EP2739607A1

EP2739607A1 - Substituted 3-(biphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one

Info

Publication number: EP2739607A1
Application number: EP12740620.5A
Authority: EP
Inventors: Ningshu Liu; Kai Thede; Ursula MÖNNING; Arne Scholz; Christoph-Stephan Hilger; Ulf Bömer; Reiner Fischer
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2011-08-04
Filing date: 2012-07-31
Publication date: 2014-06-11
Also published as: DE102011080406A1; KR20140051378A; CU20140012A7; IL230609A0; BR112014002674A2; DOP2014000022A; WO2013017600A1; AP2014007469A0; US9278925B2; ECSP14013192A; HK1198167A1; MX2014001393A; CO6870039A2; CR20140063A; AU2012292069A1; SG2014005235A; US20140275199A1; CN103842337A; TN2014000046A1; CA2843809A1

Abstract

The invention concerns substituted 3-(biphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one, more particularly for therapeutic purposes, pharmaceutical means and the use thereof in treatment, in particular for prophylaxis and for the treatment of tumorous diseases.

Description

Substituted 3- (biphenyl-3-yl) -4-faydroxy-8-metfaoxy-1-azaspiro [4.5] dec-3-en-2-ones

The present invention relates to substituted 3 - (biphenyl-3-yl) -4-hydroxy-8-methoxy-1-azaspiro [4.5] dec-3-en-2-ones, in particular for therapeutic purposes, pharmaceutical agents containing the invention compounds 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 takes place as two half reactions, a biotin carboxylase (BC) reaction and a carboxyltransferase (CT) reaction, is the first introductory step in fatty acid biosynthesis and is the rate-limiting step for the pathway.

Two human ACC isoforms are known, ACCl and ACC2, which are encoded by two different genes (LuTFI ABU-ELHEIGA et al, 1995, Jane WIDMER, et al., 1996). ACCl is expressed in lipogenic tissue (liver, adipose tissue), localized 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 the fatty acid oxidation by inhibiting the C -nurin palmitate trans f eras e I, the enzyme that facilitates the 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, the ACC activity is strictly controlled by a number of dietary, hormonal and other

physiological mechanisms such as forward allosteric activation by citrate, feedback inhibition by long-chain fatty acids, reversible phosphorylation and / or inactivation or modulation of enzyme production by altered gene expression.

ACCl knockout mice are embryonic lethal (S Winnen, 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 of total body fat, increased levels of UCP3 in skeletal muscle (indicative of increased levels)

Energy consumption), decreased body weight, decreased levels of plasma free fatty acids, decreased plasma glucose levels, decreased levels of tissue glycogen, and so on 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 for inhibiting 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 / EP99 / 01787, published as WO 99/48869 corresponding to European patent EP 1 066 258 BI, relates to novel arylphenyl-substituted cyclic ketoenols, to a majority of the processes for their preparation and their use as Pesticides and herbicides.

Of 3-acylpyrrolidine-2,4-diones, pharmaceutical properties are described above (Suzuki, S. et al., Chem. Pharm. Bull., 11, 20 (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 21 1 and 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 1 H-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 95/26 954, 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, WO 10/063380, WO10 / 066780, WO 10/102758, WO2010 / 135,914,

WO2011 / 067131, WO2011 / 067135, WO2011 / 067203 and WO2011 / 067240. In addition, ketalsubstituted 1 -H-arylpyrrolidine-2,4-diones from WO 99/16748 and (spiro) - ketalsubstituted N-alkoxy-alkoxy-substituted aryl-pyrrolidindione 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. 4'-biphenyl-substituted tetronic acid derivatives are disclosed in WO 2008/022725 for the therapy of viral diseases.

WO 2005/089118 and WO2007 / 039286 generically disclose nitrogen-containing bicyclic structures for therapy, 5'-biphenyl-substituted cyclic ketoenols not being specifically mentioned.

The structurally closest prior art could be compounds which have a methyl group instead of a trifluoromethyl group or a methoxymethyl group in position 8 of the azaspiro [4.5] dec-3-en-2-one ring system. Such compounds are partly state of the art and are disclosed, for example, in WO10 / 063378.

The structurally closest prior art could also be compounds which have a hydrogen atom instead of a methoxy group in position 8 of the azaspiro [4.5] dec-3-en-2-one ring system. Such compounds are partly state of the art and are disclosed, for example, in WO 07/048545 (Example I-1-a-5).

WO10 / 063378 and WO 07/048545 relate to inventions in another field, namely in the field of herbicides.

The nearby structures of the prior art are invariably known in the field of herbicides, insecticides or fungicides. On the one hand, it is not known for these structures, and on the other hand, it is unpredictable whether they inhibit human ACC. The more it is for this Structures unknown and unpredictable, whether they possess selectivity against any of the human ACC isoforms.

Starting from this prior art, the object of the present invention is to provide structures for the therapy of human and animal diseases.

In particular, the structures of the invention for the prophylaxis and therapy of

Tumors are suitable and have advantages over known in the art structures.

In particular, structures for the therapy of diseases are to be made available, which strongly inhibit human ACC1. The sought structures are said to inhibit human ACCI more than human ACC2, i. have a selectivity against human ACC2.

Preferably, structures are to be provided for the therapy of diseases which additionally possess one, more preferably, or even all, of the following properties: they inhibit human ACC1 after single measurement or better on the average from several measurements with an IC50 of less than 300 nM, better of less than 200 nM, more preferably less than 100 nM in the described assay, they inhibit human ACC2 after single measurement or better on average from several measurements with an IC50 of more than 0.5 μΜ, better of more than 1.5 μΜ, still better than 2 μΜ in the described assay, the ratio of the IC50 for the inhibition of human ACC2 to the IC50 for the inhibition of human ACC1 after injection or, better, in the mean of several measurements is at least a factor 8, better at least one factor 15, more preferably at least a factor of 20, they inhibit the tumor cell proliferation of MCF7 cells after single measurement or better in the mean of several measurements with an IC50 of less than 250 nM, better less than 100 nM, even better less than 50 nM in the described assay, they have a logP / D value of less than 3, better less than 2.5 after single measurement or better in the mean of several measurements in the described assay, they have a logMA value of less than 3, better still less than 2.5, even better less than 2 after single measurement or better in the mean of several measurements in the described assay, they have a protein binding constant at HSA greater than 1 μηιοΐ / ΐ after single measurement or better in the mean value several measurements in the described assay, they have a free fraction of more than 0.1%, better of more than 0.2% after single measurement or better in the mean of several measurements in the described assay with respect to the binding to human plasma protein, they have a ratio of the free fractions the binding of mouse plasma protein and human plasma protein by a factor of less than 15, better still less than 10 after single measurement or better in the mean of several measurements, they have a ratio of the free fractions with respect to the binding to the plasma protein of different species, which results in an acceptable, estimated human dose, it h Also, pharmacokinetic parameters that result in an acceptable, estimated human dose and permit administration as a drug. they have a low clearance. they have a high bioavailability, they have a moderate to high volume of distribution, they have an acceptable relative bioavailability, which leads to an acceptable, estimated human dose and allows administration as a drug, they have an estimated human half-life of not more than two weeks, they have an in vivo effect in the PC3 xenograft mouse model, they have an effect in the PC3 xenograft mouse model with plasma levels that result in an acceptable, estimated human dose, which is the human daily dose estimated for them by the described method below 2g, better below 1g per patient. It has now surprisingly been found that compounds of the formula (I)

in which

R ^{1 represents} a trifluoromethyl or methoxymethyl group and

R ^{■ is} hydrogen or fluorine

and their salts

are particularly well suited for the therapy of diseases and solve the task of the invention.

It was unpredictable whether and which of the structures known as insecticides or herbicides achieves the object according to the invention, namely a structure which can be used in the therapy of human and / or animal diseases. It was all the less predictable whether and which of the structures known as insecticides or herbicides inhibited human ACC, let alone whether and which has selectivity against any of the human isoforms.

From the large group of known as insecticides, fungicides or herbicides cyclic ketoenols, the compounds of formula (I) have surprisingly highlighted by a good enzyme inhibition of human ACCl. In this case, the compounds of the invention have an increased selectivity against human ACC2 and inhibit especially ACCl. This property was unpredictable and qualifies the compounds of the invention for therapy with reduced side effects. Undesirable side effects are probably due to the simultaneous inhibition of human ACC2, while the effects are mainly due to the inhibition of human ACC1.

The selectivity towards human ACC2 seems to be structurally based on the trans-methoxy group in position 8 of the azaspiro [4.5] dec-3-en-2-one ring system of the structures according to the invention. If this trans-M ethoxy group e is already realized in related structures of the prior art, it was unknown at the time of the invention whether and with which Selectivity of these structures inhibit human ACC's.

Also to be regarded as covered by the present invention is the use of the physiologically acceptable salts of the compounds of the invention.

Also contemplated as encompassed by the present invention is the use of the tautomeric forms of the compounds of formula (I) of the invention, e.g.

Physiologically acceptable salts of the compounds of this invention also include salts of conventional bases, such as, by way of example and by way of example, alkali metal salts (e.g., sodium and potassium)

Potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as by way of example 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 medicaments containing the

Compounds according to the invention and at least one or more further active compounds, 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, it 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, the compounds of the invention in crystalline and / or amorphised and / or dissolved Form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules in the oral cavity (For example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing an εβθ ΐίοηββϋΐττεββ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as forms of application u.a. Injection and

Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For the other routes of administration are suitable, for example Inhalation medicines (i.a.

