the invention, namely structures which can be used in the therapy of human diseases.

The Applicant is not aware that in the prior art 5 'biphenyl-substituted cyclic ketoenols according to the present invention for the treatment of diseases are described, in particular not for the treatment of tumor diseases.

The object is achieved by compounds of the formula (I). It has now been found that compounds of the formula (I)

in which

X is halogen, nitro or cyano or

for a mono- or polysubstituted or optionally substituted by halogen Ci-C _ö alkyl, Ci-Cö-alkoxy, Ci-Cö-alkoxy-Ci-Cö-alkoxy, C3-C ₇ -cycloalkyl or a

C ₃ -C ₇ -cycloalkyl-C ₁ -C ₆ -alkoxy, and

W and Y independently of one another represent hydrogen, nitro, cyano or halogen or

for a mono- or polysubstituted or unsubstituted or halogen-substituted Ci-C _ö alkyl,

C ₁ -C ₆ -alkoxy or C ₃ -C ₇ -cycloalkyl, and

V ¹ , V ² and V ³ independently of one another represent hydrogen, halogen, nitro or cyano or a C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogeno Ci-C ₆ -alkoxy,

C ₁ -C ₆ -alkylthio, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-,

C ₃ -C ₀ cycloalkyl or a monocyclic heterocycloalkyl group, and / or V ¹ and V ² with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ having 4 to 7 ring atoms whose ring-forming atoms with halogen and / or a Ci-Cö-alkyl radical may be monosubstituted or polysubstituted, the same or different,

CKE for one of the groups

wherein U is -S-, -S (O) -, -S (O) ₂ -, -O-,

O

, a substituted ^. C = N group or represents an optionally substituted by Q ³ and Q ⁴ Ci-C ₄ alkylene group, and

A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl- or

C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkyl radical or

for a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl or for a monocyclic heterocyclyl or heterocyclyl-C ₁ -C ₄ -alkyl radical,

toggle _ö with halogen and / or with a C-C alkyl radical may be substituted or polysubstituted by identical or different or

_ö an aryl, aryl-Ci-C alkyl, or heteroaryl, optionally substituted with

Halogen, cyano, nitro and / or a Ci-C ₆ -alkyl, halo-C ₆ alkyl, Ci-C _ö alkoxy and / or halogen-Ci-C _ö alkoxy mono- or poly- , may be substituted, identical or different, and

B is hydrogen or a Ci-C _ö alkyl or

Ci-C _ö alkoxy-Ci-C _ö alkyl group, or

A and B together with the carbon atom to which they are attached, a saturated or unsaturated, optionally containing at least one heteroatom

Form cycle T ² with 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen, hydroxy or cyano or

b) for an optionally substituted in the alkyl moiety with hydroxy

C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-,

Ci-C _ö -alkylcarbonyl, Ci-C _ö alkoxycarbonyl, Ci-C _ö alkylaminocarbonyl, Ci-C ₆ alkylthio, Ci-C ₆ -Alkylsulfmyl-, Ci-C ₆ alkylsulfonyl,

C ₁ -C ₆ -alkylaminosulfonyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, halogeno-C ₁ -C ₆ -alkyl or halogeno-C ₁ -C ₆ -alkoxy, or

c) an aryl, arylcarbonyl, arylsulfonyl, arylamino, heteroraryl, heteroarylcarbonyl, heteroarylsulfonyl or heteroarylamino radical, or d) a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkylcarbonyl,

C ₃ -C ₇ -cycloalkylsulfonyl, heterocyclyl, heterocyclylcarbonyl or heterocyclylsulfonyl radical,

where the radicals mentioned under c) and d) are optionally substituted on the ring system by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl radical,

Ci-C ₆ alkoxy, halogen-C ₆ -alkyl, halo-C ₆ alkoxy, Ci-C ₆ alkoxy-C ₆ alkyl, C ₃ -C -cycloalkyl ₀ - and / or a 3- to 6-membered heterocycloalkyl may be mono- or polysubstituted by identical or different substituents, and / or

e) two of the radicals R ¹ , R ² and R ³ together with the ring or the atoms of

Cycle T ² , to which they are attached, can form a further saturated or unsaturated, optionally at least one heteroatom-containing cycle T ³ having 3 to 7 ring atoms, which may be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a Ci-C _ö alkyl or Ci-C ₆ alkoxy, and

D is hydrogen or

for a CC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or Ci-C ₆ alkoxy-C C ₆ - alkyl radical or

for a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl or for a monocyclic heterocyclyl or heterocyclyl-C ₁ -C ₄ -alkyl radical or for an aryl, aryl-C ₁ -C ₄ -alkyl radical C _ö alkyl, heteroaryl or heteroaryl-C _ö alkyl radical, wherein said radicals are optionally substituted with halogen, hydroxy, cyano, nitro and / or a Ci-C ₆ -alkyl, halo-C ₆ - Alkyl, C ₁ -C ₆ -alkoxy,

Halo-Ci-C ₆ alkoxy, Ci-C ₆ -alkoxy-C can ₆ alkyl, C ₃ -C mono- ₀ cycloalkyl and / or a monocyclic heterocycloalkyl or polysubstituted by identical or different substituents , or

A and D together with the atoms to which they are attached, a saturated or unsaturated and optionally at least one further heteroatom

form cycle ⁴ containing 3 to 7 ring atoms, which may be bridged and whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ⁷ , R ⁸ and R ⁹ ,

wherein R ⁷ , R ⁸ and R ⁹ independently of one another represent hydroxyl, halogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy radical, and A and Q ¹ together with the atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁵ having 5 to 7 ring atoms whose ring-forming atoms are halogen, hydroxy, cyano, nitro and / or with a C ₁ -C ₆ -alkyl,

Halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy,

Ci-C _ö alkoxy-Ci-C _ö alkyl and / or C ₃ -C mono- ₀ cycloalkyl, or may be multiple, identical or different substituents,

with the proviso that B and Q ^{2 represent} a bond when the cycle T ⁵ formed by A and Q ¹ is aromatic,

Q ^{1 is} hydrogen or

for an optionally with halogen, hydroxy and / or a

Ci-C _ö alkoxy one or more times, the same or different substituted Ci-C ₆ alkyl or Ci-C ₆ alkoxy or

a _C3-C7 cycloalkyl, C3-C ₇ cycloalkyl Ci-C4-alkyl or a monocyclic heterocyclyl or heterocyclyl-Ci-C4-alkyl,

optionally substituted by halogen, hydroxy and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy and / or halogen-Ci-C _ö alkoxy group one or more times, may be the same or different substituted or

a phenyl radical which is optionally substituted by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy,

Halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and / or

C3-Cio-cycloalkyl may be mono- or polysubstituted by identical or different substituents, and

Q ² , Q ⁴ , Q ⁵ and Q ⁶ are each independently hydrogen or one

Ci-C ₆ alkyl, and

Q ^{3 is} hydrogen or

represents an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₆ alkyl or Ci-C _ö alkoxy or

is a phenyl radical optionally substituted with halo, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy,

Halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and / or

C ₃ -C ₀ cycloalkyl mono- or may be multiple, identical or different substituents,

or

Q ¹ and Q ² together with the carbon atom to which they are attached, a

saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁶ having 3 to 7 ring atoms whose ring-forming atoms with halogen, hydroxy, cyano, nitro and / or a Ci-C ₆ alkyl, halogen-Ci-C ₆ - Alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy,

Ci-C _ö alkoxy-Ci-C _ö alkyl and / or C ₃ -C mono- ₀ cycloalkyl or polysubstituted by identical or different substituents can be, or

Q ³ and Q ⁴ together with the carbon atom to which they are attached, a

form a saturated or unsaturated and optionally at least one heteroatom-containing cycle T ⁷ having 3 to 7 ring atoms whose ring-forming

Atoms with halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogeno-C ₁ -C ₆ -alkoxy, C i -C _ö alkoxy-Ci-C _ö alkyl and / or C ₃ -C mono- ₀ cycloalkyl group may be substituted or polysubstituted by identical or different,

are suitable for use as pharmaceuticals.

The medicaments are suitable for the prophylaxis and / or therapy of human or animal diseases, in particular for the prophylaxis and / or therapy of tumor diseases. The compounds according to the invention are particularly suitable for the prophylaxis and / or therapy of cancer.

The present invention therefore 5'-biphenyl-substituted ketoenols of the formula (I) for therapeutic purposes, pharmaceutical agents and their use in therapy, in particular for the prophylaxis and / or therapy of tumor diseases.

The therapy of diseases is preferred. The invention is based on the following definitions: alkyl:

Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (Ci-C ₆ - alkyl), preferably 1 to 4 _(Ci-C4 alkyl), and particularly preferably 1 to 3 carbon atoms (C C ₃ alkyl).

Examples and preferred are:

Methyl, ethyl, propyl, butyl, pentyl, hexyl, o-propyl, o-butyl, sec-butyl, ieri-butyl, o-pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, eo-pentyl,

1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,

2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl-1,2-dimethylbutyl ,

Particularly preferred is a methyl, ethyl, propyl or isopropyl radical.

Alkylene = alkanediyl:

Alkylene is a linear or branched, saturated, divalent hydrocarbon radical having generally 1 to 6 (C ₁ -C ₆ -alkylene), preferably 1 to 4 (C ₁ -C 4 -alkylene), and more preferably 1 to 3 (C 1 -C 3) alkylene) carbon atoms.

Examples and preferred are:

Methylene, ethylene, propylene, butylene, pentylene, hexylene, "o-propylene," o-butylene, sec-butylene, ieri-butylene, "o-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene,

1,2-dimethylpropylene, eo-pentylene, 1,1-dimethylpropylene, 4-methylpentylene,

3-methylpentylene, 2-methylpentylene, 1-methylpentylene, 2-ethylbutylene, 1-ethylbutyl,

3.3-dimethylbutyl, 2,2-dimethylbutylene, 1,1-dimethylbutylene, 2,3-dimethylbutylene, 1, 3-dimethylbutylene-1, 2-dimethylbutylene.

Particularly preferred is methylene, ethylene or propylene.

alkenyl:

Alkenyl is a linear or branched, monovalent hydrocarbon radical having at least one double bond and usually 2 to 6 (C ₂ -C ₆ alkenyl), preferably 2 to 4 (C ₂ -C 4 alkenyl), and particularly preferably 2 or 3 (C ₂ -C ₃ alkenyl) carbon atoms.

Examples and preferred are:

Vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -but-2-enyl, (Z) -but-2-enyl-, ( E) -but-1-enyl, (Z) -but-1-enyl, 4-pentyl-enyl, (1) -pent-3-enyl, (2) -pent-3-enyl, (E) pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl , (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -Hex -2-enyl, (Z) -hex-2-enyl, (E) -Hex-l- enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -l- Methylprop-1-enyl, (Z) -l-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut -2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -l-methylbut-2-enyl, (Z) -l Methylbut-2-enyl, (E) -3-methylbut-1-enyl,

(Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl -, (Z) -l-methylbut-1-enyl, 1, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl,

1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl,

1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3-methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2- Methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -l-methylpent-3-enyl, (Z) -l-methylpent-3-enyl-, (E) - 4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, (E) -3-methylpent-2-enyl,

(Z) -3-methylpent-2-enyl, (E) -2-methylpent-2-enyl, (Z) -2-methylpent-2-enyl, (E) -l-methylpentane

2-enyl, (Z) -l-methylpent-2-enyl, (E) -4-methylpent-1-enyl, (Z) -4-methylpent-1-enyl,

(E) -3-methylpent-1-enyl, (Z) -3-methylpent-1-enyl, (E) -2-methylpent-1-enyl, (Z) -2-methylpentane

1-enyl, (E) -l-methylpent-1-enyl, (Z) -l-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1 Ethylbut-3-enyl, (E) -3-ethylbut-2-enyl, (Z) -3-ethylbut-2-enyl, (E) -2-ethylbut-2-enyl-, (Z) -2-Ethylbut-2-enyl, (E) -1-ethyl-but-2-enyl, (Z) -1-ethyl-but-2-enyl, (E) -3-ethyl-but-1-enyl, ( Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) -1-ethylbut-1-enyl, (Z) -1-ethylbut-1-enyl,

2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E) -2-propylprop-1-enyl, ( Z) -2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z) -1-propylprop-1-enyl, (E) -2-isopropylprop-1-enyl , (Z) -2-isopropylprop-1-enyl, (E) -1-isopropylprop-1-enyl, (Z) -1-isopropylprop-1-enyl, (E) -3,3-dimethylpropyl 1-enyl, (Z) -3, 3-dimethylprop-1-enyl, 1- (1,1-dimethylethyl) ethenyl, buta-1, 3-dienyl, penta-1,4-dienyl, hexa -l, 5-dienyl,

Methylhexadienyl.

Particularly preferred is vinyl or allyl. Alkenylene = alkenediyl:

Alkenylene is a linear or branched, divalent hydrocarbon radical having at least one double bond and usually 2 to 6 (C ₂ -C ₆ alkenylene), preferably 2 to 4 (C ₂ -C ₄ alkenylene), and particularly preferably 2 or 3 ( C2-C3 alkenylene) carbon atoms.

alkynyl:

Alkynyl represents a linear or branched, monovalent hydrocarbon radical having at least one triple bond and generally 2 to 6 (C ₂ -C ₆ alkynyl), preferably 2 to 4 (C ₂ -C 4 alkynyl), and particularly preferably 2 or 3 (C ₂ -C ₄ -alkynyl) C3 alkynyl) carbon atoms. Examples and preferred are:

Ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl , Pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl , 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl,

3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3 inyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl,

4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl -, l-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, l, l-dimethylbut-3-inyl, l, l-dimethylbut-2-ynyl or a 3,3-dimethylbut -l-ynyl.

Particularly preferred is ethynyl, prop-1-ynyl or prop-2-ynyl.

Cycloalkyl:

Cycloalkyl is a mono- or bicyclic, saturated, monovalent

Hydrocarbon radical with usually 3 to 10 (C3-Cio-cycloalkyl), preferably 3 to 8

(C ₃ -C ₈ cycloalkyl), and more preferably 3 to 7 (C ₃ -C ₇ cycloalkyl) carbon atoms.

By way of example and with preference for monocyclic cycloalkyl radicals, mention may be made:

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.

Examples of bicyclic cycloalkyl radicals are:

Perhydropentalenyl, decalinyl.

Cvcloalkylcarbonyl

Cycloalkylcarbonyl represents the group -C (O) -cycloalkyl. Cvcloalkylsulfonyl

Cycloalkylsulfonyl represents the group -S (O) ₂ -cycloalkyl. Cvcloalkylalkyl:

Cycloalkylalkyl is an alkyl radical containing a cyclic, saturated,

Hydrocarbon ring is substituted.

Cn-Cyclcoalkyl-C _m -alkyl means that the alkyl moiety m carbon atoms and the

Cycloalkylteil has n carbon atoms.

Examples and preferred are:

Cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl. Cycloalkylalkoxy:

Cycloalkylalkoxy is an alkoxy radical which is cyclic, saturated,

Hydrocarbon ring is substituted.

C "-Cyclcoalkyl-C _m -alkoxy means that the alkoxy part has m carbon atoms and the cycloalkyl part has n carbon atoms.

Examples and preferred are:

Cyclopropylmethoxy, cyclobutylethoxy, cyclopentylethoxy.

alkoxy:

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

Examples and preferred are:

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

alkylthio

Alkylthio represents a linear or branched, saturated alkylthioether radical of the formula -S-alkyl having generally 1 to 6 (C ₁ -C ₆ -alkylthio), preferably 1 to 4 (C 1 -C ₄ -alkylthio), and particularly preferably 1 to 3 (C 1 -C 3 -alkylthio) carbon atoms.

alkoxyalkyl

Alkoxyalkyl is an alkoxy-substituted alkyl radical.

In this case, C 1 -alkoxy-C _m -alkyl means that the alkoxy moiety has n carbon atoms and the alkyl moiety, via which the moiety is bonded, has m carbon atoms.

Examples and preferred are:

Methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.

alkylthioalkyl

Alkylthioalkyl represents an alkyl radical substituted with alkylthio.

C "-Alkylthio-C _m -alkyl means that the alkylthio part has n carbon atoms and the alkyl part, via which the radical is attached, has m carbon atoms.

alkoxyalkoxy

Alkoxyalkoxy is an alkoxy-substituted alkoxy radical.

C "-Alkoxy-C _m -alkoxy means that the outer alkoxy part has n carbon atoms and the alkoxy part, via whose oxygen function the radical is bonded, has m carbon atoms. Examples and preferred are: Methoxyethoxy and ethoxyethoxy. alkylamino

Alkylamino represents an amino radical having one or two (independently selected) alkyl substituents with generally 1 to 6, preferably 1 to 3 carbon atoms.

(C 1 -C 3) -alkylamino is, for example, a monoalkylamino radical having 1 to 3

Carbon atoms or a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent. Examples include:

Methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-n-propylamino, N-isopropyl N-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

alkylcarbonyl

Alkylcarbonyl is the group -C (O) -alkyl having generally 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms in the alkyl moiety.

Examples include:

Acetyl and propanoyl. alkoxycarbonyl

Alkoxycarbonyl is the group -C (O) -O-alkyl having usually 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms in the alkyl moiety.

Examples include:

Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

alkylaminocarbonyl

Alkylaminocarbonyl stands for the group -C (O) -alkylamino with one or two

(independently selected) alkyl substituents. with usually 1 to 6, preferably 1 to 3 carbon atoms.

(C 1 -C 3) -alkylaminocarbonyl is, for example, a monoalkylammocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having 1 to 3 in each case

Carbon atoms per alkyl substituent. Examples include:

Methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N -Isopropyl-Nn-propylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

alkylsulfinyl

Alkylsulfinyl is a linear or branched, saturated radical of the formula -S (O) -alkyl having generally 1 to 6 (C ₁ -C ₆ -alkylsulfmyl), preferably 1 to 4 (C 1 -C ₄ -alkylsulfmyl), and especially preferably 1 to 3 (C 1 -C 3 -alkylsulfinyl) carbon atoms.

Examples and preferred are:

Methylsulfinyl, ethylsulfinyl, propylsulfinyl.

alkylsulfonyl

Alkylsulfonyl is a linear or branched, saturated radical of the formula -S (O) 2-alkyl having generally 1 to 6 (C ₁ -C ₆ -alkylsulfonyl), preferably 1 to 4 (C ₁ -C 4 -alkylsulfonyl), and especially preferably 1 to 3 (C 1 -C 3 -alkylsulfonyl) carbon atoms.

Examples and preferred are:

Methylsulfonyl, ethylsulfonyl, propylsulfonyl.

alkylaminosulfonyl

Alkylaminosulfonyl stands for the group -S (0) 2-alkylamino with one or two

(C 1 -C 3) -alkylaminosulfonyl is, for example, a monoalkylammosulfonyl radical having 1 to 3 carbon atoms or a dialkylammosulfonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Examples include:

Methylaminosulfonyl, ethylaminosulfonyl, n -propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-Nn-propylaminosulfonyl, N-isopropyl -Nn-propylaminosulfonyl, Nt-butyl-N-methylaminosulfonyl, N-ethyl-Nn-pentylaminosulfonyl and Nn-hexyl-N-methylaminosulfonyl. aryl

Aryl is a monovalent, aromatic mono- or bicyclic ring system without a heteroatom having 6 or 10 carbon atoms.

Examples and preferred are:

Phenyl (C ₆ -aryl), naphthyl (Cio-aryl).

Preference is given to phenyl.

arylcarbonyl

Arylcarbonyl is the group -C (O) -aryl.

arylsulfonyl

Arylsulfonyl represents the group -S (0) ₂ -aryl. arylamino

Arylamino represents the group -NR-aryl, where R is hydrogen or alkyl. arylalkyl

Arylalkyl represents a linear or branched, saturated, monovalent alkyl group which is substituted by an aromatic mono- or bicyclic ring system without heteroatom.

C "-Aryl-C _m -alkyl means that the alkyl moiety has m carbon atoms and the aryl moiety has n carbon atoms.

Exemplary and preferred are:

Phenylmethyl, phenylethyl. heteroatoms

Heteroatoms are oxygen, nitrogen or sulfur atoms. heteroaryl

Heteroaryl is a monovalent, mono- or bicyclic ring system having at least one heteroatom and at least one aromatic ring. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur. The bond valency may be at any aromatic carbon atom or at a nitrogen atom. A monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms.

For example, heteroaryl radicals having 5 ring atoms include the rings:

Thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.

Heteroaryl radicals having 6 ring atoms include, for example

Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

A bicyclic heteroaryl group according to the present invention has 9 or 10 ring atoms.

For example, heteroaryl radicals having 9 ring atoms include the rings:

Phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl, benzothiazolyl,

Benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.

Heteroaryl radicals with 10 ring atoms include, for example, the rings:

Isoquinolinyl, quinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl

1,7- or 1,8-naphthyridinyl, pteridinyl, chromanyl.

Monocyclic heteroaryl rings with 5 or 6 ring atoms are preferred.

heteroarylcarbonyl

Heteroarylcarbonyl represents the group -C (0) heteroaryl. heteroarylsulfonyl

Heteroarylsulfonyl represents the group -S (0) ₂ heteroaryl.

heteroarylamino

Heteroarylamino represents the group -NR-heteroaryl, where R is hydrogen or alkyl.

heteroarylalkyl

Heteroarylalkyl represents a linear or branched, saturated, monovalent alkyl group substituted with an aromatic, mono- or bicyclic ring system having at least one heteroatom other than a carbon atom.

Monocyclic heteroaryl-C _m -alkyl means that the alkyl moiety with m carbon atoms and the heteroaryl moiety is monocyclic and therefore has 5 or 6 ring atoms. heterocyclyl

Heterocyclyl in the context of the invention is a non-aromatic mono- or bicyclic

Ring system with at least one heteroatom or a hetero group. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur. As hetero groups, -S (O) -, -S (O) ₂ - or -N ^ O ^" ) - may occur.

A monocyclic heterocyclyl according to the present invention may have 3 to 8, preferably 5 to 8, particularly preferably 5 or 6 ring atoms.

By way of example and with preference for monocyclic heterocyclyl radicals having 3 ring atoms, mention may be made of aziridinyl.

Exemplary and preferred for monocyclic heterocyclyl radicals having 4 ring atoms are: azetidinyl, oxetanyl. Exemplary and preferred for monocyclic heterocyclyl radicals having 5 ring atoms are: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dioxolanyl and tetrahydrofranyl.

Exemplary and preferred for monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, dioxanyl, tetrahydropyranyl and thiomorpholinyl.

Exemplary and preferred for monocyclic heterocyclyl radicals having 7 ring atoms are: azepanyl, oxepanyl, [1,3] -diazepanly, [1,4] -diazepanyl.

Exemplary and preferred for monocyclic heterocyclyl radicals having 8 ring atoms are: oxocanyl, azocanyl.

A bicyclic heterocyclyl group according to the present invention may have 5 to 12, preferably 8 to 10, ring atoms. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S.

Particularly preferred are morpholinyl, piperidinyl and pyrolidinyl. Heterocylylalkyl:

Heterocyclylalkyl represents an alkyl radical which is substituted by a heterocyclyl radical.

By way of example, a monocyclic heterocyclyl-C _m -alkyl radical here means that the alkyl moiety has m carbon atoms and the heterocyclyl moiety has 3 to 8 ring atoms.

Heterocvclylcarbonyl Heterocyclylcarbonyl represents the group -C (0) -heterocyclyl.

Heterocvclylsulfonyl

Heterocyclylsulfonyl represents the group -S (0) ₂ -heterocyclyl. halogen

The term halogen includes fluorine, chlorine, bromine and iodine.

Preference is given to fluorine and chlorine.

haloalkyl:

Haloalkyl is an alkyl radical having at least one halogen substituent.

Examples and preferred are:

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

Preference is given to perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.

haloalkoxy

Haloalkoxy is an alkoxy radical having at least one halogen substituent.

Preference is given to fluoroalkoxy radicals.

Examples and preferred are:

Difluoroethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy.

cycle

Cycle includes all ring systems.

Unsaturated cycle

An unsaturated cycle includes ring systems having at least one double bond in the ring and aromatic ring systems.

A group which may be mono-, di- or poly-substituted is a group without, with one, two or more substituents.

In the formula (I), X may stand for:

Halogen, nitro or cyano or

Ci-C ₆ alkoxy, Ci-C ₆ alkoxy alkoxy-Ci-C _6, C ₃ -C ₇ -cycloalkyl or a

C ₃ -C ₇ -cycloalkyl-C ₁ -C ₆ -alkoxy. In the formula (I), X may preferably stand for:

Halogen or an optionally halogen-mono- or polysubstituted Ci-C ₃ alkyl or Ci-C ₃ alkoxy.

In the formula (I), W and Y may be independently of one another for:

Hydrogen, nitro, cyano or halogen or

C ₁ -C ₆ -alkoxy or C ₃ -C ₇ -cycloalkyl radical.

In the formula (I), W and Y independently of one another may preferably stand for:

Hydrogen, cyano or halogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-C3-alkyl or Ci-C ₃ alkoxy.

In the formula (I), W and Y independently of one another may more preferably stand for:

Hydrogen or halogen or

In the formula (I), W and Y independently of one another may particularly preferably stand for: hydrogen or an optionally mono- or polysubstituted by halogen

Ci-C ₃ -alkyl radical.

In the formula (I), V ¹ , V ² and V ^{3 may} independently represent:

Hydrogen, halogen, nitro or cyano or for a Ci-C ₆ alkyl, halo-Ci-C ₆ alkyl, Ci-C ₆ alkoxy, halo-Ci-C ₆ alkoxy, CC ₆ alkylthio -, CC ₆ -alkylsulfmyl-,

C _j -C ₈ alkylsulfonyl, Ci-C ₆ alkoxy alkyl-Ci-C _6, C ₃ -C ₀ cycloalkyl or for a

monocyclic heterocycloalkyl radical, and / or V ¹ and V ² form with the carbon atoms to which they are attached, a saturated or unsaturated and optionally containing at least one further heteroatom cycle T ¹ with 4 to 7 ring atoms, the ring-forming atoms, with halogen and / or a Ci- C _ö - Alkyl radical may be mono- or polysubstituted by identical or different substituents.

In the formula (I), V ¹ , V ² and V ^{3 may} independently of one another preferably stand for:

Hydrogen, halogen or cyano, or a Ci-C ₃ alkyl, Ci-C ₃ haloalkyl,

Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or Ci-C ₃ alkoxy-Ci-C ₃ alkyl, and / or

V ¹ and V ² form, with the carbon atoms to which they are attached, a cycle containing saturated or unsaturated and optionally at least one further heteroatom

T ¹ with 5 or 6 ring atoms whose ring-forming atoms may be monosubstituted or polysubstituted by the same or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical.

In the formula (I) may be V ^1, V ² and V ³ independently of one another, more preferably represent hydrogen or halogen or a Ci-C ₃ alkyl, Ci-C ₃ haloalkyl,

Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or Ci-C ₃ alkoxy-Ci-C ₃ alkyl, and / or

V ¹ and V ² together with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ having 5 or 6 ring atoms whose ring-forming atoms are halogen and / or C ₁ -C ₃ - Alkyl radical may be mono- or polysubstituted by identical or different substituents.

In the formula (I) may be V ^1, V ² and V ³ independently of one another particularly preferably represent hydrogen, halogen or a Ci-C ₃ alkyl or _Ci-C3 haloalkyl. The group CKE can stand for one of the following groups:

The group CKE may more preferably stand for one of the following groups:

In the group CKE of the formula (I), U can stand for:

-S-, -S (O) -, -S (O) ₂ -, -O-,

O

, a substituted ^ C = N group or an optionally substituted by Q ³ and Q ⁴ Ci-C ₄ alkylene group.

In the group CKE of the formula (I), U may preferably be an optionally substituted by Q ³ and Q ⁴ methylene group. In the group CKE of the formula (I), A can stand for:

Hydrogen or

C ₂ -C ₆ alkenyl, Ci-C ₆ alkoxy-C ₆ alkyl or Ci-C ₆ -alkylthio-C ₆ alkyl group or a _C3-C7 cycloalkyl, C3- C ₇ -cycloalkyl-C 1 -C 4 -alkyl or for a monocyclic heterocyclyl or heterocyclyl-C 1 -C ₄ -alkyl radical which react with halogen and / or with a

Mono- Ci-C _ö alkyl group may be substituted or polysubstituted by identical or different, or an aryl, aryl-Ci-C _ö alkyl or heteroaryl, optionally substituted with halogen, cyano, nitro and / or a Ci-C _6- alkyl, halo-Ci-C ₆ -alkyl, Ci-C ₆ alkoxy and / or a halogeno-Ci-C _ö alkoxy one or more times, the same or different substituted. In the group CKE of the formula (I), A may preferably stand for:

Hydrogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-Cö-alkyl or C l -Cö-alkoxy-C i -Cö-alkyl or

for a C ₃ -C ₇ -cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C 1 -C 3 -alkyl radical, or

for a phenyl, phenyl-C ₁ -C ₃ -alkyl or monocyclic heteroaryl radical which is optionally substituted by halogen, cyano and / or a C ₁ -C ₃ -alkyl, halogeno-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ - Alkoxy and / or a halogeno-C 1 -C 3 alkoxy may be mono- or polysubstituted by identical or different substituents.

In the group CKE of the formula (I), A may more preferably stand for:

Hydrogen or

for an optionally mono- or polysubstituted with halogen Ci-Cö-alkyl or C i -C ₆ - alkoxy-C i -C ₆ alkyl or

for a C ₃ -C ₇ -cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C 1 -C 3 -alkyl radical.

In the group CKE of the formula (I), A may be particularly preferably:

Hydrogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-Cö-alkyl or Ci-C ₆ -alkoxy-Ci-C ₆ -alkyl or

for a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical.

In the group CKE of the formula (I), B can stand for:

Is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical.

In the group CKE of the formula (I), B may preferably stand for:

Is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical.

In the group CKE of the formula (I), A and B together with the carbon atom to which they are attached may form:

a saturated or unsaturated, optionally containing at least one heteroatom cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen, hydroxy or cyano or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C _ö alkyl, Ci-C _ö alkoxy, Ci-C ₆ alkoxy-Ci-C ₆ alkyl, Ci-C ₆ alkylcarbonyl, Ci -C ₆ alkoxycarbonyl,

C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkylthio, C ₁ -C ₆ -alkylsulfmyl, C ₁ -C ₆ -alkylsulfonyl,

C ₁ -C ₆ -alkylaminosulphonyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, halogeno-C ₁ -C ₆ -alkyl or halogeno-C ₁ -C ₆ -alkoxy, or

c) an aryl, arylcarbonyl, arylsulfonyl, arylamino, heteroraryl, heteroarylcarbonyl, heteroarylsulfonyl or heteroarylamino radical, or

d) a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkylcarbonyl, C ₃ -C ₇ -cycloalkylsulfonyl-,

Heterocyclyl, heterocyclylcarbonyl or heterocyclylsulfonyl radical,

where the radicals mentioned under c) and d) are optionally substituted on the ring system by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkyl- , halo-Ci-C _ö alkoxy, Ci-C _ö alkoxy-Ci-C _ö alkyl, C3-Cio-cycloalkyl and / or a 3- to 6-membered heterocycloalkyl radical once or more times, identically or may be substituted differently, and / or

e) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached form a further saturated or unsaturated, optionally containing at least one heteroatom cycle T ³ having 3 to 7 ring atoms can be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and

R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a Ci-C _ö alkyl or

Ci-C ₆ -alkoxy.

In the group CKE of the formula (I), A and B may together form, together with the carbon atom to which they are bonded,

a saturated or unsaturated, optionally containing one or two heteroatoms cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently a) for halogen or hydroxy or

b) for a optionally substituted in the alkyl moiety with hydroxy Ci-C ₅ alkyl, Ci-C ₅ alkoxy, Ci-C ₃ alkoxy-Ci-C ₃ alkyl, Ci-C ₃ alkylcarbonyl, Ci -C ₃ alkoxycarbonyl,

C ₁ -C ₃ -alkylaminocarbonyl, C ₁ -C ₃ -alkylthio, C ₁ -C ₃ -alkylsulfmyl, C ₁ -C ₃ -alkylsulfonyl, C ₁ -C ₃ -alkylaminosulfonyl, C ₁ -C ₃ -alkoxy-C ₁ -C 4 -alkyl ₃ -alkoxy, halo-Ci-C ₃ -alkyl- or

Halogeno-Ci-C ₃ -alkoxy or

c) for a phenyl, phenylcarbonyl, phenylsulfonyl or phenylamino radical, or

d) a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkylcarbonyl, C ₃ -C ₇ -cycloalkylsulfonyl or in each case 4- to 7-membered monocyclic heterocyclyl, heterocyclylcarbonyl or heterocyclylsulfonyl radical,

wherein the radicals mentioned under c) and d) optionally on the ring system with halogen, hydroxy and / or a Ci-C ₃ alkyl, halo-Ci-C ₃ alkyl, Ci-C ₃ alkoxy, halogen-Ci - C ₃ alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents, and / or

e) two of the radicals R ¹ , R ² and R ³ together with the one or more ring atoms of the cycle T ² to which they are attached, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently of one another a Ci-C ₃ alkyl or

CC ₃ alkoxy radical.

In the group CKE of the formula (I), A and B together with the carbon atom to which they are attached may more preferably form:

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl-, Ci-C ₃ -alkoxy-Ci-C ₃ - alkoxy, halo-Ci-C ₃ -alkyl or halogeno-Ci-C ₃ -alkoxy or

c) for a C ₃ -C ₇ -cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical which is optionally substituted on the ring system by halogen, hydroxy and / or a C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl -, CC C ₃ alkoxy and / or Ci-C ₃ alkoxy-Ci-C ₃ alkoxy, halogen-C ₃ - alkyl radical mono- or polysubstituted by identical or different substituents can be, and / or d) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are bonded, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently of one another a Ci-C3-alkyl or

Ci-C ₃ alkoxy.

In the group CKE of the formula (I), A and B together with the carbon atom to which they are attached may also form more preferably:

a saturated, optionally containing a heteroatom cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently

a) for hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C3-alkoxy, Ci-C2-alkoxy-Ci-C3-alkyl, Ci-C3-alkoxy-Ci-C3-alkoxy, Halogeno-C 1 -C 3 -alkyl or halogenated

Ci-C3 alkoxy group.

In the group CKE of the formula (I), A and B together with the carbon atom to which they are attached may particularly preferably form:

a saturated, optionally one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently

a) for a optionally substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C3-alkoxy, Ci-C3-alkoxy-Ci-C3-alkyl, Ci-C3-alkoxy-Ci-C3-alkoxy- or Halo-Ci-C3-alkoxy, and / or

b) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached form a further saturated or aromatic, optionally containing at least one oxygen atom cycle T ³ having 5 to 7 ring atoms can be substituted one or more times with a Ci-C3-alkyl radical.

In the group CKE of the formula (I), A and B together with the carbon atom to which they are attached may also form particularly preferably:

a saturated, optionally containing an oxygen atom cycle T ² with 5 to 6

Ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently of one another a) for hydroxy or b) a C ₁ -C ₃ -alkyl, hydroxy-methyl, C ₁ -C ₂ -alkoxy, methoxy-C ₁ -C ₂ -alkyl,

Trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy.

In the group CKE of the formula (I) D can stand for:

Hydrogen or

₆ -alkoxy-C alkyl radical or a Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, _C2-C6 alkynyl or Ci-C ₆ for a C3-C ₇ cycloalkyl , C ₃ -C ₇ -cycloalkyl-C 1 -C 4 -alkyl or for a monocyclic heterocyclyl or heterocyclyl-C 1 -C ₄ -alkyl radical, or

_ö an aryl, aryl-Ci-C alkyl, heteroaryl or heteroaryl-C _ö alkyl group,

where the radicals mentioned are optionally substituted by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogeno-C ₁ -C ₆ - C ₃ -C ₀ cycloalkyl and / or a monocyclic heterocycloalkyl group may be mono- or polysubstituted by identical or different substituents from alkoxy, _Ci-C6 alkoxy-Ci- _C6 alkyl. In the group CKE of the formula (I), D may preferably stand for:

Hydrogen or

for a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

for a C ₃ -C ₇ -cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical or for a phenyl- or phenyl-C 1 -C 3 -alkyl radical,

wherein the radicals mentioned optionally with halogen, hydroxy, cyano and / or a

C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halogen-C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl- and / or C ₃ -C ₇ -cycloalkyl may be mono- or polysubstituted by identical or different substituents. In the group CKE of the formula (I), D may be more preferably:

Hydrogen or

for a C ₃ -C ₇ -cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical, where the radicals mentioned are optionally substituted by halogen and / or hydroxyl or a

CC ₃ alkyl, halo-C ₃ alkyl, CC ₃ alkoxy, halo-C ₃ alkoxy and / or

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents. In the group CKE of the formula (I), D may be particularly preferably:

for hydrogen or

for a C ₁ -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl radical,

where the radicals mentioned may be mono- or polysubstituted by identical or different substituents with halogen, hydroxy and / or a C 1 -C 3 -alkyl radical.

In the group CKE of the formula (I), A and D together with the atoms to which they are attached may alternatively form:

a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁴ having 3 to 7 ring atoms, which may be bridged and the ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ⁷ , R ⁸ and R ⁹ .

wherein R ⁷ , R ⁸ and R ^{9 are} independently hydroxy, halogen or a Ci-C ₆ alkyl or CC ₆ alkoxy.

If the group CKE of the formula (I) is the group 8, A and D together with the atoms to which they are attached may alternatively form preferentially:

a saturated or unsaturated and optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms, which may be bridged and whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical. Alternatively, when the group CKE of formula (I) is group 8, A and D together with the atoms to which they are attached may more preferably form:

a saturated, optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms, which may be bridged and the ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ⁷ , R ⁸ and R ⁹ ,

where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C 1 -C ³ -alkyl radical.