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 of the invention can be converted into the mentioned application 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 the compounds 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 to pharmaceutical preparations takes place in a manner known per se, by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.

As auxiliaries may, for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, and Αά8θ ίϊοη8ηώΐ6ΐ, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, Stabilisierangs-, wetting agents, salts for altering the osmotic Pressure or buffer 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 compounds according to the invention.

They can be used for the prophylaxis and treatment of human diseases, in particular tumors.

The compounds of the invention can be used in particular to the

Inhibit or reduce cell proliferation and / or cell division and / or 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.

For example, hematological tumors are treatable

- multiple myeloma,

Lymphomas or

Leukemias.

For example, treatable as breast tumors are:

- breast cancer with positive hormone receptor status

Mammary carcinomas with negative hormone receptor status

Her-2 positive breast cancers

Hormone receptor and Her-2 negative breast cancers

BRC ^'A -associated M ammakarzinome

- 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 treatable

gliomas,

glioblastomas,

astrocytomas,

- Meningiomas and

Medulloblastomas. For example, as tumors of the male reproductive organs are treatable: prostate carcinomas,

Malignant testicular tumors and

Pancreatic carcinomas.

For example, tumors of the female reproductive organs are treatable:

endometrial

Cervical carcinomas

ovarian cancer

- vaginal carcinomas

Vulvarkarzinome

For example, tumors of the gastrointestinal tract are treatable:

Colorectal carcinomas

- Anal carcinomas

Breast cancers

P ark askarzinome

esophageal cancer

Gallbladder carcinomas

- Small intestinal carcinomas

Species of carcinoma

Neuro endocrine 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

For example, tumors of the liver are treatable:

- Hepatocellular carcinomas

Cholangiocellular carcinomas For example, tumors of the skin are treatable:

Malignant melanomas

Basal cell carcinomas

squamous

Kaposi's sarcoma

Merkel cell carcinoma

For example, tumors of the head and neck are treatable:

laryngeal cancer

Carcinomas 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

Hairy cell leukemia

Advantageously, the compounds according to the invention can be used for the prophylaxis and / or therapy of:

Breast cancer, in particular of hormone receptor negative, hormone receptor positive or BRCA-associated breast carcinoma, 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. The compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of amma carcinomas, in particular hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate carcinomas, in particular androgen receptor-negative prostate carcinomas or non-small cell lung carcinomas.

These diseases are well characterized in humans but also exist in other mammals.

An object of the present application are the compounds of the formula (I) according to the invention, in particular the compounds:

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

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

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

- (5r, 8r) -3- (4'-chloro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-ene 2-on A further subject of the present application are the compounds according to the invention 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 invention for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas,

Renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma, colorectal carcinoma or prostate carcinoma. The present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of mammary carcinomas, in particular hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate carcinomas, in particular androgen receptor-negative prostate carcinomas or non-small cell bronchial carcinomas. Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament. Another object of the present application is the use of the compounds of the invention 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 of the invention for the manufacture of a medicament for the prophylaxis and / or treatment of breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma, Endom etriumkarzinomen, colorectal carcinoma or Pro static carcinomas.

Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or treatment of breast cancer, in particular hormone receptor-positive breast cancer, colorectal carcinoma, prostate cancer, especially androgerrreceptor-negative prostate cancer or non-small cell bronchial carcinoma.

Another object of the present application is the use of the compound for the prophylaxis and / or therapy of tumor diseases. Another object of the present application is the use of the compounds of the invention for the prophylaxis and / or treatment 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.

The present application further relates to the use of the compounds according to the invention for the prophylaxis and / or therapy of breast cancers, in particular hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate carcinomas, in particular androgen receptor-negative prostate carcinomas or non-small cell bronchial carcinomas.

Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of breast cancer, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer. Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention for the prophylaxis and / or treatment of mammary carcinomas, especially hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate carcinomas, especially androgen receptor-negative prostate carcinomas or non-small cells lung cancer.

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. Another object of the present invention are therefore pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.

For example, the compounds according to the invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances 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, Be statin, beta-methasone 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, Fars clay, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formane, Fosteabin, Fotemustin, fulvestrant, Gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtine, hydrocortone, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2a , Interferon-alpha-2β, interferon-alpha-n1, interferon-alpha-n3, interferon-beta, interferon-gamma-la, interleukin-2, intron A, Iressa, irinotecan, cytril, lapatinib, lentinan sulfate, letrozole .

Leucovorin, leuprolide, leuprolide acetate, levamisole, Le folfolic acid -Calcium alz, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, metroxyproge sterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine , Mesna, Methotrexate, Metvix, Miltefosine, Minocycline, Mitomycin C, Mitotane, Mitoxantrone, Modrenal, Myocet, Nedaplatin, Neulas ta, 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, raititrex ed, RDEA 1 1 , Rebif, Rhenium-186-Etidronate, Rituximab, Roferon-A, Romurtide, Salagen, Sando Statin, Sargramostim, Semustin, Sizofiran, Sobuzoxan, Solu-Medrol, Streptozocin, Strontium-89-Chloride, Synthroid, Tamoxifen, Tamsulosin, Tasonermin, 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, lonfarnib, miproxifen, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastate, nolatrexed, oblimersen, onco-TCS, osmidem , Paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1 49. raloxifene, ranpirnas, 13-cw-retinoic acid, satrapinate, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha-1, tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, entporfin, vinflunine, Z-100, Zoledronic acid, as well as combinations thereof.

In a preferred embodiment, the compounds according to the invention can be combined with anti-hyperproliferative agents, which can be by way of example-without this enumeration being conclusive- Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, 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, iV-phosphono acetyl-L-aspartate (PALA), plicamycin, prednisolone, prednisone, procarbazine, raloxifene, semustin, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thi otepa, 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, reindeer, 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 following objectives can be pursued with the combination of the compounds according to the invention with other cytostatic or cytotoxic agents:

• 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. 1. Synthesis Routes for Compounds According to Formula (I)

The compounds of the formula (I) according to the invention can be prepared

Synthesis Routes A and / or B.

Synthesis route A

An arylbromide derivative of the formula (II)

in which W has the abovementioned meaning, is reacted in a Suzuki coupling with compounds of the formula (III)

in which R has the meaning given above and

A is -B (OH) 2, a boronic acid ester, preferably boronic acid pinacol ester, or

stands.

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 for Suzuki reaction conditions are conventional palladium catalysts, 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, preference is given to additional reagents, e.g. 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 sulphoxides, such as dimethyl sulphoxide, 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) can be prepared by reacting compounds of the formula (IV)

in which R ^{1 has} the meaning given above and

B is Ci-Ce-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-butyl acetate, 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 alkylsulfoxides, such as dimethylsulfoxide, or alcohols, such as methanol or ethanol, preference being given to dimethylformamide. The compounds of the formula (IV) can be prepared by reacting compounds of the formula (V) or a salt of compounds of the formula (V)

i

in which R ¹ and B have the meanings given above, with the compound of the formula (VI)

reacted 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 dehydration 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 metal carbonates, such as sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, for example triethylamine, NM emylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. As Dehydratisierangsreagenzien located here, for example, carbodiimides such as Ν, Ν'- diethyl, N, N, 'dipropyl, iV, A ^r' -Diisopropyl-, 7V, A '-dicyclohexylcarbodiimide, 7V- suitable (3-di- methylaminoisopropyl ) -iV'-ethylcarbodiimide hydrochloride (EDC), iV-cyclohexylcarbodiimide-V '- 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-sulfate 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, Ν, Ν ', N'-tet methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) - 1,1, 3,3 -tetramethyluroni- umtetrafluoroborat (TPTU) or 0- (7-azabenzotriazol-l-yl) -A, iV, V ', ^{7V'-tetramethyl-uroniumhexa-?} fluorophosphate (HATU), or 1-hydroxybenztriazo l (HOBt), or benzotriazole-1-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or benzotriazole-1-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or iV-hydroxysuccinimide, or mixtures thereof 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. SOCk, 80 ° C, 2. triethylamine, dichloromethane, room temperature,

b): KOtBu, DMF 80 ° C;

c): cat. Dichloro [1,1 'bis (diphenylphosphino) ferrocene] palladium dichloromethane complex, CS2CO3, Reflux. S ntheseroiite B

Alternatively, the compounds of the formula (I) according to the invention can be prepared by reacting a compound of the formula (VII)

in which R ^! , R ² and B have the meanings given above, under the conditions given above in a Dieckmann condensation reaction.

The compounds of the formula (VII) can be prepared by reacting compounds of the formula (V) or a salt of compounds of the formula (V) in which R ^s and B have the meanings indicated above, with compounds of the formula (VIII)

in which R ^{2 has} the abovementioned meaning, under the abovementioned amide coupling conditions.

The compounds of formula (VIII) can be prepared by

the compound of formula (VI) in a Suzuki reaction among those indicated above

Conditions with compounds of formula (III), in which R ² and A have the meanings given above, is reacted. The method described above is illustrated by the following synthesis scheme:

a): cat. Palladium (II) acetylacetonate, cat. Tri-tert-butylphosphonium tetrafluoroborate, NaOH,

THF / water;

b): 1. SOCl ₂ , 80 ° C, 2. K 2 CO 3, acetonitrile, room temperature;

c): KOtBu, DMF, room temperature.

The compounds of the formula (V) required for synthesis route A and B or salts of compounds of the formula (V) in which R ¹ and B have the abovementioned meanings can be prepared by reacting compounds of the formula (I) or a salt of compounds of the formula (ΓΧ)

in which R ^{1 has} the abovementioned meaning, esterified by known methods, for example analogously to WO2002 / 02532 or WO2010 / 063378. Compounds of the formula (IX) or salts of compounds of the formula (IX) in which R ^{1 has} the abovementioned meaning can be prepared by reacting compounds of the formula

(X)

Ϊ

in which R ^{1 has} the abovementioned meaning, cleaves by known methods, for example analogously to WO2002 / 02532 or WO2010 / 063378.

Compounds of the formula (X) in which R ^{s has} the abovementioned meaning can be prepared by reacting compounds of the formula (XI)

(XI)

in which R ^{s has} the abovementioned meaning, is reacted by known methods in a Bucherer-Bergs reaction, for example analogously to WO2002 / 02532 or WO2010 / 063378. In the formation of the hydantoin of the formula (X), isomer mixtures are formed from the cis isomer of the formula (X) and its trans isomer of the formula (Xa)

The separation of the trans isomer of the formula (Xa) can be carried out in this synthesis step. Alternatively, the isomer mixture can be further reacted and the separation of the respective trans-isomeric intermediate in one of the further synthesis steps or in the final stage of the formula (I). Alternatively, with the aid of the Strecker synthesis, amino nitriles can be prepared from the ketones of the formula (XI) by known processes, which can be hydrolyzed to the amino acids of the formula (II) by known processes. Compounds of the formula (XI) in which R 'has the abovementioned meaning can be prepared by reacting compounds of the formula (XII)

in which R ^{1 has} the abovementioned meaning, subjecting a ketal cleavage (see Protective Croups in Organic Synthesis, Theodora W. Greene).

Compounds of the formula (XII) in which R ^{s has} the abovementioned meaning can be prepared by reacting compounds of the formula (XIII)

(Xiii),

in which R ^{1 has} the abovementioned meaning, methylated by known methods, for example analogously to WO2010 / 063378.

The method described above is illustrated by the following synthesis scheme:

a): NaH, methyl iodide, THF, room temperature;

b): toluenesulfonic acid monohydrate, acetone / water;

c): NaCN, (NH) ₂ C0 ₃ , water / ethanol, 60 ° C;

d): KOH or NaOH, water, reflux;

e): SOCl ₂ , methanol, 40 ° C to reflux. The compound of the formula (XIII) in which R ^{s is} a trifluoromethyl group can be prepared by reacting the compound of the formula (XIV)

(iv),

with (trifluoromethyl) trimethylsilane.

The reaction of the colon of formula (XIV) with (trifluoromethyl) trimethylsilane to the

Compounds of the formula (XIII) 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 metal or alkaline earth metal 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 sulphoxides, such as dimethyl sulphoxide, dimethylformamide being preferred. The primary silyl derivatives of the formula (XIII) are finally cleaved according to methods known to the person skilled in the art (see Protective Croups in Qrganic Synthesis, Theodora W. Greene).

The compound of the formula (XIII) in which R ^{1 is} a methoxymethyl group can be prepared by reacting the epoxide of the formula (XV)

(XV),

opens according to known methods, e.g. analogous to Rodriguez, Benjamin; Torre, Maria C. de la; Perales, Aurea; Malakov, Peter Y .; Papanov, Y .; et al., Tetrahedron, 1994, Vol. 50, pp. 5451-5468.

The epoxide of formula (XV) is known and can be prepared from the compound of formula (XIV) (Ciaccio, James A. Drahus, Antoinette L, Meis, Regina M, Tingle, Carice T, Smrtka, Michael; Geneste, Richard, Synthetic Communications, 2003, Vol. 33, pages 2135-2444).

Abbreviations and acronyms:

about circa

DMF dimethylformamide

DM SO dimethylsulfoxide

d. Th. Of theory (at yield)

ELSD light scattering detector

ESI electrospray ionization (in MS)

h hour (s)

HPLC high pressure, high performance liquid chromatography

IX - MS liquid chromatography-coupled mass spectrometry

min minute (s)

MS mass spectrometry

Neg negative

NMR nuclear magnetic resonance spectrometry

pos positive

RP reversed phase (in chromatography)

RT room temperature

Retention time (on HPLC)

tertiary tertiary

TH F tetrahydrofuran

UPLC Ultra Performance Liquid Chromatography

LC-MS and HPLC Method: 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; ELSD.

Method 2 (UPLC-MS):

Instrument: Waters Acquity UPLC-MS SQD; 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; ELSD.

Method 3 (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 inl / niin; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nM Production of comparative and exemplary embodiments

Starting compounds and intermediates:

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 under argon was added 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.

Ή NMR (300MHz, DMSO-d ₆ ): 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).

I-MS (Method 1): R _t = 1.31 min; MS (ESIneg): mz = 277 [MH j.

Example 2A

(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.

Ή 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 3A

(5-Bromo-2-methylphenyl) acyl chloride

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.

Ή NMR (300MHz, CDCl3): δ [ppm] = 2.26 (s, 3H), 4.12 (s, 2H), 7.09 (d, 1H), 7.34 (d, 1H), 7.37 (dd, 1H).

Example 4A

(4'-Chloro-3'-fluoro-4-methylbiphenyl-3-yl) acyl chloride

10.00 g (35.88 mmol) of (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) acetic acid (Example 1A) were dissolved in 24.33 g (204.51 mmol) of thionyl chloride. The reaction mixture was stirred for one hour at 80 ° C and then evaporated in vacuo. After drying in a fine vacuum, 10.54 g (99% of theory) of the title compound were obtained as a brownish oil.

Ή NMR (300MHz, CDCl ₃ ): δ [ppm] = 2.36 (s, 3H), 4.22 (s, 2H), 7.26-7.39 (m, 4H), 7.41-7.49 (m, 2H). Example 5A

Trimethyl {[8- (trifluoromethyl) -l, 4-dioxaspiro [4.5] dec-8-yl] oxy} silane

5.00 g (32.01 mmol) of 1,4-dioxaspiro [4.5] decan-8-one were dissolved in 50 ml of 1,2-dimethoxyethane and treated with 14.60 g (44.82 mmol) of cesium carbonate. To the resulting suspension was added dropwise at an internal temperature of less than 30 ° C 36.42 g (256.11 mmol) of trimethyl (trifluoromethyl) silane, dissolved in 100 ml of 1, 2-dimethoxyethane, and the reaction mixture was stirred overnight at room temperature. For work-up, about 600 ml of water were added dropwise to the mixture, and the target molecule was extracted by means of dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulfate and evaporated in vacuo. After drying, 10.6 g (100% of theory) of the title compound were obtained as a brownish oil.

Ή-NMR (400MHz, DMSO-de): δ [ppm] = O. I I (s, 9H), 1.57-1.78 (m, 8H), 3.85 (s, 4H). Example 6A

l, 7,10-Trioxadispiro [2.2.4.2] dodecane

To a homogeneous mixture of 50.7 g (231 mmol) of trimethylsulfoxonium iodide and 25.9 g (231 mmol) of potassium tert-butoxide was added a solution of 30.0 g (192 mmol) of 1,4-cyclohexanedione monoethyl acetal in 750 ml of dichloromethane and the reaction mixture was allowed to stand for one hour Room temperature stirred. It was mixed with ice water, the phases were separated, the aqueous phase extracted several times with dichloromethane, the combined organic phases were washed several times with water, dried over sodium sulfate, filtered and concentrated. This gave 28.3 g (87% of theory) of the title compound. Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.41-1.52 (m, 2H), 1.65-1.76 (m, 6H), 2.61 (s, 2H), 3.88 (s, 4H). Beisoici 7A

8- (trifluoromethyl) -1,4-dioxaspiro [4.5] d (

12.20 g (40.89 mmol) of trimethyl {[8- (trifluoromethyl) -1,4-dioxaspiro [4.5] dec-8-yl] oxy} silane (Example 5A) were dissolved at 0 ° C. in 164 ml of 1 molar tetrabutylammonium fluoride solution in Dissolved tetrahydrofuran and stirred at room temperature for 3 hours. For work-up, about 600 ml of water were added to the batch, and the target molecule was extracted by means of dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulfate and evaporated in vacuo. Drying gave 9.33 g (100% of theory) of the title compound as a brownish oil.

^! H-NMR (400MHz, DMSO-de): δ [ppm] = 1.49 - 1.58 (m, 2H), 1.59 - 1.77 (m, 6H), 3.83 (s, 4H), 5.78 (s, 1H).

Example 8 A

8- (methoxymethyl) -l, 4-dioxaspiro [4.5] decan-8-ol

4.56 g (26.8 mmol) of the compound from Example 6A were admixed in 150 ml of methanol with 75 ml of a 25% strength methanolic sodium methoxide solution and stirred at 60 ° C. overnight. After cooling, the reaction mixture was concentrated, the residue taken up in saturated aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 3.23 g (60% of theory) of the title compound were obtained.

Ή-NMR (400MHz, DMSO-de): δ [ppm] = 1.37-1.47 (m, 4H), 1.50-1.63 (m, 2H), 1.68-1.80 (m, 2H), 3.10 (s, 2H), 3.25 (s, 3H), 3.82 (s, 4H), 4.24 (s, 1H). Example 9A

8-Metlioxy-8- (trifluoromethyl) -l, 4-dioxaspiro [4.5] decane

16.23 g (71.75 mmol) of 8- (trifluoromethyl) -1,4-dioxaspiro [4.5] decan-8-ol (Example 7A) were dissolved at 0 ° C. in 582 ml of tetrahydrofuran, in portions with 5.74 g (143.50 mmol) of sodium hydride ( 60% in paraffin oil) and stirred for 1 hour at room temperature. To the resulting suspension, 50.92 g (358.76 mmol) of iodomethane was dropped, and the reaction mixture was stirred at room temperature overnight. For working up, it was poured onto about 1 L of ice water and the product was extracted with dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulfate and evaporated in vacuo. After drying, 17.34 g (100% of theory) of the title compound were obtained as a brownish oil.