In the group CKE of the formula (I), A and Q ¹ together with the atoms to which they are attached can form:

a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁵ having 5 to 7 ring atoms whose ring-forming atoms are halogenated,

Hydroxy, cyano, nitro and / or with a Ci-C ₆ -alkyl, halogen-Ci-C ₆ -alkyl, Ci-C ₆ -alkoxy, halogen-Ci-C ₆ -alkoxy, Ci-C ₆ alkoxy-Ci-C ₆ alkyl and / or C ₃ -C cycloalkyl mono- or ₀ can be substituted several times, the same or different,

with the proviso that B and Q ^{2 represent} a bond when the cycle T ⁵ formed by A and Q ¹ is aromatic. In the group CKE of the formula (I), A and Q ^1, together with the atoms to which they are attached, may preferably form:

an unsaturated and optionally at least one further heteroatom-containing cycle T ⁵ having 5 to 7 ring atoms whose ring-forming atoms with halogen and / or a

C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halogen-C ₁ -C ₃ -alkoxy and / or

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents,

with the proviso that B and Q ^{2 represent} a bond when the cycle T ⁵ formed by A and Q ¹ is aromatic. Can in the group CKE of the formula (I) A and Q ¹ together with the atoms to which they are attached, form particularly preferred:

an aromatic cycle T ⁵ having 6 ring atoms whose ring-forming atoms may be monosubstituted or polysubstituted by halogen,

with the proviso that B and Q ² then stand for a bond.

In the group CKE of the formula (I) Q ^{1 can} stand for:

Hydrogen or

represents an optionally substituted by halogen, hydro xy and / or a mono- or Ci-C _ö alkoxy polysubstituted by identical or different substituents, Ci-C ₆ alkyl or Ci-C ₆ alkoxy or a C ₃ -C ₇ - Cycloalkyl, C ₃ -C ₇ -cycloalkyl-C ₁ -C ₄ -alkyl or for a monocyclic heterocyclyl or heterocyclyl-C ₁ -C ₄ -alkyl radical which is optionally substituted by halogen, hydroxyl and / or a C ₁ -C ₆ -alkyl radical , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy and / or C ₁ -C ₆ -haloalkoxy once or more than once, the same or may be substituted differently or

for a phenyl radical which is optionally substituted by halogen, hydroxy, cyano, nitro and / or a

Ci-C ₆ -alkyl, halo-C ₆ alkyl, Ci-C ₆ alkoxy, halogen-C ₆ alkoxy, Ci-C ₆ alkoxy-Ci- C alkyl _ö and / or C ₃ -Cio-cycloalkyl may be mono- or polysubstituted by identical or different substituents. In the group CKE of the formula (I), Q ^{1 may} preferably stand for:

Hydrogen or

for an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₃ alkyl or Ci-C ₃ alkoxy or for a C ₃ -C ₇ - Cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical which is optionally substituted by halogen, hydroxy and / or a C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-, C ₃ alkoxy-Ci-C ₃ alkoxy, and / or halogeno-Ci-C ₃ alkoxy may be mono- or polysubstituted by identical or different substituents. In the group CKE of the formula (I), Q ¹ can be particularly preferably:

Hydrogen or a Ci-C ₃ -alkyl radical.

In the group CKE of the formula (I) Q ^2, Q ^4, Q ⁵ and Q ⁶ are independently hydrogen or a Ci-C _ö alkyl.

In the group CKE of the formula (I), Q ² , Q ⁴ , Q ⁵ and Q ⁶ independently of one another may preferably be hydrogen or a C ₁ -C ₃ -alkyl radical.

In the group CKE of the formula (I) Q ^{3 can} stand for:

Hydrogen or

mono- or an optionally _ö with halogen, hydroxy and / or a Ci-C alkoxy polysubstituted by identical or different substituents, Ci-C ₆ alkyl or Ci-C ₆ alkoxy or a C ₃ -C 7 cycloalkyl , C ₃ -C 7 -cycloalkyl-C ₁ -C 4 -alkyl- or for a monocyclic heterocyclyl or heterocyclyl-C 1 -C ₄ -alkyl radical which is optionally substituted by halogen, hydroxyl and / or a C ₁ -C ₆ -alkyl-, halogen- C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy and / or C ₁ -C ₆ -alkoxy, substituted one or more times, identically or differently or can be

for a phenyl radical which is optionally substituted by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogeno-C ₁ -C ₆ alkoxy, Ci-C ₆ alkoxy-Ci- C ₆ alkyl and / or C ₃ -C mono- ₀ cycloalkyl, or may be multiple, identical or different substituents.

In the group CKE of the formula (I), Q ^{3 may} preferably stand for:

Hydrogen or

for an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₃ alkyl or Ci-C ₃ alkoxy. In the group CKE of the formula (I), Q ³ particularly preferably represents:

Hydrogen or a Ci-C3-alkyl radical.

In the group CKE of the formula (I) Q ¹ and Q ² together with the carbon atom to which they are attached may form a saturated or unsaturated cycle T ⁶ having 3 to 7 ring atoms and containing at least one further heteroatom, the ring-forming atoms of which with halogen, hydroxy, cyano, nitro and / or a Ci-C ₆ -alkyl, halo-C ₆ alkyl, Ci-C ₆ - alkoxy, halo-Ci-C ₆ alkoxy, Ci- C ₆ alkoxy-C ₆ alkyl and / or C ₃ -C mono- ₀ cycloalkyl, or may be multiple, identical or different substituents.

In the group CKE of the formula (I) Q ³ and Q ⁴ together with the carbon atom to which they are attached may form:

a saturated or unsaturated and optionally at least one heteroatom-containing cycle T ⁷ having 3 to 7 ring atoms whose ring-forming atoms with halogen, hydroxy, cyano, nitro and / or a Ci-C ₆ alkyl, halo-Ci-C ₆ alkyl , C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -

Alkoxy, Ci-C ₆ alkoxy-C ₆ alkyl and / or C ₃ -C mono- ₀ cycloalkyl, or may be multiple, identical or different substituents.

In the group CKE of the formula (I), Q ³ and Q ⁴ together with the carbon atom to which they are attached may preferably form:

a saturated and optionally at least one heteroatom-containing cycle T ⁷ having 5 to 7 ring atoms whose ring-forming atoms with halogen, hydroxy and / or a Ci-C ₃ alkyl, halo-Ci-C ₃ alkyl, Ci-C ₆ alkoxy, halo-Ci-C ₃ alkoxy and / or Ci-C ₃ alkoxy-Ci-C ₃ - alkyl mono- or polysubstituted by identical or different substituents.

In the group CKE of the formula (I), Q ³ and Q ⁴ together with the carbon atom to which they are attached may particularly preferably form:

a saturated cycle T ⁷ having 6 ring atoms, the ring-forming atoms, with halogen and / or a C-C single _ö alkyl group may be substituted or polysubstituted by identical or different. A preferred group of compounds of general formula (I) for use as medicaments are compounds of general formula (I)

in which

X is halogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-C3-alkyl or

Ci-C ₃ alkoxy, and

W and Y independently of one another represent hydrogen, cyano or halogen or

Ci-C3-alkoxy, and

V ^1, V ² and V ³ independently of one another are hydrogen, halogen or cyano, or a Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy - or

C i -C ₃ alkoxy-C i -C ₃ alkyl radical, and / or

V ¹ and V ² with the carbon atoms to which they are attached, a saturated or

unsaturated and optionally at least one further heteroatom-containing cycle T ¹ with 5 or 6 ring atoms whose ring-forming atoms with halogen and / or a C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents,

CKE for one of the groups

wherein

U is an optionally substituted by Q ³ and Q ⁴ methylene group, and A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C i -C ₆ alkyl or C i -C ₆ alkoxy-C i -C ₆ alkyl or

a C3-C ₇ -cycloalkyl or 4- to 7-membered monocyclic

Heterocyclylrest which may be mono- or polysubstituted by identical or different substituents with halogen and / or a Ci-C3-alkyl radical or

a phenyl, phenyl-C ₁ -C ₃ -alkyl or monocyclic heteroaryl radical which is optionally substituted by halogen, cyano and / or a C ₁ -C ₃ -alkyl radical,

Halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy and / or a halogeno-C ₁ -C ₃ -alkoxy radical may be mono- or polysubstituted by identical or different substituents, and B is hydrogen or C ₁ -C _ö alkyl or

Ci-C _ö alkoxy-Ci-C _ö alkyl group, or

A and B together with the carbon atom to which they are attached form a saturated or unsaturated, optionally one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy

C 1 -C 1 -alkyl-, C ₁ -C ₅ -alkoxy-, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl-,

C ₁ -C ₃ -alkylcarbonyl, C ₁ -C ₃ -alkoxycarbonyl, C ₁ -C ₃ -alkylaminocarbonyl, C ₁ -C ₃ -alkylthio, C ₁ -C ₃ -alkylsulfinyl, C ₁ -C ₃ -alkylsulfonyl,

C ₁ -C ₃ -alkylaminosulfonyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy-,

Halo-Ci-C ₃ -alkyl or halo-Ci-C ₃ -alkoxy and / or

c) for a phenyl, phenylcarbonyl, phenylsulfonyl or phenylamino radical, or

d) a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkylcarbonyl,

C ₃ -C ₇ cycloalkylsulfonyl or in each case 4- to 7-membered monocyclic

Heterocyclyl, Heterocyclylcarbonyl- or Heterocyclylsulfonylrest, wherein said radicals under c) and d) optionally on the ring system with halogen, hydroxy and / or a Ci-C ₃ alkyl, halo-Ci-C ₃ alkyl, Ci-C ₃ alkoxy, halogeno-Ci-C ₃ -alkoxy and / or Ci-C ₃ -alkoxy-Ci-C ₃ - alkyl residue one or more times, same or differently substituted be, and / or

e) two of the radicals R ¹ , R ² and R ³ together with the ring or the atoms of Cycle T ² , to which they are attached, can form a further saturated or aromatic, optionally one or two heteroatoms containing cycle T ³ with 5 to 7 ring atoms, which may be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently a Ci-C ₃ alkyl or Ci-C ₃ alkoxy, and

D is hydrogen or

a C3-C ₇ -cycloalkyl or 4- to 7-membered monocyclic

Heterocyclyl radical or

for a phenyl or phenyl-C 1 -C 3 -alkyl radical,

where the radicals mentioned are optionally substituted by halogen, hydroxy, cyano and / or a C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-,

Halogen-C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl and / or

C ₃ -C ₇ cycloalkyl may be mono- or polysubstituted by identical or different substituents, or

if CKE is group 8,

A and D alternatively together with the atoms to which they are attached form a saturated or unsaturated and optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms, which may be bridged and the ring-forming atoms one or more times, the same or may be substituted differently with the radicals R ⁷ , R ⁸ and R ⁹ ,

wherein R ⁷ , R ⁸ and R ^{9 are} independently halogen or a

C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy, and

A and Q ¹ together with the atoms to which they are attached form an unsaturated and optionally at least one further heteroatom-containing cycle T ⁵ having 5 to 7 ring atoms, the ring-forming atoms with halogen and / or a

CC ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halogen-C ₃ -alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or can be substituted several times, the same or different,

with the proviso that B and Q ^{2 represent} a bond when the cycle T ⁵ formed by A and Q ¹ is aromatic, and

Q ^{1 is} hydrogen or

for an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₃ alkyl or

Ci-C ₃ alkoxy represents or

for a C ₃ -C ₇ cycloalkyl or 4- to 7-membered monocyclic Heterocyclyl radical which is optionally substituted by halogen, hydroxy and / or a C ₁ -C ₃ -alkyl, halogeno-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ - alkoxy, and / or halogeno-C ₁ -C ₃ -alkoxy may be mono- or polysubstituted by identical or different substituents, and

Q ² _> Q ⁴ _> Q ⁵ and Q ⁶ independently of one another represent hydrogen or one

Ci-C ₃ alkyl, and

Q ^{3 is} hydrogen or

represents an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₃ alkyl or Ci-C ₃ alkoxy, or

Q ³ and Q ⁴ together with the carbon atom to which they are attached, a

saturated and optionally containing at least one heteroatom cycle T ⁷ with 5 to 7 ring atoms whose ring-forming atoms with halogen, hydroxy and / or a Ci-C ₃ alkyl, halo-Ci-C ₃ alkyl, Ci-C _ö Alkoxy, halo-C ₃ -C ₃ alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents.

A more preferred group of compounds of general formula (I) for use as medicaments are compounds of general formula (I),

in which

X is halogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-C ₃ alkyl or Ci-C ₃ alkoxy and

W and Y are independently hydrogen or halogen or

for a halogen optionally mono- or polysubstituted Ci-C ₃ alkyl or

Ci-C ₃ alkoxy, and

V ¹ , V ² and V ^{3 are} independently hydrogen or halogen or a

Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or

C i -C ₃ alkoxy-C i -C ₃ alkyl radical, and / or

V ¹ and V ² with the carbon atoms to which they are attached, a saturated or

CKE for one of the groups

wherein

U is an optionally substituted by Q ³ and Q ⁴ methylene group, and

A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

a C3-C ₇ -cycloalkyl or 4- to 7-membered monocyclic

Heterocyclylrest which may be mono- or polysubstituted by identical or different substituents with halogen and / or a Ci-C3-alkyl radical, and

B is hydrogen or a Ci-C _ö alkyl or

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical, or A and B together with the carbon atom to which they are attached form a saturated or unsaturated, optionally one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy

Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₃ alkoxy, alkyl-C _3,

C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, halogen-C 1 -C 3 -alkyl or halogeno-C 1 -C 3 -alkoxy or

c) a C ₃ -C ₇ cycloalkyl or 4- to 7-membered monocyclic

Heterocyclyl radical which is optionally substituted on the ring system by halogen, hydroxy and / or a C ₁ -C ₃ -alkyl radical, halogeno-C ₁ -C ₃ -alkyl radical, C ₁ -C ₃ -alkoxy radical,

Halo-C 1 -C 3 -alkoxy- and / or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl radical may be mono- or polysubstituted by identical or different substituents, and / or d) two of the radicals R ¹ , R ² and R ³ together with the ring atom (s) of the cycle T ² to which they are attached can form a further saturated or aromatic, optionally containing one or two heteroatoms, cycle T ³ having 5 to 7 ring atoms which is mono- or polysubstituted by identical or different substituents may be with the radicals R ⁴ , R ⁵ and R ⁶ ,

where R ⁴ , R ⁵ and R ⁶ independently of one another represent a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical, and

D is hydrogen or a C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl radical or a C ₃ -C ₇ -cycloalkyl or 4- to 7-membered monocyclic heterocyclyl radical,

where the radicals mentioned are optionally substituted by halogen and / or hydroxyl and / or a C ₁ -C ₃ -alkyl, halogen-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-,

Halogeno-C ₁ -C ₃ -alkoxy- and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents, or

if CKE is group 8,

A and D alternatively together with the atoms to which they are attached form a saturated or unsaturated and optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms, which may be bridged and the ring-forming atoms one or more times, the same or may be substituted differently with the radicals R ⁷ , R ⁸ and R ⁹ , wherein R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical, and

C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halogen-C ₃ -C 4 -alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl may be monosubstituted or polysubstituted, the same or different,

Q ^{1 is} hydrogen or

represents an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₃ alkyl or Ci-C ₃ alkoxy or

for a C ₃ -C ₇ cycloalkyl or 4- to 7-membered monocyclic

Heterocyclylrest which optionally with halogen, hydroxy and / or a CC ₃ alkyl, halogeno-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy- , and / or halogeno-C ₁ -C ₃ -alkoxy may be mono- or polysubstituted by identical or different substituents, and

Q ² , Q ⁴ , Q ⁵ and Q ⁶ are each independently hydrogen or one

Ci-C ₃ alkyl, and

Q ^{3 is} hydrogen or

Q ³ and Q ⁴ together with the carbon atom to which they are attached, a

saturated and optionally containing at least one heteroatom cycle T ⁷ having 5 to 7 ring atoms, the ring-forming atoms with halogen, hydroxy and / or a Ci-C ₃ alkyl, halo-Ci-C ₃ alkyl, Ci-C ₆ Alkoxy, halo-C ₃ -C ₃ alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents. A particularly preferred group of compounds of the general formula (I) for use as medicaments form compounds of the general formula (I),

in which

X is halogen or an optionally halogen with one or more times

substituted C ₁ -C ₃ -alkyl radical, and

W and Y independently of one another represent hydrogen or a C 1 -C 3 -alkyl radical which is optionally monosubstituted or polysubstituted by halogen,

V ¹ , V ² and V ³ independently of one another represent hydrogen, halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -haloalkyl radical, and

CKE one of the groups

(1 1) stands,

wherein

U represents an optionally substituted by Q ³ and Q ⁴ methylene group,

A is hydrogen or an optionally halogen with or

polysubstituted C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or a C ₃ -C ₆ -cycloalkyl radical which is mono- or polysubstituted by halogen and / or a C ₁ -C ₃ -alkyl radical or differently substituted, and

B is hydrogen or a Ci-Cö-alkyl or

C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl radical, or A and B together with the carbon atom to which they are attached form a saturated cycle optionally containing one or two heteroatoms T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ , wherein R ¹ , R ² and R ^{3 are} independently

a) for an optionally substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C ₃ -alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy- or halo-Ci-C ₃ -alkoxy, and / or

b) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached form a further saturated or aromatic, optionally containing at least one oxygen atom cycle T ³ having 5 to 7 ring atoms can be substituted one or more times with a Ci-C ₃ alkyl, and

D is hydrogen or a Ci-C _ö alkyl or C ₃ -C ₇ cycloalkyl radical, wherein said radicals with halogen, hydroxy and / or Ci-C ₃ alkyl mono- or polysubstituted by identical or different substituents or if CKE is Group 8,

A and D alternatively together with the atoms to which they are attached form a saturated, optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms, which may be bridged and its ring-forming atoms mono- or polysubstituted by identical or different may be with the radicals R ⁷ , R ⁸ and R ⁹ ,

where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl radical, or

A and Q ¹ together with the atoms to which they are attached, an aromatic

Form cycle T ⁵ with 6 ring atoms whose ring-forming atoms may be monosubstituted or polysubstituted by halogen,

with the proviso that B and Q ^{2 are} then a bond, and Q ^{1 is} hydrogen or a C ₁ -C ₃ -alkyl radical, and

Q ² , Q ⁴ , Q ⁵ and Q ⁶ are each independently hydrogen or one

Ci-C ₃ alkyl, and

Q ^{3 is} hydrogen or a C ₁ -C ₃ -alkyl radical, or

Q ³ and Q ⁴ together with the carbon atom to which they are attached, a

form saturated cycle T ⁷ with 6 ring atoms whose ring-forming atoms with halogen and / or a Ci-C _ö alkyl radical may be mono- or polysubstituted by identical or different substituents.

Within the group of compounds of the general formula (I), depending on the CKE Group the following subgroups:

Compounds of the general formula (1-1)

Compounds of the general formula (1-2)

Compounds of the general formula (1-3)

Compounds of the general formula (1-4) Compounds of the general formula (1-5)

Compounds of the general formula (1-6)

Compounds of the general formula (1-7)

Compounds of the general formula (1-9)

Compounds of the general formula (1-11)

A preferred subgroup of compounds of general formula (I) for use as pharmaceuticals are compounds of general formula (1-1),

in which

X is halogen or

for a mono- or polysubstituted or optionally substituted by halogen Ci-C3-alkyl or Ci-C ₃ alkoxy, and

W and Y are independently hydrogen or halogen or

for a mono- or polysubstituted or unsubstituted or halogen-substituted C 1 -C 3 -alkyl radical, and

V ¹ , V ² and V ^{3 are} independently hydrogen or halogen or a

Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or

C _l -C ₃ alkoxy-C i -C ₃ alkyl radical, and / or

V ¹ and V ² with the carbon atoms to which they are attached, a saturated or

A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

for a C ₃ -C 7 -cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which is monosubstituted or polysubstituted by halogen and / or a C ₁ -C ₃ -alkyl radical, is identical or can be substituted differently, and

B is hydrogen or a Ci-Cö-alkyl or

C 1 -C ₃ alkoxy-C 1 -C ₃ -alkyl radical, or

A and B together with the carbon atom to which they are attached, a saturated or unsaturated, optionally containing one or two heteroatoms cycle T ² with 3 bis

8 form ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl,

C 1 -C ₄ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy, halogeno-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C 4 -alkyl C ₃ alkoxy radical and / or

c) two of the radicals R ¹ , R ² and R ³ together with the one or more ring atoms of the cycle T ² to which they are bonded, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7

Can form ring atoms which may be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ ,

wherein R ⁴ , R ⁵ and R ⁶ independently of one another represent a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical, and

D is hydrogen or

for a C ₃ -C ₇ -cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical, where the radicals mentioned are optionally substituted by halogen and / or hydroxyl and / or a C ₁ -C ₃ -alkyl radical, halogeno-C ₁ -C ₃ - Alkyl, C ₁ -C ₃ -alkoxy, halogeno-C ₁ -C ₃ -alkoxy and / or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical may be mono- or polysubstituted by identical or different substituents, or

A and D together with the atoms to which they are bound, a saturated or

unsaturated and possibly another heteroatom-containing cycle T ^{4 form} with 5 to 7 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ⁷ , R ⁸ and R ⁹ ,

where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical. In the formula (II), X can stand for:

for halogen or for a optionally mono- or polysubstituted with halogen Ci-C ₃ alkyl or dC ₃ alkoxy. In the formula (II) X may preferably stand for:

for chlorine, bromine or for a methyl, ethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

In the formula (I-1), X may be particularly preferably:

for chlorine or for a methyl radical.

In the formula (I-1), W and Y may independently stand for:

Hydrogen or halogen or an optionally mono- or polysubstituted with halogen Ci-C3-alkyl radical.

In the formula (I-1), W and Y independently of each other may preferably stand for:

Hydrogen, fluorine, chlorine or a methyl, ethyl or trifluoromethyl radical.

In the formula (I-1), W and Y independently of one another more preferably represent: hydrogen or a methyl radical.

In the formula (I-1), X, W and Y may be dependent on each other for:

X is chlorine or a methyl radical, W is hydrogen or a methyl radical and Y is hydrogen, fluorine, chlorine or a methyl radical, or

X and W are methyl and Y is hydrogen, or

X and Y are methyl and W is hydrogen, or

X is methyl, W is hydrogen and Y is chlorine or fluorine.

In the formula (I-1), X, W and Y, depending on one another, preferably stand for:

X is a methyl radical and W and Y are hydrogen, or

X and W are methyl and Y is hydrogen, or

X and Y are methyl and W is hydrogen. In the formula (II), V ¹ , V ² and V ^{3 may be} independently of one another for:

Hydrogen or halogen or

a Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical, and / or

V ¹ and V ² together with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ having 5 or 6 ring atoms whose ring-forming atoms are halogen and / or C ₁ -C ₃ - Alkyl radical may be mono- or polysubstituted by identical or different substituents. In the formula (II), V ¹ , V ² and V ^{3 may} independently of one another preferably stand for:

Hydrogen or fluorine, chlorine, bromine or

a methyl, -, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy,

Trifluoromethoxy or a Ci-C ₃ -alkoxy-Ci-C ₃ -alkylrest and / or

T ¹ with 5 or 6 ring atoms whose ring-forming atoms with fluorine, chlorine and / or a methyl or ethyl radical may be mono- or polysubstituted by identical or different substituents. In the formula (II), V ¹ , V ² and V ^{3 may} independently of one another preferably stand for:

is hydrogen, chlorine or fluorine or a methyl or trifluoromethyl radical.

In the formula (II), V ¹ , V ² and V ³ more preferably represent:

V ^{1 represents} hydrogen, chlorine or fluorine or a methyl or a trifluoromethyl radical, and

V ² and V ^{3 are} independently hydrogen, chlorine or fluorine.

In formula (II), V ¹ , V ² and V ^{3 may be} particularly preferably:

V ^{1 represents} chlorine, fluorine or a methyl radical

and

V ² and V ^{3 are} independently hydrogen, chlorine or fluorine.

In the formula (II), V ¹ can be extremely preferably chlorine or fluorine, in particular chlorine.

In formula (I-1), A can stand for:

for hydrogen or for a mono- or polysubstituted or optionally substituted by halogen Ci-C _ö alkyl or C i -C ₆ - alkoxy-C i -C ₆ alkyl or

In the formula (1-1), A may preferably stand for:

is hydrogen or an optionally halogen-substituted Ci-C4-alkyl or Ci-C3-alkoxy-Ci-C3-alkyl radical or

for a C3-C6-cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C 1 -C 3 -alkyl radical.

In the formula (1-1), A may more preferably stand for:

is hydrogen or an optionally halogen-substituted C 1 -C 4 -alkyl or C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl radical or a C 3 -C 6 -cycloalkyl radical.

In the formula (1-1), A may particularly preferably stand for:

Is hydrogen or a C ₁ -C ₄ -alkyl, methoxy-C ₁ -C ₂ -alkyl or C ₃ -C ₆ -cycloalkyl radical, in particular a methyl, ethyl, i-propyl, n-propyl, iso-butyl, sec-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclopentyl or cyclohexyl.

In the formula (1-1), B may stand for:

Is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical. In the formula (1-1), B may preferably stand for:

Is hydrogen or a C 1 -C 3 -alkyl radical, in particular a methyl, ethyl or n-propyl radical.

In the formula (1-1), B may more preferably stand for:

Is hydrogen or a methyl radical. In the formula (1-1), A and B together with the carbon atom to which they are bonded may form:

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halo-Ci-C ₃ -alkyl or halo-Ci-C ₃ -alkoxy and / or

c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ^{6 are} independently of one another a Ci-C ₃ alkyl or

Ci-C ₃ alkoxy.

In the formula (1-1), A and B together with the carbon atom to which they are attached may preferably form:

a saturated, optionally containing one or two hetero atom-containing cycle T ² of 3 to 8 ring atoms, one whose ring-forming atoms, or may be disubstituted by identical or different substituents selected from the radicals R ¹ and R ^2, wherein R ¹ and R2 ³ are independently a) for a optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy or halo-Ci-C ₃ alkoxy, and / or

b) the radicals R ¹ and R ^3, together with the ring atom of the cycle T ² to which they are attached, can form a further saturated cycle T ³ having 5 to 7 ring atoms and optionally containing one or two oxygen atoms, which is C ₃ alkyl may be mono- or di-substituted, or

b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² , to which they are attached, can form a further aromatic cycle T ³ having 6 ring atoms, which is mono- or disubstituted by a C ₁ -C ₃ -alkyl radical may be substituted In the formula (1-1), A and B together with the carbon atom to which they are attached may also preferably form:

a saturated, optionally containing one or two heteroatoms cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) for hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halo-C ₁ -C ₃ -alkoxy.

In the formula (1-1), A and B together with the carbon atom to which they are bonded may more preferably form:

a) a Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₃ alkoxy-Ci-C ₃ alkyl, Ci-C ₃ alkoxy-Ci-C ₃ - alkoxy, or Halogen-Ci-C ₃ -alkoxy, and / or

bi) R ¹ and R ² may form containing cycle T ³ with 5 to 7 ring atoms, the radicals, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, optionally containing one or two oxygen atoms, with a Ci- C ₃ alkyl may be mono- or di-substituted, or

b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² , to which they are attached, can form a further aromatic cycle T ³ with 6 ring atoms. In the formula (1-1), A and B together with the carbon atom to which they are attached may also more preferably form:

a) for hydroxy or

b) for a optionally substituted in the alkyl moiety with hydroxy Ci-C ₃ alkyl, Ci-C ₃ alkoxy, Ci-C2-alkoxy-Ci-C ₃ alkyl, Ci-C ₃ alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy. In the formula (II), A and B together with the carbon atom to which they are attached may also more preferably form:

a saturated, optionally containing an oxygen atom cycle T ² with 3 to 8

Ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) is a Ci-C ₃ alkyl, Ci-C ₄ Alkoxy, methoxy-Ci-C ₃ -alkyl, Ci-C ₂ -alkoxy-ethoxy- or 2,2,2-trifluoroethoxy and / or

bi) the radicals R ¹ and R ² together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms, the one or two times may be substituted with a methyl radical, or

bi) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² , to which they are attached, can form a further aromatic cycle T ³ having 6 ring atoms. In the formula (II), A and B together with the carbon atom to which they are attached may particularly preferably form:

a saturated, optionally containing an oxygen atom cycle T ² with 5 to 6

Ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) is a Ci-C3-alkyl, Ci-C4-alkoxy -, methoxy-Ci-C ₂ -alkyl or 2,2,2-trifluoroethoxy and / or

b) the radicals R ¹ and R ² together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms, the one or two times may be substituted with a methyl radical.

In the formula (I-1), A and B may also form particularly preferably together with the carbon atom to which they are attached:

a saturated, optionally containing an oxygen atom cycle T ² with 5 to 6

Ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently of one another a) for hydroxy or

b) a C ₁ -C ₃ -alkyl, hydroxy-methyl, C ₁ -C ₂ -alkoxy, methoxy-C ₁ -C ₂ -alkyl,

Trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy. In the formula (1-1), A and B together with the carbon atom to which they are bonded may extremely preferably form:

a saturated, optionally an oxygen atom-containing cycle T ² having 6 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² ,

where R ¹ and R ² independently of one another are a C ₁ -C 3 -alkyl, C ₁ -C 4 -alkoxy, methoxy-C ₁ -C ₂ -alkyl or 2,2,2-trifluoroethoxy radical.

In the formula (1-1), A and B together with the carbon atom to which they are attached may very preferably form a cyclohexane ring or tetrahydropyran ring.

When A and B together with the carbon atom to which they are attached form a

Form cyclohexane ring, then optionally present substituents R ¹ , R ² and R ^{3 of} the cycle formed by A and B T ^{2 are} preferably independently of one another hydroxy or a substituted in the alkyl moiety with hydroxy Ci-C ₃ alkyl, Ci-C2 Alkoxy- or methoxy-C ₁ -C ₂ -alkyl radical or for a pentafluoroethyl, trifluoromethyl or 2,2,2-trifluoroethoxy radical.

When A and B together with the carbon atom to which they are attached form a

Form cyclohexane ring, then the optionally present substituents R ^! and R ^{2 of} the cycle T ² formed by A and B more preferably independently of one another hydroxy or a C ₁ -C ₃ -alkyl, hydroxy-methyl, C ₁ -C ₂ -alkoxy, methoxy-C ₁ -C ₂ -alkyl -, trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy.

When A and B together with the carbon atom to which they are attached form a

Cyclohexane ring form, then is particularly preferred only one substituent, wherein R ^{1 is} a Ci-C ₃ alkyl, Ci-C ₂ alkoxy, methoxy-Ci-C ₂ alkyl, trifluoromethyl or

2,2,2-trifluoroethoxy radical.

In the formula (1-1), D may stand for:

Is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

for a C ₃ -C ₇ -cycloalkyl- or 4- to 7-membered monocyclic heterocyclyl radical, where the radicals mentioned are optionally substituted by halogen and / or hydroxy and / or a C ₁ -C ₃ -alkyl, -halo-C ₁ -C ₃ -alkyl -, Ci-C ₃ -alkoxy, halogen-Ci-C ₃ -alkoxy- or Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl radical one or more times, the same or different can be substituted. In the formula (1-1), D may preferably stand for:

Is hydrogen or a C ₁ -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl radical.

In the formula (1-1), D may more preferably stand for:

Is hydrogen or a C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl radical, in particular a methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentyl or cyclohexyl radical.

In the formula (1-1), D may particularly preferably stand for:

Hydrogen.

In the formula (1-1), A and D taken together with the atoms to which they are attached may form: a cycle T ⁴ having 5 to 7 ring atoms, its ring-forming atoms, or a saturated or unsaturated and optionally another heteroatom can be substituted several times, identically or differently with the radicals R ⁷ , R ⁸ and R ⁹ ,

where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical.

In the formula (1-1), A and D together with the atoms to which they are attached may preferably form:

a saturated optionally another heteroatom-containing cycle T ⁴ with 5 to 7 ring atoms.

In the formula (1-1), A and D together with the atoms to which they are bonded may more preferably form:

a saturated optionally sulfur as another heteroatom-containing cycle T ⁴ with

5 to 7 ring atoms.

In the formula (1-1), A and D together with the atoms to which they are attached may particularly preferably form:

a saturated optionally sulfur as another heteroatom-containing cycle T ⁴ with

6 ring atoms. A preferred subgroup of compounds of general formula (II) for use as medicaments are compounds of general formula (II),

in which

X is chlorine or a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ¹ , V ² and V ^{3 are} independently hydrogen, chlorine or fluorine or a

Methyl or a trifluoromethyl radical, and

A is hydrogen or an optionally substituted with halogen

C 1 -C ₄ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or

for a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical, and

B is hydrogen or a C ₁ -C ₃ -alkyl radical, or

A and B together with the carbon atom to which they are attached form a saturated,

optionally form one or two heteroatoms containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently

a) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl,

C 1 -C ₄ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy or halogeno-C ₁ -C ₃ -alkoxy, and / or

bi) R ¹ and R ² may form containing cycle T ³ with 5 to 7 ring atoms, the radicals, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, optionally containing one or two oxygen atoms, with a Ci- C ₃ alkyl may be monosubstituted or disubstituted, or b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² to which they are attached form a further aromatic cycle T ³ having 6 ring atoms, which may be monosubstituted or disubstituted by a C ₁ -C ₃ -alkyl radical, and

D is hydrogen or a Ci-C _ö alkyl or C ₃ -C ₇ cycloalkyl. A more preferred subgroup of compounds of general formula (II) to

Use as medicaments form compounds of the general formula (I-1),

in which

X is chlorine or a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ¹ , V ² and V ^{3 are} independently hydrogen, chlorine or fluorine or a

Methyl or a trifluoromethyl radical, and

A is hydrogen or an optionally substituted with halogen

Ci-C4-alkyl or Ci-C3-alkoxy-Ci-C3-alkyl residue or for a C3-C6-Cycloalkylrest, and B stands for hydrogen or for a Ci-C3-Alkylrest, or

optionally form a heteroatom-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently of one another a) for a C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-ci-

C ₃ alkoxy- or halo-C ₁ -C ₃ alkoxy, and / or

bi) R ¹ and R ² may form containing cycle T ³ with 5 to 7 ring atoms, the radicals, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, optionally containing one or two oxygen atoms, with a Ci- C3-alkyl radical may be monosubstituted or disubstituted, or b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² to which they are attached form a further aromatic cycle T ³ with 6 ring atoms, and

D is hydrogen or a Ci-C _ö alkyl or _C3-C7 cycloalkyl.

Another more preferred subgroup of compounds of general formula (I-1) for use as pharmaceuticals are compounds of general formula (I-1),

in which

X is chlorine or is a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ^{1 is} hydrogen, chlorine or fluorine or is a methyl or a

Trifluoromethyl radical, and

V ² and V ³ independently of one another represent hydrogen, chlorine or fluorine,

A is hydrogen or a Ci-C4-alkyl, methoxy-Ci-C2-alkyl or

is a C3-C6-cycloalkyl radical,

B is hydrogen or methyl, or

A and B together with the carbon atom to which they are attached form a saturated, optionally form an oxygen atom-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) one C ₁ -C ₃ -alkyl, C ₁ -C ₄ -alkoxy, methoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₂ -alkoxyethoxy or 2,2,2-trifluoroethoxy radical and / or

bi) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² , to which they are attached, can form a further aromatic cycle T ³ with 6 ring atoms, and

is hydrogen or a Ci-C4-alkyl or C3-C6-cycloalkyl radical. A particularly preferred subgroup of compounds of general formula (I-1) for use as medicaments are compounds of general formula (I-1),

in which

X is chlorine or is a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ^{1 is} chlorine, fluorine or a methyl radical, and

A and B together with the carbon atom to which they are attached form a saturated, optionally oxygen-containing cycle T ² having 5 to 6 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² ,

wherein R ¹ and R ^{2 are} independent of each other

a) for a Ci-C3-alkyl, Ci-C4-alkoxy, methoxy-Ci-C2-alkyl- or

2,2,2-trifluoroethoxy radical and / or

b) the radicals R ¹ and R ² together with the ring atom of the cycle T ² , to which they are attached, another saturated, optionally one or two

Cycle containing oxygen atoms T ^{3 can form} with 5 or 6 ring atoms, which may be mono- or di-substituted by a methyl radical, and

D stands for hydrogen. An equally particularly preferred subgroup of compounds of general formula (II) for use as medicaments form compounds of general formula (II) in which

X is chlorine or is a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ^{1 is} chlorine, fluorine or a methyl radical, and

A and B together with the carbon atom to which they are attached form a saturated, optionally oxygen-containing cycle T ² having 6 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , where R ¹ and R ² are each independently hydroxy or a C ₁ -C ₃ -alkyl, hydroxy-methyl, C ₁ -C ₂ -alkoxy-,

Methoxy-C 1 -C 2 -alkyl, trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy, and

D stands for hydrogen.

A preferred subgroup of compounds of general formula (I) for use as pharmaceuticals also form compounds of general formula (1-2),

in which

X is halogen or

W and Y are independently hydrogen or halogen or

V ¹ , V ² and V ^{3 are} independently hydrogen or halogen or a

C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy or C 1 -C ₃ -alkoxy-C 1 -C ₃ -alkyl, and / or V ¹ and V ² with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom containing cycle T ¹ with 5 or 6 ring atoms whose ring-forming atoms with halogen and / or a Ci-C3-alkyl radical may be monosubstituted or polysubstituted, the same or different,

A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

for a C3-C7-cycloalkyl radical or 4- to 7-membered monocyclic heterocyclyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C 1 -C 3 -alkyl radical, and

B is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical, or A and B together with the carbon atom to which they are bonded, a saturated or unsaturated, if appropriate form one or two heteroatoms containing cycle T ² with 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl,

C 1 -C ₄ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy, halogeno-C ₁ -C ₃ -alkyl- or halogen- Ci-C ₃ alkoxy and / or

c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached, another saturated or aromatic, optionally containing one or two heteroatoms cycle T ³ with 5 to 7 ring atoms can form mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ ,

where R ⁴ , R ⁵ and R ⁶ independently of one another represent a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical.

In the formula (1-2), X may stand for:

In the formula (1-2), X may preferably stand for:

chlorine, bromine or a methyl, ethyl, trifluoromethyl, difluoromethoxy or

Trifluoromethoxy.

In the formula (1-2), X may preferably stand for: Chlorine or a methyl radical.

In the formula (1-2), W and Y may independently stand for:

In the formula (1-2), W and Y independently of each other may preferably stand for:

Hydrogen, fluorine, chlorine or a methyl, ethyl or trifluoromethyl radical. In the formula (1-2), W and Y independently of each other may more preferably stand for:

Hydrogen or a methyl radical.