'H-NMR (300MHz, DMSO-de): δ [ppm] = 1.50-1.75 (m, 6H), 1.85-1.98 (m, 2H), 3.30 (s, 3H), 3.84 (s, 411).

example

8-methoxy-8- (methoxymethyl) -l, 4-dioxaspiro [4.5] decane

3.40 g (16.8 mmol) of the compound from Example 8A were dissolved in 170 ml of tetrahydrofuran, admixed with 1.01 g (25.2 mmol) of sodium hydride (60% in paraffin oil) and stirred at room temperature for 0.5 hours. Subsequently, 3.58 g (25.2 mmol) of iodomethane were added and the reaction mixture was stirred for two hours at room temperature. Subsequently, 3.58 g (25.2 mmol) of iodomethane were added and the reaction mixture was stirred for two hours at room temperature. It was mixed with water, extracted several times with ethyl acetate, the combined organic phases were dried over sodium sulfate, filtered and concentrated. 3.35 g (92% of theory) of the title compound were obtained. Ή NMR (300MHz, DMSO-de): δ [ppm] = 1.37-1.7 (m, 8H), 3.11 (s, 3H), 3.25 (s, 5H), 3.83 (s, 4H). Example IIA

4-methoxy-4- (trifluoromethyl) cyclohexanone

11.80 g (49.12 mmol) of 8-methoxy-8- (trifluoromethyl) -l, 4-dioxaspiro [4.5] decane (Example 9A) were dissolved in 236 ml of acetone and 118 ml of water, with 1.50 g (7.86 mmol) of 4-toluenesulfonic acid monohydrate spiked and refluxed overnight. The mixture was then poured onto 1.2 L of water and the product extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The resulting residue was distilled in vacuo (boiling point: 106-110 ° C at 40 mbar). This gave 6.86 g (71% of theory) of the title compound as a yellowish oil.

Ή NMR (300MHz, CDCb): δ [ppm] = 1.90 - 2.07 (m, 2H), 2.26 - 2.43 (m, 4H), 2.48 - 2.65 (m, 2H), 3.52 (s, 3H).

Example 1 2A

4-methoxy-4- (methoxymethyl) cyclohexanone

13.3 g (61.5 mmol) of the compound from Example 10A were dissolved in 200 ml of acetone and 100 ml of water, treated with 1.87 g (9.84 mmol) of 4-toluenesulfonic acid monohydrate and stirred for two days at room temperature. Subsequently, the acetone was distilled off, the aqueous residue was neutralized by the addition of sodium bicarbonate and treated with 23.2 g of sodium chloride. It was extracted several times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 10.3 g (97% of theory) of the title compound were obtained. Ή-NMR (400MHz, DMSO-de): δ [ppm] = 1.61-1.76 (m, 2H), 1.97-2.12 (m, 4H), 2.34-2.46 (m, 2H), 3.22 (s, 3H), 3.28 (s, 3H), 3.36 (s, 2H). Beisoici 13A

8-methoxy-8-rnethyl-l, 3-diazaspiro [4.5] decane-2,4-dione

608 g (6.33 mol) of ammonium carbonate and 68.2 g (1.39 mmol) of sodium cyanide were dissolved in 2800 ml of water. 180 g (1.27 mmol) of 4-methoxy-4-methylcyclohexanone (described in WO 2010/063378) were added dropwise at room temperature and the mixture was stirred at 60 ° C. overnight. The solid was filtered off with suction and dried. 169.6 g (19% of theory) of the title compound were obtained as a 4/1 trans / cis diastereomer mixture, which was reacted without further purification.

Example I 4A

8-Methoxy-8- (trifluoromethyl) -l, 3-diazaspiro [4.5] decane-2,4-dione

8.80 g (44.86 mmol) of 4-methoxy-4- (trifluoromethyl) cyclohexanone (Example IA), 4.40 g (89.72 mmol) of sodium cyanide and 17.24 g (179.44 mmol) of ammonium carbonate were suspended in 102 ml of ethanol and 102 ml of water. The resulting suspension was stirred at 60 ° C for 20 hours. The precipitated product was filtered off, washed with water and dried in vacuo. This gave 10.05 g (84% of theory) of the title compound as a white powder.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.38-2.20 (m, 8H), 3.31 (s, 3H), 7.87 (s, 0.25H), 8.70 (s, 0.75H), 10.64 ( s, 1H). Example ISA

(5R, 8R) -8-methoxy-8- (methoxymethyl) -l, 3-diazaspiro [4.5] decane-2,4-dione

28.6 g (298 mmol) of ammonium carbonate and 3.21 g (65.5 mmol) of sodium cyanide were dissolved in 130 ml of water. 10.3 g (59.5 mmol) of the compound from Example 12A were added dropwise at room temperature and the mixture was stirred at 60 ° C. overnight. The solid was filtered off, washed with a little water and dried. 8.67 g (60% of theory) of the title compound were obtained. Ή-NMR (400MHz, DMSO-de): δ [ppm] = 1.26-1.34 (m, 2H), 1.39-1.50 (m, 2H), 1.71-1.88 (m, 4H), 3.12 (s, 3H), 3.23 (s, 2H), 3.26 (s, 3H), 8.43 (s, 1H), 10.54 (s, 1H).

Example 16A

8-methoxy-8- (methoxymethyl) -l, 3-diazaspiro [4.5] decane-2,4-dione

5.74 g (59.7 mmol) of ammonium carbonate and 1.46 g (29.8 mmol) of sodium cyanide were dissolved in 33 ml of water. 2.57 g (14.9 mmol) of a solution of the compound from Example 12A in 33 ml of ethanol were added dropwise at room temperature and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated to one quarter of the original volume, extracted several times with dichloromethane and ethyl acetate, the organic phases were dried over sodium sulfate, filtered and concentrated. This gave 675 mg (19% of theory) of the title compound as a diastereomeric mixture, which was reacted without further purification. Example 17A

l-amino-4-methoxy-4-methylcyclohexancarbonsäurehydrogenchlorid

169.5 g of the compound from Example 13A were refluxed in 970 ml of 30% aqueous potassium hydroxide solution for 20 hours. After cooling, the reaction mixture was adjusted to a pH of 2 by addition of 670 ml of concentrated, aqueous hydrogen chloride solution, the precipitate was filtered off with suction and the filtrate was concentrated. This gave 10.7 g of a crude product as diastereomeric mixture which still contains salts and was reacted without further purification.

Example 1 8A

l-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylic acid

10.00 g (37.56 mmol) of 8-methoxy-8- (trifluoromethyl) -1,1-diazaspiro [4.5] decane-2,4-dione (Example 14A) were suspended in 125 ml of 3 molar aqueous sodium hydroxide solution and kept under 3 days Reflux conditions stirred. Subsequently, a pH of 6 was adjusted with concentrated aqueous hydrochloric acid, the precipitated product was filtered off, washed with water and dried in vacuo. This gave 12.20 g (135% of theory, product contains inorganic salts) of the title compound as a white powder. Ή-NMR (400MHz, methanol-c): δ [ppm] = 1.64-1.79 (m, 3.6H), 1.89 - 2.08 (m, 2.4H), 2.24 - 2.40 (m, 2H), 3.40 (q, 0.5 H), 3.42 (q, 2.5H). Example 19A

trans-1-amino-4-methoxy-4- (metto

8.67 g (35.8 mmol) of the compound from Example 15A were refluxed in 52 ml of 30% aqueous potassium hydroxide solution for 36 hours. After cooling, the reaction mixture was concentrated to one quarter of the original volume, adjusted by addition of concentrated aqueous hydrogen chloride solution to a pH of 2 and completely concentrated. This gave 40.4 g of a crude product that still contains salts and was reacted without further purification.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.57-1.77 (m, 6H), 1.87-2.05 (m, 2H), 3.08 (s, 3H), 3.23 (s, 3H), 3.27 ( s, 2H), 8.50 (s, 3H).

Example 20A

l-amino-4-methoxy-4- (methoxymethyl) cyclohexancarbonsäurehydrogenchlorid

670 mg of the compound from Example 16A were refluxed in 4 ml of 30% aqueous potassium hydroxide solution for 18 hours. After cooling, the reaction mixture was concentrated to one quarter of its original volume, adjusted to pH 2 by addition of concentrated, aqueous hydrogen chloride solution, and concentrated. This gave 4.70 g of a crude product as a diastereomer mixture that still contains salts and was reacted without further purification. Example 21A

Methyl-trans-l-amino-4-methoxy

To 110.5 g of the compound from Example 17A in 2500 ml of methanol under nitrogen were added dropwise at 5 ° C 172 ml (2.36 mol) of thionyl chloride. The mixture was stirred at 0 ° C. for 30 minutes and at 40 ° C. for 24 hours. After cooling, the solid was filtered off with suction, the filtrate was concentrated, and the residue was stirred for 10 minutes in a mixture of 1000 ml of methyl tert-butyl ether and 300 ml of acetonitrile, and the solid was filtered off with suction. This gave 37.1 g (12% of theory starting from 4-methoxy-4-methylcyclohexanone from Example 13A) of the title compound, which was reacted without further purification.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.08 (s, 3H), 1.60-1.79 (m, 6H), 1.94-2.11 (m, 2H), 3.07 (s, 3H), 3.75 ( s, 3H), 8.68 (s, 3H).

Example 22A

Methyl 1-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate

12.20 g (corresponds to about 37.58 mmol) of l-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylic acid (Example 18A) were suspended in 210 ml of methanol and treated at 0 ° C with 10.4 ml (142.80 mmol) of thionyl chloride. Refluxed for 2 hours, cooled, added 10.4 mL (142.80 mmol) of thionyl chloride again at 0 ° C and refluxed for a further 2 hours. The reaction was cooled, added again with 10.4 ml (142.80 mmol) of thionyl chloride and refluxed to complete the reaction overnight. For workup, about 100 ml of methanol were distilled off and the concentrate was poured into 1 L of saturated, aqueous sodium carbonate solution. The product was extracted with ethyl acetate and the organic phase was over Dried sodium sulfate. Evaporation gave 7.01 g (73% of theory) of the title compound as a yellowish oil.

Ή NMR (400MHz, DMSO-de): δ [ppm] = 1.39-2.00 (m, 10H), 3.28 (q, 3H), 3.59 (s, 2.4H), 3.60 (s, 0.6H).

Example 23A

Methyl-trans-l-amino-4-methoxy-4- (methoxymethyl) cyclohexanecarboxylate

To 40.4 g of the compound from Example 19A in 400 ml of methanol were added dropwise at 0 ° C 34.8 ml (478 mmol) of thionyl chloride. The mixture was stirred at 0 ° C. for 0.5 hours and at 40 ° C. for 24 hours. After cooling, the residue was concentrated in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, the aqueous phase extracted several times with ethyl acetate and dichloromethane, the combined organic phases were dried over sodium sulfate, filtered and concentrated. 7.16 g (87% of theory starting from Example 15A) of the title compound were obtained. Ή-NMR (400MHz, DMSO-de): δ [ppm] = 1.27-1.35 (m, 2H), 1.46 - 1.55 (m, 211), 1.58 - 1.72 (m, 4H), 1.74 - 1.84 (m, 2H ), 3.09 (s, 3H), 3.23 (s, 2H), 3.25 (s, 3H), 3.60 (s, 3H).

Example 24A

Methyl 1-amino-4-methoxy-4- (methoxymethyl) cyclohexanecarboxylate

To 4.70 g of the compound from Example 20A in 50 ml of methanol were added dropwise at 0 ° C 4.1 ml (55.60 mmol) of thionyl chloride. The mixture was stirred at 0 ° C. for 0.5 hours and at 40 ° C. overnight. To After cooling, the residue was concentrated in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, the aqueous phase extracted several times with ethyl acetate, the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 392 mg (61% of theory starting from Example 16A) of the title compound as a diastereomeric mixture, which was reacted without further purification.

Example 2 SA

Methyl trans-1 - {[(4'-chloro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4-methoxy-4-methylcyclohexanecarboxylate

8.08 g (31.0 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetic acid (EP 2029531 Al and US 2009/298828 Al) were dissolved in 12.9 ml (428 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 70 ml of acetonitrile. 6.00 g (25.2 mmol) of the compound from Example 21A were admixed with ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase extracted several times with ethyl acetate, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was mixed in 120 ml of acetonitrile with 12.2 g (88.3 mmol) of potassium carbonate. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred for two days at room temperature. It was then concentrated, the residue was taken up in water, extracted several times with dichloromethane, the combined organic phases were washed several times with IN aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase: hexane / ethyl acetate gradient). 7.87 g (68% of theory) of the title compound were obtained. Ι-NMR (400MHz, DMSO-de): δ [ppm] = 0.98 (s, 3H), 1.34-1.46 (m, 2H), 1.54-1.64 (m, 2H), 1.74-1.87 (m, 4H), 2.28 (s, 3H), 3.04 (s, 3H), 3.51 (s, 3H), 3.58 (s, 2H), 7.23 (d, 1H), 7.43 (dd, 1H), 7.47 - 7.53 (m, 2H) , 7.55 (d, 1H), 7.61-7.68 (m, 2H), 8.23 (s, 1H).

IX - MS (Method 2): R _t = 1.41 min; MS (ESIpos): m / z = 444 [M + HJ Example 26A

Methyl cis- 1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-

(Trifluoromethyl) cyclohexanecarboxylate

5.00 g (19.09 mmol) of methyl cis-1-amino-4- (trifluoroniethyl) 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 N, N 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 2A) in 40 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 was 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.

^S H NMR (300MHz, DMSO-de): δ [ppm] = 1.35-1.80 (m, 611). 2.05 - 2.18 (m, 2H), 2.24 (s, 3H), 2.25 - 2.40 (m, IH), 3.49 (s, 3H), 3.56 (s, 2H), 7.19 (d, IH), 7.40 (dd, IH), 7.42-7.52 (m, 3H), 7.56-7.65 (m, 2H), 8.34 (s, IH).

LC-MS (Method 1): R _t = 1.50 min; MS (ESIpos): m / z = 468 [M + H] ⁺ .

Example 27A

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 in 45 ml of dichloromethane at room temperature. Subsequently, a solution of 6.29 g (25.41 mmol) of (5-bromo-2-methylphenyl) ac etyl chloride (Example 3A) in 45 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. 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, 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 28A

Methyl trans-1 - {[(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4-methoxy-4-methylcyclohexanecarboxylate

20.9 g (75.0 mmol) of the compound from Example 1A were dissolved in 31.2 ml (428 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 200 ml of acetonitrile. 16.0 g (67.3 mmol) of the compound from Example 21 A were admixed with ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase extracted several times with ethyl acetate, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was admixed in 250 ml of acetonitrile with 28.5 g (206 mmol) of potassium carbonate. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred overnight at room temperature. The mixture was then concentrated, the residue was taken up in water, extracted several times with dichloromethane, the combined organic phases were washed several times with IN aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. For further purification was taken up again in dichloromethane, washed several times with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. This gave 23.6 g (76% of theory) of the title compound, which were reacted without further purification.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.98 (s, 3H), 1.32-1.45 (m, 2H), 1.55-1.63 (m, 2H), 1.74-1.86 (m, 4H) , 2.29 (s, 3H), 3.04 (s, 3H), 3.52 (s, 3H), 3.58 (s, 2H), 7.24 (d, 1H), 7.46 - 7.55 (m, 2H), 7.59 - 7.73 (m , 3H), 8.23 (s, 1H).

LC-MS (method 2): R _t = 1.46 min; MS (ESIpos): m / z = 462 [M + H] ⁺ .

Example 29A

Methyl-cis-l - {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate

10.00 g (38.22 mmol) of methyl cis-i-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 N, N Dimethylaminopyridine was dissolved in 95 ml of dichloromethane at room temperature. Subsequently, a solution of 9.46 g (38.22 mmol) of (5-bromo-2-methylphenyl 1) acyl chloride (Example 3A) in 95 ml of dichloromethane was added dropwise to the batch. The resulting reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous, saturated sodium bicarbonate solution and 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 30A

Methyl cis 1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4- (methoxy-methyl) -cyclohexanecarboxylate

28.3 g (1 19 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate hydrochloride (described in WO 2007/048545) were dissolved in 100 ml of water, treated with 20.0 g (238 mmol) of sodium bicarbonate and extracted several times with ethyl acetate , The combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 9.88 g of methyl cis-1-amino-4- (methoxymethyl) cyclohexanecarboxylate. 5.93 g (29.4 mmol) of methyl cis-l-amino-4- (methoxymethyl) cyclohexanecarboxylate in 50 ml of acetonitrile were mixed 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 2A 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 sulphate, filtered and concentrated. This gave 10.5 g of the title compound, which were reacted without further purification.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.05-1.25 (m, 2H), 1.44-1.65 (m, 5H), 2.01-2.12 (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).

LI-MS (Method 1): R, = 1.43 min; MS (ESIpos): m / z = 444 [M + H] ⁺ Example 31A

Methyl-cis-l - {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (methoxyme

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-1-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, the combined organic phases were washed with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated. This gave 3.11 g (91% of theory) of the title compound, which were reacted without further purification.

Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.07-1.29 (m, 2H), 1.47-1.66 (m, 511), 2.01-2.12 (m, 2H), 2.20 (s, 3H) , 3.13 (d, 2H), 3.22 (s, 3H), 3. 1 (s, 2H), 3.54 (s, 3H), 7.10 (d, IH), 7.30 (dd, IH), 7.41 (d, IH ), 8.22 (s, IH).

LC-MS (Method 1): R _t = 1.25 min; MS (ESIpos): mz = 412 [M + H] ⁺ . Example 32A

Methyl 1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-methoxy-4- (trifluoromethyl) -cyclohexanecarboxylate

3.94 g (15.44 mmol) of methyl 1-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate (Example 22A) and 1.56 g (15.44 mmol) of triethylamine were dissolved in 56 ml of dichloromethane. 3.92 g (14.03 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetyl chloride (Example 2A), dissolved in 56 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred overnight at room temperature. For working up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous, saturated sodium bicarbonate solution and with aqueous 1% citric acid. After drying over sodium sulfate, it was evaporated and dried. This gave 6.81 g (97% of theory) of the title compound as a white powder.