In the formula (1-2), X, W and Y may be dependent on each other for:

X and W are methyl and Y is hydrogen, or

X and Y are methyl and W is hydrogen, or

X is methyl, W is hydrogen and Y is chlorine or fluorine. In the formula (1-2), X, W and Y depending on each other may preferably stand for:

X is a methyl radical and W and Y are hydrogen, or

X and W are methyl and Y is hydrogen, or

X and Y are methyl and W is hydrogen. In the formula (1-2), V ¹ , V ² and V ^{3 may be} independently represented by:

Is hydrogen or halogen or a Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or Ci-C ₃ alkoxy-Ci-C ₃ - Alkyl radical, and / or

V ¹ and V ² together with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ having 5 or 6 ring atoms whose ring-forming atoms are halogenated and / or are halogenated.

C ₃ alkyl may be mono- or polysubstituted by identical or different substituents. In the formula (1-2), V ¹ , V ² and V ³ independently of each other may preferably stand for:

Hydrogen or fluorine, chlorine, bromine or

a methyl, -, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy,

Trifluoromethoxy or a Ci-C3-alkoxy-Ci-C3-alkyl radical and / or

V ¹ and V ² form with the carbon atoms to which they are attached a saturated or unsaturated and optionally at least one further heteroatom containing cycle T ¹ with 5 or 6 ring atoms whose ring-forming atoms with fluorine, chlorine and / or a methyl or Ethyl radical may be mono- or polysubstituted by identical or different substituents.

In the formula (1-2), V ¹ , V ² and V ³ independently of each other may preferably stand for:

is hydrogen, chlorine or fluorine or a methyl or trifluoromethyl radical.

In the formula (1-2), V ¹ , V ² and V ³ more preferably represent:

V ² and V ^{3 are} independently hydrogen, chlorine or fluorine.

In the formula (1-2), V ¹ , V ² and V ^{3 may} particularly preferably stand for:

V ^{1 represents} chlorine, fluorine or a methyl radical

and

V ² and V ^{3 are} independently hydrogen, chlorine or fluorine.

In the formula (1-2), V ¹ can be extremely preferably chlorine or fluorine, in particular chlorine.

In the formula (1-2), A may preferably stand for:

Hydrogen or

for a optionally substituted by halogen Ci-C4-alkyl or Ci-C3-alkoxy-Ci-C3-alkyl or

In the formula (1-2), A may more preferably stand for:

Hydrogen or

for an optionally halogen-substituted Ci-C4-alkyl or Ci-C3-alkoxy-Ci-C3-alkyl radical or for a C3-C6-cycloalkyl radical.

In the formula (1-2), A may particularly preferably stand for: Hydrogen or

for a C ₁ -C ₄ -alkyl, methoxy-C ₁ -C ₂ -alkyl- or for a C ₃ -C ₆ -cycloalkyl radical, in particular for a methyl, ethyl, i-propyl, n-propyl, iso- Butyl, sec.butyl, methoxymethyl,

Methoxyethyl, cyclopropyl, cyclopentyl or cyclohexyl.

In the formula (1-2), B may stand for:

In the formula (1-2), B may preferably stand for:

Hydrogen or a Ci-C3-alkyl radical.

In the formula (1-2), B may more preferably stand for:

Is hydrogen or a methyl radical.

In the formula (1-2), A and B together with the carbon atom to which they are attached may form:

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy and / or

Ci-C ₃ alkoxy.

In the formula (1-2), A and B together with the carbon atom to which they are bonded may preferably form: a saturated, optionally containing an oxygen atom cycle T ² with 3 to 8

Ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , where R ¹ and R ^{2 are} independently a) for a Ci-C3-alkyl optionally substituted in the alkyl moiety with hydroxy , C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy or halogeno-C ₁ -C ₃ -alkoxy, and / or

b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² , to which they are attached, can form a further aromatic cycle T ³ having 6 ring atoms, which is mono- or disubstituted by a C ₁ -C ₃ -alkyl radical may be substituted. In the formula (1-2), A and B together with the carbon atom to which they are attached may also preferably form:

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halo-C ₁ -C ₃ -alkoxy. In the formula (1-2), A and B together with the carbon atom to which they are bonded may more preferably form:

a saturated, optionally an oxygen or sulfur atom-containing cycle T ² having 5 to 7 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² ,

wherein R ¹ and R ^{2 are} independent of each other

a) a Ci-C ₃ alkyl, Ci-C ₃ alkoxy, Ci-C ₃ alkoxy-Ci-C ₃ alkyl or halo-Ci-C ₃ - alkoxy group and / or

b) the radicals R ¹ and R ² together with the ring atom of the cycle T ² , to which they are attached, can form a further saturated, optionally one or two oxygen atoms containing cycle T ³ with 5 or 6 ring atoms.

In the formula (1-2), A and B together with the carbon atom to which they are attached may also more preferably form: a saturated, optionally containing a heteroatom cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently

a) for hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C3-alkoxy, Ci-C ₂ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halo-C ₁ -C ₃ -alkoxy.

In the formula (1-2), A and B together with the carbon atom to which they are bonded may particularly preferably form:

a saturated, optionally containing an oxygen atom cycle T ² with 5 to 6

Ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , where R ¹ and R ^{2 are} independently of one another a) is a C ₁ -C ₃ -alkyl-, C ₁ -C 4 -alkyl radical Alkoxy, methoxy-Ci-C2-alkyl or 2,2,2-trifluoroethoxy and / or

In the formula (1-1), A and B together with the carbon atom to which they are attached may also particularly preferably form:

a saturated, optionally containing an oxygen atom cycle T ² with 5 to 6

Trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy. In the formula (1-2), A and B together with the carbon atom to which they are bonded may extremely preferably form:

a saturated, optionally an oxygen atom-containing cycle T ² having 6 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently

for a C ₁ -C ₃ -alkyl, C ₁ -C 4 -alkoxy, methoxy-C ₁ -C 2 -alkyl or 2,2,2-trifluoroethoxy radical. In the formula (1-2), A and B together with the carbon atom to which they are attached may very preferably form a cyclohexane ring or tetrahydropyran ring. When A and B together with the carbon atom to which they are attached form a

Form cyclohexane ring, then optionally present substituents R ¹ , R ² and R ^{3 of} the cycle formed by A and B T ^{2 are} preferably independently of one another hydroxy or a substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C2- Alkoxy or methoxy-Ci-C ₂ - alkyl radical or pentafluoroethyl, trifluoromethyl or 2,2,2-trifluoroethoxy.

When A and B together with the carbon atom to which they are attached form a

Cyclohexane ring form, then is particularly preferred only one substituent, wherein R ^{1 is} a Ci-C ₃ alkyl, CC ₂ alkoxy, methoxy-Ci-C ₂ alkyl, trifluoromethyl or 2,2,2-trifluoroethoxy stands.

A preferred subgroup of compounds of general formula (1-2) for use as pharmaceuticals are compounds of general formula (1-2),

in which

X is chlorine or a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ¹ , V ² and V ³ independently of one another are hydrogen, chlorine or fluorine or a methyl or a trifluoromethyl radical, and

A is hydrogen or an optionally substituted with halogen

C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical or

a C ₃ -C _Ö - cycloalkyl group which is monosubstituted by halogen and / or a Ci-C ₃ alkyl or polysubstituted by identical or different substituents can be, and

B is hydrogen or a C ₁ -C ₃ -alkyl radical, or

optionally form an oxygen atom-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) one optionally in the alkyl moiety with hydroxy-substituted C ₁ -C ₃ -alkyl,

C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy or halogeno-C ₁ -C ₃ -alkoxy, and / or bi) R ¹ and R ² may form containing cycle T ³ with 5 to 7 ring atoms, the radicals, together with the ring atom of the cycle T ^2, to which they are attached form a further saturated, optionally containing one or two oxygen atoms, with a Ci- C3-alkyl radical may be monosubstituted or disubstituted, or b2) the radicals R ¹ and R ² together with the adjacent ring atoms of the cycle T ² to which they are attached, can form a further aromatic cycle T ³ with 6 ring atoms, the may be mono- or disubstituted by a Ci-C3-alkyl radical. A more preferred subgroup of compounds of general formula (1-2) for use as pharmaceuticals are compounds of general formula (1-2),

in which

X is chlorine or a methyl radical, and

W and Y independently of one another represent hydrogen or a methyl radical,

V ^{1 is} hydrogen, chlorine or fluorine, and

A is hydrogen or a C ₁ -C ₃ -alkyl or C ₃ -C ₆ -cycloalkyl radical, and

B is hydrogen or methyl, or

A and B together with the carbon atom to which they are attached, a saturated, optionally containing an oxygen or sulfur atom cycle T ² with 5 to 7

Form ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² ,

wherein R ¹ and R ^{2 are} independent of each other

a) for a Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl- or

Halo-Ci-C ₃ -alkoxy and / or

A first group of the compounds of formula (I) described in the experimental part form compounds belonging to the prior art by way of specific disclosure. As far as is known, these are characterized in the present application by reference to the example number or table in the disclosing document.

A second group of the compounds of formula (I) described in the experimental section form compounds which fall under a generic disclosure of the prior art. These are characterized by the term "compound according to." A third group of the compounds of formula (I) described in the experimental section form compounds which are neither part of a specific disclosure of the prior art nor fall under a generic disclosure of the prior art

An object of the present application are the compounds of the second and third groups of the compounds of the formula (1-1) described in the experimental part:

- (5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene -2-one

- (5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-one

- (5s, 8s) -3- (4,4'-dichloro-3'-fluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -οη

- (5s, 8s) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3 -en-2-one

- 3- (4'-chloro-3,6-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2- on

- (5s, 8s) -4-hydroxy-8- (trifluoromethyl) -3- (3 ', 4', 5-trifluoro-4-methylbiphenyl-3-yl) -l-azaspiro [4.5] dec-3-ene -2-one

- 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 on

- (5s, 8s) -3- (4-chloro-3 ', 4'-difluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -οη

3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3 en-2-οη

- (5s, 8s) -3- (3 ^ 4'-difluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-one

- (5s, 8s) -3- (4'-chloro-3 ^ 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) azaspiro [4.5] dec-3-ene-2 -one

- (5s, 8s) -3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene -2-one

- (5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2- οη

- (5s, 8s) -4-hydroxy-8-methoxy-3- (3 ', 4', 5-trifluoro-4-methylbiphenyl-3-yl) -1-azaspiro [4.5] dec-3-ene

2- on

- (5s, 8s) -3- (4 ', 6-dichloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] decane

3-en-2-on

- (5s, 8s) -3- (4 ', 6-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (hydroxymethyl) -1-azaspiro [4.5] dec-3-ene-2-one

- (5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2-one

- (5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

- (5r, 8r) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] d ^ 3-ene-2 on

- (5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3 -en-2-one

- (5r, 8r) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene -2-one

- (5r, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-one

- (5r, 8r) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec -3-en-2-one

- (5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-one - (5s, 8s) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azas

3-en-2-one

- (5r, 8r) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-h ^

3-en-2-one

- (5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -1-azaspiro [4.5] dec-3 -en-2-on)

- (5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-yl en-2-one

- (5S, 7S) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2-one

- (5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 οη

- (5S, 7S) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one - 3 - (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8,8-dimethyl-1-azaspiro [4.5] dec-3-en-2-one

- 3 - (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-ene-2-one

- 3 - (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3 -ene-2-one

- (5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-isopropyl-1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (2'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 -οη

A further subject of the present application are the compounds of the formula (1-1) described in the experimental part for use as medicaments: - 3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8 oxa-l-azaspiro [4.5] dec-3-en-2-one

(1-1),

- (5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex. 1-2),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7-methyl-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex. 3)

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-en-2-one (Ex. 1-4) .

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-5),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-6), 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

(1-7), 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-7-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-8)

3- (4'-Chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-9 )

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-7-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-10),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-11),

4-hydroxy-3- [4-methyl-4 '- (trifluoromethyl) biphenyl-3-yl] -1-azaspiro [4.5] dec-3-en-2-one (Ex 1-12);

3 - (4,4'-dimethylbiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene-2-one (Ex. 1-13), 3- (4,4'- Dimethylbiphenyl-3-yl) -4-hydroxy-7-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-14), 3- (4,4'-dimethylbiphenyl-3-) yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-15), 3 - (4'-chloro-4-methylbiphenyl-3-yl) 4-hydroxy-1-methyl-1,5-dihydro-2H-pyrrol-2-one

(1-16),

3 - (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1 - (propan-2-yl) -1,5-dihydro-2H-pyrrol-2-one (Ex 1-17 )

3 - (4'-chloro-4-methylbiphenyl-3-yl) -1-cyclopropyl-4-hydroxy-1,5-dihydro-2H-pyrrol-2-one (Ex: 1-18),

3 - (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-5-methyl-1- (propan-2-yl) -1,5-dihydro-2H-pyrrol-2-one (Ex 1-19),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8,8-dimethyl-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-20),

7- (4'-chloro-4-methyl-biphenyl-3-yl) -8-hydroxy-1,3,8,8-tetrahydro-6H-pyrrolo [2, 1-c] [1,4-thiazine-6 on (ex: 1-21),

3 - (4'-chloro-4-methylbiphenyl-3-yl) -1-cyclohexyl-4-hydroxy-1,5-dihydro-2H-pyrrol-2-one (Ex: 1-22),

3 - (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-1-azaspiro [4.7] dodec-3-ene-2-one

(1-23),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8- (propan-2-yl) -1-azaspiro [4.5] dec-3-en-2-one (Ex -24)

4 '- (4'-Chloro-4-methylbiphenyl-3-yl) -3' -hydroxy-1,3-dihydrospiro [indene-2,2'-pyrrole] -5 '(rH) -one (Ex. 1 -25)

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.6] undec-3-en-2-one (Ex: 1-26), 3 - (4 ') Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1- (2-methylpropyl) -1,5-dihydro-2H-pyrrol-2-one (Ex: 1-27), 3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

(1-28),

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-3-ene-2 -οη (Ex. 1-29),

(5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -l-azaspiro [4.5] dec-3 -en-2-on (Ex: 1-30),

3- (4'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-3-ene-2-one ( Ex. 1-31),

3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) dec-3-ene -l-azaspiro [4.5]

2- on (Ex. 1-32),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-3-ene

2- on (Ex: 1-33),

1 l- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -12-hydroxy-1-oxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10-one (Ex. 34)

1 l- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -12-hydroxy-1-oxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10-one (Ex -35)

4-Hydroxy-3- (3 ', 4', 5'-trifluoro-4-methylbiphenyl-3-yl) -8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex -36)

3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-37) .

3- (4-Chloro-3,4 ', 5'-trifluorobiphenyl-3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-38 )

3- (4-Chloro-3'-fluoro-4'-methylbiphenyl-3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one (Ex. 39)

3- (4'-Fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-40), 3 - (4 -Chloro-4'-fluorobiphenyl-3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3 -ene-2-one (Ex: 1-41), (5s, 8s) - 3- (4'-Fluoro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2-one (Ex 1-42 )

(5s, 8s) -3- (3'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 οη (Ex. 1-43),

(5s, 8s) -3- (4-chloro-4'-fluorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex -44)

(5s, 8s) -3- (4'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-ene

2- on (Ex. 1-45),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-5- (methoxymethyl) -5-methyl-1,5-dihydro-2H-pyrrol-2-one (Ex 1-46 )

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-5- (2-methoxyethyl) -5-methyl-l, 5-dihydro-2H- pyrrol-2-one (Ex. 1-47),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-7-methoxy-1-azaspiro [4.4] non-3-en-2-one (Ex: 1-48),

Rel- (5R, 7R) -3- (4'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-7- (2-methyl-propoxy) -l-azaspiro [4.4] non-3-ene-2 -on (Ex. 1-49),

Rel- (5R, 7S) -3- (4'-chloro-4-methylbiphenyl-3-yl) -7- (2-ethoxyethoxy) -4-hydroxy-1-azaspiro [4.4] non-3-ene-2 -on (Ex. 1-50),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (methoxymethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-51),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (methoxymethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-52),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-ene

2- on (Ex: 1-53),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-54),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethyl) -l-azaspiro [4.5] dec-3-ene

2- on (Ex. 1-55),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-56),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (2-methoxyethyl) -l-azaspiro [4.5] dec-3-ene

2- on (Ex. 1-57),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-en-2-one (Ex: 1-58),

3 - (4'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-ene

2- on (Ex. 1-59),

1 l- (4'-chloro-4-methylbiphenyl-3-yl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-l 1-ene

10- on (Ex: 1-60),

1 l- (4,4'-dichlorobiphenyl-3-yl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10-one (Ex 1-61 )

11- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -12-hydroxy-2-methyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10- οη (Ex. 1-62),

1 l- (4'-chloro-4-methylbiphenyl-3-yl) -12-hydroxy-2-methyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10-one (1-63),

1 1- (4'-chloro-4-methylbiphenyl-3-yl) -12-hydroxy-2,3-dimethyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10 -oη (Ex. 1-64),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1, 1-dimethyl-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-en-2-one (1-65), 3 - (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-11-methyl-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-en-2-one (Ex 1-66),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-1,1,1-dimethyl-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-ene-2 on (Ex. 1-67),

1 l- (4,4'-dichlorobiphenyl-3-yl) -12-hydroxy-2-methyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-l-en-10-oo (Ex 1-68),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1-methyl-9,13-dioxa-1-azadispiro [4.2.5.2] pentadec-3-en-2-one (Ex. 1-69),

I l- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-l-en-10-oo (Ex 1-70),

II - (4,4'-dichlorobiphenyl-3-yl) -1,2-hydroxy-2,3-dimethyl-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10-one (1-71),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-7-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-72),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -7-ethoxy-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-73),

Rel- (5R, 7R) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethoxy) -1-azaspiro [4.5] dec-3-en-2-one (1-74),

3- (4'-Chloro-2,4,6-trimethyl-biphenyl-3-yl) -8-ethoxy-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-75 )

3 - (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-ene-2-one

(1-76),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex.1-77), 3- (4 ') Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-5-methyl-5- (propan-2-yl) -l, 5-dihydro-2H-pyrrol-2-one (Ex 1-78);

3- (3'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

(1-79),

3- (2 ', 5'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-80) .

3 - (3 ', 4'-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2-one (Ex 1-81) .

3 - (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-7-methyl-1-azaspiro [4.5] dec-3 -ene-2-one

(1-82), 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-propyl-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-83),

6- (4'-chloro-4-methyl-biphenyl-3-yl) -7-hydroxy-4-azaspiro [2.4] hept-6-en-5-one (Ex: 1-84), 3- (4 ') Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.4] non-3-en-2-one (Ex 1 -85), 3- (4'-chloro-4-methylbiphenyl) 3-yl) -5-cyclopropyl-4-hydroxy-5-methyl-1,5-dihydro-2H-pyrrol-2-one (Ex: 1-86),

(5r, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-8-methyl-1-azaspiro [4.5] dec-3-ene-2 -on (Ex. 1-87),

(5r, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -8-ethyl-4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 -on (Ex. 1-88),

(5r, 8r) -8-ethyl-3- (4'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 -on (Ex. 1-89),

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-on (Ex. 1-90

(5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one (Ex. 1-91)

(5s, 8s) -3- (4,4'-dichloro-3'-fluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] d en-2-one (Ex 1-92)

(5s, 8s) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-on (Ex. 1-93)

3- (4'-Chloro-3-6-difluoro-4-methylbiphenyl-3-yl) - ^

3-en-2-one (Example 1-94)

(5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4,3,3-en-2-one ( Ex. 1-95)

(5s, 8s) -4-hydroxy-8- (trifluoromethyl) -3- (3 4 ', 5-trifluoro-4-methylbiphenyl-3-yl) -l-azaspiro [4.5] dec-3-ene-2 on (Ex. 1-96)

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hyd

on (Ex. 1-97)

(5s, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4,3,3-en-2-one ( Ex. 1-98)

(5s, 8s) -3- (4-chloro-3,4'-difluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] de-ene-2-one (Ex -99)

3- (4'-Chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one (Ex -100)

(5s, 8s) -3- (3 ^ 4'-Difluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one (Ex. 1-101)

(5s, 8s) -3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l- azaspiro [4.5] dec-3-en-2-one (Ex. 1-102)

(5s, 8s) -3- (4,4'-dichloro-3'-fluorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one ( Ex. 1-103)

(5s, 8s) -3- (4-chloro-3,4'-difluorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex. 1-104)

(5s, 8s) -3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene 2-on (Ex. 1-105)

(5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2-one (Example 1-106)

(5s, 8s) -4-hydroxy-8-methoxy-3- (3 4 5-trifluoro-4-methylbiphenyl-3-yl) -1-azaspiro [4.5] dec-3-ene

2- on (Ex. 1-107)

(5s, 8s) -3- (4 ', 6-dichloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-

3-en-2-one (Ex. 1-108)

(5s, 8s) -3- (4 ', 6-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-109)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methyl-l-azaspiro [4.5] dec-3-ene

2- on (Ex. 1-110)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-ene 2-on (Example 1-111)

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-ene-2 on (Ex. 1-112)

(5s, 8s) -3- (4,4-dichloro-3'-fluoro-biphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-

3-en-2-one (Example 1-113)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (2-methoxyethyl) -l-azaspiro [4.5] dec-3 en-2-on (Example 1-114)

3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex: 1-115) (5s, 8s ) -3- (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-azaspiro [4.5] dec-3-ene-2-one (Ex 1-116 )

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (hydroxymethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex 1-117)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 οη (Ex. 1-118)

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] de-ene-2-one (Ex. 119) (5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-120 )

(5s, 8s) -3- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-121)

(5r, 8r) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one (1-122)

(5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-on (Ex. 1-123)

(5r, 8r) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-on (Ex. 1-124)

(5r, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one (Ex. 1-125)

(5r, 8r) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] decyl 3-en-2-one (Ex. 1-126)

(5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene -2-on (Ex. 1-127)

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro-3-en-2-one (Ex -128)

(5r, 8r) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec 3-en-2-one (1-129)

(5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-yl en-2-on (Ex. 1-130)

(5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-ene -2-on (Ex. 1-131)

(5s, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-132)

(5S, 7S) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex 1-133)

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex -134)

(5s, 8s) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2-one (1-135)

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one ( Ex. 1-136)

(5S, 7S) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one (Ex -137)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8,8-dimethyl-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-138) 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-139)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex 1-140)

- (5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-isopropyl-1-azaspiro [4.5] dec-3-en-2-one (Ex.

1-141)

- (5s, 8s) -3- (4'-chloro-2'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 -οη (Ex. 1-142)

- (5s, 8s) -3- (2 ', 4'-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Example 1-143)

- (5s, 8s) -3- (2'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 -οη (Ex. 1-144)

- (5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex. 1-146)

- (5r, 8r) -3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one (Ex. 1-147)

The present application further relates to the compounds of the formula (I-2) described in the experimental part for use as medicaments: 3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethyl-4-hydroxy -l-oxaspiro [4.5] dec-3-en-2-one (ex. 2-1),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex. 2-2),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-5,5-dimethylfuran-2 (5H) -one (Ex. 2-3),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-4),

3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-5,5-dimethylfuran-2 (5H) -one (Ex. 2-5), 4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-6),

- 3- (2'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one

(2-7),

6- (4'-chloro-4-methylbiphenyl-3-yl) -7-hydroxy-4-oxaspiro [2.4] hept-6-en-5-one (Ex: 2-8),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1,1-dioxaspiro [4.5] dec-3-en-2-one (Ex. 2-9), (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-10),

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-11) .

3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 12)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-13),

- 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-14),

1 l- (4'-chloro-4-methylbiphenyl-3-yl) -12-hydrox

on (ex: 2-15),

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-16),

3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-oxa-spiro [4.5] dec-3-ene

2- on (ex. 2-17),

3- (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-18 )

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (2-methoxyethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-19),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-20),

3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-21), 3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex: 2-22), 3 - (3'-Chloro-4 '-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-ene-2-one

(Ex. 2-23),

3- (4-chloro-3 ', 4', 5'-trifluorobiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one (Ex. 2-24), 3- (4-chloro-3 ', 4'-difluorobiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-25), (5s, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-1,9-dioxadispiro [4.2.4.2] tetradec-3-ene-2-one (Ex. 26)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-l, 9-dioxadispiro [4.2.4.2] tetradec-3-en-2-one

(Ex. 2-27),

(5r, 8s) -3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1,1'-dioxadispiro [4.2.4.2] tetradec-3-en-2-one (Ex. 2 -28)

3- (4'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-1,1'-dioxadispiro [4.2.4.2] tetradec-3-en-2-one (Ex. 2-29),

(5r, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1,1'-dioxadispiro [4.2.4.2] tetradec-3-ene-2-one (Ex 2-30),

(5r, 8s) -3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1,1'-dioxadispiro [4.2.4.2] tetradec-3-ene-2-one (2-31),

3- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) -1-oxaspiro [4.5] dec-3-en-2-one (2-32),

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (2,2,2-trifluoroethoxy) dec-3-ene -l-oxa-spiro [4.5]

2- on (Ex. 2-33),

3- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (2-34),

5-tert-butyl-3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxyfuran-2 (5H) -one (Ex: 2-35), 3- (4'-Chloro-4 -methylbiphenyl-3-yl) -4-hydroxy-8-propyl-1-oxaspiro [4.5] dec-3-en-2-one (ex: 2-36),

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-1,1,8-dioxaspiro [4.5] dec-3-en-2-one (Ex: 2-37), 3- (4 '-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 2-38), 3- (4'-chloro-4- methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex. 2-39),

3- (4'-chloro-4-methylbiphenyl-3-yl) -5-cyclohexyl-4-hydroxy-5-methyl-furan-2 (5H) -one

(2-40),

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1,8-dioxaspiro [4.5] dec-3-en-2-one (Ex. 2 41),

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxa-8-thiaspiro [4.5] dec-3-en-2-one (Ex: 2-42),

3- (4'-Chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 2-43), 3- (4 '-Chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-44),

3- (4'-Chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-5-methylfuran-2 (5H) -one (Ex: 2-45), 3- (4'-Chloro-4 , 6-dimethylbiphenyl-3-yl) -4-hydroxy-1,1-dioxaspiro [4.5] dec-3-en-2-one (Ex. 2 46),

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-propoxy-1-oxaspiro [4.5] dec-3-en-2-one (Ex: 2-47),

3- (4'-chloro-2,4,6-trimethylbiphenyl-3-yl) -4-hydroxy-l-oxa-spiro [4.6] undec-3-en-2-one

(2-48),

3- (4'-chloro-2,4,6-trimethylbiphenyl-3-yl) -4-hydroxy-l-oxa-spiro [4.4] non-3-en-2-one

(2-49),

3- (3'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.6] undec-3-en-2-one (Ex: 2-50),

A further subject of the present application are the compounds of the formula (1-3), (1-6), (1-7), (1-8), (1-9), (1-10) described in the experimental part. and (1-11) for use as drugs: 3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-thiaspiro [4.5] dec-3-ene-2 -on (Example 3-1)

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1-thiaspiro [4.5] dec-3-en-2-one (Ex. 3-2)

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-1-thiaspiro [4.5] dec-3-en-2-one (Ex. 3-3)

3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-1-thiaspiro [4.5] dec-3-en-2-one (Ex 3-4) - 3 - (4,4'-dimethylbiphenyl-3-yl) -4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex. 6-1)

3- (2 ', 4'-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex. 6-2)

3- (3'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex 6-3)

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxyspiro [4.4] non-3-en-2-one (Ex 6-4)

3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethyl-4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex 6-5) - 3- (4 ' -Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8-propyl-spiro [4.5] dec-3-en-2-one (Ex 6-6)

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-spiro [4.6] undec-3-en-2-one (Ex 6-7)

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex 6-8)

3- (4'-chloro-2,4,6-trimethyl-biphenyl-3-yl) -4-hydroxy-spiro [4.5] dec-3-en-2-one (Ex 6-9)

2- (4'-chloro-4-methylbiphenyl-3-yl) -3-hydroxy-5-methylcyclohex-2-en-1-one (Ex 7-1) - 3- (4'-chloro-4 -methylbiphenyl-3-yl) -4-hydroxyspiro [5.5] undec-3-en-2-one (Ex 7-2)

2- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -3-hydroxy-5,5-dimethylcyclohex-2-en-1-one (Ex 7-3)

2- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -3-hydroxy-4,4-dimethylcyclohex-2-en-1-one (Ex 7-4)

2- (4'-chloro-4-methylbiphenyl-3-yl) -3-hydroxy-5,5-dimethylcyclohex-2-en-1-one (Ex 7-5)

2- (4'-fluoro-2,4-dimethylbiphenyl-3-yl) tetrahydro-1H-pyrazolo [1,2-a] pyridazine-1,3-2H-dione (Ex 8-1)

2- (4,4'-dichlorobiphenyl-3-yl) -tetrahydro-1H-pyrazolo [1,2-a] pyridazine-1,3 (2H) -dione (Ex 8-2)

2- (4'-CMor-4-methylbiphenyl-3-yl) tetrahydro-1H-pyrazolo [1,2-a] pyridazine-1,3-2H-dione (Ex 8-3)

2- (3 ', 4-dichloro-4'-fluorobiphenyl-3-yl) tetrahydro-1H-pyrazolo [1,2-a] pyridazine-1,3-2H-dione (Ex. 8-4)

- 8- (2 4'-difluoro-4-methylbiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex. 8-5)

8- (4'-chloro-4-methylbiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex. 8 -6)

- 8- (4'-fluoro-2,4-dimethylbiphenyl-3-yl) -tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex 8-7) 8- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex. 8-8)

8- (2 4,4'-trichlorobiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex 8-9 )

8- (3,4,4'-trichlorobiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex 8-10 )

8- (4-chloro-2 ', 4'-difluorobiphenyl-3-yl) tetrahydro-7H-pyrazolo [1,2-d] [l, 4,5] oxadiazepine-7,9 (8H) -dione (Ex 8-11)

2- (4'-Chloro-4-methyl-biphenyl-3-yl) -6-fluoro-6-methyl-dihydro-1H, 5H-pyrazolo [1,2-a] pyrazol-1,3 (2H) -dione (Ex. 8-12)

2- (4,4'-dichlorobiphenyl-3-yl) -6-fluoro-6-methyl-dihydro-1H, 5H-pyrazolo [1,2-a] pyrazol-1,3 (2H) -dione (Ex. 13)

4- (4'-Chloro-4-methyl-biphenyl-3-yl) -l, 2-dimethyl-1H-pyrazole-3,5 (2H, 4H) -dione (Ex: 8-14) 4- (4,4 '-Dichlorobiphenyl-3-yl) -1,2-dimethyl-1H-pyrazole-3,5 (2H, 4H) -dione (Ex 8-15)

2- (4'-Chloro-4-methyl-biphenyl-3-yl) -tetrahydro-1H-5,8-methano-pyrazolo [1,2-a] pyridazine-1,3 (2H) -dione (Ex 8-16)

2- (4,4'-dichlorobiphenyl-3-yl) tetrahydro-1H-5,8-methano-pyrazolo [1,2-a] pyridazine-1,3 (2H) -dione (Ex 8-17)

3 - (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-6,6-dimethyl-5,6-dihydropyridine-2 (1H) -one (Ex. 9-1)

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-5,5-dimethyl-5,6-dihydropyridine-2 (1H) -one (Ex. 9-2)

4- (4'-Chloro-4-methyl-biphenyl-3-yl) -5-hydroxy-2-azaspiro [5.5] undec-4-en-3-one (Ex 9-3)

3 - (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxy-1, 6,6-trimethyl-5,6-dihydropyridin-2 (1H) -one (Ex 9-4) 9

3- (4'-Chloro-4-methylbiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex. 9-5)

7-Chloro-4-hydroxy-3- [4-methyl-4 '- (trifluoromethyl) biphenyl-3-yl] quinoline-2 (1H) -one (Ex: 9-6) 7-Chloro-3- (3 ', 4'-dichloro-4-methylbiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex: 9-7) 3- (4'-chloro-4-methylbiphenyl-3-yl) - 7-fluoro-4-hydroxyquinoline-2 (1H) -one (Ex 9-8)

7-Fluoro-3- (4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex. 9-9)

7-Fluoro-4-hydroxy-3- [4-methyl-4 '- (trifluoromethyl) biphenyl-3-yl] quinoline-2 (1H) -one (Ex 9-10) 7-Chloro-3- (4 '-chloro-4-methylbiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex 9-11)

7-Chloro-3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex 9-12) 7-Chloro-3- (4,4 '-dichlorobiphenyl-3-yl) -4-hydroxyquinoline-2 (1H) -one (Ex 9-13)

3- (4'-Chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-5,5,6,6-tetramethyl-5,6-dihydropyridin-2 (1H) -one (Ex. 9-14) 3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-5,5,6,6-tetramethyl-5,6-dihydro-2H-pyran-2-one (Ex. 10-1)

3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-5,5,6,6-tetramethyl-5,6-dihydro-2H-pyran-2-one (Ex. 2)

4- (4'-chloro-4-methylbiphenyl-3-yl) -2,6,6-trimethyl-1,2-oxazinan-3,5-dione (Ex 11-1)

Saturated or unsaturated hydrocarbon radicals such as alkyl, alkanediyl or alkenyl may also be used in conjunction with heteroatoms, e.g. in alkoxy, as far as possible, in each case straight-chain or branched.

Unless otherwise specified, optionally substituted radicals may be monosubstituted or polysubstituted, with multiple substituents the substituents being the same or different.

Also to be considered as encompassed by the present invention are all compounds which result from any combination of the above-mentioned possible, preferred and particularly preferred meanings of the substituents.

Particular embodiments of the invention moreover exist in compounds which result from combination of the substituent meanings disclosed directly in the examples.

Also to be considered as encompassed by the present invention is the use of the physiologically acceptable salts of the compounds.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of

Hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine. Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these routes of administration, the compounds of the invention can be used in suitable

Administration forms are administered.

For the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and

Information preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For the other routes of administration, for example, inhalation medicaments (ia

Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or

Ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g.

Sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g.

Antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

As excipients, for example, vehicles, fillers, disintegrants,

Binders, humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts to change the osmotic pressure or buffers are used.

Reference may be made to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980). The pharmaceutical formulations can

in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or

in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, tinctures, suspensions or emulsions.

For the purposes of the invention, auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,

Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.

For oral or oral administration, in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.

For parenteral administration in particular suspensions, emulsions and above all solutions in question.

The present invention relates to the use of the compounds according to formulas (I), (I-I) and (I-2) for the prophylaxis and therapy of human diseases, in particular of tumor diseases.

The compounds according to the formulas (I), (I-I) and (I-2) can be used in particular to inhibit or reduce cell proliferation and / or cell division and / or to induce apoptosis.

The compounds of the invention are particularly suitable for the prophylaxis and / or treatment of hyper-proliferative diseases such as

Psoriasis,

Keloids and other skin-related hyperplasias

- benign prostate hyperplasia (BPH),

solid tumors and

hematological tumors. As solid tumors according to the invention, for example, tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland, are treatable Bone and connective tissue and metastases of these tumors.

As haematological tumors according to the invention, for example, treatable multiple myelomas, lymphomas or leukemias.

For example, treatable as breast tumors are:

- Breast cancer with positive hormone receptor status

Breast cancer with negative hormone receptor status

Her-2 positive breast cancers

Hormone receptor and Her-2 negative breast cancers

BRCA-associated breast cancer

- inflammatory breast cancer.

For example, tumors of the respiratory tract are treatable

non-small cell lung cancers and

small cell bronchial carcinomas.

For example, tumors of the brain are treated;

gliomas,

glioblastomas,

astrocytomas,

Meningiomas and

Medulloblastomas.

As tumors of the male reproductive organs, for example, be treated;

prostate cancers,

Malignant testicular tumors and

Penis cancer. Treatable as tumors of the female reproductive organs, for example: endometrial carcinomas

cervical cancer

ovarian cancer

- vaginal carcinomas

Vulvarkarzinome

For example, tumors of the gastrointestinal tract are treatable:

Colorectal carcinomas

- Anal carcinomas

gastric cancers

pancreatic cancer

Ösophagukarzinome

Gallbladder carcinomas

- Small intestinal carcinomas

Salivary gland carcinomas

Neuroendocrine tumors

Gastrointestinal stromal tumors As tumors of the urogenital tract, for example, are treatable:

bladder cancer

Renal cell carcinoma

Carcinomas of the renal pelvis and the urinary tract As tumors of the eye, for example, are treatable:

retinoblastoma

Intraocular melanomas

Treatable as tumors of the liver, for example:

- Hepatocellular carcinomas

Cholangiocellular carcinomas For example, tumors of the skin are treatable:

Malignant melanomas

Basal cell carcinomas

squamous

- Kaposi's sarcoma

Merkel cell carcinoma

Tumors of the head and neck, for example, are treatable:

laryngeal cancer

- Carcinoma of the pharynx and oral cavity

For example, sarcomas are treatable:

Soft tissue sarcomas

osteosarcomas

For example, lymphomas are treatable:

Non-Hodgkin's lymphoma

Hodgkin's lymphoma

Cutaneous lymphoma

- Lymphomas of the central nervous system

AIDS-associated lymphomas

Treatable as leukemias, for example:

Acute myeloid leukemias

Chronic myeloid leukemias

Acute lymphocytic leukemia

Chronic lymphocytic leukemia

Hair Cell Leukemias The compounds according to the formula (I), (I-1) and (1-2) can be used with particular advantage for the prophylaxis and / or therapy of:

Breast cancers, in particular of hormone receptor negative, hormone receptor positives or BRCA-associated breast carcinomas, as well as

Pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma, colorectal carcinoma and prostate carcinoma.

These diseases are well characterized in humans but also exist in others Mammals.

Another object of the present application are the compounds according to the formula (I), (I-l) or (1-2) for use as medicaments, in particular for the prophylaxis and / or therapy of tumor diseases.

A further subject of the present application are the compounds according to the formula (I), (I-1) or (1-2) for the prophylaxis and / or therapy of breast cancers,

Pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, non-small cell carcinomas, bronchial carcinomas, endometrial carcinomas, colorectal carcinomas or prostate cancers.

Another object of the invention is the use of the compounds of the general formula (I) according to the invention, in particular also of the formulas (I-I) and (1-2) for the preparation of a medicament.