LC-MS (Method 1): R _t = 1.51 min; MS (ESIpos): m / z = 498 [M + H] ⁺ . Example 33A

Methyl 1 - {[(4'-chloro-3'-fluoro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-methoxy-4- (trifluoromethyl) -cyclohexanecarboxylate

20.50 g (80.32 mmol) of methyl 1-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate (Example 22A) and 8.13 g (80.32 mmol) of triethylamine were dissolved in 280 ml of dichloromethane. To this solution was added dropwise 21.70 g (73.02 mmol) of (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) acetyl chloride (Example 4A) dissolved in 280 ml of dichloromethane and the reaction mixture was stirred overnight at room temperature , For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous, saturated sodium bicarbonate solution and with aqueous 1% citric acid. After drying over sodium sulfate, it was evaporated and dried. 37.05 g (98% of theory) of the title compound were obtained as a beige powder. LC-MS (Method 1): R _t = 1.51 min; MS (ESIpos): m / z = 516 [M + H] ⁺ . Example 34A

Methyl trans-1 - {[(4'-chloro-3'-fluoro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-methoxy-4- (methoxymethyl) -cyclohexanecarboxylate

4.48 g (16.1 mmol) of the compound from Example 1A were dissolved in 5.6 ml (76.4 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. 3.10 g (13.4 mmol) of the compound from Example 23 A in 30 ml of acetonitrile were mixed with 6.48 g (46.9 mmol) of potassium carbonate. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred overnight at room temperature. It was then added to ice-water, extracted several times with dichloromethane, washed the combined organic phases several times with IN aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. This gave 6.59 g (96% of theory) of the title compound, which were reacted without further purification.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.32-1.49 (m, 2H), 1.54-1.66 (m, 2H), 1.70-1.91 (m, 4H), 2.29 (s, 3H), 3.09 (s, 3H), 3.14 (s, 2H), 3.20 (s, 3H), 3.52 (s, 3H), 3.57 (s, 2H), 7.24 (d, 1H), 7.46 - 7.56 (m, 2H) , 7.58 - 7.74 (m, 3H), 8.27 (s, 1H).

LC-MS (Method 2): R = 1.38 min; MS (ESIpos): mz = 492 [M + Hf. Example 35A

Methyl 1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4-methoxy-4-

(Methoxymethyl) cyclohexanecarboxylate

574 mg (2.20 mmol) of (4'-chloro-4-methylbiphenyl-3-yl) acetic acid (EP 2029531 Al and US 2009/298828 Al) were dissolved in 0.9 ml (12.5 mmol) of thionyl chloride. The reaction mixture was stirred for 1 h at 80 ° C and then concentrated. The residue was dissolved in 5 ml of acetonitrile. 390 mg (1.69 mmol) of the compound from Example 24 A in 10 ml of acetonitrile were admixed with 816 mg (5.90 mmol) of potassium carbonate. Under ice-cooling, the solution of the acid chloride was added dropwise and stirred overnight at room temperature. It was then concentrated, taken up in ice-water, extracted several times with dichloromethane, the combined organic phases were washed several times with IN aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. This gave 570 mg of the title compound as a diastereomeric mixture, which were reacted without further purification.

LC-MS (Method 2): R _t = 1.36 min; MS (ESIpos): m / z = 474 [M + H] ⁺ .

Example 36A

Methyl 1 - {[(5-bromo-2-methylphenyl) acetyl] amino} -4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate

3.00 g (11.75 mmol) of methyl 1-amino-4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate (Example 22A) and 1.19 g (11.75 mmol) of triethylamine were dissolved in 40 ml of dichloromethane. To this Solution was added dropwise 2.65 g (10.69 mmol) (5-bromo-2-methylphenyl) ac etyl chloride (Example 3A), dissolved in 40 ml of dichloromethane, and the reaction mixture was stirred overnight at room temperature. For working up, it was diluted with dichloromethane and the organic phase was washed with aqueous, saturated sodium bicarbonate solution and with aqueous, 1% citric acid. After drying over sodium sulfate, it was evaporated and dried. 4.79 g (87% of theory) of the title compound were obtained as a beige powder.

LC-MS (Method 1): R, = 1.33 min; MS (ESIpos): m / z = 468 [M + Hf.

Example 37A

(5s, 8s) -3- (5-bromo-2-methylphenyl) -4-hydroxy-8- (trifluoromethyl) -l-azaspiro [4.5] d (

To 8.80 g (20.17 mmol) of methyl cis-1- {[(5-bromo-2-methylphenyl) acetyl] amino} -4- (trifluoromethyl) cyclohexanecarboxylate (Example 29A) 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 purified by chromatography on silica gel (eluent: hexane / ethyl acetate gradient). Drying gave 5.23 g (64% of theory) of the title compound.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.40-1.50 (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 3): R _t = 1.18 min; MS (ESIpos): m / z = 406 [M + H] ⁺ . Example 38A

11 - (5-Bromo-2-methylphenyl) - 12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10-one

To 3.64 g (8.54 mmol) of methyl 8- {[(5-bromo-2-methylphenyl) acetyl] amino} -1, 4-dioxaspiro [4.5] de c of 8-arboxylate (Example 27A) in 43 ml Ν, Ν-Dimethylformamide was 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 39A

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 11- (5-bromo-2-methylphenyl) -12-hydroxy-1,4-dioxa-9-azadispiro [4.2.4.2] tetradec-1-en-10-one (Example 38A ) in 26 ml of acetone and 13 ml of water was 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 sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Drying gave 1.97 g (89% of theory) of the title compound.

Ή-NMR (400MHz, DMSO-d ₆ ): 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 3): R _t = 0.87 min; MS (ESIpos): m / z = 352 [M + H] ⁺ . Example 40A

(5R, 8R) -3- (5-Broni-2-methylphenyl) -4,8-dihydroxy-8- (lxifluormethyl) -l-az

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 39A) in 8.3 ml Ν, Ν Dimethylformamide, 521 mg (1.60 mmol) of cesium carbonate and 975 mg (6.85 mmol) of (trifluoromethyl) trimethylsilane were added. 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 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.

Ή-NMR (400MHz, methanol-d): 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 1): R _t = 0.96 min; MS (ESIpos): m / z = 420 [M + Hf.

Example 41A

(5s, 8s) -3- (5-bromo-2-methylphenyl) -4-hydroxy-8- (methoxymethyl) -l-azaspiro [4.5] di

To 3.11 g (7.54 mmol) of the compound from Example 31A in 11 ml of Ν, Ν-dimethylformamide were added 1.69 g (15.1 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, 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. 2.83 g (96% of theory) of the title compound were obtained.

Ή-NMR (300MHz, DMSOde): 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 _t = 1.05 min; MS (ESIpos): m / z = 380 [M + H] ⁺ .

Example 42A

3- (5-bromo-2-methylphenyl) -4-hydroxy-8-methoxy-8- (trifluoromethyl) -l-azaspiro [4.5] di

To 4.70 g (10.08 mmol) of methyl 1 - {[(5-bromo-2-methylphenyl) acetyl] amino} -4-methoxy-4- (trifluoromethyl) cyclohexanecarboxylate (Example 36A) in 50 ml of Ν, Ν-dimethylformamide Added 2.26 g (20.16 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 and dried. 3.68 g (84% of theory) of the title compound were obtained as a beige powder.

Ή-NMR (400MHz, methanol-d): δ [ppm] = 1.39-2.45 (m, 11H), 3.42-3.46 (m, 3H), 7.12-7.18 (m, 1H), 7.25-2.29 (m , 1H), 7.32 - 7.38 (m, 1H). for Example 1-1

V. l-a (= compound from Table 1, line 20, p. 40 of WO 10/063378)

(5r, 8r) -3- (4'-chloro-4-memylbiphenyl-3-yl) -4-hydroxy-8-methoxy-8-memyl-1-azaspiro [4.5] dec-3-ene-2-one

To 7.83 g (17.6 mmol) of the compound from Example 25A in 75 ml of N, N-dimethylformamide were added under nitrogen 2.18 g (19.4 mmol) of potassium tert-butoxide. The reaction mixture was stirred for 15 minutes at room temperature. It was then concentrated, the residue was taken up in ice-water, acidified with 1N aqueous hydrogen chloride solution, stirred for 30 minutes, filtered off with suction, washed with water and dried the precipitate. For further purification, the product was dissolved in 1N aqueous sodium hydroxide solution, filtered, precipitated by acidification of the filtrate with aqueous 1N hydrochloric acid, washed with water, filtered off and dried. 4.78 g (65% of theory) of the title compound were obtained.

Ή-NMR (400MHz, DMSO-de): δ [ppm] = 1.09 (s, 3H), 1.12-1.20 (m, 2H), 1.60-1.71 (m, 2H), 1.71-1.80 (m, 2H), 2.04-2.14 (m, 2H), 2.18 (s, 3H), 3.10 (s, 3H), 7.30 (d, 1H), 7.34 (d, 1H), 7.46-7.52 (m, 3H), 7.62-7.68 ( m, 2H), 8.15 (s, 1H), 10.79 (s, 1H).

LC-MS (Method 2): R _t = 1.23 min; MS (ESIpos): m / z = 412 [M + H] ⁺ .

V.l-b

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

2-one

l To 6.36 g (13.59 mmol) of methyl cis-1 - {[(4'-chloro-4-methyl-biphenyl-3-yl) -acetyl] -amino} -4- (trifluoromethyl) -cyclohexanecarboxylate (Example 26A) in 68 ml of Ν, Ν -Dimethylformamide was 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. Ι-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.40 - 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 1): R _t = 1.32 min; MS (ESIpos): m / z = 436 [M + H] ⁺ . VJ-c

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

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 40A) in 13 ml of degassed 1,2-dimethoxyethane under argon were added 24 mg (0.030 mmol) of dichloro [1,1 '-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. Ή-NMR (400MHz, methanol-d,): δ [ppm] = 1.41 - 1.53 (m, 2H), 1.85 - 2.01 (m, 4H), 2.24 (s, 3H), 2.33 - 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 _t = 1.19 min; MS (ESIpos): m / z = 452 [M + H] ⁺ . for embodiment 1-2

V.2-a (= compound from Table 2, line 10, page 45 of WO10 / 063378)

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

To 23.5 g (50.4 mmol) of the compound from Example 28A in 250 ml of N, N-dimethylformamide 6.22 g (55.4 mmol) of potassium tert-butoxide were added under nitrogen. The reaction mixture was stirred at room temperature for 5 minutes. It was then concentrated, the residue was taken up in water, acidified with 1N aqueous hydrogen chloride solution, stirred for 30 minutes, filtered off with suction, washed with water and dried the precipitate. This gave 21.4 g (about 90% purity, 89% of theory) of the title compound.

Ή NMR (300MHz, DMSO-de): δ [ppm] = 1.08 (s, 3H), 1.10-1.22 (m, 2H), 1.56-1.81 (m, 4H). 1.99 - 2.14 (m, 2H), 2.19 (s, 3H), 3.10 (s, 3H), 7.29 (d, 1H), 7.40 (d, 1H), 7.46 - 7.56 (m, 2H), 7.60 - 7.72 ( m, 2H), 8.05 (s, 1H), 10.86 (s, 1H).

LC-MS (Method 1): R = 1.25 min; MS (ESIpos): mz = 430 [M + H] ⁺ . V_2J_

(5s, 8s) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8- (trifluoro

azaspiro [4.5] dec-3-en-2-o

To 5.00 g (12.4 mmol) of the compound of Example 37A in 500 ml of degassed 1,2-dimethoxyethane were added under argon 1.01 g (1.24 mmol) of dichloro [1,1-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 h. After cooling, 10 ml of concentrated, aqueous hydrogen chloride solution were added, the aqueous phase was separated off, treated with magnesium sulfate, filtered through silica gel, washed with ethyl acetate and concentrated. Purification of the crude product by chromatography on silica gel (eluent: hexane / ethyl acetate gradient) and crystallization from ethyl acetate gave 2.48 g (44% of theory) of the title compound.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.45-1.57 (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 _t = 1.34 min; MS (ESIpos): m / z = 454 [M + H] ⁺ .

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

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 40A) in 13 ml of degassed 1,2-dimethoxyethane under argon were added 24 mg (0.030 mmol) of dichloro [1,1 '-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.

Ή-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 1): R _t = 1.19 min; MS (ESIpos): m / z = 470 [M + H] ⁺ . for embodiment 1-3

V.3-a (= V.l-a) = compound from Table 1, line 20, p. 40 of WO10 / 063378

Y)

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

To 10.4 g (23.4 mmol) of the compound from Example 30A 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 in 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.

Ή-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), 1.81-1.97 (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 3): R _t = 1.25 min; MS (ESIpos): m / z = 412 [M + H] ⁺ .

The substance was disclosed as an isomer mixture as Example 1-1 -a-5 of WO 07/048545. for embodiment 1-4

V.4-a (= V.2-a) = compound from Table 2, line 10, page 45 of WO10 / 063378)

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

To 2.00 g (5.26 mmol) of the compound of Example 41A and 215 mg (0.26 mmol) of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex in 213 ml of degassed 1,2-dimethoxyethane were added under argon Add 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 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 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. Tl-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:21 to 1:47 (m, 4H), 1:48 - 1.64 (m, IH), 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, IH), 7.40 (d, IH), 7.48 - 7.57 (m, 2H), 7.60 - 7.74 (m, 2 H l, 8.13 (s, IH), 10.79 (s, IH).

LC-MS (Method 1): R _t = 1.26 min; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Table V shows the comparative examples, which Applicant regards as the closest prior art in the overview.

Ausführungshdspiclc:

Example 1-1

(5R, 8R) -3- (4'-chloro-4-methylbiphe

azaspiro [4.5] dec-3-ene-2-one

To 6.80 g (13.66 mmol) of methyl 1 - {[(4'-chloro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4-methoxy-4- (trifluoromethyl) -cyclohexanecarboxylate (Example 32A) in 68 mL of Ν , Ν-Dimethylformamide was added to 3.07 g (27.31 mmol) of potassium tert-butoxide. The reaction mixture was stirred at 80 ° C for 60 minutes. For work-up, the cooled reaction mixture was poured onto 1500 ml of ice-water and acidified with aqueous hydrochloric acid. The crude product was filtered off, dried and prepurified by chromatography (column: Chiralpak LA 5μπι, 250x30mm, hexane / ethanol gradient in the presence of 0.1% formic acid). Evaporation and crystallization from diethyl ether gave 3.57 g (56% of theory) of the title compound.

Ή-NMR (300MHz, DMSO-de): δ [ppm] = 1.25-1.41 (m, 2H), 1.83-1.99 (m, 4H), 2.00-2.14 (m, 2H), 2.15 (s, 3H), 3.34 (s, 3H), 7.28 (d, 1H), 7.32 (d, 1H), 7.42 - 7.51 (m, 3H), 7.58 - 7.67 (m, 2H), 8.41 (s, 1H), 10.98 (s, 1H).

LC-MS (method 1): R _t = 1.31 min; MS (ESIpos): m / z = 466 [M + H] ⁺ .

Example 1-2

(5R, 8R) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-8- (tri

azaspiro [4.5] dec-3-ene-2-one

To 300.00 mg (0.69 mmol) of 3- (5-bromo-2-methylphenyl) -4-hydoxy-8-methoxy-8- (trifluoromethyl) -1-azaspiro [4.5] dec-3-en-2-one (Example 42A) in 28 ml of degassed 1,2-dimethoxyethane was added under argon 67.70 mg (0.083 mmol) of dichloro [1,1-bis (diphenylphosphino) ferrocene] palladium dichloromethane complex. The mixture was stirred at room temperature for 5 minutes and then 216.83 mg (1.24 mmol) were added. and a solution of 945.40 mg (2.90 mmol) of cesium carbonate in 1 ml of degassed water. The reaction mixture was heated to 150 ° C in the microwave for 40 minutes. After cooling, 0.4 ml of concentrated, aqueous hydrogen chloride solution were added, filtered, the precipitate was washed with dichloromethane and with methanol, and the combined organic phases were evaporated in vacuo. The crude product was pre-purified by chromatography on silica gel (mobile phase: hexane / ethyl acetate gradient). The final purification was carried out by RP chromatography (mobile phase: water / formic acid / acetonitrile gradient). 43 mg (13% of theory) of the title compound were obtained.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.27-1.39 (m, 2H), 1.85-1.99 (m, 4H), 2.00-2.13 (m, 2H), 2.16 (s, 3H) , 3.34 (s, 3H), 7.29 (d, 1H), 7.38 (d, 1H), 7.45-7.54 (m, 2H), 7.57-7.70 (m, 2H), 8.36 (s, 1H), 10.97 (s , 1H).

LC-MS (Method 1): R _t = 1.34 min; MS (ESIpos): m / z = 484 [M + H] ⁺ .

Alternatively, the target structure could be made as follows:

To 35.00 g (67.84 mmol) of methyl 1 - {[(4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -acetyl] -amino} -4-methoxy-4- (trifluoromethyl) -cyciohexanecarboxylate (Example 33A ) in 350 ml of N, N-dimethylformamide was added 15.22 g (135.68 mmol) of potassium tert-butylate. The reaction mixture was stirred for 30 minutes at room temperature. For workup was the cooled The reaction mixture was poured onto 8000 ml of ice-water and acidified with aqueous hydrochloric acid. The crude product was filtered off, dried and prepurified by silica gel chromatography (dichloromethane / ethyl acetate gradient). The resulting solid was crystallized from diethyl ether. 9.33 g (28% of theory) of the title compound were obtained.

Example 1-3

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

To 570 mg (1.20 mmol) of the compound from Example 35 A in 5 ml of Ν, Ν-dimethylformamide were added under nitrogen 148 mg (1.32 mmol) of potassium tert-butoxide. The reaction mixture was stirred. 5 minutes at room temperature. It was then concentrated, the residue was taken up in ice-water, acidified with 1N aqueous hydrogen chloride solution, stirred for 30 minutes, filtered off with suction, washed with water and dried the precipitate. By twice preparative HPLC [1. Column: Chromatorex C18, 10 μm, 125 mm × 30 mm; Eluent: water / acetonitrile gradient with addition of 0.1% formic acid; 2nd column: Chiralpak IC, 5 μπι, 250 mm x 20 mm; Eluent: hexane / ethanol = 80/20 with addition of 0.1% formic acid; Flow: 25 ml / min; Temperature: RT], the diastereomers were separated. 105 mg (20% of theory) of the title compound were obtained.

^! H-NMR (300MHz, DMSO-d _6): δ [ppm] = 1:12 to 1:27 (m, 2H), 1:48 - 1 .65 (m, 2H), 1.75 - 1.88 (m, 2H), 1.99 - 2.14 ( m, 2H), 2.18 (s, 3H), 3.15 (s, 3H), 3.28 (m, 5H), 7.30 (d, 1H), 7.34 (d, 1H), 7.44 - 7.54 (m, 3H), 7.61 - 7.69 (m, 2H), 8.10 (s, 1H), 10.83 (s, 1H).