Another object of the present application is the use of the compounds according to the formula (I), (I-l) or (1-2) for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases. Another object of the present application is the use of the compounds according to the formula (I), (II) or (1-2) for the manufacture of a medicament for the prophylaxis and / or therapy of breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cells,

Bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or

Prostate cancer.

A further subject of the present application is the use of the compounds according to the formula (I), (II) or (1-2) for the prophylaxis and / or therapy of tumor diseases. A further subject of the present application is the use of the compounds of the formula (I), (II) or (1-2) for the prophylaxis and / or therapy of breast cancers, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, not Single cell, bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer. A further subject of the present application are pharmaceutical formulations in the form of tablets containing a compound according to formula (I), (1-1) or (1-2) for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignancies Melanoma and other skin tumors, non-small cells, bronchial carcinomas, endometrial carcinomas, colorectal carcinomas or prostate cancers.

Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. The present invention therefore further relates to medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the prophylaxis and / or therapy of the abovementioned disorders.

For example, the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers. The combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.

Examples of suitable combination active ingredients are:

Afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabine, arsenic trioxide, aromasine, 5-azacytidine, azathioprine, BCG or tice-BCG, Bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefeson, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, DaunoXome, Decadron, Decadron Phosphate, Delestrogen, Denileukin Diftitox, Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxorubicin, Dronabinol, DW-166HC, Eligard, Elitek, Ellence, Emend, Epirubicin , Epoetin-alfa, Epogen, Eptaplatin, Ergamisole, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid, Etopophos, Etoposide, Fadrozole, Farst on, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, Fosteabin, Fotemustin, fulvestrant, Gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocortone, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2a , Interferon-alpha-2β, Interferon-alpha-nl, Interferon-alpha-n3, Interferon-beta, Interferon-gamma-1α, Interleukin-2, Intron A, Iressa, Irinotecan, Kytril, Lapatinib, Lentinan sulfate, Letrozole .

Leucovorin, Leuprolide, Leuprolide Acetate, Levamisole, Levofolic Acid Calcium Salts, Levothroid, Levoxyl, Lomustine, Lonidamine, Marinol, Mechlorethamine, Mecobalamin, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan, Menest, 6-Mercaptopurine, Mesna, Methotrexate, Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotane, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Nolvadex, NSC-631570, OCT-43, Octreotide,

Ondansetron Hydrochloride, Orapred, Oxaliplatin, Paclitaxel, Pediapred, Pegaspargase, Pegasys, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium, Prednimustine, Prednisolone, Prednisone, Premarin, Procarbazine, Procrit, Raltitrexed, RDEA119, Rebif, Rhenium-186-etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustin, sizofiran, sobuzoxan, solu-medrol, streptozocin, strontium-89-chloride, synthroid, tamoxifen, tamsulosin, tasonermine, tastolactone, taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexall,

Trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizine, zinecard, zinostatin stalinamer, zofran; ABI-007, Acolbifen, Actimmun, Affinitak, Aminopterin, Arzoxifen, Asoprisnil, Atamestan, Atrasentan, BAY 43-9006 (Sorafenib), Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium 166-DOTMP, ibandronic acid, interferon gamma, intron PEG, ixabepilone, keyhole limpet Hemocyanin, L-651582, Lanreotide, Lasofoxifene, Libra, Lonavalnib, Miproxifen, Minodronate, MS-209, Liposomal MTP-PE, MX-6, Nafarelin, Nemorubicin, Neovastat, Nolatrexed, Oblimersen, Onko-TCS, Osidem, Paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnas, 13-c-retinoic acid, satrapinate, seocalcitol, T-138067, tarceva, taxoprexin, thymosin-alpha -1, tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledron acid, as well as combinations thereof. In a preferred embodiment, the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:

Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,

Dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodoxycytidine, docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin, ifosfamide, interferon, irinotecan, leucovorin, lomustine,

Mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, prednisolone, prednisone, Procarbazine, raloxifene, semustin, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, trimethylmelamine, uridine, vinblastine, vincristine, vindesine and vinorelbine.

Promisingly, the compounds of the invention may also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.

The compounds according to the invention can also achieve positive effects in combination with other anti-angiogenic therapies, for example with avastin, axitinib, regorafenib, recentin, sorafenib or sunitinib. Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.

In general, the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims:

• improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;

• the possibility of using the chemotherapeutic agents used in lower doses than in monotherapy;

• the possibility of a more tolerable therapy with fewer side effects compared to a single dose;

• the ability to treat a wider range of tumors; • achieving a higher response rate to therapy;

• longer patient survival compared to today's standard therapy.

In addition, the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.

Comparative Examples

Table V.1 lists related structures of the prior art and indicates in which law manufacturing is disclosed.

Table V.l

Compounds according to formula (II)

The compounds of the formula (I-1) according to the invention are known and / or can be prepared using the synthesis routes A and / or B.

Synthesis route A

An arylbromide derivative of the form

in which A, B, D, W, X and Y have the meanings given above, is reacted in a Suzuki coupling with Verbindun (III)

in which V ¹ , V ² and V ^{3 have} the meanings given above, and

Z ^{1 is} -B (OH) ₂ , a boronic acid ester, preferably boronic acid pinacol ester, or -BF ₃ T.

The Suzuki couplings are generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, preferably in a temperature range from room temperature to 130 ° C at atmospheric pressure. The reactions can also be carried out in a closed vessel with heating in the microwave.

For example, catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium on carbon, palladium (II) acetate,

Palladium (II) acetate / triscyclohexylphosphine, palladium (II) acetoacetonate / tri-tert-butylphosphonium tetrafluoroborate, dichloro [1,1 '-bis (diphenylphosphino) ferrocene] palladium

Dichloromethane complex or palladium (II) acetate with a ligand such as dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl-2-yl] phosphine.

Additional reagents are, for example, potassium or cesium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride, potassium phosphate or sodium or

Potassium hydroxide, preferred are additional reagents such as cesium carbonate and / or aqueous Sodium hydroxide solution.

Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, or alkyl sulfoxides, such as dimethyl sulfoxide, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is 1,2-dimethoxyethane.

The compounds of the formula (II) are known and / or can be prepared by reacting compounds of the formula (IV)

in which A, B, D, W, X and Y have the meanings given above, and

Z ^{2 is} Ci-C _ö alkyl, preferably ethyl or methyl, is reacted under Dieckmann condensation conditions.

The Dieckmann condensations are generally carried out in inert solvents in the presence of a base, preferably in a temperature range from room temperature to 130 ° C at

Normal pressure.

Examples of bases are alkali metal or alkaline earth metal alkoxides, such as sodium or potassium tert-butoxide, sodium methoxide or ethoxide, potassium tert-butoxide being preferred.

Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, or alkyl sulfoxides, such as dimethyl sulfoxide, or alcohols, such as methanol or ethanol, preference being given to dimethylformamide ,

The compounds of the formula (IV) are known and / or can be prepared by reacting compounds of the formula (V) or a salt of compounds of the formula (V)

in which A, B, D and Z ^{2 have} the meanings given above, with compounds of the formula (VI)

in which X, Y and W have the meanings given above, under amide coupling conditions. The reaction is generally carried out in inert solvents by reacting the compounds of the formula (VI) first with thionyl chloride or an equivalent reagent known to those skilled in the art and in the second stage with compounds of the formula (V) or a salt of

Compounds of formula (V) in the presence of a base such as. B. triethylamine or

Be implemented potassium carbonate. In an alternative method, the reaction in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably in a temperature range of -30 ° C to 50 ° C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, nitromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred are acetonitrile, dichloromethane, dimethylformamide, tetrahydrofuran or toluene.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Examples of suitable dehydrating reagents are carbodiimides such as N, N-diethyl, N, N'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo) 3-oxazolidinyl) -phosphoryl chloride, or 0- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) 1, 1, 3, 3-tetramethyluronic acid tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -NNN'N'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide, or mixtures thereof, with bases.

Preferably, the condensation is carried out with PyBOP, TBTU or with EDC in the presence of HOBt.

The method described above is illustrated by the following synthesis scheme:

a): 1. SOCl ₂ , 80 ° C, 2. K ₂ C0 ₃ , acetonitrile, room temperature;

b): KOtBu, DMF, 80 ° C;

c): cat. Dichloro [l, r-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex, CS2CO3,

1, 2-dimethoxyethane / water, reflux. Synthesis route B

Alternatively, the compounds of the formula (1-1) according to the invention can be prepared by reacting a compound of the formula (VII)

in which A, B, D, W, X, Y, V ¹ , V ² , V ³ and Z ^{2 have} the if aannggeeggeebbeenen meanings, under the above conditions in a Dieckmann condensation reaction.

The compounds of the formula (VII) are known and / or can be prepared by reacting compounds of the formula (V) or a salt of compounds of the formula (V) in which A, B, D and Z ^{2 have} the meanings given above , with compounds of the formula (VIII)

in which X, Y, W, V ¹ , V ² and V ^{3 have} the meanings given above, under the abovementioned amide coupling conditions.

The compounds of the formula (VIII) are known and / or can be prepared by reacting compounds of the formula (IX)

in which X, Y and W have the abovementioned meanings, in a Suzuki reaction under the abovementioned conditions with compounds of the formula (III) in which V ¹ , V ² , V ³ and Z ^{1 have} the meanings given above, implements.

b)

a): cat. Palladium (II) acetylacetonate, cat. Tri-tert-butylphosphonium tetrafluoroborate, NaOH,

THF / water;

b): 1. SOCl ₂ , 80 ° C, 2. K ₂ C0 ₃ , acetonitrile, room temperature;

c): KOtBu, DMF, 80 ° C].

The compounds of the formulas (I-I) and (II) prepared by the abovementioned processes optionally carry protective groups which can be eliminated by the conditions known to the person skilled in the art in order to obtain further compounds of the formulas (I-I) and (II).

Thus, e.g. Compounds of the formula (I-la) according to the invention

in which D, X, Y, W, V ¹ , V ² and V ^{3 have} the meanings given above,

in which D, X, Y, W, V ¹ , V ² and V ^{3 have} the meanings given above, cleaves. The reaction is generally carried out in inert solvents by reacting the compounds of formula (I-Ib) with sodium iodide / trimethylsilyl chloride or with trimethylsilyl iodide or with boron tribromide or with boron trichloride or with hydrogen bromide / acetic acid or with

Aluminum tribromide / ethanethiol or equivalent reagent known to those skilled in the art may under certain circumstances be reacted in the presence of a base in a temperature range from -78 ° C. to the reflux of the particular solvent at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, tetrahydrofuran, 1,4-dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred are acetonitrile and dichloromethane. Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preferably, the cleavage is carried out with sodium iodide / trimethylsilyl chloride in acetonitrile.

Thus, e.g. Compounds of the formula (IIa) according to the invention

in which D, X, Y and W have the meanings given above, and

Z ^{3 is} fluorine or trifluoromethyl, prepared by reacting ketones of the formula (IIb)

in which D, X, Y and W have the meanings given above, with

(Trifluoromethyl) trimethylsilane or (pentafluoroethyl) trimethylsilane. The reactions of the ketones of the formula (IIb) with (trifluoromethyl) trimethylsilane or

(Pentafluoroethyl) trimethylsilane to the compounds of formula (IIa) are generally carried out in inert solvents, in the presence of a catalyst, preferably in a temperature range from -20 ° C to 100 ° C at atmospheric pressure. Catalysts are, for example, alkali or

Alkaline earth carbonates such as sodium, potassium or cesium carbonate. Furthermore, alkali metal, alkaline earth fluorides such as lithium and cesium fluoride and fluoride salts of organic bases such as tetraethylammonium fluoride or tetrabutylammonium fluoride can be used to catalyze the desired reaction. Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or carboxylic acid amides, such as

Dimethylformamide, dimethylacetamide or N-methylpyrrolidone, or alkyl sulfoxides such as dimethyl sulfoxide, preferred is dimethylformamide. The primary silyl derivatives of the formula (IIa) are finally cleaved according to methods known to those skilled in the art (see Protective Groups in Organic Synthesis, Theodora W. Greene).

The compounds of the formula (IIb) are known and / or can be prepared by reacting the ketal protecting group in compounds of the formula (IIc)

in which D, W, X and Y have the abovementioned meanings, according to methods known to those skilled in the art (see Protective Groups in Organic Synthesis, Theodora W. Greene). Abbreviations and acronyms:

Ac acetyl

Bn benzyl

Bu Butyl

cat. catalytic

CI chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

d. Th. Of theory (at yield)

EI electron impact ionization (in MS)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

EtOAc ethyl acetate

h hour (s)

HPLC high pressure, high performance liquid chromatography i. Vak. in a vacuum

conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

Me methyl

min minute (s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Ph phenyl

RT room temperature

R, retention time (by HPLC)

THF tetrahydrofuran

UV ultraviolet spectrometry

aq. aqueous, aqueous solution LC-MS and HPLC methods:

Method 1 (UPLC-MS)

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7

50x2.1mm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nM.

Method 2 (UPLC-MS):

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nM. Method 3 (UPLC-MS):

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7

Method 4 iHPLC-MS):

Instrument MS: Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column: Acquity BEH C18 (Waters), 50 mm x 2.1 mm, 1.7 μιη; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile (Lichrosolv Merck); Gradient: 0.0 min 99% A - 1.6 min 1% A - 1.8 min 1% A - 1.81 min 99% A - 2.0 min 99% A; Oven: 60 ° C; Flow: 0.800 ml / min; UV detection PDA 210-400 nm.

Table 1 lists some structures of the prior art formula (I-1) and indicates in which law the preparation is disclosed.

Table 1

3:54

(m, -

2H), (d, -

(m, - (d, -

Starting compounds and intermediates for compounds of the formula (1-1):

Example 1A

(4'-chloro-4-methylbiphenyl-3-yl) acetyl chloride

5.00 g (19.18 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetic acid (EP 2029531 Al and US 2009/298828 Al) were dissolved in 36.51 g (306.84 mmol) of thionyl chloride. The reaction mixture was stirred for four hours at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 5.4 g (100% of theory) of the title compound were obtained as a brownish oil.

'H-NMR (300MHZ, CDC1 ₃ ): δ [ppm] = 2.36 (s, 3H), 4.22 (s, 2H), 7.29 (d, 1H), 7.35-7.55 (m, 6H). Example 2A

Methyl cis- 1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4- (trifluoromethyl) -cyclohexanecarboxylate

5.00 g (19.09 mmol) of methyl cis-l-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (EP 1220841 A2 and WO 2001/23354 A3), 4.83 g (47.73 mmol) of triethylamine and 117 mg (0.955 mmol) of Ν, Ν- Dimethylaminopyridine was dissolved at room temperature in 40 ml of dichloromethane. Subsequently, a solution of 5.33 g (19.09 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetyl chloride (Example 1A) in 40 ml of dichloromethane was added dropwise to the batch. The resulting

Reaction mixture was stirred at room temperature overnight. For workup was with Dilute dichloromethane and the organic phase washed with aqueous, 5% citric acid. After drying over sodium sulfate, the mixture was evaporated and the residue was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). Evaporation and drying gave 6.36 g (71% of theory) of the title compound.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.35-1.80 (m, 6H), 2.05-2.18 (m, 2H), 2.24 (s, 3H), 2.25-2.40 (m, 1H), 3.49 (s, 3H), 3.56 (s, 2H), 7.19 (d, 1H), 7.40 (dd, 1H), 7.42 - 7.52 (m, 3H), 7.56 - 7.65 (m, 2H), 8.34 (s, 1H). LC-MS (Method 3): R, = 1.50 min; MS (ESIpos): m / z = 468 [M + H]

Example 3A

(4,4'-dichlorobiphenyl-3-yl) acetyl chloride

40.40 g (143.70 mmol) of (4,4'-dichlorobiphenyl-3-yl) acetic acid (EP 1943218 A2 and US Pat

2009/215624 Al) were dissolved in 350 g (2946 mmol) of thionyl chloride. The reaction mixture was stirred for six hours at 80 ° C and then evaporated in vacuo. To

Drying in a fine vacuum gave 43.10 g (100% of theory) of the title compound as a brownish oil.

^! H-NMR (300MHz, CDC1 ₃ ): δ [ppm] = 4.35 (s, 2H), 7.37-7.60 (m, 7H). Example 4A

Methyl cis 1 - {[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -4-methoxycyclohexanecarboxylate

35.24 g (157.52 mmol) of methyl cis-1-amino-4-methoxycyclohexanecarboxylate hydrochloride (EP 1791816 A1 and WO 2006/29799 A1) and 31.88 g (315.00 mmol) of triethylamine were dissolved in 350 ml of dichloromethane at room temperature. Then, while cooling with ice, a solution of 42.90 g (143.2 mmol) of (4,4'-dichlorobiphenyl-3-yl) -acetyl chloride (Example 3A) in 350 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was allowed to stand for three days

Room temperature stirred. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated sodium bicarbonate solution, aqueous, 5%

Citric acid and water washed. After drying over sodium sulfate, the mixture was evaporated and the residue was stirred in diethyl ether. Filtration and drying yielded 54.56 g (85% of theory) of the title compound.

Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.31-1.47 (m, 2H), 1.56-1.70 (m, 2H), 1.71-1.84 (m, 2H), 1.97-2.10 (m, 2H), 3.07-3.17 (m, 1H), 3.19 (s, 3H), 3.48 (s, 3H), 3.68 (s, 2H), 7.44-7.56 (m, 4H), 7.62-7.69 (m, 3H) , 8.35 (s, 1H). LC-MS (method 2): R, = 1.34 min; MS (ESIpos): m / z = 450 [M + H].

Example 5A

(3-bromo-2,6-dimethylphenyl) acetyl chloride

6.00 g (24.68 mmol) of (3-bromo-2,6-dimethylphenyl) acetic acid (WO 97/36868) were dissolved in 29.36 g (246.81 mmol) of thionyl chloride. The reaction mixture was stirred for four hours at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 6.36 g (99% of theory) of the title compound were obtained as a brownish oil.

^! H-NMR (400MHz, CDC1 ₃ ): δ [ppm] = 2.29 (s, 3H), 2.41 (s, 3H), 4.28 (s, 2H), 6.94 (d, 1H), 7.45 (d, 1H). Example 6A

Methyl cis- 1 - {[(3-bromo-2,6-dimethylphenyl) acetyl] amino} -4-methoxycyclohexanecarboxylate

1.87 g (8.34 mmol) of methyl cis-l-amino-4-methoxycyclohexanecarboxylate hydrochloride (EP 1791816 A1 and WO 2006/29799 A1), 2.11 g (20.84 mmol) of triethylamine and 0.051 g (0.417 mmol) of Ν, Ν-dimethylaminopyridine were at Room temperature dissolved in 22 ml of dichloromethane. Then, while cooling with ice, a solution of 2.18 g (8.34 mmol) of (3-bromo-2,6-dimethylphenyl) acetyl chloride (Example 5A) in 22 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated

Sodium bicarbonate solution, aqueous, 5% citric acid and water. After drying over sodium sulfate was evaporated and the residue by

Chromatography on silica gel (eluent: ethyl acetate). Evaporation and drying gave 3.02 g (88% of theory) of the title compound.

^! H-NMR (400MHZ, DMSO-d ₆ ): δ [ppm] = 1.28-1.46 (m, 2H), 1.54-1.70 (m, 2H), 1.71-1.8 2H), 1.94-2.07 (m, 2H), 2.17 (s, 3H), 2.29 (s, 3H), 3.06-3.18 (m, 1H), 3.20 (s, 3H), 3.48 (s, 3.63 (s, 2H), 6.90 (d, 1H), 7.31 ( d, 1H), 8.26 (s, 1H).

LC-MS (Method 2): R, = 1.23 min; MS (ESIpos): m / z = 414 [M + H] ⁺ .

Example 7A

(5s, 8s) -3- (3-bromo-2,6-dimethylphenyl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

To 3.00 g (7.28 mmol) of methyl cis-1 - {[(3-bromo-2,6-dimethylphenyl) acetyl] amino} -4- Methoxycyclohexanecarboxylate (Example 6A) in 30 ml of Ν, Ν-dimethylformamide was added 1.63 g (14.55 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 30 minutes. For work-up, the cooled reaction mixture was poured onto 150 ml of ice-water and acidified with aqueous hydrochloric acid. The crude product was filtered off. After drying, 2.61 g (94% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-de): δ [ppm] = 1.33-1.58 (m, 4H), 1.79-1.99 (m, 4H), 2.00 (s, 3H), 2.12 (s, 3H), 3.03 3.17 (m, 1H), 3.23 (s, 3H), 6.96 (d, 1H), 7.39 (d, 1H), 8.15 (s, 1H), 10.81 (s, 1H).

LC-MS (Method 2): R, = 1.01 min; MS (ESIpos): m / z = 382 [M + H] ⁺ .

Example 8A

(5-bromo-2-methylphenyl) acetylchlori

6.00 g (26.19 mmol) of (5-bromo-2-methylphenyl) acetic acid (EP 1791816 A1 and WO 2006/29799 A1) were dissolved in 31.20 g (261.92 mmol) of thionyl chloride. The reaction mixture was stirred for two hours at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 6.29 g (97% of theory) of the title compound were obtained as a brownish oil.

^! H-NMR (300MHz, CDC1 ₃ ): δ [ppm] = 2.26 (s, 3H), 4.12 (s, 2H), 7.09 (d, 1H), 7.34 (d, 1H), 7.37 (dd, 1H).

Example 9A

Methyl 8- {[(5-bromo-2-methylphenyl) acetyl] amino} -1,4-dioxaspiro [4.5] decane-8-carboxylate

5.47 g (25.41 mmol) of methyl 8-amino-1,4-dioxaspiro [4.5] decane-8-carboxylate [T. Satoh et al. Tetrahedron 63 (2007), 4806-4813], 3.86 g (38.12 mmol) of triethylamine and 155 mg (1.27 mmol) of Ν, Ν-dimethylaminopyridine were dissolved at room temperature in 45 ml of dichloromethane.

Subsequently, a solution of 6.29 g (25.41 mmol) of (5-bromo-2-methylphenyl) acetyl chloride (Example 8A) in 45 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated

Washed sodium bicarbonate solution. After drying over sodium sulfate, the mixture was evaporated and the residue was purified by chromatography on silica gel (eluent:

Hexane / ethyl acetate gradient / 1% triethylamine). After evaporation and drying, 3.64 g (34% of theory) of the title compound were obtained, which was used without further characterization in the subsequent stage.

Example 10A

1 1 - (5-bromo-2-methylphenyl) - 12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1 1 -ene-10-one

To 3.64 g (8.54 mmol) of methyl 8- {[(5-bromo-2-methylphenyl) acetyl] amino} -1,4-dioxaspiro [4.5] decane-8-carboxylate (Example 9A) in 43 ml of Ν, Ν -Dimethylformamide were added 1.92 g (17.08 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 30 minutes. For working up, the cooled reaction mixture was poured onto 500 ml of ice-water and acidified to pH = 4 with aqueous hydrochloric acid. The crude product was filtered off. Drying gave 2.49 g (74% of theory) of the title compound, which was used without further characterization in the subsequent stage. Example IIA

3- (5-bromo-2-methylphenyl) -4-hydroxy-l-azaspiro [4.5] dec-3-ene-2,8-dione

To 2.49 g (6.32 mmol) of 1- (5-bromo-2-methylphenyl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10-one (Example 10A) in 26 ml of acetone and 13 ml of water were added 192 mg (1.01 mmol) of 4-toluenesulfonic acid monohydrate. The reaction mixture was stirred overnight at 80 ° C. For workup, the cooled reaction mixture was diluted with water and acetone removed on a rotary evaporator. The precipitated crude product was extracted with ethyl acetate. The organic phase was washed with saturated, aqueous

Washed sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Drying gave 1.97 g (89% of theory) of the title compound. ^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.68-1.78 (m, 2H), 2.09 (s, 3H), 2.21-2.34 (m, 4H), 2.64-2.78 (m, 2H), 7.15 (d, 1H), 7.23 (d, 1H), 7.35 (dd, 1H), 8.53 (s, 1H), 11.12 (s, 1H).

LC-MS (Method 2): R, = 0.87 min; MS (ESIpos): m / z = 352 [M + H] ⁺ .

Example 12A

(5R, 8R) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] di

To 400 mg (1.14 mmol) of 3- (5-bromo-2-methylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene-2,8-dione (Example 11A) in 8.3 ml of Ν, To dimethylformamide was added 521 mg (1.60 mmol) cesium carbonate and 975 mg (6.85 mmol) (trifluoromethyl) trimethylsilane. One touched the

Reaction mixture for three hours at room temperature. It was then diluted with water, acidified to pH = 4.5 with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 5 ml of tetrahydrofuran, treated with 1 ml of 4N aqueous hydrochloric acid, stirred for one hour at room temperature and then diluted with water. The crude product was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The residue was purified by evaporation in vacuo by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). After evaporation and drying, 367 mg (76% of theory) of the title compound were obtained. 'H-NMR (400MHZ, methanol ^): δ [ppm] = 1.39-1.50 (m, 2H), 1.84-1.98 (m, 4H), 2.15 (s, 3H), 2.30-2.43 (m, 2H), 7.15 (d, 1H), 7.27 (d, 1H), 7.34 (dd, 1H).

LC-MS (Method 3): R, = 0.96 min; MS (ESIpos): m / z = 420 [M + H] ⁺ . Example 13A

Methyl-8 - {[(3-bromo-2,6-dimethylphenyl) acetyl] amino} -l, 4-dioxaspiro [4.5] decane-8-carboxylate

5.23 g (24.32 mmol) of methyl 8-amino-1,4-dioxaspiro [4.5] decane-8-carboxylate [T. Satoh et al., Tetrahedron 63 (2007), 4806-4813], 3.69 g (36.47 mmol) triethylamine and 150 mg (1.22 mmol) Ν, Ν-dimethylaminopyridine were dissolved at room temperature in 45 ml dichloromethane.

Subsequently, a solution of 6.36 g (25.32 mmol) of (3-bromo-2,6-dimethylphenyl) acetyl chloride (Example 5A) in 45 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated

Hexane / ethyl acetate gradient / 1% triethylamine). After evaporation and drying, 7.33 g (69% of theory) of the title compound were obtained, which was used without further characterization in the subsequent stage.

Example 14A

1 l- (3-bromo-2,6-dimethylphenyl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10-one

To 7.33 g (16.65 mmol) of methyl 8 - {[(3-bromo-2,6-dimethylphenyl) acetyl] amino} -1,4-dioxaspiro [4.5] decane-8-carboxylate (Example 13A) in 40 ml of Ν , Ν-Dimethylformamide were added 3.74 g (33.29 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 30 minutes. For working up, the cooled reaction mixture was poured onto 500 ml of ice-water and acidified to pH = 4 with aqueous hydrochloric acid. The crude product was filtered off. Drying gave 5.48 g (81% of theory) of the title compound which was used without further characterization in the subsequent stage.

Example 15A

3 - (3-Bromo-2,6-dimethylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3 -ene-2, 8-dione

To 1.16 g (2.84 mmol) of 1- (3-bromo-2,6-dimethylphenyl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10-one (Example 14A) in 17 ml of acetone and 9 ml of water were added 87 mg (0.46 mmol) of 4-toluenesulfonic acid monohydrate. The reaction mixture was stirred overnight at 80 ° C. For workup, the cooled reaction mixture was diluted with water and acetone removed on a rotary evaporator. The precipitated product was filtered off. Drying gave 0.93 g (90% of theory) of the title compound.

^! H-NMR (300MHz, DMSO-de): δ [ppm] = 1.65-1.81 (m, 2H), 2.03 (s, 3H), 2.15 (s, 3H), 2.20-2.35 (m, 4H), 2.61 - 2.81 (m, 2H), 6.98 (d, 1H), 7.41 (d, 1H), 8.46 (s, 1H), 11.05 (s, 1H).

LC-MS (Method 3): R, = 0.90 min; MS (ESIpos): m / z = 366 [M + HJ

Example 16A (5r, 8r) -3- (3-bromo-2,6-dimethylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -l-az 2-one

To 400 mg (1.10 mmol) of 3- (3-bromo-2,6-dimethylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene-2,8-dione (Example 15A) in 8 ml of Ν , Ν-Dimethylformamide, 500 mg (1.54 mmol) of cesium carbonate and 937 mg (6.59 mmol) of (trifluoromethyl) trimethylsilane were added. One touched the

Reaction mixture for three hours at room temperature. It was then diluted with water, acidified to pH = 4.5 with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 10 ml of tetrahydrofuran, mixed with 2 ml of 4N aqueous hydrochloric acid, stirred for one hour at room temperature and then diluted with water. The crude product was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The residue was purified by evaporation in vacuo by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). After evaporation and drying, 298 mg (62% of theory) of the title compound were obtained.

Ή-NMR (300MHz, methanol-d ₄ ): δ [ppm] = 1.40 - 1.55 (m, 2H), 1.83 - 2.00 (m, 4H), 2.12 (s, 3H), 2.26 (s, 3H), 2.32 - 2.47 (m, 2H), 6.99 (d, 1H), 7.42 (d, 1H).

LC-MS (Method 3): R, = 1.02 min; MS (ESIpos): m / z = 436 [M + HJ

Example 17A

(5-Bromo-4-fluoro-2-methylphenyl) acetyl chloride

22.00 g (89.00 mmol) of (5-bromo-4-fluoro-2-methylphenyl) acetic acid (WO 2010/52161 A2) were dissolved in 170.00 g (1425.00 mmol) of thionyl chloride. The reaction mixture became six hours stirred at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 23.47 g (99% of theory) of the title compound were obtained as a brownish oil.

'H-NMR (300MHZ, CDC1 ₃ ): δ [ppm] = 2.27 (s, 3H), 4.10 (s, 2H), 7.00 (d, 1H), 7.38 (d, 1H).

Example 18A

Methyl-8 - {[(5-bromo-4-fluoro-2-methylphenyl) acetyl] amino} -l, 4-dioxaspiro [4.5] decane-8-carboxylate

19.03 g (88.39 mmol) of methyl 8-amino-1,4-dioxaspiro [4.5] decane-8-carboxylate, 13.42 g (132.59 mmol) of triethylamine and 540 mg (4.42 mmol) of Ν, Ν-dimethylaminopyridine were added

Room temperature dissolved in 163 ml of dichloromethane. A solution of 23.47 g (88.39 mmol) of (5-bromo-4-fluoro-2-methylphenyl) acetyl chloride (Example 17A) in 163 ml of dichloromethane was subsequently added dropwise. The resulting reaction mixture was added overnight

Room temperature stirred. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous, saturated sodium bicarbonate solution. After drying over sodium sulfate was evaporated and the residue by crystallization

Ethyl acetate / hexane (1: 1). After drying, 25.71 g (65% of theory) of the

Title compound, which was used without further characterization in the next stage.

Example 19A

11 - (5-Bromo-4-fluoro-2-methylphenyl) - 12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-11-ene-10-one

To 28.90 g (65.05 mmol) of methyl 8 - {[(5-bromo-4-fluoro-2-methylphenyl) -acetyl] -amino} -l, 4-dioxaspiro [4.5] decane-8-carboxylate (Example 18A) in 325 ml of Ν, Ν-dimethylformamide were added 14.60 g (130.09 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 60 minutes. For workup, the cooled reaction mixture was poured onto 3000 ml of ice water and acidified to pH = 4.5 with aqueous hydrochloric acid. The crude product was filtered off. After drying, 24.40 g (91% of theory) of the title compound were obtained, which without further

Characterization was used in the next stage.

Example 20A

3- (5-bromo-4-fluoro-2-methylphenyl) -4-hydroxy-l-azaspiro [4.5] dec-3-ene-2,8-dione

To 24.40 g (59.19 mmol) of 1- (5-bromo-4-fluoro-2-methylphenyl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-ene-10 -One (Example 19A) in 438 ml of acetone and 219 ml of water were added 1.80 g (9.47 mmol) of 4-toluenesulfonic acid monohydrate. One touched the

Reaction mixture for twelve hours at 80 ° C. For workup was the cooled

Reaction mixture diluted with water and acetone removed on a rotary evaporator. The product was filtered off. After drying, 21.50 g (99% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.65-1.80 (m, 2H), 2.11 (s, 3H), 2.17-2.34 (m, 4H), 2.60-2.80 (m, 2H), 7.24 (d, 1H), 7.33 (d, 1H), 8.53 (s, 1H), 11.13 (s, 1H).

LC-MS (Method 3): R, = 0.90 min; MS (ESIpos): m / z = 368 [M + H] ⁺ .

Example 21A

(5r, 8r) -3- (5-bromo-4-fluoro-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2-one

To 400 mg (1.09 mmol) 3- (5-bromo-4-fluoro-2-methylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene 2,8-dione (Example 20A) in 7.9 ml of Ν, Ν-dimethylformamide, 496 mg (1.52 mmol)

Cesium carbonate and 927 mg (6.52 mmol) of (trifluoromethyl) trimethylsilane. The reaction mixture was stirred at room temperature for three hours. It was then diluted with water, acidified to pH = 4.5 with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 10 ml of tetrahydrofuran, mixed with 2 ml of 4N aqueous hydrochloric acid, stirred for one hour at room temperature and then diluted with water. The crude product was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The residue was purified by evaporation in vacuo by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). After evaporation and drying, 382 mg (80% of theory) of the title compound were obtained.

^! H-NMR (300MHZ, methanol ^): δ [ppm] = 1.39-1.51 (m, 2H), 1.84-1.97 (m, 4H), 2.17 (s, 3H), 2.29-2.46 (m, 2H), 7.10 (d, 1H), 7.34 (d, 1H).

LC-MS (Method 3): R, = 0.98 min; MS (ESIpos): m / z = 438 [M + H] ⁺ .

Example 22A

(3 ', 4'-difluoro-4-methylbiphenyl-3-yl) acetic acid

23.75 g (103.68 mmol) of (5-bromo-2-methylphenyl) acetic acid and 16.37 g (103.68 mmol) of (3,4-difluorophenyl) boronic acid were dissolved in 63 ml of aqueous 3.3 N sodium hydroxide solution and treated with 668 mg (2.07 mmol) of tetra- n-butylammonium bromide and 55 mg of palladium on carbon (10%). The reaction mixture was stirred for five hours at 80 ° C and then diluted with water to twice the volume. After acidification with concentrated, aqueous hydrochloric acid was extracted with ethyl acetate, the organic phase dried over sodium sulfate and evaporated in vacuo. The crude product was purified by stirring in hexane / methyl tert-butyl ether (9: 1). Drying gave 19.77 g (73% of theory) of the title compound. ^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 2.22 (s, 3H), 3.63 (s, 2H), 7.22 (d, 1H), 7:40 to 7:53 (m, 4H), 7.64 - 7.74 (m, 1H). Example 23A

(3 ', 4'-difluoro-4-methylbiphenyl-3-yl) acetyl chloride

9.70 g (36.99 mmol) of (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) acetic acid (Example 22A) were dissolved in 70.41 g (591.78 mmol) of thionyl chloride. The reaction mixture was stirred for four hours at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 10.28 g (99% of theory) of the title compound were obtained as a brownish oil.

'H NMR (400MHZ, CDC1 ₃ ): δ [ppm] = 2.36 (s, 3H), 4.23 (s, 2H), 7.17-7.45 (m, 6H).

Example 24A

Methyl cis- 1 - {[(3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

6.00 g (22.93 mmol) of methyl cis-l-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (EP 1220841 A2 and WO 2001/23354 A3), 5.80 g (57.32 mmol) of triethylamine and 140 mg (1.15 mmol) of Ν, Ν- Dimethylaminopyridine was dissolved in 60 ml of dichloromethane at room temperature. Subsequently, a solution of 6.44 g (22.93 mmol) of (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -acetyl chloride (Example 23 A) in 60 ml of dichloromethane was added dropwise to the batch. The resulting

Reaction mixture was stirred at room temperature overnight. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated

Sodium bicarbonate solution and washed with aqueous, 5% citric acid. To Drying over sodium sulfate was evaporated and the residue was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). Evaporation and drying gave 6.57 g (61% of theory) of the title compound, which was used without further characterization in the subsequent stage.

Example 25A

(5r, 8r) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (pentafluoroethyl) -1-azaspiro [4.5] dec-3-en-2-one

To 700 mg (2.00 mmol) of 3- (5-bromo-2-methylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene-2,8-dione (Example 11A) in 14.6 ml of Ν, Ν-Dimethylformamide was added 912 mg (2.80 mmol) of cesium carbonate and 2.31 g (11.99 mmol) of (pentafluoroethyl) trimethylsilane. One touched the

Reaction mixture for five days at room temperature. It was then diluted with water, acidified to pH = 4.5 with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 50 ml of tetrahydrofuran, added with 10 ml of 2N aqueous hydrochloric acid, stirred for forty hours at room temperature and then diluted with water. The

Crude product was extracted with ethyl acetate, washed with water and the organic phase was dried over sodium sulfate. The residue was purified by evaporation in vacuo by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). Evaporation and drying gave 490 mg (52% of theory) of the title compound. ^! H-NMR (300 MHz, methanol-d _4): δ [ppm] = 1:39 to 1:50 (m, 2H), 1.91 - 2:03 (m, 4H), 2.15 (s, 3H), 2:32 to 2:48 (m, 2H) , 7.15 (d, 1H), 7.26 (d, 1H), 7.34 (dd, 1H).

LC-MS (Method 3): R, = 1.13 min; MS (ESIpos): m / z = 472 [M + H] ⁺ . Example 26A

(5r, 8r) -3- (5-bromo-4-fluoro-2-methylphenyl) -4,8-dihydroxy-8- (pentaniloethyl) -1-azaspiro [4.5] 3-en-2-one

To 700 mg (1.90 mmol) of 3- (5-bromo-4-fluoro-2-methylphenyl) -4-hydroxy-1-azaspiro [4.5] dec-3-ene-2,8-dione (Example 20A) in 14 ml of Ν, Ν-dimethylformamide was 867 mg (2.66 mmol)

Cesium carbonate and 2.19 g (1.11 mmol) of (pentafluoroethyl) trimethylsilane. The reaction mixture was stirred at room temperature for three days. It was then diluted with water, acidified to pH = 4.5 with aqueous citric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 50 ml of tetrahydrofuran, treated with 10 ml of 2N aqueous hydrochloric acid, stirred for twenty hours at room temperature and then diluted with water. The crude product was extracted with ethyl acetate, washed with water and the organic phase was dried over sodium sulfate. The residue was purified by evaporation in vacuo by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). After evaporation and drying, 595 mg (64% of theory) of the title compound were obtained.

^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:38 to 1:50 (m, 2H), 1.92 - 2:00 (m, 4H), 2.16 (s, 3H), 2:31 to 2:47 (m, 2H) , 7.09 (d, 1H), 7.33 (d, 1H).

LC-MS (Method 3): R, = 1.08 min; MS (ESIpos): m / z = 488 [M + H] ⁺ . Example 27A

Methyl cis -1 - {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

10.00 g (38.22 mmol) of methyl cis-1-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (EP 1220841 A2 and WO 2001/23354 A3), 9.67 g (95.54 mmol) of triethylamine and 233 mg (1.91 mmol) of Ν, Ν-dimethylaminopyridine were dissolved at room temperature in 95 ml of dichloromethane. Subsequently, a solution of 9.46 g (38.22 mmol) of (5-bromo-2-methylphenyl) acetyl chloride (Example 8A) in 95 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. For workup, the mixture was diluted with dichloromethane and the organic phase with aqueous, saturated

Sodium bicarbonate solution and washed with aqueous, 5% citric acid. After drying over sodium sulfate, the mixture was evaporated and the residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol gradient). Evaporation and drying gave 8.84 g (53% of theory) of the title compound, which was used without further characterization in the subsequent stage.

Example 28A

-3- (5-bromo-2-methylphenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

To 8.80 g (20.17 mmol) of methyl cis-1- {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate (Example 27A) in 100 ml of Ν, Ν-dimethylformamide was added 4.53 g (40.34 mmol) of potassium tert-butoxide was added. The reaction mixture was stirred at 80 ° C for 60 minutes. For workup, the cooled reaction mixture was poured onto 800 ml of ice water and acidified with aqueous hydrochloric acid. The crude product was filtered off and passed through

Chromatography on silica gel (eluent: hexane / ethyl acetate gradient). Drying gave 5.23 g (64% of theory) of the title compound.

'H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:40 to 1:50 (m, 2H), 1.58 - 1.72 (m, 2H), 1.77 - 1.86 (m, 2H), 1.86 - 1.96 (m , 2H), 2.07 (s, 3H), 2.12-2.28 (m, 1H), 7.14 (d, 1H), 7.19 (d, 1H), 7.33 (dd, 1H), 8.33 (s, 1H), 11.01 ( s, 1H). LC-MS (Method 2): R, = 1.18 min; MS (ESIpos): m / z = 406 [M + H] ⁺ .

Example 29A Methyl 1 - {[(5-bromo-3-fluoro-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

17.3 g (70.0 mmol) of (5-bromo-3-fluoro-2-methylphenyl) acetic acid (described in WO2009 / 049851, page 95) were dissolved in 29 ml (399 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 210 ml of acetonitrile, 30 ml of this solution were added dropwise with ice cooling to a mixture of 2.00 g (7.64 mmol) of methyl cis-1-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (described in EP 1220841 A2 and WO 2001 / 23354 A3) and 3.70 g (26.8 mmol) of potassium carbonate in 15 ml of acetonitrile and stirred overnight at room temperature. It was then concentrated, taken up in water, extracted with dichloromethane, washed the combined organic phases with IN aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over

Magnesium sulfate, filtered and concentrated.

This gave 2.25 g (65% of theory) of the title compound as a mixture of diastereomers.

^! H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.42 - 1.58 (m, 2.3H), 1.63 - 1.83 (m, 3.7H), 2.06 (d, 0.45H), 2.10 (d, 2.55 H), 2.09 - 2.19 (m, 1.7H), 2.25 - 2.45 (m, 1.3H), 3.51 (s, 0.3H), 3.56 (s, 3H), 3.60 (s, 1.7H), 7.25 - 7.27 ( m, 0.15H), 7.29-7.31 (m, 0.85H), 7.36 (dd, 1H), 8.42 (s, 0.85H), 8.58 (s, 0.15H).

LC-MS (Method 1): R, = 1.37 min; MS (ESIpos): m / z = 454 [M + H] ⁺ .

Example 30A

3- (5-bromo-3-fluoro-2-methylphenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

To 2.25 g (4.95 mmol) of the compound from Example 29A in 10 ml of Ν, Ν-dimethylformamide were added Add 1.11 g (9.91 mmol) of potassium tert-butoxide. The reaction mixture was heated at 80 ° C for 15 minutes. After cooling, the mixture was added to ice-water, added dropwise IN aqueous hydrogen chloride solution and stirred for 0.5 h. The precipitate was filtered off with suction, washed with water and dried. This gave 1.91 g (90% pure, 82% of theory) of the title compound as

Diastereomeric mixture.

'H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:46 to 1:54 (m, 1.7H), 1:59 - 1.76 (m, 2.3h), 1.81 - 2:00 (m, 4H), 2:00 (d , 3H), 2.17 - 2.44 (m, 1H), 7.11 - 7.14 (m, 1H), 7.41 (dd, 1H), 7.88 (s, 0.15H), 8.44 (s, 0.85H), 11.22 (s, 1 H). LC-MS (method 1): R, = 1.18, 1.21 min; MS (ESIpos): m / z = 422 [M + H] ⁺ .

Example 31A

(5s, 8s) -methyl-1- {[(5-bromo-chloro-phenyl) -acetyl] -amino} -4- (trifluoromethyl) -cyclohexanecarboxylate

9.00 g (36.1 mmol) of (5-bromo-2-chlorophenyl) acetic acid (described in WO1998 / 05638, page 114) were dissolved in 15 ml (206 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 85 ml of acetonitrile. 2.62 g (10.0 mmol) of methyl cis-1-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (described in EP 1220841 A2 and WO 2001/23354 A3) were dissolved in saturated, aqueous

Sodium bicarbonate solution taken, extracted with ethyl acetate, over

Dried sodium sulfate, filtered and concentrated. The residue was dissolved in 20 ml of acetonitrile and admixed with 4.84 g (35.0 mmol) of potassium carbonate. 30 ml of the solution of

Acid chloride under ice cooling and stirred overnight at room temperature. It was then concentrated, taken up in water, extracted with dichloromethane, washed the combined organic phases with IN aqueous hydrogen chloride solution and saturated, aqueous

Sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. This gave 2.80 g of the title compound.

LC-MS (Method 1): R, = 1.35 min; MS (ESIpos): m / z = 456 [M + H] ⁺ .

Example 32A 3- (5-bromo-2-chloφhenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

To 2.80 g (6.13 mmol) of the compound from Example 31A in 20 ml of Ν, Ν-dimethylformamide were added 1.38 g (12.3 mmol) of potassium tert-butoxide. The reaction mixture was heated at 80 ° C for 15 minutes. After cooling, the mixture was added to ice-water, added dropwise IN aqueous hydrogen chloride solution and stirred for 0.5 h. The precipitate was filtered off with suction, washed with water and dried. This gave 2.17 g (83% of theory) of the title compound as a mixture of diastereomers. ^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:43 to 1:54 (m, 1.7H) 1.57 - 1.77 (m, 2.3h), 1.79 - 2:02 (m, 4H), 2:17 to 2:37 ( m, 1H), 7.39-7.45 (m, 2H), 7.51 (dd, 1H), 7.83 (s, 0.15H), 8.40 (s, 0.85H), 11.33 (s, 1H).

LC-MS (method 1): R, = 1.16, 1.20 min; MS (ESIpos): m / z = 424 [M + H] ⁺ .

Example 33A

(5s, 8s) -3- (5-bromo-2,6-dimethylphenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] d <

In analogy to Example 32A, the title compound was obtained as a cis / trans isomer mixture melting point 262 C.

^! H NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.47-1.52 (m, 1H), 1.66-1.75 (m, 2H), 1.85-2.00 (m, 5H), 2.05, 2.17 (2s, 3H each), 2.21-2.40 (m, 1H), 7.00 (d, 1H), 7.43 (d, 1H), 7.76, 8.30 (2s, 1H), 10.91, 10.92 (2s, 1H). Example 34A

Methyl 1 - {[(5-bromo-4-fluoro-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

1.80 g (7.29 mmol) of (5-bromo-4-fluoro-2-methylphenyl) acetic acid (described in WO2009 / 049851) were dissolved in 3.0 ml (41.5 mmol) of thionyl chloride. The reaction mixture was stirred for 2 h at 80 ° C and then concentrated. Dissolved 0.35 g of the residue in 1 ml of acetonitrile, this solution was added dropwise with ice cooling in a mixture of 0.52 g (2.00 mmol) of methyl cis-l-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (described in EP 1220841 A2 and WO 2001 / 23354 A3) and 0.65 g (4.67 mmol) of potassium carbonate in 8.0 ml of acetonitrile and stirred two

Days at room temperature. The mixture was then combined with water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. 271 mg (90% purity, 40% of theory) of the title compound were obtained as mixture of diastereomers.

^! H NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.40-1.58 (m, 2.3H), 1.62-1.84 (m, 3.7H), 2.08-2.20 (m, 1.7H), 2.18 (s , 0.45H), 2.21 (s, 2.55 H), 2.25 - 2.45 (m, 1.3H), 3.43 (s, 0.3H), 3.52 (s, 1.7H), 3.56 (s, 3H), 7.20 (d, 1H), 7.46 (d, 0.15H), 7.51 (d, 0.85H), 8.38 (s, 0.85H), 8.54 (s, 0.15H).

LC-MS (Method 2): R, = 1.35 min; MS (ESIpos): m / z = 454 [M + H] ⁺ .

Example 35A

3- (5-bromo-4-fluoro-2-methylphenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

To 262 mg (0.58 mmol) of the compound from Example 34A in 1.5 ml of N, N-dimethylformamide 129 mg (1.15 mmol) of potassium tert-butylate were added under nitrogen. The reaction mixture was heated at 80 ° C for 15 minutes. After cooling, it was poured onto ice water, added dropwise IN aqueous hydrogen chloride solution and stirred for 0.5 h. The precipitate was filtered off with suction, washed with water and dried. This gave 217 mg (89% of theory) of the title compound as a mixture of diastereomers.

^! H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.44-1.54 (m, 1.7H), 1.58-1.77 (m, 2.3H), 1.80-2.02 (m, 4H), 2.13 (s, 3H), 2.17-2.37 (m, 1H), 7.27 (d, 1H), 7.34 (d, 1H), 7.83 (s, 0.15H), 8.40 (s, 0.85H), 11.08 (s, 1H).

LC-MS (Method 1): R, = 1.18 min; MS (ESIpos): m / z = 422 [M + H] ⁺ .

Example 36A

Methyl 1 - {[(4'-chloro-4,6-dimethylbiphenyl-3-yl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

4.40 g (16.0 mmol) of (4'-chloro-4,6-dimethylbiphenyl-3-yl) acetic acid (described in WO99 / 48869, Example XXVII-1, page 186) were dissolved in 6.7 ml (91.3 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 28 ml of acetonitrile, and 5 ml of this solution were added dropwise with ice cooling to a mixture of 714 mg (2.73 mmol) of methyl cis-l-amino-4- (trifluoromethyl) cyclohexanecarboxylate hydrochloride (described in EP 1220841 A2 and WO 2001 / 23354 A3) and 880 mg (6.37 mmol) of potassium carbonate in 5 ml of acetonitrile and stirred at room temperature for seven days. The mixture was then combined with water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. 571 mg (90% pure, 59% of theory) of the title compound were obtained as mixture of diastereomers.

^! H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.38 - 1.57 (m, 2.3H), 1.60 - 1.82 (m, 3.7H), 2.07 - 2.41 (m, 9H), 3.42 (s, 0.3H), 3.47 (s, 0.45H), 3.48 (s, 2.55H), 3.51 (s, 1.7H), 6.99 - 7.10 (m, 2H), 7.27 - 7.35 (m, 2H), 7.44 - 7.51 ( m, 2H), 8.32 (s, 0.85H), 8.46 (s, 0.15H).

LC-MS (Method 1): R, = 1.58 min; MS (ESIpos): m / z = 482 [M + H] ⁺ .

Example 37A Methyl cis- 1 - {[(4'-chloro-4-methylbiphenyl-3-yl) -acetyl] amino} -4- (methoxymethyl) cyclohexanecarboxylate

28.3 g (119 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate hydrochloride (described in WO 2007/048545) were dissolved in 100 ml of water, admixed with 20.0 g (238 mmol) of sodium bicarbonate and extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 9.88 g of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate. 5.93 g (29.4 mmol) of methyl cis-1-amino-4- (methoxymethyl) cyclohexanecarboxylate in 50 ml of acetonitrile were treated with 7.46 g (54.0 mmol) of potassium carbonate. While cooling with ice, a solution of 6.85 g (24.5 mmol) of the compound from Example 1A in 50 ml of acetonitrile was added dropwise and the mixture was stirred for one day at room temperature. It was then concentrated, the residue was combined with water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. This gave 10.5 g of the title compound, which were reacted without further purification.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:05 to 1:25 (m, 2 H) 1.44 - 1.65 (m, 5H), 2:01 to 2:12 (m, 2H), 2.28 (s, 3H) , 3.04 (d, 2H), 3.17 (s, 3H), 3.51 (s, 3H), 3.58 (s, 2H), 7.23 (d, 1H), 7.43 (dd, 1H), 7.47 - 7.57 (m, 3H ), 7.62 - 7.68 (m, 2H), 8.21 (s, 1H).

LC-MS (Method 1): R, = 1.43 min; MS (ESIpos): m / z = 444 [M + H] ⁺ .

Example 38A

(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) acetic acid

To a solution of 40.0 g (175 mmol) of (5-bromo-2-methylphenyl) acetic acid (EP 1791816 and WO 2006/29799) in a mixture of 437 ml (437 mmol) of degassed IN aqueous

Sodium hydroxide solution, 160 ml of degassed water and 160 ml of degassed tetrahydrofuran were added under argon 33.5 g (192 mmol) of (4-chloro-3-fluorophenyl) boronic acid. The mixture was stirred for 10 minutes, treated with 507 mg (1.75 mmol) of tri-tert-butylphosphonium tetrafluoroborate and 532 mg (1.75 mmol) of palladium (II) acetylacetonate and stirred for 20 h at room temperature. Then toluene and water were added, adjusted to pH 1-2 with concentrated aqueous hydrogen chloride solution, stirred for 10 minutes, the phases separated, extracted twice with toluene, the combined organic phases dried over sodium sulfate, filtered and concentrated one. The residue was stirred in 300 ml of a 6/1 mixture of n-hexane / tert-butyl methyl ether for 30 minutes, filtered off with suction, washed with n-hexane and dried in vacuo. 38.0 g (78% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-de): δ [ppm] = 2.27 (s, 3H), 3.67 (s, 2H), 7.27 (d, 1H), 7.49-7.59 (m, 3H), 7.61-7.75 ( m, 2H), 12.4 (s, 1H). LC-MS (Method 1): R, = 1.31 min; MS (ES Ineg): m / z = 277 [M-Hf.

Example 39A

Methyl cis- 1 - {[(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4-methoxycyclohexanecarboxylate

10.0 g (35.9 mmol) of the compound from Example 38A were dissolved in 14.9 ml (205 mmol).

Thionyl chloride dissolved. The reaction mixture was stirred for 1 h at 90 ° C and then concentrated. 10.8 g (100% of theory) of (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -acetyl chloride were obtained. 10.6 g (35.7 mmol) of (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -acetyl chloride were dissolved in 120 ml of acetonitrile. 12.0 g (53.7 mmol) of methyl cis-1-amino-4-methoxycyclohexanecarboxylate hydrochloride (described in EP 1791816 and WO 2006/29799) were taken up in ethyl acetate and washed with saturated, aqueous

Sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 8.50 g of methyl cis-1-amino-4-methoxycyclohexanecarboxylate were obtained. 8.02 g (42.8 mmol) of methyl cis-1-amino-4-methoxycyclohexanecarboxylate in 120 ml of acetonitrile were mixed with 17.3 g (125 mmol).

Potassium carbonate added. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred overnight at room temperature. It was then concentrated, the residue was combined with water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. This gave 15.7 g (98% of theory) of the title compound, which were reacted without further purification. ^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:30 to 1:47 (m, 2H), 1.60 - 1.74 (m, 2H), 1.75 - 1.85 (m, 2H), 1.99 - 2.11 (m, 2H), 2.28 (s, 3H), 3.09-3.20 (m, 1H), 3.21 (s, 3H), 3.52 (s, 3H), 3.58 (s, 2H), 7.24 (d, 1H), 7.46 - 7.55 (m, 2H), 7.57 (d, 1H), 7.61-7.72 (m, 2H), 8.30 (s, 1H).

LC-MS (Method 2): R, = 1.36 min; MS (ESIpos): m / z = 448 [M + H] Example 40A

(5s, 8s) -3- (5-bromo-2-chloφhenyl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from methyl cis-l-amino-4-methoxycyclohexanecarboxylate hydrochloride (described in EP 1791816 and WO 2006/29799) and (5-bromo-2-chlorophenyl) acetic acid (described in WO1998 / 05638, page 114). analogously to the synthesis of the compounds from Example 31A and Example 32A. There were 2.99 g of the title compound receive.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:40 to 1:56 (m, 4H), 1.82 - 2:01 (m, 4H), 3:07 to 3:18 (m, 1H), 3.26 (s, 3H) , 7.38 - 7.44 (m, 2H), 7.50 (dd, 1H), 8.26 (s, 1H), 11.21 (s, 1H). LC-MS (Method 1): R, = 0.98 min; MS (ESIpos): m / z = 386 [M + H] ⁺ . Example 41A

(5s, 8s) -3- (5-bromo-4-chloro-2-methylphenyl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from methyl cis-l-amino-4-methoxycyclohexanecarboxylate hydrochloride (described in EP 1791816 and WO 2006/29799) and (5-bromo-4-chloro-2-methylphenyl) acetic acid (preparation analogous to that described in WO 1997/01535 for the preparation of Examples XXIV-1, XXV-1 and XXVI-1) analogously to the synthesis of the compound of Example 40A. There were obtained 0.86 g of the title compound.

^! H-NMR (300 MHz, DMSO-de): δ [ppm] = 1.38-1.59 (m, 4H), 1.82-2.02 (m, 4H), 2.11 (s, 3H), 3.06-3.18 (m, 1H), 3.26 (s, 3H), 7.39 (s, 1H), 7.50 (s, 1H), 8.26 (s, 1H), 11.04 (s, 1H). LC-MS (Method 1): R, = 1.07 min; MS (ESIpos): m / z = 402 [M + H] ⁺ . Example 42A

Methyl cis 1 - {[(5-bromo-3-fluoro-2-methylphenyl) acetyl] amino} -4-methoxycyclohexanecarboxylate

2.21 g (8.94 mmol) of (5-bromo-3-fluoro-2-methylphenyl) acetic acid (described in WO2009 / 049851, page 95) were dissolved in 3.7 ml (51.0 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 15 ml of acetonitrile. 3.00 g (13.4 mmol) of methyl cis-1-amino-4-methoxycyclohexanecarboxylate hydrochloride (described in EP 1791816 and WO 2006/29799) were dissolved in 30 ml of acetonitrile and admixed with 4.33 g (31.3 mmol) of potassium carbonate. The solution of the acid chloride was added dropwise with ice cooling and stirred overnight at room temperature. The mixture was then concentrated in half, taken up in ice-water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC [column: Xbridge C18, 5 μm, 150 mm × 30 mm; Eluent: water / acetonitrile gradient with addition of 0.1% formic acid] to give 1.59 g (43% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.32-1.44 (m, 2H), 1.62-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.99-2.06 (m, 2H), 2.09 (d, 3H), 3.11-3.21 (m, 1H), 3.23 (s, 3H), 3.54 (s, 3H), 3.59 (s, 2H), 7.27 - 7.30 (m, 1H), 7.36 (dd, 1H), 8.36 (s, 1H).

LC-MS (Method 1): R, = 1.20 min; MS (ESIpos): m / z = 416 [M + H] ⁺ .

Example 43A

(5s, 8s) -3- (5-bromo-3-fluoro-2-methylphenyl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] di

The preparation of the title compound was carried out starting from the compound from Example 42A analogously to the synthesis of the compounds from Example 32A. 1.40 g (95% purity, 91% of theory) of the title compound were obtained.

^! H NMR (400MHz, DMSO-de): δ [ppm] = 1.39-1.59 (m, 4H), 1.83-2.02 (m, 4H), 2.00 (d, 3H), 3.06-3.19 (m, 1H), 3.26 (s, 3H), 7.10 - 7.13 (m, 1H), 7.40 (dd, 1H), 8.29 (s, 1H), 11.12 (s, 1H). LC-MS (Method 1): R, = 1.01 min; MS (ESIpos): m / z = 384 [M + H] Example 44A

Methyl 1 - {[(5-bromo-2-methylphenyl) acetyl] amino} cyclohexanecarboxylate

2.06 g (9.00 mmol) of (5-bromo-2-methylphenyl) acetic acid (described in EP 1791816 and WO 2006/29799) were dissolved in 3.7 ml (51.3 mmol) of thionyl chloride. The reaction mixture was stirred for 2 h at 80 ° C and then concentrated. The residue was dissolved in 20 ml of dichloromethane. 2.09 g (10.8 mmol) of methyl 1-amino-cyclohexanecarboxylate hydrochloride were dissolved in 25 ml

Dissolved dichloromethane, treated with 55 mg (0.45 mmol) of 4-dimethylaminopyridine and 3.1 ml (22.5 mmol) of triethylamine and stirred for 0.5 h at room temperature. One dripped the solution of the

Acid chloride and stirred for 36 h at room temperature. It was then diluted with dichloromethane, washed with water, IN aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. This gave 2.80 g (84% of theory) of the title compound.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:15 to 1:31 (m, 1H), 1:37 to 1:58 (m, 5H), 1:59 - 1.73 (m, 2H), 1.86 - 1.99 (m, 2H), 2.19 (s, 3H), 3.51 (s, 2H), 3.54 (s, 3H), 7.10 (d, 1H), 7.30 (dd, 1H), 7.39 (d, 1H), 8.26 (s, 1H ).

LC-MS (Method 1): R, = 1.30 min; MS (ESIpos): m / z = 368 [M + H] ⁺ .

Example 45A

3- (5-bromo-2-methylphenyl) -4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

The title compound was prepared starting from the compound of Example 44A analogously to the synthesis of the compounds from Example 32A. 2.33 g (90% of theory) of the title compound were obtained.

'H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:09 to 1:27 (m, 1H), 1:30 to 1:41 (m, 2H), 1:51 - 1.72 (m, 5H), 1.76 - 1.90 (m , 2H), 2.11 (s, 3H), 7.17 (d, 1H), 7.22 (d, 1H), 7.36 (dd, 1H), 8.19 (s, 1H), 10.87 (s, 1H).

LC-MS (Method 1): R, = 1.09 min; MS (ESIpos): m / z = 336 [M + H] ⁺ .

Example 46A

Methyl-l - {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (2-methoxyethyl) cyclohexanecarboxylate

2.18 g (9.53 mmol) of (5-bromo-2-methylphenyl) acetic acid (described in EP 1791816 and WO 2006/29799) were dissolved in 4.0 ml (54.3 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 20 ml of acetonitrile. 2.00 g (7.94 mmol) of methyl 1-amino-4- (2-methoxyethyl) cyclohexanecarboxylate hydrochloride

(described in WO2007 / 048545, Example XIV-5, page 145) were dissolved in 15 ml of acetonitrile and treated with 3.84 g (27.8 mmol) of potassium carbonate. The solution of the acid chloride was added dropwise and the mixture was stirred overnight at room temperature. Then you narrowed, took the

Residue in water, extracted with dichloromethane, washed with 1N aqueous

Hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. This gave 1.72 g (51% of theory) of the title compound as a mixture of diastereomers.

LC-MS (Method 1): R, = 1.28 min; MS (ESIpos): m / z = 426 [M + H] ⁺ . Example 47A

3- (5-bromo-2-methylphenyl) -4-hydroxy-8- (2-methoxyethyl) -l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from the compound from Example 46A analogously to the synthesis of the compounds from Example 32A. There were obtained 1.17 g (90% purity, 67% of theory) of the title compound as a mixture of diastereomers.

^! H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.22-1.48 (m, 6H), 1.49-1.72 (m, 3H), 1.74-2.01 (m, 2H), 2.08 (s, 0.3H) , 2.1 1 (s, 2.7H), 3.22 (s, 2.7H), 3.23 (0.3H), 3.33 - 3.39 (m, 2H), 7.17 (d, 1H), 7.22 (d, 1H), 7.36 (dd , 1H), 8.18 (s, 0.9H), 8.19 (s, 0.1H), 10.85 (s, 0.9H), 10.87 (s, 0.1H).

LC-MS (Method 1): R, = 1.10 min; MS (ESIpos): m / z = 394 [M + H] ⁺ . Example 48A

Methyl cis- 1 - {[(5-bromo-2-chlorophenyl) acetyl] amino} -4- (methoxymethyl) cyclohexanecarboxylate

55.3 g (232 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate hydrochloride (described in WO 2007/048545, page 144) were dissolved in 200 ml of water, treated with 39.0 g (465 mmol) of sodium bicarbonate and washed several times with Extracted ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 17.2 g of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate were obtained. 9.00 g (36.1 mmol) of (5-bromo-2-chlorophenyl) acetic acid (described in WO1998 / 05638, page 114) were dissolved in 15 ml (206 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 85 ml of acetonitrile. 2.01 g (10.0 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate in 20 ml of acetonitrile were admixed with 4.84 g (35.0 mmol) of potassium carbonate. Under ice-cooling, 30 ml (12.0 mmol) of the solution of Acid chloride and stirred overnight at room temperature. It was then concentrated, the residue was combined with water, extracted with dichloromethane, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. 4.34 g (100% of theory) of the title compound were obtained, which were reacted without further purification.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:12 to 1:30 (m, 2H), 1:47 - 1.67 (m, 5H), 2:02 to 2:13 (m, 2H), 3.14 (d, 2H) , 3.22 (s, 3H), 3.55 (s, 3H), 3.65 (s, 2H), 7.38 (d, IH), 7.47 (dd, IH), 7.60 (d, IH), 8.30 (s, IH).

LC-MS (Method 1): R, = 1.25 min; MS (ESIpos): m / z = 432 [M + H]

Example 49A

(5s, 8s) -3- (5-bromo-2-chloφhenyl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from the compound from Example 48A analogously to the synthesis of the compounds from Example 32A. There was obtained 3.43 g (84% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:22 to 1:44 (m, 4H), 1:49 - 1.61 (m, IH), 1.65 - 1.74 (m, 2H), 1.79 - 1.89 (m, 2H), 3.15 (d, 2H), 3.23 (s, 3H), 7.40 (d, IH), 7.41 (d, IH), 7.50 (dd, IH), 8.20 (s, IH), 11.17 (s, IH ).

LC-MS (Method 1): R, = 1.05 min; MS (ESIpos): m / z = 400 [M + H] ⁺ . Example 50A

Methyl cis- 1 - {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (methoxymethyl) cyclohexanecarboxylate

55.3 g (232 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate hydrochloride (described in WO 2007/048545, page 144) were dissolved in 200 ml of water, treated with 39.0 g (465 mmol) of sodium bicarbonate and washed several times with Extracted ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 17.2 g of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate were obtained. 1.90 g (8.30 mmol) of (5-bromo-2-methylphenyl) acetic acid (described in EP 1791816 and WO 2006/29799) were dissolved in 3.5 ml (47.3 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 15 ml of acetonitrile. 2.00 g (9.94 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate in 20 ml of acetonitrile were mixed with 2.52 g (18.2 mmol) of potassium carbonate. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred for 24 h at room temperature. It was then concentrated, the residue was combined with water, extracted with dichloromethane, and the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated, aqueous

Sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. This gave 3.11 g (91% of theory) of the title compound, which were reacted without further purification.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:07 to 1:29 (m, 2H), 1:47 - 1.66 (m, 5H), 2:01 to 2:12 (m, 2H), 2.20 (s, 3H) , 3.13 (d, 2H), 3.22 (s, 3H), 3.51 (s, 2H), 3.54 (s, 3H), 7.10 (d, 1H), 7.30 (dd, 1H), 7.41 (d, 1H), 8.22 (s, 1H).

LC-MS (Method 1): R, = 1.25 min; MS (ESIpos): m / z = 412 [M + H] ⁺ . Example 51A

(5s, 8s) -3- (5-bromo-2-methylphenyl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-e

The preparation of the title compound was carried out starting from the compound from Example 50A analogously to the synthesis of the compounds from Example 32A. 2.83 g (96% of theory) of the title compound were obtained. Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.22-1.44 (m, 4H), 1.46-1.63 (m, 1H), 1.65-1.75 (m, 2H), 1.80-1.85 (m, 2H), 2.11 (s, 3H), 3.15 (d, 2H), 3.23 (s, 3H), 7.17 (d, 1H), 7.22 (d, 1H), 7.36 (dd, 1H), 8.16 (s, 1H ), 10.89 (s, 1H).

LC-MS (Method 1): R, = 1.05 min; MS (ESIpos): m / z = 380 [M + H] ⁺ . Example 52A

Methyl-cis-l - {[(5-bromo-2-methylphenyl) acetyl] amino} -4-methylcyclohexane carboxylate

6.39 g (27.9 mmol) of (5-bromo-2-methylphenyl) acetic acid (described in EP 1791816 and WO

2006/29799) were dissolved in 11.6 ml (159 mmol) of thionyl chloride. The reaction mixture was stirred for 1.5 h at 80 ° C and then concentrated, taken up in toluene and concentrated. The residue was dissolved in 38 ml of acetonitrile. 8.69 g (41.8 mmol) of methyl 1-amino-4-methylcyclohexanecarboxylate hydrochloride (described in EP596298) were dissolved in 64 ml of acetonitrile, and 13.5 g (97.6 mmol) of potassium carbonate were added. One dripped the solution of the

Acid chloride with ice cooling and stirred for 5 days at room temperature. It was then added to ice-water, extracted with dichloromethane, washed with 0.5N aqueous hydrogen chloride. Solution and saturated, aqueous sodium bicarbonate solution, dried, filtered and concentrated. 5.98 g (56% of theory) of the title compound were obtained.

^! H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.86 (d, 3H), 1 .06 - 1 .20 (m, 2H), 1 .27 - 1 .40 (m, 1H), 1 .55 - 1 .52 (m, 2H), 1 .54 - 1.64 (m, 2H), 2.00 - 2.08 (m, 2H), 2.20 (s, 3H), 3.51 (s, 2H), 3.54 (s, 3H), 7.10 (d, 1H), 7.30 (dd, 1H), 7.42 (d, 1H), 8.21 (s, 1H).

LC-MS (Method 1): R, = 1 .38 min; MS (ESIpos): m / z = 382 [M + H] ⁺ .

Example 53A

(5s, 8s) -3- (5-bromo-2-methylph. 5] d <

The preparation of the title compound was carried out starting from the compound from Example 52A analogously to the synthesis of the compounds from Example 32A. There were obtained 5.32 g (97% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-de): δ [ppm] = 0.90 (d, 3H), 1.27-1.40 (m, 5H), 1.57-1.65 (m, 2H), 1.83-1.94 (m, 2H), 2.1 1 (s, 3H), 7.17 (d, 1H), 7.22 (d, 1H), 7.36 (dd, 1H), 8.16 (s, 1H), 10.86 (s, 1H). LC-MS (Method 1): R, = 1.18 min; MS (ESIpos): m / z = 350 [M + H] ⁺ . Example 54A

Methyl cis 1 - {[(4'-chloro-4,6-dimethylbiphenyl-3-yl) -acetyl] amino} -4-methoxycyclohexanecarboxylate

10 g (40 mmol) of (4'-chloro-4,6-dimethylbiphenyl-3-yl) acetic acid (described in WO99 / 48869 Example XXVII-1) were dissolved in 15.2 ml (200 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 40 ml of acetonitrile. 17.88 g (80 mmol) of methyl cis-1-amino-4-methoxycyclohexanecarboxylate hydrochloride (described in EP 1791816 and WO 2006/29799) were dissolved in 80 ml of acetonitrile and admixed with 22 g (160 mmol) of potassium carbonate. The solution of the acid chloride was added dropwise with ice cooling and stirred for one hour at room temperature. It was then stirred with 500 ml of ice water, extracted with dichloromethane, the combined organic phases were washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with methylene chloride / ethyl acetate 3: 1 as the eluent. This gave 11.13 g (62% of theory) of the title compound of melting point 76 ° C.

^! H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.14-1.24 (m, 1H), 1.30-1.38 (m, 1H), 1.72-1.91 (m, 4H), 1.87-2.05 (m, 1H ), 2.06 - 2.11 (m, 1H), 2.16, 2.32 (2s, 3H each), 3.13 - 3.21 (m, 1H), 3.31 (s, 3H), 3.56 (s, 2H), 3.67 (s, 3H) , 7.04 (s, 1H), 7.13 (s, 1H), 7.22 - 7.26 (m, 3H), 7.36 - 7.40 (m, 2H).

Example 55A

Methyl (1S, 3S) -1 - {[(4'-chloro-4-methylbiphenyl-3-yl) acetyl] amino} -3- (trifluoromethyl) cyclohexanecarboxylate

2.62 g (11 mmol) of methyl 1-amino-3-trifluoromethylcyclohexanecarboxylate hydrochloride (prepared analogously to Example XIV-1 WO 2001/23354) were dissolved in 40 ml of tetrahydrofuran and treated with 3.3 ml of triethylamine and stirred for 5 min. Thereafter, 2.61 g (10 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetic acid (described in WO99 / 48869) were added and stirred at RT for 15 min. A further 2.2 ml of triethylamine were added and immediately added dropwise 0.56 ml of phosphorus oxychloride that the solution was moderately boiling. It was refluxed for another 30 minutes. It was then poured into 200 ml of ice water, extracted with dichloromethane, the combined organic phases were washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with n-hexane / ethyl acetate 2: 1 as the eluent. This gave 2.33 g (50% of theory) of the title compound of melting point 149 ° C. ^! H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 0.96-1.11 (m, 1H), 1.18-1.28 (m, 1H), 1.54-1.63 (m, 1H), 1.69-1.92 (m, 5H ), 2.36 (s, 3H), 2.56 - 2.62 (m, 1H), 3.66 (s, 2H), 3.71 (s, 3H), 5.37 (s, 1H), 7.31 - 7.33 (m, 1H), 7.33 - 7.46 (m, 4H), 7.50 - 7.52 (m, 2H).

Example 56A

Methyl cis 1 - {[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

In analogy to Example 55A gave the title compound of melting point 187 ° C.

^! H-NMR (400 MHz, CDC1 _3): δ [ppm] = 1:27 to 1:35 (m, 2H), 1.71 - 1.85 (m, 4H), 1.98 - 2:08 (m, 1H), 2:23 to 2:29 (m, 2H ), 3.67 (s, 3H), 3.77 (s, 2H), 5.66 (s, 1H), 7.39 - 7.51 (m, 6H), 7.64 - 7.69 (m, 1H).

Example 57A

Methyl cis -1 - {[(4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) acetyl] amino} -4-methoxycyclohexanecarboxylate

In analogy to Example 55A gave the title compound of melting point 101 ° C.

^! H NMR (400 MHz, CD ₃ CN): δ [ppm] = 1.28-1.39 (m, 2H), 1.72-1.88 (m, 3H), 2.05-2.09 (m, 2H), 2.32 (s, 1H) , 3.13 - 3.20 (m, 1H), 3.25 (s, 3H), 3.54 (s, 2H), 3.55 (s, 3H), 6.47 (s, 1H), 7.01 - 7.04 (d, 1H), 7.32 - 7.34 (d, 1H), 7.43-7.46 (m, 2H), 7.51-7.54 (m, 1H). Example 58A

(5s, 8s) -3- (5-bromo-2-methylphenyl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] di

In analogy to Example 32A gave the title compound of melting point 218 ° C.

^! H NMR (400 MHz, D ₆ -DMSO): δ [ppm] = 1.42-1.57 (m, 4H), 1.87-1.99 (m, 4H), 2.10 (s 3.09-3.16 (m, 1H), 3.25 ( s, 3H), 7.15 - 7.17 (m, 1H), 7.21 - 7.22 (m, 1H), 7.34 - 7.36 (m 8.13 (s, 1H), 10.83 (s, 1H).

Example 59A

Methyl (1S, 3S) -1 - [[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -3- (trifluoromethyl) cyclohexanecarboxylate

In analogy to Example 55A gave the title compound of melting point 148 ° C. Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.20-1.38 (m, 2H), 1.58- 1.67 (m, 1H), 1.76-1.83 (m, 2H), 1.87-1.99 (m, 3H ), 2.57 - 2.62 (m, 1H), 3.69 (s, 3H), 3.77 (s, 2H), 5.37 (s, 1H), 7.40 - 7.51 (m, 6H), 7.57 - 7.58 (m, 1H). Example 60A

Methyl 1 - {[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -4,4-dimethylcyclohexanecarboxylate

In analogy to Examples 34 and V-58 from EP595130 gave the title compound of melting point 128 ° C.

^! H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 0.85, 0.9 (2s, 3H each), 1.09-1.17 (m, 2H), 1.19-1.29 (m, 2H), 1.90-1.94 (m, 4H), 3.67 (s, 3H), 3.75 (s, 2H), 5.70 (s, 1H), 7.40 - 7.45 (m, 3H), 7.48 - 7.51 (m, 3H), 7.58 - 7.59 (m, 1H) ,

Example 61A

Methyl 1 - {[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -4-methylcyclohexanecarboxylate

In analogy to Example 55A, the title compound was obtained as a viscous oil.

^! H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 0.83 (d, 3H), 0.85-0.93 (m, 1H), 1.26-1.39 (m, 1H), 1.55-1.62 (m, 3H), 1.69 - 1.77 (m, 2H), 2.09 - 2.12 (m, 2H), 3.66 (s, 3H), 3.76 (s, 2H), 5.69 (s, 1H), 7.40 - 7.51 (m, 6H), 7.58 - 7.59 (d, 1H). Example 62A

Methyl 1 - {[(4,4'-dichlorobiphenyl-3-yl) -acetyl] -amino} -cyclohexanecarboxylate

Analogously to Example 55A gave the title compound of melting point 124 ° C.

^! H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.25-1.33 (m, 4H), 1.52-1.63 (m, 2H), 1.75-1.82 (m, 2H), 1.98-2.02 (m, 2H ), 3.66 (s, 3H), 3.75 (s, 2H), 5.72 (s, 1H), 7.40 - 7.45 (m, 3H), 7.48 - 7.51 (m, 3H), 7.58 - 7.59 (m, 1H).

Example 63A

Methyl cis 1 - {[(4,4'-dichlorobiphenyl-3-yl) acetyl] amino} -4-isopropylcyclohexanecarboxylate

In analogy to Example 55A gave the title compound of melting point 109 ° C.

^! H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 0.78 (d, 6H), 0.88-0.95 (m, 2H), 1.02-1.07 (m, 1H), 1.29-1.39 (m, 2H), 1.66 - 1.74 (m, 2H), 2.07 - 2.15 (m, 2H), 3.67 (s, 3H), 3.76 (s, 2H), 5.66 (s, 1H), 7.40 - 7.45 (m, 3H), 7.47 - 7.51 (m, 3H), 7.58 - 7.59 (m, 1H).

Example 64A

3- (5-bromo-2-methylphenyl) -8-ethoxy-4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out in analogy to the synthesis of the compound from Example 40A as cis / trans isomeric mixture of melting point 138 ° C. Example 1-90 (= compound according to WO08 / 067911)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2

To 5.00 g (12.4 mmol) of the compound of Example 28A in 500 ml of degassed 1,2-dimethoxyethane were added under argon 1.01 g (1.24 mmol) of dichloro [l, l-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 3.24 g (18.5 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 14.1 g (43.3 mmol) of cesium carbonate in 30 ml of degassed water were added. The reaction mixture was refluxed for 2 hours. After cooling, 10 ml of concentrated, aqueous

Hydrogen chloride solution was added, the aqueous phase separated, added with magnesium sulfate, filtered through silica gel, washed with ethyl acetate and concentrated. After purification of the crude product by chromatography on silica gel (mobile phase: hexane / ethyl acetate gradient) and by crystallization from ethyl acetate, 2.48 g (44% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:45 to 1:57 (m, 2H), 1.62 - 1.79 (m, 2H), 1.81 - 2:05 (m, 4H), 2.19 (s, 3H) , 2.20-2.33 (m, 1H), 7.32 (d, 1H), 7.41 (d, 1H), 7.49-7.58 (m, 2H), 7.64 (t, 1H), 7.70 (dd, 1H), 8.33 (s , 1H), 10.95 (s, 1H). LC-MS (Method 1): R, = 1.34 min; MS (ESIpos): m / z = 454 [M + H] ⁺ .

Example 1-91

(5s, 8s) -3- (4'-chloro-5-iluor-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -one

To 450 mg (1.07 mmol) of the compound from Example 30A and 43.5 mg (0.053 mmol) of dichloro [l, l-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex in 23 ml of degassed 1,2-dimethoxyethane were added under argon 250 mg (1.60 mmol) of (4-chlorophenyl) boronic acid and a solution of 1.22 g (3.73 mmol) of cesium carbonate in 2 ml of degassed water. The

Reaction mixture was refluxed for 3 hours. Subsequently, another 83 mg (0.53 mmol) of (4-chlorophenyl) boronic acid and a spatula tip of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex were added and the mixture was heated under reflux for 2 h. After cooling, 550 μΐ concentrated, aqueous hydrogen chloride solution and sodium sulfate were added, filtered through silica gel and sodium sulfate, washed with

Ethyl acetate and concentrated. By twice preparative HPLC [1. Column: Xbridge C18, 5 μm, 150 mm × 30 mm; Eluent: water / methanol gradient with the addition of 0.1%

formic acid; Flow: 0.8 ml / min; Temperature: RT; 2nd column: Chiralpak IC, 5 μm, 150 mm x 4.6 mm; Eluent: hexane / ethanol = 85/15 with the addition of 0.1% trifluoroacetic acid; Flow: 1 ml / min; Temperature: RT], the diastereomers were separated. The separated diastereomer was again purified by preparative HPLC (XBridge C18, 5 μm, 100 mm × 30 mm;

Water / acetonitrile gradient with the addition of 0.1% formic acid) and gave 55.2 mg (11% of theory) of the title compound. 'H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:46 to 1:58 (m, 2H), 1.62 - 1.79 (m, 2H), 1.81 - 2:04 (m, 4H), 2:08 (d, 3H ), 2.18-2.34 (m, 1H), 7.25 (d, 1H), 7.44 (dd, 1H), 7.48-7.54 (m, 2H), 7.67-7.74 (m, 2H), 8.41 (s, 1H) , 11.11 (s, 1 H).

LC-MS (Method 1): R, = 1.32 min; MS (ESIpos): m / z = 454 [M + H] Example 1-92 (= compound according to WO08 / 067911)

(5s, 8s) -3- (4,4'-dichloro-3'-iluorbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-ene-2-one

To 150 mg (0.35 mmol) of the compound of Example 32A and 14.4 mg (0.018 mmol) of dichloro [l, l-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex in 15 ml of degassed 1,2-dimethoxyethane were added under argon 73.9 mg (0.42 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 403 mg (1.24 mmol) of cesium carbonate in 0.9 ml of degassed water. The reaction mixture was 10 minutes at 150 ° C in a closed vessel under

Microwave irradiation heated. After cooling, 300 .mu.l of concentrated, aqueous hydrogen chloride solution and sodium sulfate were added, filtered through silica gel and sodium sulfate, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC (XBridge C18, 5 μm, 100 mm × 30 mm, eluent: water / acetonitrile gradient with the addition of 0.1% formic acid), giving 45.3 mg (90% purity, 24% of theory). the title link.

^! H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.46-1.57 (m, 2H), 1.61-1.79 (m, 2H), 1.81-2.04 4H), 2.19-2.37 (m, 1H), 7.54-7.61 (m, 3H), 7.64-7.72 (m, 2H), 7.78 (dd, 1H), 8.40 (s, 1 11.22 (s, 1H).

LC-MS (Method 1): R, = 1.34 min; MS (ESIpos): m / z = 474 [M + H] ⁺ .

Example 1-93 (= compound according to WO08 / 067911)

(5s, 8s) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-one

To 150 mg (0.36 mmol) of the compound from Example 33A in 15 ml of degassed 1,2-dimethoxyethane was added under argon 29.3 mg (0.036 mmol) of dichloro [l, bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred for 5 minutes at room temperature and then 93.8 mg (0.54 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 409 mg (1.26 mmol) of cesium carbonate in 0.9 ml of degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 300 .mu.l of concentrated, aqueous hydrogen chloride solution and magnesium sulfate were added, filtered through silica gel and magnesium sulfate, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC (XBridge C18, 5 μm, 100 mm × 30 mm;

Water / acetonitrile gradient with the addition of 0.1% formic acid) to give 93.1 mg (56% of theory) of the title compound. ^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:43 to 1:56 (m, 1H), 1.60 - 1.79 (m, 2H), 1.80 - 2:08 (m, 8H), 2.13 (s, 3H) , 2.20-2.40 (m, 1H), 7.06-7.18 (m, 3H), 7.28-7.34 (m, 1H), 7.64 (t, 1H), 7.76 (s, 0.5H), 8.29 (s, 0.5H) , 10.85 (s, 1 H).

LC-MS (Method 1): R, = 1.36 min; MS (ESIpos): m / z = 468 [M + HJ Example 1-94 (= compound according to WO08 / 067911)

3- (4'-Chloro-3,6-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro-ene-2-one

The title compound was prepared starting from 103 mg (0.24 mmol) of the compound from Example 35A analogously to the synthesis of the compound from Example 1-93. There were obtained 55.1 mg (43% of theory) of the title compound as a mixture of diastereomers.

Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.46-1.54 (m, 2H), 1.62-1.76 (m, 2H), 1.81-2.02 (m, 4H), 2.20 (s, 3H) , 2.20 - 2.31 (m, 1H), 7.20 - 7.28 (m, 2H), 7.41 (d, 1H), 7.58 (d, 1H), 7.69 (t, 1H), 8.36 (s, 1H), 11.00 (s , 1 H).

LC-MS (Method 1): R, = 1.35 min; MS (ESIpos): m / z = 472 [M + H] ⁺ .

Example 1-95 (= connection according to W099 / 48869)

(5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2-one

The title compound was prepared starting from 150 mg (0.36 mmol) of the compound from Example 33A analogously to the synthesis of the compound from Example 1-93. 55.1 mg (43% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:44 to 1:54 (m, 1H), 1.60 - 1.77 (m, 2H), 1.81 - 2:06 (m, 8H), 2.13 (s, 3H) , 2.20-2.44 (m, 1H), 7.05 (d, 1H), 7.13 (d, 1H), 7.28-7.33 (m, 2H), 7.46-7.52 (m, 2H), 7.76 (s, 0.5H), 8.29 (s, 0.5H), 10.85 (s, 1H).

LC-MS (Method 1): R, = 1.35 min; MS (ESIpos): m / z = 450 [M + H] ⁺ . Example 1-96

(5s, 8s) -4-hydroxy-8- (^^ trifluormeth

3-en-2-one

The preparation of the title compound was carried out starting from 450 mg (1.07 mmol) of the compound from Example 30A analogously to the synthesis of the compound from Example 1-91. 194 mg (40% of theory) of the title compound were obtained.

Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.47 - 1.58 (m, 2H), 1.61 - 1.80 (m, 2H), 1.82 - 2.04 (m, 4H), 2.08 (d, 3H) , 2.18-2.34 (m, 1H), 7.27 (s, 1H), 7.44-7.58 (m, 3H), 7.75-7.85 (m, 1H), 8.42 (s, 1H), 11.11 (s, 1H) ,

LC-MS (Method 3): R, = 1.28 min; MS (ESIpos): m / z = 456 [M + H] ⁺ .

Example 1-97 (= connection according to W099 / 48869)

3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

To 557 mg (90%, 1.04 mmol) of the compound from Example 36A in 1.5 ml of N, N-dimethylformamide was added 233 mg (2.08 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 15 minutes. After cooling, one narrowed, dissolved the Residue in water and the solution dripped into 2N aqueous hydrogen chloride solution.

The solid was filtered off with suction, washed with water and dried. 510 mg (90%, 98% of theory) of a 10/1 mixture of (5s, 8s) and (5r, 8r) diastereomers were obtained

Title compound.

Example 1-98 (= connection according to W099 / 48869)

(5s, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2-one

By twice preparative HPLC [1. Column: Chiralpak IA, 5 μm, 250 mm × 20 mm; Eluent: hexane / ethanol = 85/15 with the addition of 0.1% trifluoroacetic acid; Flow: 20 ml / min; Temperature: RT; 2nd column: Xbridge C18, 5 μm, 150 mm × 19 mm; Eluent: water / acetonitrile gradient with addition of 0.2% ammonia; Flow: 25 ml / min; Temperature: RT], the diastereomers of the compound from Example 1-97 were separated. The ammonium salt of the main diastereomer was taken up in a mixture of 0.5N aqueous hydrogen chloride solution and ethyl acetate, the phases were separated, the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 220 mg of the title compound were obtained.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:42 to 1:51 (m, 2H), 1.62 - 1.75 (m, 2H), 1.80 - 1.89 (m, 2H), 1.89 - 2:00 (m, 2H), 2.15 (s, 3H), 2.21 (s, 3H), 2.23 - 2.31 (m, 1H), 6.90 (s, 1H), 7.15 (s, 1H), 7.33 - 7.37 (m, 2H), 7.46 - 7.51 (m, 2H), 8.29 (s, 1H), 10.83 (s, 1H). LC-MS (Method 1): R, = 1.37 min; MS (ESIpos): m / z = 450 [M + HJ Example 1-99 (= compound according to WO08 / 067911)

(5s, 8s) -3- (4-chloro-3 4'-difluoro-biphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4 _^ 2-en-οη

The title compound was prepared starting from 150 mg (0.35 mmol) of the compound from Example 32A analogously to the synthesis of the compound from Example 1-92. There were obtained 61.8 mg (90% purity, 34% of theory) of the title compound.

^! H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.45-1.57 (m, 2H), 1.60-1.79 (m, 2H), 1.80-2.04 (m, 4H), 2.17-2.37 (m, 1H), 7.47-7.58 (m, 4H), 7.64 (dd, 1H), 7.74-7.85 (m, 1H), 8.39 (s, 1H), 11.22 (s, 1H).

LC-MS (Method 1): R, = 1.29 min; MS (ESIpos): m / z = 458 [M + H] ⁺ .

Example 1-100 (= connection according to W099 / 48869)

3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene

2-one

The title compound was prepared starting from 103 mg (0.24 mmol) of the compound from Example 35A analogously to the synthesis of the compound from Example 1-93. There were obtained 58 mg (43% of theory) of the title compound as a mixture of diastereomers. Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.46-1.54 (m, 2H), 1.61-1.76 (m, 2H), 1.81-2.02 (m, 4H), 2.19 (s, 3H) , 2.20 - 2.31 (m, 1H), 7.17 - 7.23 (m, 2H), 7.50 - 7.58 (m, 4H), 8.35 (s, 1H), 10.99 (s, 1H).

LC-MS (Method 1): R, = 1.33 min; MS (ESIpos): m / z = 454 [M + H] ⁺ . Example 1-101 (= compound according to WO08 / 067911)

(5s, 8s) -3- (3 ', 4'-difluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2

The title compound was prepared starting from 150 mg (0.36 mmol) of the compound from Example 33A analogously to the synthesis of the compound from Example 1-92. 95 mg (59% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:43 to 1:55 (m, 1H), 1.60 - 1.79 (m, 2H), 1.81 - 2:06 (m, 8H), 2.13 (s, 3H) , 2.20-2.44 (m, 1H), 7.04-7.16 (m, 3H), 7.27-7.36 (m, 1H), 7.43-7.55 (m, 1H), 7.74 (s, 0.5H), 8.28 (s, 0.5 H), 10.85 (s, 1 H).

LC-MS (Method 1): R, = 1.31 min; MS (ESIpos): m / z = 452 [M + H] ⁺ . Example 1-102

(5s, 8s) -3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-one

The preparation of the title compound was carried out starting from 450 mg (1.07 mmol) of the compound from Example 30A analogously to the synthesis of the compound from Example 1-91. After purification of the crude product by two-fold chromatography on silica gel (1st column:

Dichloromethane / methanol gradient; 2nd column: hexane / ethyl acetate gradient), the product was purified by preparative HPLC [column: Xbridge Cl 8, 5 μm, 150 mm × 30 mm; eluent:

Water / acetonitrile gradient with the addition of 0.1% formic acid; Flow: 50 ml / min; Temperature: RT] finely cleaned. 130 mg (26% of theory) of the title compound were obtained.

^! H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.47-1.57 (m, 2H), 1.60-1.79 (m, 2H), 1.81-2.04 (m, 4H), 2.08 (d, 3H) , 2.18-2.34 (m, 1H), 7.31 (d, 1H), 7.51 (dd, 1H), 7.57 (dd, 1H), 7.66 (t, 1H), 7.78 (dd, 1H), 8.38 (s, 1 H), 11.12 (s, 1 H).

LC-MS (Method 2): R, = 1.35 min; MS (ESIpos): m / z = 472 [M + H] ⁺ .

Example 1-103 (= compound from Table 1, p. 25 of WO08 / 067910)

(5s, 8s) -3- (4,4-dichloro-3'-fluoro-biphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

The title compound was prepared starting from 150 mg (0.39 mmol) of the compound from Example 40A analogously to the synthesis of the compound from Example 1-92. There were obtained 54.2 mg (32% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:42 to 1:59 (m, 4H), 1.84 - 2:03 (m, 4H), 3:09 to 3:18 (m, 1H), 3.26 (s, 3H) , 7.53 - 7.59 (m, 3H), 7.65 - 7.70 (m, 2H), 7.78 (dd, 1H), 8.25 (s, 1H), 11.11 (s,

1H).

LC-MS (Method 1): R, = 1.22 min; MS (ESIpos): m / z = 436 [M + H] ⁺ . Example 1-104 (= compound from Table 1, p. 25 of WO08 / 067910)

The title compound was prepared starting from 150 mg (0.39 mmol) of the compound from Example 40A analogously to the synthesis of the compound from Example 1-92. 64.5 mg (40% of theory) of the title compound were obtained.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.42 - 1.59 (m, 4H), 1.84 - 2.03 (m, 4H), 3.09 - 3.18 (m, 1H), 3.26 (s, 3H) , 7.48-7.56 (m, 4H), 7.63 (dd, 1H), 7.75-7.83 (m, 1H), 8.25 (s, 1H), 11.10 (s, 1H).

LC-MS (Method 1): R, = 1.16 min; MS (ESIpos): m / z = 420 [M + H] ⁺ .

Example 1-105

-3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-

The title compound was prepared starting from 150 mg (0.39 mmol) of the compound from Example 43 A analogously to the synthesis of the compound from Example 1-92. There were obtained 80.4 mg (48% of theory) of the title compound.

^! H-NMR (300MHz, DMSO-de): δ [ppm] = 1.40-1.62 (m, 4H), 1.83-2.04 (m, 4H), 2.08 (d, 3H), 3.07-3.20 (m, 1H), 3.26 (s, 3H), 7.30 (d, 1H), 7.50 (d, 1H), 7.56 (dd, 1H), 7.66 (t, 1H), 7.78 (dd, 1H), 8.25 (s, 1H), 11.02 (s, 1H).

LC-MS (method 1): R, = 1.24 min; MS (ESIpos): m / z = 434 [M + H] ⁺ .

Example 1-106 (5s, 8s) -3- (4'-chloro-5-fluoro-4-methyM

2-one

The title compound was prepared starting from 150 mg (0.39 mmol) of the compound from Example 43 A analogously to the synthesis of the compound from Example 1 -92. 72.4 mg (48% of theory) of the title compound were obtained.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.41-1.61 (m, 4H), 1.83-2.04 (m, 4H), 2.08 (d, 3H), 3.07-3.20 (m, 1H), 3.26 (s, 3H), 7.23 (d, 1H), 7.43 (dd, 1H), 7.48 - 7.54 (m, 2H), 7.66 - 7.73 (m, 2H), 8.27 (s, 1H), 11.00 (s, 1H).

LC-MS (method 1): R, = 1.23 min; MS (ESIpos): m / z = 416 [M + H] ⁺ .

Example 1-107

(5s, 8s) -4-hydroxy-8-methoxy-3- (3 ', 4', 5-trifluoro-4-methylbiphenyl-3-yl) -1-azaspiro [4.5] d (on

The title compound was prepared starting from 150 mg (0.39 mmol) of the compound from Example 43A analogously to the synthesis of the compound from Example 1-92. 20.3 mg (48% of theory) of the title compound were obtained.

^! H NMR (300MHz, DMSO-de): δ [ppm] = 1.40-1.62 (m, 4H), 1.84-2.04 (m, 4H), 2.07 (d, 3H), 3.07-3.20 (m, 1H), 3.26 (s, 3H), 7.25 (d, 1H), 7.43-7.56 (m, 3H), 7.74-7.84 (m, 1H), 8.27 (s, 1H), 11.00 (s, 1H).

LC-MS (Method 1): R, = 1.18 min; MS (ESIpos): m / z = 418 [M + H] ⁺ .

Example 1-108 (= compound according to WO08 / 067910) (5s, 8s) -3- (4 ', 6-dichloro-3'-fluoro-4-methylbiphenyl-3-yl) ^

3-en-2-one

The title compound was prepared starting from 150 mg (0.37 mmol) of the compound from Example 41A analogously to the synthesis of the compound from Example 1-92. There were obtained 73.8 mg (44% of theory) of the title compound.

^! H NMR (300MHZ, DMSO-de): δ [ppm] = 1.37-1.59 (m, 4H), 1.82-2.02 (m, 4H), 2.18 (s, 3H), 3.05-3.18 (m, 1H), 3.25 (s, 3H), 7.12 (s, 1H), 7.29 (dd, 1H), 7.42 - 7.51 (m, 2H), 7.67 (t, 1H), 8.23 (s, 1H), 10.96 (s, 1H) ,

LC-MS (Method 1): R, = 1.29 min; MS (ESIpos): m / z = 450 [M + H] ⁺ .

Example 1-109 (= connection according to W099 / 48869)

(5s, 8s) -3- (4 ', 6-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

The title compound was prepared starting from 150 mg (0.37 mmol) of the compound from Example 41A analogously to the synthesis of the compound from Example 1-92. There were obtained 71.6 mg (44% of theory) of the title compound.

^! H NMR (300MHz, DMSO-de): δ [ppm] = 1.37-1.59 (m, 4H), 1.82-2.02 (m, 4H), 2.18 (s, 3H), 3.05-3.18 (m, 1H), 3.25 (s, 3H), 7.09 (s, 1H), 7.40-7.48 (m, 3H), 7.49-7.55 (m, 2H), 8.21 (s, 1H), 10.96 (s, 1H).

LC-MS (Method 1): R, = 1.28 min; MS (ESIpos): m / z = 432 [M + H] ⁺ . Example 1-110 (= compound of Table 1, p. 41 in combination with Table 2, p. 45 of WO08 / 067911)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3-ene-2 on

The title compound was prepared starting from 150 mg (0.43 mmol) of the compound from Example 53A analogously to the synthesis of the compound from Example 1-93. There were obtained 33.5 mg (20% of theory) of the title compound. Ή-NMR (400MHz, DMSO-de): δ [ppm] = 0.91 (d, 3H), 1.28-1.43 (m, 5H), 1.56-1.68 (m, 2H), 1.84-1.96 (m, 2H), 2.19 (s, 3H), 7.31 (d, 1H), 7.39 (d, 1H), 7.49-7.56 (m, 2H), 7.64 (t, 1H), 7.70 (dd, 1H), 8.12 (s, 1H) , 10.76 (s, 1H).

LC-MS (Method 2): R, = 1.33 min; MS (ESIpos): m / z = 400 [M + H] Example 1-111 (= compound of Table 1, p. 41 in combination with Table 2, p

WO08 / 067911)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] dec-3-ene 2

To 2.00 g (5.26 mmol) of the compound from Example 51A and 215 mg (0.26 mmol) of dichloro [l, l-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex in 213 ml of degassed 1,2-dimethoxyethane were added under argon 1.10 g (6.31 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 6.00 g (18.4 mmol) of cesium carbonate in 13 ml of degassed water. The reaction mixture was refluxed for 2 hours. After cooling, 2.5 ml was added concentrated aqueous hydrochloric acid solution and sodium sulfate, filtered through silica gel and sodium sulfate, washed with ethyl acetate and concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). The mixture was then stirred with aqueous sodium bicarbonate solution, made acidic with concentrated, aqueous hydrogen chloride solution, filtered off with suction, washed with water and dried. This gave 1.50 g (65% of theory) of the title compound.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:21 to 1:47 (m, 4H), 1:48 - 1.64 (m, 1H), 1.65 - 1.78 (m, 2H), 1.81 - 1.97 (m, 2H), 2.19 (s, 3H), 3.16 (d, 2H), 3.24 (s, 3H), 7.31 (d, 1H), 7.40 (d, 1H), 7.48 - 7.57 (m, 2H), 7.60 - 7.74 (m, 2H), 8.13 (s, 1H), 10.79 (s, 1H).

LC-MS (Method 1): R, = 1.26 min; MS (ESIpos): m / z = 430 [M + H]

Example 1-112 (= compound of Table 1, p. 41 in combination with Table 2, p

WO08 / 067911)

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-azaspiro [4.5] dec-3-ene-2 on

The title compound was prepared starting from 4.00 g (10.5 mmol) of the compound from Example 51A analogously to the synthesis of the compound from Example 1-111. The product after chromatography on silica gel was washed with water, sodium bicarbonate and 2N

Sodium hydroxide solution stirred, made acidic with concentrated aqueous hydrogen chloride solution, filtered off with suction and washed with water. 2.86 g (65% of theory) of the title compound were obtained. ^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:21 to 1:47 (m, 4H), 1:48 - 1.64 (m, 1H), 1.65 - 1.78 (m, 2H), 1.81 - 1.97 (m, 2H), 2.18 (s, 3H), 3.16 (d, 2H), 3.24 (s, 3H), 7.30 (d, 1H), 7.36 (d, 1H), 7.43 - 7.54 (m, 3H), 7.64 - 7.76 (m, 1H), 8.14 (s, 1H), 10.78 (s, 1H).

LC-MS (method 1): R, = 1.21 min; MS (ESIpos): m / z = 414 [M + H] Example 1-113 (= compound of Table 1, p. 40 in combination with Table 2, p. 47 of WO08 / 067911)

(5s, 8s) -3- (4,4'-dichloro-3'-fluorobiphenyl-3-yl) -4-hydroxy-8- (methoxymethyl) -1-azaspiro [4.5] dec-3-ene-2 οη

The preparation of the title compound was carried out starting from 450 mg (1.12 mmol) of the compound from Example 49A analogously to the synthesis of the compound from Example 1-92. The product after chromatography was dissolved in dichloromethane and concentrated. 144 mg (28% of theory) of the title compound were obtained.

^! H-NMR (300MHZ, DMSO-d ₆ ): δ [ppm] = 1.21-1.47 (m, 4H), 1.48-1.64 (m, 1H), 1.65-1.78 (m, 2H), 1.80-1.94 (m, 2H), 3.16 (d, 2H), 3.24 (s, 3H), 7.51-7.60 (m, 3H), 7.62-7.71 (m, 2H), 7.77 (dd, 1H), 8.14 (s, 1H), 11.08 (s, 1H). LC-MS (Method 1): R, = 1.27 min; MS (ESIpos): m / z = 450 [M + H] ⁺ .

Example 1-114 (= compound of Table 1, p. 41 in combination with Table 2, p. 47 of

WO08 / 067911)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (2-methoxyethyl) -l-azaspiro [4.5] dec-3 en-2-one

To 500 mg (1.27 mmol) of the compound from Example 47A and 51.8 mg (0.063 mmol) of dichloro [l, l-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex in 23 ml of degassed 1,2-dimethoxyethane were added under argon 332 mg (1.90 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 1.45 g (4.44 mmol) of cesium carbonate in 2.2 ml of degassed water. The reaction mixture was refluxed for 3 hours. Then, another 111 mg (0.63 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a spatula tip of dichloro [l, bis (diphenylphosphino) ferrocene] palladium dichloromethane complex were added and heated under reflux for 2 h. After cooling, 0.6 ml of concentrated, aqueous hydrogen chloride solution and sodium sulfate were added, filtered through silica gel and sodium sulfate, washed with

formic acid; Flow: 50 ml / min; Temperature: RT; 2nd column: Chiralpak IA, 5 μm, 250 mm × 20 mm; Eluent: hexane / ethanol = 85/15 with the addition of 0.1% trifluoroacetic acid; Flow: 40 ml / min;

Temperature: RT], the diastereomers were separated. 191 mg (33% of theory) of the title compound were obtained.

Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26-1.50 (m, 7H), 1.61-1.74 (m, 2H), 1.79-1.96 (m, 2H), 2.19 (s, 3H) , 3.23 (s, 3H), 3.37 (t, 2H), 7.31 (d, 1H), 7.39 (d, 1H), 7.48-7.57 (m, 2H), 7.64 (t, 1H), 7.70 (dd, 1H ), 8.16 (s, 1H), 10.74 (s, 1H).

LC-MS (Method 3): R, = 1.28 min; MS (ESIpos): m / z = 444 [M + H] ⁺ .

Example 1-115 (= compound of Table 1, p. 41 in combination with Table 2, p. 44 of

WO08 / 067911)

3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

The title compound was prepared starting from 150 mg (0.45 mmol) of the compound from Example 45A analogously to the synthesis of the compound from Example 1-93. There were obtained 49.3 mg (30% of theory) of the title compound.

^! H NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.13-1.25 (m, 1H), 1.34-1.43 (m, 2H), 1.54-1.71 (m, 5H), 1.78-1.90 (m, 2H), 2.18 (s, 3H), 7.29 (d, 1H), 7.36 (d, 1H), 7.46-7.52 (m, 3H), 7.67-7.74 (m, 1H), 8.14 (s, 1H), 10.76 (s, 1H).

LC-MS (method 1): R, = 1.24 min; MS (ESIpos): m / z = 370 [M + H] ⁺ . Example 1-116 i = Compound Ila-5 of WO07 / 048545)

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8 - (^

en-2-οη

To 10.4 g (23.4 mmol) of the compound from Example 37A in 35 ml of Ν, Ν-dimethylformamide were added 5.26 g (46.9 mmol) of potassium tert-butoxide. The reaction mixture was heated at 80 ° C for 15 minutes. After cooling, the mixture was concentrated, the residue was taken up in water and dripped into 2N aqueous hydrogen chloride solution. The precipitate was filtered off with suction, washed with water and dried. This gave 9.3 g of the title compound.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:21 to 1:47 (m, 4H), 1:48 - 1.64 (m, 1H), 1.65 - 1.78 (m, 2H), 1.81 - 1.97 (m, 2H), 2.18 (s, 3H), 3.16 (d, 2H), 3.24 (s, 3H), 7.30 (d, 1H), 7.34 (d, 1H), 7.44 - 7.53 (m, 3H), 7.61 - 7.68 (m, 2H), 8.13 (s, 1H), 10.77 (s, 1H).

LC-MS (Method 2): R, = 1.25 min; MS (ESIpos): m / z = 412 [M + H] ⁺ . Example 1-117 (= compound according to WO07 / 048545)

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (hydroxymethyl) -1-azaspiro [4.5] dec-3-en-2-one

To 2.00 g (4.86 mmol) of the compound from Example 1-116 and 1.46 g (9.71 mmol) of sodium iodide in 50 ml of acetonitrile under argon, a solution of 1.23 ml (9.71 mmol) of trimethylsilyl chloride in 1.5 ml of acetonitrile are slowly added dropwise. The reaction mixture was refluxed overnight. After cooling, the mixture was filtered, concentrated, and the residue dissolved in

Ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (eluent:

Hexane / ethyl acetate gradient). It was then washed with water and 2N aqueous

Sodium hydroxide solution and stirred, made acidic with 2N aqueous hydrogen chloride solution, filtered off with suction, washed with water and dried. 1.13 g (57% of theory) of the title compound were obtained. ^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:15 to 1:50 (m, 5H), 1.67 - 1.80 (m, 2H), 1.81 - 1.95 (m, 2H), 2.19 (s, 3H) , 3.24 (s, 2H), 7.30 (d, 1H), 7.34 (d, 1H), 7.46-7.53 (m, 3H), 7.62-7.68 (m, 2H), 8.11 (s, 1H), 10.75 (s , 1H).

LC-MS (Method 1): R, = 1.13 min; MS (ESIpos): m / z = 398 [M + H] ⁺ . Example 1-118 (= compound from Table 1, p. 26 of WO08 / 067910)

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 οη

To 15.7 g (35.0 mmol) of the compound from Example 39A in 60 ml of Ν, Ν-dimethylformamide were added under nitrogen 4.32 g (38.5 mmol) of potassium tert-butoxide. The reaction mixture was stirred for 20 minutes at room temperature. Then the reaction mixture was added to ice water, added dropwise 160 ml of 1 N aqueous hydrochloric acid solution, stirred for 30 minutes, filtered off with suction, washed with water and dried the precipitate. This gave 14.2 g (97% of theory) of the title compound.

^! H NMR (300MHz, DMSO-de): δ [ppm] = 1.40-1.62 (m, 4H), 1.85-2.04 (m, 4H), 2.19 (s, 3.07-3.20 (m, 1H), 3.27 ( s, 3H), 7.31 (d, 1H), 7.39 (d, 1H), 7.48-7.57 (m, 2H), 7.60-7.73 2H), 8.20 (s, 1H), 10.82 (s, 1H).

LC-MS (Method 1): R, = 1.22 min; MS (ESIpos): m / z = 416 [M + H] ⁺ . Example 1-119 (= connection according to W099 / 48869)

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4. ^

2-one

To 6.36 g (13.59 mmol) of methyl cis-1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-

(Trifluoromethyl) cyclohexanecarboxylate (Example 2A) in 68 ml of Ν, Ν-dimethylformamide were added 3.05 g (27.18 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 60 minutes. For workup, the cooled reaction mixture was poured onto 800 ml of ice water and acidified with aqueous hydrochloric acid. The crude product was filtered off, dried and purified by chromatography on silica gel (hexane / ethyl acetate gradient). Evaporation gave 4.1 g (69% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:40 to 1:55 (m, 2H), 1.58 - 1.77 (m, 2H), 1.78 - 2:02 (m, 4H), 2.15 (s, 3H) , 2.17-2.30 (m, 1H), 7.27 (d, 1H), 7.32 (d, 1H), 7.42-7.51 (m, 3H), 7.58-7.66 (m, 2H), 8.29 (s, 1H), 10.90 (s, 1H).

LC-MS (Method 3): R, = 1.32 min; MS (ESIpos): m / z = 436 [M + H] ⁺ .

Example 1-120 (= connection according to W099 / 48869)

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methoxy-l-azaspiro [4.5] dec-3-en-2-one

To 27.80 g (61.73 mmol) of methyl cis-1 - {[(4,4'-dichlorobiphenyl-3-yl) -acetyl] -amino} -4-methoxycyclohexanecarboxylate (Example 4A) in 310 ml of Ν, Ν-dimethylformamide was added 13.90 g (123.46 mmol) of potassium tert-butoxide was added. The reaction mixture was stirred at 80 ° C for 60 minutes. For work-up, the cooled reaction mixture was poured onto 4 l of ice-water and acidified with aqueous hydrochloric acid. The crude product was filtered off, dried and purified by stirring in diethyl ether. 24.09 g (93% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:34 - 1.61 (m, 4H), 1.76 - 2:04 (m, 4H), 3:02 to 3:18 (m, 1H), 3.23 (s, 3H) , 7.44-7.53 (m, 4H), 7.57 (dd, 1H), 7.62-7.70 (m, 2H), 8.18 (s, 1H), 11.05 (s, 1H).

LC-MS (Method 2): R, = 1.17 min; MS (ESIpos): m / z = 418 [M + H] ⁺ .

Example 1-121 (= connection according to W099 / 48869)

(5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

To 200 mg (0.53 mmol) of (5s, 8s) -3- (3-bromo-2,6-dimethylphenyl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Example 7A) in 23 ml of degassed 1,2-dimethoxyethane was added under argon 43 mg (0.053 mmol) of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 123 mg (0.79 mmol) of (4-chlorophenyl) boronic acid and a solution of 600 mg (1.84 mmol) of cesium carbonate in 1.4 ml of degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 500 μΐ concentrated, aqueous hydrogen chloride solution and magnesium sulfate were added, filtered through silica gel and magnesium sulfate, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC (C18 phase, eluent:

Water / acetonitrile gradient / 0.1% formic acid) to give 65 mg (30% of theory) of the title compound.

^! H-NMR (300MHz, DMSO-de): δ [ppm] = 1.33-1.60 (m, 4H), 1.79-1.99 (m, 4H), 1.93 (s, 3H), 2.08 (s, 3H), 3.03 3.17 (m, 1H), 3.22 (s, 3H), 7.00 (d, 1H), 7.08 (d, 1H), 7.26 ("d", 2H), 7.45 ("d", 2H), 8.10 (s, 1H), 10.70 (s, 1H). LC-MS (Method 2): R, 1.23 min; MS (ESIpos): m / z = 412 [M + H] ⁺ .

Example 1-122

(5R, 8R) -3- (4'-chloro-4-methylbiph

en-2-οη

To 125 mg (0.30 mmol) of (5r, 8r) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -one (Example 12A) in 13 ml of degassed 1,2-dimethoxyethane under argon were added 24 mg (0.030 mmol) of dichloro [l, r-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 70 mg (0.45 mmol) of (4-chlorophenyl) boronic acid and a solution of 339 mg (1.04 mmol) of cesium carbonate in 815 μΐ degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) and by HPLC chromatography (C18 phase, eluent: water / acetonitrile gradient / 0.1% formic acid) to give 17.4 mg (13% of theory) of the title compound.

^! H-NMR (400MHz, methanol-d _4): δ [ppm] = 1:41 to 1:53 (m, 2H), 1.85 - 2:01 (m, 4H), 2.24 (s, 3H), 2:33 to 2:46 (m, 2H) , 7.32 (d, 1H), 7.35-7.42 (m, 3H), 7.46 (dd, 1H), 7.58 ("d", 2H).

LC-MS (Method 1): R, = 1.19 min; MS (ESIpos): m / z = 452 [M + H] Example 1-123

(5R, 8R) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4 ^

azaspiro [4.5] dec-3-en-2-

To 125 mg (0.30 mmol) of (5r, 8r) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -one (Example 12A) in 13 ml of degassed 1,2-dimethoxyethane under argon were added 24 mg (0.030 mmol) of dichloro [l, r-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 78 mg (0.45 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 340 mg (1.04 mmol) of cesium carbonate in 815 μΐ degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) to give 68 mg (49% of theory) of the title compound.

^! H-NMR (300MHz, methanol ^): δ [ppm] = 1.41- 1.56 (m, 2H), 1.85-1.99 (m, 4H), 2.25 (s, 3H), 2.32-2.48 (m, 2H), 7.10 7.25 (m, 1H), 7.34 (d, 1H), 7.40 (dd, 1H), 7.43-7.56 (m, 3H).

LC-MS (Method 3): R, = 1.19 min; MS (ESIpos): m / z = 470 [M + H] ⁺ .

Example 1-124

(5R, 8R) -3- (3 ^ 4'-difluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trirluormethy

azaspiro [4.5] dec-3-en-2-one

To 120 mg (0.29 mmol) of (5r, 8r) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -one (Example 12A) in 13 ml of degassed 1,2-dimethoxyethane was added under argon 23 mg (0.030 mmol) of dichloro [l, r-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 68 mg (0.43 mmol) of (3,4-difluorophenyl) boronic acid and a solution of 326 mg (1.00 mmol) of cesium carbonate in 780 μΐ degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) to give 58 mg (45% of th.) Of the title compound.

^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:42 to 1:56 (m, 2H), 1.83 - 2:00 (m, 4H), 2.25 (s, 3H), 2:32 to 2:49 (m, 2H) , 7.22 - 7.56 (m, 6H).

LC-MS (Method 3): R, = 1.13 min; MS (ESIpos): m / z = 454 [M + HJ Example 1-125

(5R, 8R) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4,8-d

azaspiro [4.5] dec-3-en-2-one

To 44 mg (0.10 mmol) of (5r, 8r) -3- (3-bromo-2,6-dimethylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene -2-one (Example 16A) in 4.4 ml of degassed 1,2-dimethoxyethane was added under argon 8.3 mg (0.010 mmol) of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 24 mg (0.15 mmol) of (4-chlorophenyl) boronic acid and a solution of 116 mg (0.36 mmol) of cesium carbonate in 280 μl of degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) to give 8.6 mg (18% of theory) of the title compound.

^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:39 to 1:53 (m, 2H), 1.84 - 1.98 (m, 4H), 2:03 (s, 3H), 2.19 (s, 3H), 2.31 - 2.48 (m, 2H), 7.05 (d, 1H), 7.13 (d, 1H), 7.25 ("d", 2H), 7.38 ("d", 2H).

LC-MS (method 1): R, = 1.21 min; MS (ESIpos): m / z = 466 [M + H] ⁺ . Example 1-126

(5R, 8R) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3 ^

azaspiro [4.5] dec-3-en-2-one

To 149 mg (0.34 mmol) of (5r, 8r) -3- (3-bromo-2,6-dimethylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene 2-One (Example 16A) in 15 ml of degassed 1,2-dimethoxyethane was added under argon 28 mg (0.034 mmol) of dichloro [l, bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 90 mg (0.52 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 391 mg (1.20 mmol) of cesium carbonate in 940 μΐ degassed water were added. The reaction mixture was allowed to stand for 10 minutes

Heated at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) to give 107 mg (64% of theory) of the title compound. ^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:40 to 1:55 (m, 2H), 1.85 - 2:00 (m, 4H), 2:06 (s, 3H), 2.21 (s, 3H), 2:32 - 2.50 (m, 2H), 7.05 - 7.12 (m, 2H), 7.13 - 7.21 (m, 2H), 7.48 (t, 1H).

LC-MS (Method 3): R, = 1.22 min; MS (ESIpos): m / z = 484 [M + H] ⁺ . Example 1-127

(5R, 8R) -3- (4'-chloro-6-fluoro-4-methyM ^

azaspiro [4.5] dec-3-en-2-one

To 194 mg (0.44 mmol) of (5r, 8r) -3- (5-bromo-4-fluoro-2-methylphenyl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3 -en-2-one (Example 21A) in 19 ml of degassed 1,2-dimethoxyethane under argon was added 36 mg (0.044 mmol) of dichloro [l, bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 104 mg (0.66 mmol) of (4-chlorophenyl) boronic acid and a solution of 505 mg (1.55 mmol) of cesium carbonate in 1200 μl of degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 150 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) and by HPLC chromatography (C18 phase, eluent: water / acetonitrile gradient / 0.1% formic acid) to give 60 mg (29% of theory) of the title compound.

^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:40 to 1:51 (m, 2H), 1.83 - 2:01 (m, 4H), 2.23 (s, 3H), 2:30 to 2:46 (m, 2H) , 7.08 (d, 1H), 7.21 (d, 1H), 7.37-7.43 (m, 2H), 7.49-7.56 (m, 2H).

LC-MS (method 1): R, = 1.21 min; MS (ESIpos): m / z = 470 [M + H] ⁺ . Example 1-128 (= compound according to WO08 / 067911)

(5s, 8s) -3- (3 4'-difluoro-4-methylbiphenyl-3-yl) -4-hy

en-2-οη

To 6.57 g (14.00 mmol) of methyl cis-1- {[(3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4- (trifluoromethyl) -cyclohexanecarboxylate (Example 24A) in 70 ml Ν, Ν-Dimethylformamide was added 3.14 g (28.00 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 60 minutes. For workup, the cooled reaction mixture was poured onto 1.2 1 of ice water and acidified with aqueous hydrochloric acid. The crude product was filtered off and dried. The crude product was purified by HPLC chromatography (C18 phase, eluent:

Water / acetonitrile gradient / 0.2% ammonia). The resulting residue was dissolved in 500 ml of 26 mmolar aqueous sodium hydroxide solution to liberate the acid, with aqueous 1N

Hydrochloric acid, washed with water, filtered off and dried. For further purification, the product was chromatographed on silica gel (eluent: hexane / ethyl acetate gradient). The product thus obtained was redissolved in 500 ml of 26 mm aqueous sodium hydroxide solution, acidified with aqueous 1N hydrochloric acid, washed with water, filtered off and dried. 2.18 g (36% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:42 to 1:54 (m, 2 H) 1.57 - 1.75 (m, 2H), 1.76 - 2:02 (m, 4H), 2.15 (s, 3H) , 2.19-2.29 (m, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.41-7.52 (m, 3H), 7.61-7.72 (m, 1H), 8.27 (s, 1H), 10.91 (s, 1H). LC-MS (Method 3): R, = 1.26 min; MS (ESIpos): m / z = 438 [M + H] ⁺ . Example 1-129 (= compound according to WO08 / 067911)

(5R, 8R) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azas

en-2-οη

The title compound was used as a minor component in HPLC chromatography (Cl 8 phase, eluent: water / acetonitrile gradient / 0.2% ammonia) of (5s, 8s) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3- yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one (Example 1-128) as the ammonium salt. To release the acid, 906 mg of the ammonium salt was dissolved in 170 ml of 26 mmolar aqueous sodium hydroxide solution, acidified with aqueous 1N hydrochloric acid, washed with water, filtered off and dried. This gave 855 mg of

Title compound.

'H-NMR (300MHz, DMSO-de): δ [ppm] = 1.54 - 1.71 (m, 2H), 1.76 - 2.07 (m, 6H), 2.15 (s, 3H), 2.26 - 2.42 (m, 1H) , 7.27 (d, 1H), 7.32 (d, 1H), 7.41-7.53 (m, 3H), 7.61-7.80 (m, 2H), 10.90 (s, 1H).

LC-MS (Method 3): R, = 1.30 min; MS (ESIpos): m / z = 438 [M + H] ⁺ .

Example 1-130

(5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-yl en-2-one

To 245 mg (0.52 mmol) of (5r, 8r) -3- (5-bromo-2-methylphenyl) -4,8-dihydroxy-8- (pentafluoroethyl) -l- azaspiro [4.5] dec-3-en-2-one (Example 25A) in 23 ml of degassed 1,2-dimethoxyethane was added under argon 43 mg (0.052 mmol) of dichloro [l, l 'bis (diphenylphosphinyl) ferrocene] palladium Added dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 136 mg (0.78 mmol) of (4-chloro-3-fluorophenyl) boronic acid and a solution of 594 mg (1.82 mmol) of cesium carbonate in 800 μl of degassed water were added. The reaction mixture was heated for 10 minutes at 150 ° C in a closed vessel under microwave irradiation. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) and by HPLC chromatography (C18 phase, eluent: water / acetonitrile gradient / 0.1% formic acid) to give 57 mg (21% of theory) of the title compound. ^! H NMR (300MHz, DMSO-de): δ [ppm] = 1.23-1.37 (m, 2H), 1.72-2.00 (m, 4H), 2.15 (s, 3H), 2.17-2.33 (m, 2H), 5.87 (s, 1H), 7.29 (d, 1H), 7.36 (d, 1H), 7.46-7.55 (m, 2H), 7.61 (t, 1H), 7.67 (dd, 1H), 8.36 (s, 1H) , 10.95 (s, 1H).

LC-MS (Method 3): R, = 1.26 min; MS (ESIpos): m / z = 520 [M + H] ⁺ . Example 1-131

(5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-ene -2-

To 139 mg (0.29 mmol) of (5r, 8r) -3- (5-bromo-4-fluoro-2-methylphenyl) -4,8-dihydroxy-8- (pentafluoroethyl) -1-azaspiro [4.5] dec-3 -en-2-one (Example 26A) in 13 ml of degassed 1,2-dimethoxyethane under argon was added 23 mg (0.028 mmol) of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 67 mg (0.43 mmol) of (4-chlorophenyl) boronic acid and a solution of 325 mg (1.00 mmol) of cesium carbonate in 800 μl of degassed water were added. The reaction mixture was 13 minutes at 150 ° C in a closed vessel under Microwave irradiation heated. After cooling, 100 .mu.l of concentrated, aqueous hydrogen chloride solution were added to the batch and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous, 5% citric acid (pH = 4.0-4.5) and water. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) and by HPLC chromatography (C18 phase, eluent: water / acetonitrile gradient / 0.1% formic acid) to give 4 mg (3% of theory) of the title compound.

^! H-NMR (300MHz, methanol-d _4): δ [ppm] = 1:40 to 1:53 (m, 2H), 1.93 - 2:04 (m, 4H), 2.24 (s, 3H), 2:31 to 2:50 (m, 2H) , 7.10 (d, 1H), 7.21 (d, 1H), 7.38-7.45 (m, 2H), 7.49-7.57 (m, 2H).

LC-MS (Method 3): R, = 1.28 min; MS (ESIpos): m / z = 520 [M + H] ⁺ .

Example 1-132 (= compound of Table 1, p. 69 in combination with Table 5, p

W099 / 48869)

(5s, 8s) -3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

7.00 g (55 mmol) of potassium tert-butoxide were initially charged in 18 ml of Ν, Ν-dimethylformamide (DMF). At 60 ° C was added dropwise 11.13 g (26.8 mmol) of the compound of Example 54A in 23 ml of DMF and stirred for 1 h at 80 ° C after. The reaction mixture was poured into ice-water, acidified with dilute hydrochloric acid, filtered off, washed and dried. The residue was chromatographed on silica gel with methylene chloride / ethyl acetate (3: 2). 5.67 g (51% of theory) of the title compound were obtained. ^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.40 - 1.55 (m, 4H), 1.87 - 1.99 (m, 4H), 2.15 (s, 3H), 2.21 (s, 3H), 3.08 - 3.16 (m, 1H), 3.26 (s, 3H), 6.90 (s, 1H), 7.24 (s, 1H), 7.34 - 7.36 (m, 2H), 7.47 - 7.49 (m, 2H), 8.14 (s, 1H).

LC-MS (Method 1): R, = 1.26 min; MS (ESIpos): m / z

Example 1-133 (= connection according to W099 / 48869) (5S, 7S) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl)

2-one

1.30 g (27 mmol) of potassium tert-butoxide were initially charged in 4 ml of Ν, Ν-dimethylformamide (DMF). At 20-40 ° C was added dropwise 2.33 g (5 mmol) of the compound from Example 55A in 5 ml of DMF and stirred for 1 h at 40 ° C after. The reaction mixture was poured into ice-water, acidified with dilute hydrochloric acid, filtered off, washed and dried. The residue was chromatographed on silica gel with methylene chloride / acetone (5: 1). 0.9 g (41% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:24 to 1:26 (m, 1H), 1:42 to 1:45 (m, 1H), 1:56 to 1:59 (m, 1H), 1.67 - 1.70 (m, 1H), 1.83 - 1.94 (m, 4H), 2.19 (s, 3H), 2.67 - 2.70 (m, 1H), 7.30 - 7.32 (m, 1H), 7.38 - 7.39 (m, 1H), 7.49 - 7.51 ( m, 3H), 7.65-7.68 (m, 2H), 8.23 (s, 1H).

LC-MS (Method 1): R, = 1.35 min; MS (ESIpos): m / z = 436 [M + H] ⁺ .

Example 1-134 (= connection according to W099 / 48869)

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

1.67 g (36 mmol) of potassium tert-butoxide were initially charged in 5 ml of Ν, Ν-dimethylformamide (DMF). At 20-40 ° C was added dropwise 3.13 g (6.4 mmol) of the compound of Example 56A in 9 ml of DMF and stirred for 1 h at 40 ° C after. The reaction mixture was poured into ice-water, acidified with dilute hydrochloric acid, filtered off, washed and dried. The residue was chromatographed on silica gel with methylene chloride / acetone (5: 1). 1.77 g (60% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.50-1.53 (m, 2H), 1.68-1.74 (m, 2H), 1.85-1.98 (m, 4H), 2.23-2.24 (m, 1H), 7.50-7.56 (m, 4H), 7.61-7.63 (m, 1H), 7.69-7.71 (m, 1H), 7.73-7.78 (m, 1H), 8.37 (s, 1H).

LC-MS (Method 1): R, = 1.32 min; MS (ESIpos): m / z = 456 [M + H] ⁺ . Example 1-135 (= connection according to W099 / 48869)

(5s, 8s) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

72.5 g (21.2 mmol) of potassium tert-butoxide were initially charged in 10 ml of Ν, Ν-dimethylacetamide (DMA). At 30 ° C., 4.3 g (9.6 mmol) of the compound from Example 57A in 10 ml of DMA were added dropwise and the mixture was stirred at 30 ° C. for 4 h. The reaction mixture was poured onto ice-water, acidified with dilute hydrochloric acid, extracted with methylene chloride, dried and evaporated. The residue was chromatographed on silica gel with methylene chloride / ethyl acetate (3: 1). 2.8 g (72% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.45-1.60 (m, 4H), 1.89-2.00 (m, 4H), 2.19 (s, 3H), 3.11-3.18 (m, 1H), 3.27 (s, 3H), 7.13 - 7.19 (m, 2H), 7.48-7.50 (m, 4H), 7.94 (s, 1H).

LC-MS (Method 2): R, = 1.21 min; MS (ESIpos): m / z = 416 [M + H] ⁺ . Example 1-136 (compound from Table 1, p. 26 of WO08 / 067910)

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

0.59 g (1.5 mmol) of the compound from Example 58A, 0.36 g (2.3 mmol) 3,4-

Trifluorophenylboronic acid and 0.8 g (7.5 mmol) of sodium carbonate were placed in 15 ml of water. 0.037 g (0.15 mmol) of palladium (II) nitrate dihydrate was added and the mixture was heated at 130 ° C. overnight at reflux. The reaction mixture was then acidified with dilute hydrochloric acid and the precipitate was filtered off with suction. The aqueous phase was extracted by shaking with methylene chloride, dried and i. Vak. evaporated. Purification was first by MPLC on silica gel with cyclohexane / acetone 0-50% gradient and subsequent RP-chromatography water / acetonitrile 0-100% gradient. The residue was stirred with methyl tert-butyl ether and filtered with suction. 0.2 g (33% of theory) of the title compound were obtained.

^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.46 - 1.58 (m, 4H), 1.94 - 2.01 (m, 4H), 2.19 (s, 3H), 3.27 (s, 3H), 7.27 - 7.29 (m, 1H), 7.33-7.34 (m, 1H), 7.42-7.48 (m, 3H), 7.59-7.63 (m, 1H), 7.90 (s, 1H).

LC-MS (Method 1): R, = 1.19 min; MS (ESIpos): m / z = 400 [M + H] ⁺ .

Example 1-137 (= connection according to W099 / 48869)

(5S, 7S) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

l The preparation of the title compound was carried out starting from the compound from Example 59A analogously to the synthesis of the compound from Example 1-133.

^! H NMR (400MHZ, DMSO-de): δ [ppm] = 1.24-1.26 (m, 1H), 1.42-1.46 (m, 1H), 1.57-1.60 (m, 1H), 1.66-1.73 (m, 1H ), 1.81 - 1.96 (m, 4H), 2.67 - 2.78 (m, 1H), 7.52 - 7.56 (m, 4H), 7.61 - 7.63 (m, 1H), 7.70 - 7.72 (m, 2H), 8.27 (s , 1H).

LC-MS (Method 1): R, = 1.34 min; MS (ESIpos): m / z = 456 [M + H] ⁺ .

Example 1-138 (= connection according to W099 / 48869)

3- (4,4'-dichlorobiphenyl-3-y4-hydroxy-8,8-dimethyl-1-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from the compound from Example 60A analogously to the synthesis of the compound from Example 1-140. ^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 0.94 (s, 3H), 0.95 (s, 3H), 1:24 to 1:33 (m, 4 H) 1.57 - 1.63 (m, 2H), 1.91 - 2.09 (m, 2H), 7.48 - 7.55 (m, 4H), 7.59 - 7.65 (m, 1H), 7.68 - 7.71 (m, 2H), 8.20 (s, 1H).

LC-MS (Method 1): R, = 1.40 min; MS (ESIpos): m / z = 416 [M + H] ⁺ . Example 1-139 (= connection according to W099 / 48869)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methyl-l-azaspiro [4.5] dec-3-en-2-one

l The preparation of the title compound was carried out starting from the compound from Example 61 A analogously to the synthesis of the compound from Example 1-140.

^! H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.91 (d, 3H), 1.35-1.40 (m, 5H), 1.62 (m, 2H), 1.84-1.91 (m, 2H), 7.50 - 7.55 (m, 4H), 7.59-7.61 (m, 1H), 7.69-7.71 (m, 2H), 8.16 (s, 1H).

LC-MS (Method 2): R, = 1.36 min; MS (ESIpos): m / z = 402 [M + H] ⁺ .

Example 1-140 (= connection according to W099 / 48869)

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

2.31 g (18.9 mmol) of potassium tert-butoxide were initially charged in 7 ml of Ν, Ν-dimethylformamide (DMF). At 20-40 ° C was added dropwise 3.54 g (8.4 mmol) of the compound of Example 62A in 8 ml of DMF and stirred for 1 h at 40 ° C after. The reaction mixture was poured into ice-water, acidified with dilute hydrochloric acid, filtered off, washed and dried. The residue was chromatographed on silica gel with methylene chloride / acetone (3: 1). This gave 2.79 g (85% of theory) of the title compound.

^! H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1:16 to 1:26 (m, 1H), 1:31 to 1:41 (m, 2H), 1:55 - 1.66 (m, 5H), 1.79 - 1.91 (m, 2H), 7.50-7.54 (m, 4H), 7.60-7.62 (m, 1H), 7.68-7.71 (m, 2H), 8.30 (s, 1H).

LC-MS (Method 1): R, = 1.29 min; MS (ESIpos): m / z = 388 [M + H] ⁺ . Example 1-141 (= connection according to W099 / 48869)

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-isopropyl-l-azaspiro [4.5] dec-3-en-2-one

The preparation of the title compound was carried out starting from the compound from Example 63A analogously to the synthesis of the compound from Example 1-140.

^! H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.88-0.89 (d, 6H), 0.98-1.08 (m, 1H), 1.32-1.47 (m, 5H), 1.64 (m, 2H), 1.81- 1.88 (m, 2H), 7.50-7.55 (m, 4H), 7.59-7.61 (m, 1H), 7.69-7.71 (m, 2H), 8.18 (s, 1H).

LC-MS (method 1): R, = 1.46 min; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Example 1-142 (compound from Table 1, p. 25 of WO08 / 067910)

(5s, 8s) -3- (4'-chloro-2'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 on

To 54.9 mg (0.15 mmol) of (5s, 8s) -3- (5-bromo-2-methylphenyl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (Example 58A) in 2.9 ml of Ν, Ν-dimethylformamide, 0.1 mg of 1,1'-bis (diphenlyphosphino) ferrocenedichloro-palladium (II), 39.2 mg (0.225 mmol) of (4-chloro-2-fluorophenyl) boronic acid in 0.37 ml 1, 2 Dimethoxyethane and 171 mg (0.525 mmol)

Cesium carbonate in 0.29 mL of water. The reaction mixture was stirred at 100 ° C for 60 minutes. For working up, the cooled reaction mixture was treated with 1 ml of saturated aqueous sodium chloride solution and extracted with 3 ml of ethyl acetate. The organic phase was separated and the solvent evaporated. The purification was carried out by HPLC. 13.2 mg (21% of theory) of the title compound were obtained.

LC-MS (Method 4): R, = 1.23 min; MS (ESIpos): m / z = 416 [M + H] ⁺ . Example 1-143 (= compound from Table 1, p. 69 in combination with Table 10, p. 72 of WO99 / 48869)

(5s, 8s) -3- (2 ', 4'-dichloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

The compound was prepared in analogy to Example 1-142. 10.1 mg (15% of theory) of the title compound were obtained.

LC-MS (Method 4): R, = 1.28 min; MS (ESIpos): m / z = 432 [M + H] ⁺ .

Example 1-144 (= compound according to WO08 / 067910) (5s, 8s) -3- (2'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-l azaspiro [4.5] dec-3-en-2-one

The compound was prepared in analogy to Example 1-142. 10.0 mg (15% of theory) of the title compound were obtained.

LC-MS (Method 4): R, = 1.20 min; MS (ESIpos): m / z = 416 [M + H] Example 1-145 (= compound from Table 1, p. 41 in combination with Table 2, p

WO08 / 067911)

The preparation of the title compound was carried out starting from 1.35 g (3.85 mmol) of the compound from Example 53 A analogously to the synthesis of the compound from Example 1-90. 824 mg (54% of theory) of the title compound were obtained.

Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.92 (d, 3H), 1.28-1.42 (m, 5H), 1.56-1.68 (m, 2H), 1.84-1.96 (m, 2H) , 2.18 (s, 3H), 7.30 (d, 1H), 7.36 (d, 1H), 7.45-7.54 (m, 3H), 7.66-7.74 (m, 1H), 8.13 (s, 1H), 10.75 (s , 1H).

LC-MS (Method 1): R, = 1.30 min; MS (ESIpos): m / z = 384 [M + H] ⁺ .

Example 1-146 (= compound from Table 1 of WO99 / 48869)

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

Analogously to Example 1-118, the title compound was obtained after reversed phase chromatography with acetonitrile / water (gradient).

^! H-NMR (400 MHz, d ₆ -DMSO): δ [ppm] = 1.12 (t, 3H), 1.44-1.47 (m, 2H,), 1.51-1.61 (m, 2H), 1.91-1.98 (m, 4H), 2.19 (s, 3H), 3.22 - 3.27 (m, 1H), 3.47 - 3.52 (q, 2H), 7.31 (d, 1H), 7.34 (d, 1H), 7.48 - 7.52 (m, 3H) , 7.64 - 7.67 (m, 2H), 8.18 (s, 1H), 10.81 (s, 1H).

LC-MS (Method 1): R, = 1.28 min; MS (ESIpos): m / z = 412 [M + H] Example 1-147 (= compound from Table 1 of WO99 / 48869)

(5R, 8R) -3- (4'-chloro-4-methylbiphenyl-3-yl) -8-ethoxy-4-hydroxy-l-azaspiro [4.5] dec-3-en-2-one

Analogously to Example 1-118, the title compound was obtained by reversed phase

Chromatography with acetonitrile / water (gradient).

'H NMR (400 MHz, d ₆ -DMSO): δ [ppm] = 1.14 (t, 3H), 1.18-1.24 (m, 2H), 1.73-1.87 (m, 4H), 2.07-2.17 (m, 2H), 2.18 (s, 3H), 3.41-3.46 (m, 2H), 3.54 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (d, 1H), 7.48-7.50 (m, 3H) , 7.63-7.66 (m, 2H), 8.12 (s, 1H), 10.77 (s, 1H).

LC-MS (Method 1): R, = 1.28 min; MS (ESIpos): m / z = 412 [M + H] ⁺ .

Compounds according to formula (1-2)

Table 2 lists some structures of the prior art formula (1-2) and indicates in which law the preparation is disclosed.

Table 2

analytics

Ex. Structure / name disclosed in

'H-NMR: δ [ppm] retention time, [M + H] ⁺ , method

WO 07/048545

2-20

I-2-a-8

Cl

3- (4'-chloro-4-methylbiphenyl-3-yl) -

4-hydroxy-8- (methoxymethyl) -1-oxaspiro [4.5] dec-3-en-2-one

WO 08/067911

2-21

I-2-a-15

F

3- (4'-fluoro-4-methylbiphenyl-3-yl) -

4-hydroxy-1-oxaspiro [4.5] dec-3-ene-2-one

WO 08/067911

2-22

I-2-a-3

F F

3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one

WO 08/067911

2-23

I-2-a-4

Cl F

3- (3'-Chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-1-oxaspiro [4.4] non-3-en-2-one

Compounds according to formulas (1-3), (1-6), (1-7), (1-8), (1-9), (1-10) and (I-II)

Table 3 lists some structures of the formula 1 (1-3), (1-6), (1-7), (1-8), (1-9), (1-10) and (II) of the prior art technology and state in which law the production is revealed.

Table 3

ASSAYS

Human ACCI enzyme assay

ACC1 inhibition data were collected using two different assays (AI and Bl)

Assay AI (= (A1))

The inhibitory activity of the substances of this invention against acetyl-CoA carboxylase 1 (ACC1) was measured in the ACC1 assay described in the following paragraphs.

Basic principle of the assay is to measure the Adenosindiphoshats formed as co-product (ADP) using a HTRF ^® -based competitive immunoassay (HTRF = Homogeneous Time Resolved Fluorescence).

C-terminally FLAG-tagged recombinant human ACC1 (GenBank Accession No. NM 198834, amino acids 39- end) expressed in baculovirus-transfected insect cells (Hi5) and purified by affinity chromatography on anti- ^FLAG® M2 affinity gel (as enzyme). Sigma-Aldrich). Alternatively, commercially available C-terminal His-tagged ACC1 from BPS Bioscience (San Diego, CA, Catalog No. 50200. Amino Acids 39- End) can be used. For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were transferred to a black low-volume 384-well microtiter plate (Grein er Bio-One, Frickenhausen, Germany).

Germany), 2 μΐ of a solution of ACC1 in assay buffer [50 mM HEPES / NaOH pH 7.5, 12 mM sodium bicarbonate, 2 mM MgCl ₂ , 2 mM potassium citrate, 0.005% (w / v) bovine serum albumin (BSA)] and incubating the mixture for 15 minutes to allow pre-binding of the substances to the enzyme prior to the enzyme reaction. Then, the enzyme reaction was started by adding 3 μΐ of a solution of adenosine triphosphate (ATP, 83.5 μΜ => final concentration in 5 μΐ assay volume is 50 μΜ, Amersham Pharmacia Biotech # 27-2056-01) and acetyl-CoA (33.4 μΜ => final concentration in 5 μΐ assay volume is 20 μΜ, Roche Bioscience # 10101893001) in assay buffer and the resulting mixture for the

Reaction time of 20 min at 22 ° C incubated. The concentration of the ACC1 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 2.5 ng / μΐ.

The reaction was quenched by successive additions of 2.5 μΐ a solution of d2 labeled ADP (HTRF ^® Trans Screener ™ ADP kit, Cis biointernational, Marcoule, France) in the EDTA-containing HTRF ^® Trans Screener ™ ADP-assay buffer (in HTRF ^® Transscreener ™ ADP Kit, 50mM HEPES pH 7.0, 60mM EDTA, 0.1% (w / v) BSA, 0.02% sodium azide, 400mM potassium fluoride) and 2.5μl of a solution of europium cryptate labeled anti-ADP antibody (HTRF ^® Trans Screener ™ ADP kit) in HTRF ^® Trans Screener ™ ADP detection buffer. The resulting mixture was incubated for 1 h at 22 ° C to allow binding of the europium cryptate-labeled anti-ADP antibody to the ADP formed by the enzyme reaction and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF measuring instrument, eg a Rubystar or Pherastar (both BMG Labtechnologies, Offenburg,

Germany), the fluorescence emissions measured at 620 nm and 665 nm after excitation at 350 nm. The ratio of the emissions at 665 nm and at 622 nm was used as a measure of the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody and thus indirectly as a measure of the amount of unlabelled formed in the enzyme reaction ADP taken (higher ratio of emissions at 665 nm and at 622 nm => more complex of d2-labeled ADP and europium-cryptate-labeled anti-ADP antibody => less ADP). The data were normalized (enzyme reaction without inhibitor = 0%

Inhibition, all other assay components but no enzyme = 100% inhibition). Usually, the test substances were incubated on the same microtiter plates at 10 different concentrations in the range of 20 μΜ to 1 nM (20 μΜ, 6.7 μΜ, 2.2 μΜ, 0.74 μΜ, 0.25 μΜ, 82 ηΜ, 27 ηΜ, 9 , 2 ηΜ, 3.1 nM and 1 nM, the serial dilutions were assayed at the level of the 100-fold concentrated solution by serial 1: 3 dilutions) in duplicate for each concentration before the assay and IC50 values were calculated with a 4-parameter -Fit, for which a ZwAowse software was used.

Assay Bl (= (B1))

The hACCI inhibitory activity of the substances of this invention was measured in the hACC1 assay described in the following paragraphs.

Essentially, the enzyme activity is measured by quantifying the adenosine di-phosphate (ADP) formed as a by-product of the enzyme reactions using the ADP-Glo ™ detection system from Promega. In this case, the adenosine tri-phosphate (ATP) not consumed in the enzyme reaction is first quantitatively converted into cAMP by means of an adenylate cyclase ("ADP-GLO reagent"), the adenylate cyclase is then stopped and then ("kinase detection reagent") is then converted the formed ADP into ATP and converted this into a glow luminescence signal in a luciferase-based reaction.

The enzyme used was recombinant C-terminal FLAG-tagged human ACCL (Acetyl-Coenzyme A Carboxylase alpha transcript variant 1) (GenBank Accession No. NM 198834) (amino acids 39- end) expressed in baculovirus-infected insect cells (Hi5) and purified by anti-FLAG affinity chromatography. For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were pipetted into a white low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2.5 μl of a solution of hACCI in assay buffer [50 mM HEPES / NaOH pH 7.5, 2mM MgCl ₂ , 2mM potassium citrate, 12mM NaHCO ₃ , 2mM thio-threitol (DTT), 0.005% (w / v) bovine serum albumin (BSA)] are added and the mixture is incubated for 15h min incubated to allow a Vorbindung the substances to the enzyme prior to the enzyme reaction. Then the

Enzyme reaction started by adding 2.5 μΐ of a solution of adenosine tri-phosphate (ATP, 100 μΜ => final concentration in 5 μΐ assay volume is 50 μΜ) and acetyl-CoA (20 μΜ

=> Final concentration in 5 μΐ assay volume is 10 μΜ) in assay buffer and the resulting mixture for the reaction time of 45 min at 22 ° C incubated. The concentration of hACC1 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 1.75 ng / μΐ. The reaction was stopped by adding 2.5 μΐ of the "ADP-GLO reagent" (diluted 1: 1.5 fold) and the resulting mixture incubated for 1 h at 22 ° C to fully add the unreacted ATP into cAMP Subsequently, 2.5 μΐ of the "Kinase Detection Reagent" (1.2 times more concentrated than indicated by the manufacturer) was added, the resulting mixture incubated for 1 h at 22 ° C and then the luminescence with a suitable instrument (Viewlux or Topcount from Perkin -Elmer or Pherastar from BMG Labtechnologies). The amount of light emitted was taken as a measure of the amount of ADP formed and thus of the enzyme activity of the hACCI. The data were normalized (enzyme reaction without inhibitor = 0%

Inhibition, all other assay component but no enzyme = 100% inhibition). Typically, the test substance was incubated on the same microtiter plates at 10 different concentrations ranging from 20 μΜ to 1 nM (20 μΜ, 6.7 μΜ, 2.2 μΜ, 0.74 μΜ, 0.25 μΜ, 82 μη, 27 μη, 9.2 μη, 3.1 μM and 1 μM). dilution series were prepared before the assay at the level of 100X concentrated solution by serial 1: 3 dilutions) in duplicate for each

Concentration tested and IC ₅ o values were calculated using a 4-parameter fit using in-house software.

Human ACC2 enzyme assay

ACC2 inhibition data were collected using two different assays (A2 and B2)

Assay A2 (= (A2))

The inhibitory activity of the substances of this invention against acetyl-CoA carboxylase 2 (ACC2) was measured in the ACC2 assay described in the following paragraphs.

The basic principle of the assay is the measurement of the adenosine diphosphate formed as a co-product

(ADP) using a HTRF ^® -based competitive immunoassay (HTRF = Homogeneous Time Resolved Fluorescence). As an enzyme, commercially available C-terminal His-tagged ACC2 from BPS Bioscience (San Diego, CA, Catalog No. 50201. Amino Acids 39-end, expressed in baculovirus-infected Sf9 insect cells and purified by Ni-NTA affinity chromatography) was used.

For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were transferred to a black low-volume 384-well microtiter plate (Grein er Bio-One, Frickenhausen, Germany).

Germany), 2 μΐ of a solution of ACC2 in assay buffer [50 mM HEPES / NaOH pH 7.5, 12 mM sodium bicarbonate, 2 mM MgCl ₂ , 2 mM potassium citrate, 0.005% (w / v) bovine serum albumin (BSA)] and the mixture incubated for 15 min

Pre-binding the substances to allow the enzyme prior to the enzyme reaction. Then, the enzyme reaction was started by adding 3 μΐ of a solution of adenosine triphosphate (ATP, 83.5 μΜ => final concentration in 5 μΐ assay volume is 50 μΜ, Amersham Pharmacia Biotech # 27-2056-01) and acetyl-CoA (33.4 μΜ => final concentration in 5 μΐ assay volume is 20 μΜ, Roche Bioscience # 10101893001) in assay buffer and the resulting mixture for the

Reaction time of 20 min at 22 ° C incubated. The concentration of the ACC2 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 0.6 ng / μΐ.

The reaction was quenched by successive additions of 2.5 μΐ a solution of d2 labeled ADP (HTRF ^® Trans Screener ™ ADP kit, Cis biointernational, Marcoule, France) in the EDTA-containing HTRF ^® Trans Screener ™ ADP-assay buffer (in HTRF ^® Transscreener ™ ADP Kit, 50mM HEPES pH 7.0, 60mM EDTA, 0.1% (w / v) BSA, 0.02% sodium azide, 400mM potassium fluoride) and 2.5μl of a solution of europium cryptate labeled anti-ADP antibody (HTRF ^® Trans Screener ™ ADP kit) in HTRF ^® Trans Screener ™ ADP detection buffer.

The resulting mixture was incubated for 1 h at 22 ° C to allow binding of the europium cryptate-labeled anti-ADP antibody to the ADP formed by the enzyme reaction and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF meter, e.g. a Rubystar or Pherastar (both BMG Labtechnologies, Offenburg,

Assay B2 (= (B2))

The hACC2 inhibitory activity of the substances of this invention was measured in the hACC2 assay described in the following paragraphs.

The enzyme used was recombinant C-terminal FLAG-tagged human ACC2 (acetyl-coenzyme A carboxylase 2, GenBank Accession No. NP 001084) (amino acids 27- end) expressed in baculovirus-infected insect cells (Hi5) and purified by anti-FLAG - Affinity chromatography.

For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were pipetted into a white low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2.5 μl of a solution of hACC2 in assay buffer [50 mM HEPES / NaOH pH 7.5, 2mM MgCl ₂ , 2mM potassium citrate, 12mM NaHCO ₃ , 2mM thio-threitol (DTT), 0.005% (w / v) bovine serum albumin (BSA)] are added and the mixture is incubated for 15h min incubated to allow a Vorbindung the substances to the enzyme prior to the enzyme reaction. Then the

=> Final concentration in 5 μΐ assay volume is 10 μΜ) in assay buffer and the resulting

Mixture for the reaction time of 45 min at 22 ° C incubated. The concentration of hACC2 was adjusted to the respective activity of the enzyme and adjusted so that the assay in the linear range worked. Typical concentrations were in the range of 2 ng / μΐ. The reaction was stopped by adding 2.5 μΐ of the "ADP-GLO reagent" (1: 1, diluted 5-fold) and the resulting mixture incubated for 1 h at 22 ° C to fully add the unreacted ATP into cAMP Subsequently 2.5 μΐ of the "Kinase Detection Reagent" (l, 2x

more concentrated than indicated by the manufacturer), the resulting mixture was incubated for 1 h at 22 ° C, and then the luminescence measured with a suitable meter (Viewlux or Topcount from Perkin-Elmer or Pherastar from BMG Labtechnologies). The amount of light emitted was taken as a measure of the amount of ADP formed and thus of the enzyme activity of hACC2. The data were normalized (enzyme reaction without inhibitor = 0%

Inhibition, all other assay component but no enzyme = 100% inhibition). Typically, the test substance was incubated on the same microtiter plates at 10 different concentrations ranging from 20 μΜ to 1 nM (20 μΜ, 6.7 μΜ, 2.2 μΜ, 0.74 μΜ, 0.25 μΜ, 82 μη, 27 μη, 9.2 μη, 3.1 μM and 1 μM). the dilution series were prepared prior to assay concentrated at the level of lOOfach solution by serial 1: 3 dilutions) in duplicate values for each concentration and IC ₅ o values were calculated by a 4 parameter fit using an inhouse software was used ,

Non-human ACCase Assay The assay was performed at room temperature in a transparent 384-well microtiter plate. It determines the inorganic phosphate released from ATP in the ACCase reaction.

The assay included 50mM Tris-HCl pH 8.3, 50mM KCl, 2.5mM MgCl ₂ , 0.5mM ATP, 0.8mM dithiothreitol (DTT), 30mM NaHCO ₃ , 0.1mM acetyl-CoA, 0.04% bovine serum albumin and 0.4μg partially purified ACCase enzyme in a final volume of 40 μΐ. After 45 minutes of incubation, the reaction was stopped with 150 μM malachite green solution and the absorbance was read at 620 after 30 minutes. The malachite green (MG) solution was prepared by mixing 3 parts of 0.6 mM MG-HCl solution in distilled water with 1 part of 8.5 mM ammonium molybdate in 4 M HCl. The solution was allowed to stand for 30 minutes. After filtration through a 0.45 μιη

Polytetrafluoroethylene (PTFE) filters were added to 0.1 part of Triton X-100 (1.5%) in distilled water.

ACCase enzyme was extracted from oat seedlings harvested 9 days after seeding and partially purified by 0-40% ammonium sulfate precipitation followed by ion exchange. Chromatography on Q-Sepharose. Mode-of-Action Experiment Before determining the efficacy in the MCF-7 model, part of the test substances was examined in a "Mode of action" experiment.The principle of this experiment is that the short-term application of a test substance capable of doing so ACC1 and / or ACC2 is to be inhibited in the living organism after oral administration, resulting in a reduction of malonyl-CoA in the tumor: 2 million human MCF-7 breast cancer cells were experimentally isolated into female nude mice (NMPJ-nude (nu / nu) mice, Taconic M & B A / S, 1 day before application of a pellet for the release of estrogen over a period of at least 60 days) subcutaneously injected Once the tumor has reached an area of about 60-70 mm ² , the oral application of the test substance over a period of 1-3 days, then the intratumoral content of malonyl-CoA was determined at defined times and with the

Vehicle control compared. The method is described in Anal Chem. 2008 Aug 1; 80 (15): 5736-42. Epub 2008 Jul 9).

Cell Assays In accordance with the invention, the substances were tested in cell-based assays, which means the ability of the substances to inhibit tumor cell proliferation after a 96-hour substance incubation. Cell viability was tested using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The cells were seeded in a density of 2000-5000 cells / well (depending on the cell line) in ΙΟΟμΙ growth medium on 96 well microtiter plates. For each cell line examined, cells were seeded on a separate plate to determine luminescence at t = 0 hours and t = 96 hours. After overnight incubation at 37 ° C, the luminescence values were determined for the t = 0 samples. The dose plates for the t = 96 hour time points were treated with substances diluted in growth medium. The cells were then incubated for 96 hours at 37 ° C, then the luminescence values were determined for the t = 96-hour samples. For data analysis, the t = 0 values were subtracted from the t = 96 hours values for treated and untreated samples. The percentage differences in luminescence between substance-treated and control values were used to determine the percent growth inhibition. The substances were investigated in the following cell lines, which exemplify the indicated indications: Cell line source indication

MDA-MB-436 ATCC hormone receptor negative breast carcinoma

MDA-MB-468 ATCC hormone receptor negative breast carcinoma

HCC-1937 ATCC BRCA-associated breast carcinoma

MCF7 ATCC hormone receptor positive breast cancer

Miapaca ATCC pancreatic carcinoma

786 0 ATCC renal cell carcinoma

PLC / PRF5 ATCC hepatocellular carcinoma

A431 ATCC carcinoma of the skin

MDA-MB-435 ATCC Malignant melanoma

NCI-H2135 ATCC non-small cell lung carcinoma

DLD1 ATCC colorectal carcinoma

PC3 ATCC Pro statin carcinoma

Dul45 NCI prostate carcinoma

ECC1 ATCC endometrial carcinoma

KM12 NCI colorectal carcinoma

HEC1A ATCC endometrial carcinoma

Xenograft model

Xenograft models were used in immunosuppressed mice to determine antitumoral efficacy in the living organism.

First, the maximum tolerable dose (MTD) was determined according to the following protocol: female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) received a daily oral dose of 1, 2 or 3 weeks the test substance and were daily observed for mortality and body weight. The maximum dose administered was defined as the MTD at which no animal died during the treatment phase and during the 7-day follow-up period and did not drop more than 10%

Body weight compared to the initial weight came.

To determine the antitumoral efficacy then various xenograft models were used in which the test substances were given at their MTD and in lower dosages. Among several other models, the breast cancer model with human MCF-7 cells in female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) was used primarily. For this purpose, a pellet was added to these mice the day before the tumor cell implantation Release of estrogen administered subcutaneously for a period of at least 60 days. Two million tumor cells were injected subcutaneously into the flank of each animal the next day. Therapy with the test substance was started as soon as the tumor had reached an area of about 25 mm ² . Therapy was then continued with 2-3 times weekly measurement of tumor area and body weight until the average tumor size in the control group receiving only the vehicle of the test substance or in one of the treatment groups reached 120 mm ² . At this time, the experiment was stopped in all groups and the prepared tumors were weighed. The primary success parameter was the T / C value

(average tumor weight in the therapy group divided by the average tumor weight in the vehicle control group).

Analysis of ACC1 expression in tumor and normal tissues

The ACC1 expression was determined by means of a microrray. For this, the RNA was isolated from different tumor tissues and the corresponding normal tissues. Methodically, Trizol RNA extraction reagent (Invitrogen) was used and purification was performed using the RNeasy Mini Kit (Qiagen). In addition, DNase I (Qiagen) digestion was performed to eliminate genomic DNA. For quality control, total RNA analysis was performed using an RNA LabChip on an Agilent Bioanalyzer 2100 Platform (Agilent Technologies) and RNA concentration determined using the Peqlab NanoDrop System. For hybridization, the one-cycle eukaryotic target labeling assay from Affymetrix was used and the array was subsequently read on an Affymetrix GeneChip 3000 scanner (Affymetrix) Evaluation and quality control were performed using the Expressionist Pro 4.0 Reimer (GeneData) software.

Tablets containing Exemplified Compound 1-118 a) Preparation of the Pharmaceutical Formulation by Direct Tabletting Tablets were prepared according to the composition of the table below containing Exemplified Compound 1-118 by direct tabletting.

The pharmaceutical formulation can be prepared by any suitable method, in particular powder mixing and direct tabletting in any desired scale.

For the preparation of 50 tablets were in a Fantaschale

3.351 g mannitol, spray dried

2.004 g of cellulose, microcrystalline

0.499 g Na Croscarmellose and

3.992 g Exemplified compound 1-118

premixed by careful trituration. The mixture was transferred to a 100 ml screw-cap jar and homogenized for 10 minutes in a Turbula mixer. After addition of 0.149 g of magnesium stearate was mixed again for 1 min in the Turbula mixer.

The molding compound thus obtained was compressed by means of an eccentric tablet press (Korsch EK 2) into biconvex tablets with a diameter of 8 mm and a radius of curvature of 12 mm. b) Breaking strength

The breaking strength (by means of Schleuniger's breaking strength tester), mass and disintegration time in water at 37 ° C. (using the apparatus described in monograph 2.9.1 European Pharmacopoeia) of the tablets obtained were tested at the beginning, middle and end of the tableting process. Breaking strength Mass Disintegration time

Beginning 81N 198.7 mg 1: 28 min

Center 95N 196.8 mg 1: 28 min.

End 97N 199.0 mg 1: 32 min.

Mean 91N 198.2 mg 1: 29 min. c) In vitro dissolution of the pharmaceutical formulation

The in vitro release of the Beipsielverbindung 1-118 from the tablets produced was determined by Apparatus 2 (paddle method) according to USP. The release test was carried out in each case in 900 ml of different media at 37 ° C. and with a stirring speed of 75

Undulations per minute carried out (Figure 2). Each determination was carried out in triplicate. The content was determined by HPLC.

The following results were obtained:

SDS = sodium lauryl sulfate (added because solubility at pH 1 and pH 6.8 is not sufficient) d) Short term stability of the pharmaceutical formulation

The produced tablets were subjected to a short term stability test for 1 month at 25 ° C / 60% relative humidity and at 40 ° C / 75% relative humidity. The tablets were stable under both conditions in terms of content and degradation products, analyzed by HPLC.

Results:

Table 4 summarizes the results of the enzyme assays and the mode of action experiment with respect to the compounds of formula (I-1).

Table 4

% Inhibition of

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2)

Malonyl-CoA after 7 h, no. IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

10 mg / kg (vs vehicle)

1-1 0.46 8.8 0.245> 20.0 39

1-2 0.28 0.37 0.084 0.822 96

1-3 0.45 5.4 0.643> 20.0

1-4 0.46 0.33 0.357 0.558

1-5 0.287 8.242 0.246 11.0 82

1-6 0.30 5.2 0.133 9.34 68

1-7 1.7 0.087 1.46 0.328 89

1-8 0.79 0.81 5.81> 20.0

1-9 16,605 0.626 1 1.4 0.276

1-10 0.550 6.402 0.500 9.46

1-1 1 0.24 1.0 0.157 4.47 87

1-12 0.772 18.219 0.871> 20.0

1-13 0.353 18.936 0.216> 20.0

1-14 0.990> 20 3.07> 20.0

1-15 0.742> 20 0.522> 20.0

1-16 0.329> 20 0.241> 20.0

1-17 0.334 4.021 0.553 11.4

1-18 0.797 7.608 0.982 16.4

1-19 0.874 6.965 0.532 20.0

1-20 0.240 0.214 0.230 1.13 87

1-21 0.533 15.131 0.630 10.3

1-22 0.969 0.695 2.68 16.3

1-23 0.584 0.485 0.459 2.33

1-24 0.34 0.21 0.230 0.517 91

1-25 0.495 3.356 0.288 3.78

1-26 0.540 1.254 0.367 3.09

1-27 0.472> 20 1.94> 20.0 % Inhibition of

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2)

Malonyl-CoA after 7 h, no IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

10 mg / kg (vs vehicle)

1-28 0.443 0.192 0.438 2.11

1-29 0.27 1.9 0.153 2.62 93

1-30 0.542 0.300 0.481 0.976 82

1-31 0.963 5.956 0.811 7.89

1-32 0.86 14 0.516 19.0

1-33 0.359 0.535 0.234 2.01 88

1-34 0.47 9.4 0.297 11.4

1-35 0.298 3.998 0.388 6.91 31

1-36 0.792> 20 1.50> 20.0

1-37 0.810> 20 0.850> 20.0

1-38 0.497> 20 0.747> 20.0

1-39 0.663> 20 1.98> 20.0

1-40 1.2 15 1.32> 20.0

1-41 0.751> 20 1.14> 20.0

1-42> 20 0.669 - -

1-43 0.304 10.240 4.93> 20.0

1-44 0.915> 20 1.70> 20.0

1-45 0.776 3.608 0.701 8.83

1-46 0.812 15.779 1.13> 20.0

1-47 0.923> 20 3.19> 20.0

1-48 1,006 8,598 1.56 10.4

1-49 0.24 9.9 10.6> 20.0

1-50 0.472 6.267 11.8> 20.0

1-51 0.473 4.913 0.415 5.45

1-52 1.268> 20 1.79 16.0

1-53 0.506 0.214 0.243 0.632 43

1-54 0.22 1.1 0.157 1.35 61

1-55 0.918 0.465 0.924 3.29

1-56 0.43 0.32 0.202 0.672 84

1-57 0.79 0.22 1.29 1.68

1-58 0.362 11.486 0.434 19.9 % Inhibition of malonyl

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2)

CoA after 7 h, no IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

10 mg / kg (vs vehicle)

1-59 0.427 5.205 0.261 11.6

1-60 0.237 2.334 0.189 5.99

1-61 0.227 3.910 0.088 9.04

1-62 0.690 0.385 5.74

1-63 0.391 4.216 0.277 7.27

1-64 0.985 16.443 0.571> 20.0

1-65 0.934 9.465 1.16 14.7

1-66 0.409 1.542 0.493 3.13

1-67 0.668 1.443 0.918 5.20

1-68 0.489 4.860 0.547 5.90

1-69 0.647 10.997 0.838> 20.0

1-70 0.675 1.839 0.286 2.92

1-71 0.661> 20 0.912> 20.0

1-72 1,179 2,340 1.14 14.9

1-73 0.912 4.971 0.563> 20.0

1-74 0.656 16.428 2.42> 20.0

1-75 7,975 0.376 5.68 0.803

1-76 0.201 0.233 0.163 0.432 96

1-77 0.327 0.860 0.278 2.59 96

1-78 0.795 1,729 0.958 8.12

1-79 0.848> 20 2.32> 20.0

1-80 0.695> 20 2.18> 20.0

1-81 0.327 1.414 0.428 2.61

1-82 0.542 0.433 0.539 1.32

1-83 0.459 0.349 0.582 1.88

1-84 0.455 0.650> 20.0

1-85 0.34 4.0 0.251 9.21

1-86 0.541 3.302 0.575 6.12

1-87 0.54 7.3 0.378 10.5 71

1-88 0.825 6.898 0.452 11.7

1-89 0.858> 20 2.07 13.6 Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2) No IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ ]

1-90 0.143 0.331 0.063 0.595

1-91 0.302 5.01 0.266 4.99

1-92 0.226 1.45 0.072 1.66

1-93 0.301 0.876 0.217 4.01

1-94 0.073 0.873 0.099 2.03

1-95 0.378 0.393 0.383 2.41

1-96 0.416> 20.0 0.238> 20.0

1-97 1.94 0.138 1.1 13 0.269

1-98 2.19 0.204 1.035 0.174

1-99 0.327 6.67 0.207 11.3-100 0.091 0.988 0.096 2.47-101 0.460 6.07 0.650 10.5-102 0.214 2.95 0.243 3.82-103 0.151 1.18 0.102 4.26-104 0.329 17.9 0.270> 20.0-105 0.360 5.56 0.165 8.94-106 0.439 4.36 0.207 5.85 -107 0.804> 20.0 0.376> 20.0-108 0.460 0.346 0.204 0.753-109 0.800 0.103 0.293 0.394-110 0.194 0.640 0.080 0.488-11 1 0.177 0.592 0.126 1.12-112 0.167 3.91 0.200 8.43-113 0.260 1.35 0.101 2.71-114 0.236 2.21 0.1 13 1.64-115 0.314 5.04 0.196 10.3-116 0.232 0.280 0.092 0.591-117 0.232 0.812 0.194 4.1 1-118 0.129 0.690 0.102 1.38 Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2) No IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ ] -119 0.203 0.479 0.1 10 1.08-120 0.250 1.28 0.145 2.26-121 0.402 - 0.172 1.01-122 0.098 5.42 0.124 6.59-123 0.173 3.44 0.562 11.2-124 0.458> 20.0 0.467> 20.0-125 0.281 3.99 0.217 6.77-126 0.300 6.37 0.204 12.4-127 0.216 4.84 0.145 13.4-128 0.195 2.74 0.157 4.41-129 0.349 9.61 0.267 10.6-130 0.133 4.40 0.108 5.89-131 0.266 7.62 0.098 5.62-132 1.71 0.106 0.912 0.234-133 0.329 2.87 0.142 8.10-134 0.299 1.31 0.109 2.85 -135 0.220 0.657 0.094 1.75-136 0.239 6.49 0.233 12.5-137 0.307 7.75 0.168 7.49-138 0.262 0.633 0.172 2.19-139 0.280 0.605 0.153 4.55-140 0.323 1.52 - --141 0.247 0.625 0.161 1.38-142 0.337 0.551 0.704 0.957-143 0.282 1.02 0.161 2.15-144 0.406 4.92 0.221 8.53-145 0.194 3.31 - --146 0.197 0.455 0.1 15 0.679-147 0.195 1.25 0.150 2.03 Table 5 summarizes the results of the enzyme assays and the mode-of-action experiment with respect to the compounds of formula (1-2).

Table 5

% Inhibition of malonyl

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2)

CoA after 7 h, no. IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

10 mg / kg (vs vehicle)

2-1 0.243 4,150 1.14 15.2

2-2 0.260 5.285 2.36> 20.0

2-3 0.581 11.696 3.73> 20.0

2-4 0.19 1.5 0.175 2.70

2-5 1,478 5,715 1.26 7.34

2-6 2,151 0.139 6.85 5.42

2-7 0.500> 20 2.71> 20.0

2-8 0.420> 20 1.99> 20.0

2-9 0.334> 20 2.22> 20.0

2-10 0.161 2.354 0.067 4.70

2-11 0.666 1.547 1.26 12.4

2-12 4,173 1,152 4.26 3.42

2-13 0.816> 20 1.02> 20.0

2-14 0.562 19.353 0.772> 20.0

2-15 0.204 3.676 0.111 8.02

2-16 0.180 3.336 0.138 5.31

2-17 0.158 0.652 0.058 1.18

2-18 0.479 3.409 0.276 12.2

2-19 0.530 10.007 0.812 13.6

2-20 0.137 1,929 0.102 1.72

2-21 0.40> 20 0.874> 20.0

2-22 0.824> 20 2.23> 20.0

2-23 1.369> 20 2.09> 20.0

2-24 0.997> 20 2.09> 20.0

2-25 0.442> 20 1.20> 20.0 % Inhibition of malonyl

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2)

10 mg / kg (vs vehicle)

2-26 0.26 4.8 6.11> 20.0

2-27 0.822 4.146 0.801 7.01

2-28 0.14 2.5 0.128 4.60

2-29 0.321 0.789 0.206 3.00

2-30 0.281 0.032 0.696 0.243 36

2-31 0.88 0.048 2.00 0.076

2-32 0.45 1.6 0.339 2.82

2-33 0.229 3.586 0.227 5.00 39

2-34 0.286 1.274 - -

2-35 1.024> 20 1.19> 20.0

2-36 n.d. 1,936 0.447 2.41

2-37 0.342> 20 1.05> 20.0

2-38 0.416 3.785 0.393 7.38

2-39 0.216 3.533 0.162 5.27

2-40 1.216> 20 1.51> 20.0

2-41 0.791 4.217 0.425 6.59

2-42 0.357 1.021 0.246 1.56

2-43 0.504 0.330 0.168 0.737

2-44 0.297 0.160 0.220 0.244

2-45 0.568 17 1.83 17.5

2-46 0.580 7.610 0.420 5.26

2-47 0.592 0.453 0.402 0.389

2-48 1,800 0.204 1.54 0.417

2-49 5,776 1,281 20.0> 20.0

2-50 0.903 8.593 1.30 15.4 Table 6 summarizes the results of the enzyme assays for the compounds of formula (1-3), (1-6), (1-7), (1-8), (1-9), (1-10) and (I-ll) together.

Table 6

Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2) No. IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

3-1 0.853 1.41 15.5

3-2 0.097 1.675 - -

3-3 0.34 0.25 0.265 1.15

3-4 1,311 0.228 - -

6-1 0.655 16.024 0.411 19.7

6-2 0.337 1.688 0.263 3.23

6-3 1.390 16.220 1.17> 20.0

6-4 0.333 3.059 0.218 4.63

6-5 0.754 0.565 0.523 1.21

6-6 0.923 0.783 0.946 1.25

6-7 0.467 0.654 1.03 7.19

6-8 1,379 0.127 1.16 0.151

6-9> 20 0.387 20.0 2.12

7-1 0.678> 20 0.932> 20.0

7-2 0.578> 20 0.501> 20.0

7-3 1,589 5,337 1.74 13.0

7-4 3,673 3,711 7.11> 20.0

7-5 0.610> 20 0.906> 20.0

8-1 2.459> 20 3.56> 20.0

8-2 0.891> 20 0.401> 20.0

8-3 1.142> 20 1.05> 20.0

8-4 3.180> 20 3.92> 20.0

8-5 2.076> 20 6.94> 20.0

8-6 1.382> 20 1.28> 20.0 Eg ACC 1 (= A1) ACC 2 (= A2) ACC 1 (= B1) ACC 2 (= B2) No IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μmoll] IC50 [μιηοΐ / ΐ]

8-7 2.381> 20 6.21> 20.0

8-8 0.936 16.858 1.31> 20.0

8-9 0.457> 20 0.682> 20.0

8-10 1.126> 20 2.35> 20.0

8-11 0.713> 20 1.36> 20.0

8-12 0.587> 20 0.783> 20.0

8-13 0.640> 20 1.36> 20.0

8-14 2.399> 20 7.46> 20.0

8-15 1.966> 20 5.60> 20.0

8-16 0.662> 20 0.593> 20.0

8-17 0.913> 20 1.45> 20.0

9-1 0.319> 20 3.76> 20.0

9-2 0.806 9.080 11.2> 20.0

9-3 1,063 4,281 2.34> 20.0

9-4 5.379> 20 2.54> 20.0

9-5 0.625> 20 0.661> 20.0

9-6 1.092 18.943 1.28> 20.0

9-7 0.000 8.289 0.308 11.2

9-8 0.418> 20 0.174> 20.0

9-9 0.863> 20 2.94> 20.0

9-10 1.693> 20 1.41> 20.0

9-11 0.420 4.117 0.397 4.07

9-12 0.580 0.376 2.09

9-13 0.329 5.557 0.191 3.96

9-14 1,639 5,622 6.47> 20.0

10-1 1.367> 20 1.07> 20.0

10-2 0.586> 20 0.760> 20.0

11-1 3.996> 20 19.2> 20.0 Table 7 summarizes the results of some cell assays for compounds according to formula (1-1).

Table 7

Ex. MCF7 IC50 MDA-MB 436 MDA-MB 468 HCC 1937 MiaPaca A431

No. [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] Κ50 [μιηο1 / 1] Κ50 [μιηο1 / 1]

1-29 0.032

1-30 0.048

1-31

1-32 0.107

1-33 0.027 0.07 0.074 0.108 0.193

1-34 0.1 12

1-35 0.094

1-36

1-37

1-38

1-39

1-40

1-41

1-42 1,280

1-43 1,220

1-44

1-45 0.626

1-46

1-47

1-48 0.852

1-49 0.640

1-50

1-51 0.253

1-52 0.739

1-53 0.070

1-54 0.088

1-55

1-56 0.030 0.084 0.138 0.171 0.316 0.214

1-57 0.250

1-58

1-59

1-60

Ex. MCF7 IC50 MDA-MB 436 MDA-MB 468 HCC 1937 MiaPaca A431

-126 0.594-127 1.40-128 0.033-129 0.172-130 0.061-131 0.060-132 0.070-133 0.075-134 0.114-135 0.171-136 0.156-137 0.439-138 0.054-139 0.070-140 0.073-141 0.079-142 0.106-143 0.111-144 0.149-145 0.273-146 0.047-147 0.174

For some example compounds, additional cell line data was collected:

Table 8 summarizes the results of the cell assays for the compounds of formula (1-2).

Table 8

Ex. MCF7 MDA-MB 436 MDA-MB 468 HCC 1937 MiaPaca

No. IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ

2-1

2-2

2-3 1,060

2-4 0.624

2-5

2-6 0.724

2-7

2-8

2-9

2-10

2-11

2-12 1.240

2-13

2-14

2-15

2-16

2-17 0.400

2-18 0.935 Ex. MCF7 MDA-MB 436 MDA-MB 468 HCC 1937 MiaPaca

2-19

2-20 0.214

2-21

2-22

2-23

2-24

2-25

2-26 5,520

2-27

2-28 0.296

2-29

2-30 0.064 0.115 0.153 1.5 0.255

2-31 0.490

2-32 0.1 12

2-33 0.246

2-34 0.429

2-35

2-36

2-37

2-38

2-39

2-40

2-41

2-42 0.466

2-43 0.263

2-44 0.121

2-45 6.7

2-46

2-47 0.302

2-48 0.762

2-49

2-50 Tables 9a and 9b summarize the results of the biological assays for the compounds of formula (1-3), (1-6), (1-7), (1-8), (1-9), (1- 10) and (Il 1) together.

Tab. 9a Tab. 9b

MCF7 MCF7

Example No. Example No.

IC50 [μιηοΐ / ΐ] IC50 [μιηοΐ / ΐ]

3-1 8-9

3-2 0.461 8-10

3-3 0.575 8-1 1

3-4 1,550 8-12

6-1 0.545 8-13

6-2 0.194 8-14

6-3 8-15

6-4 8-16

6-5 0.605 8-17

6-6 0.582 9-1 1.260

6-7 0.338 9-2 1.720

6-8 0.254 9-3 1.530

6-9 1,520 9-4 3,440

7-1 9-5

7-2 1.210 9-6

7-3 0.974 9-7 1.100

7-4 2.630 9-8

7-5 0.992 9-9

8-1 9-10

8-2 0.878 9-1 1 0.299

8-3 9-12

8-4 9-13

8-5 9-14 1,460

8-6 10-1

8-7 10-2

8-8 1 1-1 3.330 Table V.2 summarizes the results of the enzyme assays for the comparator compounds.

Tab. V.2

The results make it very clear that despite structural similarity, no predictions are possible as to whether structures that inhibit non-human ACC are also inhibitors of human ACCs.

ACCl expression in tumor and normal tissue

ACCl expression in tumor and corresponding normal tissue was determined by microarray (FIG. 1). The expression of ACCL was significantly upregulated compared to normal tissue in breast cancers, colorectal carcinomas,

Bronchial carcinoma and pancreatic carcinoma.

Claims

claims

1. Compounds of the formula

in which

X is halogen, nitro or cyano or

for an unsubstituted, monosubstituted with halogen or polysubstituted Ci-C _ö alkyl, Ci-C ₆ -alkoxy-C -alkoxy- ₆ alkoxy, Ci-C _6, C ₃ -C ₇ cycloalkyl, or one

C ₃ -C ₇ -cycloalkyl-C ₁ -C ₆ -alkoxy, and

for an unsubstituted, monosubstituted with halogen or polysubstituted Ci-C _ö alkyl, Ci-C ₆ alkoxy or C ₃ -C ₇ cycloalkyl, and

V ¹ , V ² and V ³ independently of one another represent hydrogen, halogen, nitro or cyano or a C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogeno C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylthio, C ₁ -C ₆ -alkylsulfmyl, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C 3 -C 10 -alkyl Cycloalkyl or a monocyclic heterocycloalkyl radical, and / or

V ¹ and V ² with the carbon atoms to which they are attached, a saturated or

form unsaturated and optionally contains at least one further heteroatom cycle T ¹ with 4 to 7 ring atoms, the ring-forming atoms, with halogen and / or a Ci-C _ö alkyl mono- can be variously substituted or polysubstituted by identical or,

CKE for one of the groups

for -S-, -S (O) -, -S (O) ₂ -, -O-,

O

^ _, C, a substituted ^ C = N group or is an optionally substituted by Q ³ and Q ⁴ substituted Ci-C ₄ alkyl, and A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkylthio-C ₁ -C ₆ -alkyl radical or

an aryl, aryl-Ci-C _ö alkyl or heteroaryl radical, optionally alkyl substituted by halogen, cyano, nitro and / or a Ci-C ₆ -alkyl, halo-C _6,

Ci-C _ö alkoxy and / or a halogeno-C iC _ö alkoxy may be mono- or polysubstituted by identical or different substituents, and

B is hydrogen or a Ci-C _ö alkyl or

Ci-C _ö alkoxy-Ci-C _ö alkyl group, or

wherein R ¹ , R ² and R ^{3 are} independently

a) for halogen, hydroxy or cyano or

b) for an optionally substituted in the alkyl moiety with hydroxy

C 1 -C ₆ -alkylaminosulphonyl, C 1 -C ₆ -alkoxy-C 1 -C ₆ -alkoxy, halogeno-C 1 -C ₆ -alkyl or halogeno-C ₁ -C ₆ -alkoxy, or

c) an aryl, arylcarbonyl, arylsulphonyl, arylamino, heteroraryl, heteroarylcarbonyl, heteroarylsulphonyl or heteroarylamino radical, or d) a C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkylcarbonyl,

where the radicals mentioned under c) and d) are optionally substituted on the ring system by halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkyl- , Halogen-C ₁ -C ₆ -alkoxy,

Ci-C ₆ alkoxy-C ₆ alkyl, C ₃ -C ₀ cycloalkyl and / or a 3- to 6-membered heterocycloalkyl radical once or more times, identically or differently, may be substituted, and / or

e) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached form a further saturated or unsaturated, optionally containing at least one heteroatom cycle T ³ having 3 to 7 ring atoms can be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ ,

wherein R ^4, R ⁵ and R ⁶ are independently a Ci-C _ö alkyl or Ci-C ₆ alkoxy, and

is hydrogen or

and D together with the atoms to which they are attached, a saturated or unsaturated and optionally at least one further heteroatom

wherein R ⁷ , R ⁸ and R ⁹ independently of one another represent hydroxyl, halogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy radical, and

and Q ¹ together with the atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁵ having 5 to 7 ring atoms whose ring-forming atoms are halogen, hydroxy, cyano, nitro and / or with a C ₁ -C ₆ -alkyl,

Ci-C _ö alkoxy-Ci-C _ö alkyl and / or C3-Cio-cycloalkyl may be mono- or polysubstituted by identical or different substituents,

with the proviso that B and Q ^{2 represent} a bond when the cycle T ⁵ formed by A and Q ¹ is aromatic, Q ^{1 is} hydrogen or

for an optionally with halogen, hydroxy and / or a

Halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and / or

Ci-C ₆ alkyl, and

Q ^{3 is} hydrogen or

for an optionally substituted by halogen, hydroxy and / or a Ci-C _ö alkoxy one or more times, identically or differently substituted Ci-C ₆ alkyl or

Ci-C ₆ alkoxy represents or

optionally substituted by halogen, hydroxy and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy and or

Halo-Ci-C _ö alkoxy mono- or polysubstituted by identical or different may be substituted or

Halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl and / or

C ₃ -C ₀ cycloalkyl mono- or may be multiple, identical or different substituents, or

Q ¹ and Q ² together with the carbon atom to which they are attached, a

form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ⁶ having 3 to 7 ring atoms, whose ring-forming atoms are halogen, hydroxy, cyano, nitro and / or a C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy , C _ö alkoxy-Ci-C _ö alkyl and / or C ₃ -C mono- ₀ cycloalkyl, or may be multiple, identical or different substituents, or

Q ³ and Q ⁴ together with the carbon atom to which they are attached, a

saturated or unsaturated and optionally containing at least one heteroatom cycle T ⁷ having 3 to 7 ring atoms whose ring-forming atoms with halogen, hydroxy, cyano, nitro and / or a Ci-C ₆ alkyl, halogen-Ci-C ₆ alkyl C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkoxy,

for use as a medicine.

Compounds according to claim 1 according to formula (I) in which

X is halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical which is optionally monosubstituted or polysubstituted by halogen,

for use as a medicine.

Compounds according to claim 1 according to formula (I) in which

W and Y are independently hydrogen or an optionally with

Halogen mono- or polysubstituted Ci-C ₃ -alkyl radical,

for use as a medicine.

Compounds according to claim 1 according to formula (I) in which

V ^1, V ² and V ³ independently of one another represent hydrogen, halogen, or a Ci-C ₃ alkyl or Ci-C are ₃ haloalkyl,

for use as a medicine.

Compounds according to claim 1 according to formula (I) in which

A for hydrogen or

for a optionally mono- or polysubstituted with halogen Ci-C _ö alkyl or C _l -C _ö alkoxy-C i -C _ö alkyl or

for a C ₃ -C ₆ -cycloalkyl radical which may be mono- or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical,

for use as a medicine. Compounds according to claim 1 according to formula (I) in which

A and B together with the carbon atom to which they are attached

form a saturated cycle optionally containing one or two heteroatoms T ² having 3 to 8 ring atoms whose ring-forming atoms may be mono- or polysubstituted by the same or different substituents with the radicals R ¹ , R ² and R ³ ,

wherein R ¹ , R ² and R ^{3 are} independently

a) for an optionally substituted in the alkyl moiety with hydroxy Ci-C3-alkyl, Ci-C ₃ -alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy- or halo-Ci-C ₃ -alkoxy and / or

b) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² to which they are attached form a further saturated or aromatic, optionally containing at least one oxygen atom cycle T ³ having 5 to 7 ring atoms can be monosubstituted or polysubstituted by a C ₁ -C ₃ -alkyl radical,

for use as a medicine.

7. Compounds according to claim 1 according to formula (I), in which

B is hydrogen or a C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical, for use as a medicament.

8. Compounds according to one of claims 1 to 7, in which CKE for the group

stands,

defined as compounds of formula (1-1)

(1-1) in which

X is halogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy, and W and Y are independently hydrogen or halogen or

for an optionally mono- or polysubstituted with halogen

Ci-C ₃ alkyl, and

V ^1, V ² and V ³ are independently hydrogen or halogen or a Ci-C ₃ alkyl, _Ci-C3 haloalkyl, Ci-C ₃ alkoxy, _Ci-C3 haloalkoxy or

C i - C ₃ - alkoxy C i - C ₃ - Alky lr est, and / or

V ¹ and V ² with the carbon atoms to which they are attached form a saturated or unsaturated and optionally at least one further heteroatom-containing cycle T ¹ having 5 or 6 ring atoms whose ring-forming atoms are halogen and / or a C ₁ -C ₃ - Alkyl radical may be mono- or polysubstituted by identical or different substituents,

A is hydrogen or

for an optionally mono- or polysubstituted with halogen

C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl radical or

for a C ₃ -C ₇ -cycloalkyl or 4- to 7-membered monocyclic

Heterocyclyl radical which may be monosubstituted or polysubstituted by identical or different substituents with halogen and / or a C ₁ -C ₃ -alkyl radical, and

B is hydrogen or a Ci-C _ö alkyl or

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl radical, or

a) for halogen or hydroxy or

b) for an optionally substituted in the alkyl moiety with hydroxy Ci-C4-alkyl, Ci-C ₄ -alkoxy, Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl-, Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, halogeno-C ₁ -C ₃ -alkyl or halogeno-C ₁ -C ₃ -alkoxy and / or c) two of the radicals R ¹ , R ² and R ³ together with the ring or atoms of the cycle T ² , to which they are attached, a further saturated or aromatic, optionally containing one or two heteroatoms cycle T ^{3 can form} with 5 to 7 ring atoms, which may be mono- or polysubstituted by identical or different substituents with the radicals R ⁴ , R ⁵ and R ⁶ , wherein R ⁴ , R ⁵ and R ⁶ are each independently a Ci-C ₃ alkyl or Ci-C ₃ alkoxy, and D is hydrogen or

for a C ₃ -C ₇ cycloalkyl or 4- to 7-membered monocyclic

heterocyclyl

A and D together with the atoms to which they are attached form a saturated or unsaturated and optionally another heteroatom-containing cycle T ⁴ having 5 to 7 ring atoms whose ring-forming atoms may be mono- or polysubstituted by identical or different substituents Radicals R ⁷ , R ⁸ and R ⁹ , where R ⁷ , R ⁸ and R ⁹ independently of one another represent halogen or a C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy radical,

for use as a medicine

Compounds according to claim 8 according to formula (1-1), in which

A and B together with the carbon atom to which they are attached form a saturated, optionally heteroatom-containing cycle T ² having 3 to 8 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently a) for hydroxy or

b) for a optionally substituted in the alkyl moiety with hydroxy Ci-C ₃ alkyl, CC ₃ alkoxy, Ci-C ₂ alkoxy-Ci-C ₃ -alkyl, Ci-C ₃ alkoxy-Ci-C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl or halo-C ₁ -C ₃ -alkoxy.

for use as a medicine.

Compounds according to claim 8 or 9 according to formula (1-1), in which A and B together with the carbon atom to which they are attached form a cyclohexane ring or tetrahydropyran ring,

for use as a medicine Compounds according to claim 8 of general formula (1-1) in which

X is chlorine or is a methyl radical, and

W and Y independently of one another are hydrogen or a methyl radical, V ^{1 is} chlorine, fluorine or a methyl radical, and

A and B together with the carbon atom to which they are attached form a saturated, optionally oxygen-containing cycle T ² having 6 ring atoms whose ring-forming atoms may be monosubstituted or disubstituted by identical or different substituents with the radicals R ¹ and R ² , wherein R ¹ and R ^{2 are} independently hydroxy or a Ci-C3-alkyl, hydroxy-methyl, Ci-C2-alkoxy, methoxy-Ci-C2-alkyl, trifluoromethyl, pentafluoroethyl or 2,2,2-trifluoroethoxy, and

D is hydrogen,

for use as a medicine

links

- (5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene 2-one

- (5s, 8s) -3- (4,4'-dichloro-3'-fluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one

- 3- (4'-chloro-3 ', 6-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 on

- (5s, 8s) -4-hydroxy-8- (trifluoromethyl) -3- (3 ', 4', 5-trifluoro-4-methylbiphenyl-3-yl) -1-azaspiro [4.5] dec-3-ene -2-one

- 3- (4'-chloro-4,6-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one

- (5s, 8s) -3- (4-chloro-3 ', 4'-difluorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene-2 -one

3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l- azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -3- (3 ^ 4'-Difluoro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one

(5s, 8s) -3- (4'-chloro-3 ^ 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) azaspiro [4.5] dec-3-ene-2 on

(5s, 8s) -3- (4'-chloro-3 ', 5-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene 2-one

(5s, 8s) -3- (4'-chloro-5-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -4-hydroxy-8-methoxy-3- (3 ', 4', 5-trifluoro-4-methylbiphenyl-3-yl) -l-azaspiro [4.5] dec-3-ene-2 on

(5s, 8s) -3- (4 ', 6-dichloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene 2-one

(5s, 8s) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (hydroxymethyl) -l-azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -3- (4'-chloro-4-methyl-biphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one (5s, 8s) - 3- (4'-Chloro-2,4-dimethylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-one

(5r, 8r) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-en-2-one

(5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-yl en-2-one

(5r, 8r) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene 2-one

(5r, 8r) -3- (4'-chloro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 -one

(5r, 8r) -3- (4'-chloro-3'-fluoro-2,4-dimethylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -1-azaspiro [4.5] decyl 3-en-2-one

(5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene -2-one

(5s, 8s) -3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2 on

(5R, 8R) -3- (3 ', 4'-difluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l- azaspiro [4.5] dec-3-en-2-one

(5r, 8r) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -1-azaspiro [4.5] dec-3-ene -2-on)

(5r, 8r) -3- (4'-chloro-6-fluoro-4-methylbiphenyl-3-yl) -4,8-dihydroxy-8- (pentafluoroethyl) -l-azaspiro [4.5] dec-3-ene -2-one

(5S, 7S) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] dec-3-ene-2-one

(5S, 7S) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-7- (trifluoromethyl) -l-azaspiro [4.5] dec-en-2-one

3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8,8-dimethyl-1-azaspiro [4.5] dec-3-en-2-one 3 - (4,4'-dichlorobiphenyl- 3 -yl) -4-hydroxy-8-methyl-1-azaspiro [4.5] dec-3 -en-2-oη 3 - (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-1-azaspiro [4.5] dec-3 -en-2-οη

(5s, 8s) -3- (4,4'-dichlorobiphenyl-3-yl) -4-hydroxy-8-isopropyl-1-azaspiro [4.5] dec-3-en-2-one

(5s, 8s) -3- (2'-chloro-4'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-ene-2 on

13. Use of a compound according to formula (I) or (1-1) according to any one of claims 1 to 12 for the manufacture of a medicament.

Use of a compound according to formula (I) or (1-1) according to any one of claims 1 to 12 for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.

Use of a compound according to formula (I) or (1-1) according to any one of claims 1 to 12 for the manufacture of a medicament for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, non-small cells , Bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate carcinoma.

A compound according to formula (I) or (1-1) according to any one of the claims

1 to 12 for the prophylaxis and / or therapy of tumor diseases. A compound according to formula (I) or (1-1) according to any one of the claims

1 to 12 for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, non-small cells, bronchial carcinomas, endometrial carcinomas, colorectal carcinomas or prostate carcinomas.

Pharmaceutical formulation in the form of a tablet containing a compound according to formula (I) or (1-1) for the prophylaxis and / or therapy of breast, pancreatic, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell, bronchial carcinoma, endometrial carcinoma, Colorectal carcinoma or prostate cancer.