LC-MS (Method 2): R _t = 1.19 min; MS (ESIpos): m / z = 442 [M + H] ⁺ . Example 1 -4

(5R, 8R) -3- (4'-chloro-3'-fluoro-4-methylbiphenyl-3-yl) -4-hydroxy-8-methoxy-8- (m

azaspiro [4.5] dec-3-ene-2-one

To 6.55 g (13.3 mmol) of the compound from Example 34A in 60 ml of Ν, Ν-dimethylformamide were added under nitrogen 1.64 g (14.7 mmol) of potassium tert-butoxide. The reaction mixture was stirred for 15 minutes at room temperature. Then the reaction mixture was added to ice-water, added dropwise IN aqueous hydrogen chloride solution to a pH of 1 -2, stirred for 30 minutes, filtered off with suction, washed with water and dried the precipitate. For further purification, the product was dissolved in 1 N aqueous sodium hydroxide solution, precipitated by acidification with aqueous 1 N hydrochloric acid, stirred for 30 minutes, washed with water, filtered off and dried. This gave 6.00 g (98% of theory) of the title compound.

Ή-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.12-1.26 (m, 2H), 1.50-1.65 (m, 2H), 1.76-1.89 (m, 2H), 1.98-2.25 m, 2H), 2.19 (s, 3H), 3.1 (s, 3H), 3.28 (s, 5H), 7.31 (d, 1H), 7.39 (d, 1H), 7.49 - 7.57 (m, 2H), 7.64 (t, 1H), 7.69 (dd, 1H), 8.14 (s, 1H), 10.82 (s, 1H).

IX - MS (Method 2): R, = 1.21 min; MS (ESIpos): m / z = 460 [M + H] ⁺ .

Assays

3.1 Human ACC Enzyme Assays The ACCl and ACC2 inhibition data were collected using both of the assays described below. Typically, a serial serial dilution series of the test substances was prepared for both measurements, and multiple copies of the substance were then made from this dilution series with a 384well 50 nL capillary pipettor (Hummingbird ™ from Genomics Solutions). These were then used in the ACC1 and ACC2 assays, respectively, so for optimal comparability both enzyme inhibition measurements with copies of them

Substance dilution series were performed.

Human ACCI Enzyme Assay The hACC 1 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 byproduct of the enzyme reactions by means of 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 NaHCOs, 2mM thio-threitol (DTT), 0.005% (w / v) bovine serum albumin (BSA)] are added and the mixture is stirred for 15 min incubated to allow Vorvorbindung 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" (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" (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). serial dilutions were assayed at the level of 100X concentrated solution by serial 1: 3 dilutions) in duplicate for each concentration prior to assay, and IC 50 values were calculated using a 4-parameter fit using in-house software. Human ACC2 enzyme assay

The hACC2 inhibitory activity of the substances of this invention was measured in the hACC2 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 by means of 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 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 transferred to a white low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). pipetted, 2.5 μΐ of a solution of hACC2 in assay buffer [50 mM HEPES / NaOH pH 7.5, 2 mM MgCl ₂ , 2 mM potassium citrate, 12 mM NaHCOs, 2 mM thio-threitol (DTT), 0.005% ( w / v) bovine serum albumin (BSA)], and the mixture is incubated for 15 min to allow pre-binding of 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 worked in the linear range. 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" (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 emitted light 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). Usually, 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 ηΜ, 27 ηΜ, 9.2 ηΜ,

3.1 η Μ and 1 nM, serial dilutions were assayed at the level of 100X concentrated solution by serial 1: 3 dilutions) in duplicate for each concentration prior to assay, and IC 50 values were calculated with a 4-parameter fit, for which a In-house software was used.

3.2 Zeü assays

In accordance with the invention, the substances were tested in cell-based assays, that is, the ability of the substances to tumor cell proliferation after 96 hours

Inhibit 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 word 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:

ATCC: American Type Culture Collection

NCI: National Cancer Institute

DMSZ: German Collection of Microorganisms and Cell Cultures GmbH 3.3 Analysis of ACC1 Expression in Tumor and Normal Tissue

The ACCi expression was determined by means of a microrray. For this, the RNA was isolated from different tumor tissues and the corresponding normal tissues. Methodologically, Trizol R NA 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 Reflner (GeneData) software. 3.4 Assays to determine the octanol-water partition coefficient (logP / D) of the membrane affinity (logMA) and

protein binding to human serum albumin (Kj USA)

Assay for determining the octane-water partition coefficient (! OgP / D):

The partition coefficient octanol / water P or D is a key parameter for estimating membrane penetration and permeability. It is defined as the ratio of the equilibrium concentrations of a substance in the two-phase system octanol / water.

cwater

P = partition

D = distribution

c octanol = concentration of the substance in the octanol phase

cWater = Concentration of the substance in the aqueous phase

It is usually given in the form of the decadic logarithm (logP or logD). The logP describes the distribution behavior of a substance that exists exclusively in its neutral form. The logD describes the distribution behavior of a substance at a certain pH value; Depending on the ionization constant pKa of the substance, part of the substance may be present in ionic form, part in neutral form. The logP / D value of the active ingredients was determined using an isocratic HPLC method (HPLC = high performance liquid chromatography) (literature: OECD Guideline for Testing of Chemicals No. 117). The method is based on the correlation of the HPLC retention time of the test substance with that of reference substances with known partition coefficients. The test substance was used as 10 mM DMSO solution (DMSO = dimethyl sulfoxide). 10 μΐ of this solution were made up to 100 μί with a methanol / water mixture in the ratio 7 + 3.

The nine reference substances were individually dissolved in methanol. The concentration is shown in Table 1. Each ΙΟΟμΙ of the stock solutions were added together in an HPLC vial and mixed with 300μ1 water. Tab. 1

To determine the dead time, a formamide solution was used. For this purpose, 7 mg of formamide were dissolved in 10 ml of methanol. ΙΟΟμΙ of this stock solution were mixed with 50 (μ) methanol and 200 1 1 water.

All solutions were chromatographed with a flow of 100 ml / min.

Chromatographic conditions:

HPLC system Waters Alliance HT 2790

UV detector DAD Waters 996

MS detector MS Micromass ZQ

HPLC software MassLynx 4.1 from Waters

Column Spherisorb ODS 3μπι 4.6 x 60 mm

Eluent methanol + water with 0.01M ammonium acetate (0.77g / liter)

75 + 25, pH 7.0

Injection volumes:

Formamide 5μ1

References 5μ1

Test substance 15μ1

Injection scheme:

Formamide, references, test substance 1, test substance 2, formamide, references. The evaluation of the retention times was carried out in the diode array detector (DAD) at 200-400nm. With the downstream mass spectrometer, the identity of the test substance was checked via the molecular mass. The HPLC run was evaluated using the Waters Masslynx 4.1 software.

The LogP / D values were calculated using the software "POW Determination" (proprietary development).

Assays for the determination of membrane anaphylactic logMA and protein binding to human serum albumin (HS A):

The determination of the membrane affinity and the protein binding to human serum albumin (HSA) took place via the Transil technology (literature: A. Loidl-Stahlhofen, A. Eckert, T. Hartmann, M. Schöttner J Pharm Sei 90, 599-606 (2001 Transil® (sold by the company Sovicell in Leipzig) is a glass bead (diameter 10 - 12 μm) on which a double-layered membrane of phosphatidylcholine (MA transil) or covalently bound human serum albumin (HSA transil) is applied.

To determine the logMA and protein binding constant on HSA, the commercially available TRANSIL Intestinal Absorbance & HSA Binding Combined Assay Kit was used. This is a 96-well microtiter plate (96 well-MTP) filled with transil, with which the binding to MA-transil and HSA-transil can be determined for every eight active substances. For each drug, a series of 12 wells on the transil plate is available. Two wells serve as reference and are filled only with buffer pH 7.4. Five more wells contain MA-Transil in varying increasing concentrations, the five remaining wells contain HSA-transil in varying increasing concentrations.

In order to determine the binding of a drug to transil, the supernatant of the wells was quantified with transil to the reference solution without transil via HPLC-MS coupling (HPLC-MS = Highp erformanc e liquid chromatography-mas s spectrometry).

The implementation of the assay in detail:

From the internal substance storage, the active ingredients were delivered in a 96 well MTP. This plate is called a mother plate. Per well 30μ1 of a 10 mmol drug solution in DMSO (dimethyl sulfoxide) were included. Two wells at the beginning (well AI) and at the end of the plate (well Hl 2) were filled with 30 μl of 10 mmol warfarin solution in DMSO. Warfarin, whose membrane binding and binding to HSA is known, is used to verify the accuracy of the measurement. From the Mother plate was prepared a daughter plate with the dilution 1 to 4000 with a mixture buffer pH 7.4 and DMSO in the ratio 1 + 1. The active ingredient concentration per well was 2.5 μπιοΙ / liter, the volume per well was 400 μΐ.

Using a Hamilton Microlab STAR pipetting robot, the 96 active ingredients from the daughter plate were distributed over a total of 12 Transil plates. Per well of the daughter plate 12 times 20μ1 were taken. The concentration per well in the transil plate was 0.25μηιο1 / Όί6Γ, a dilution of 1 to 10 accordingly. The content of DMSO was 5%.

The filled Transil plates were resuspended for two minutes, then allowed to stand at room temperature for at least two minutes and then centrifuged at 600 rpm for five minutes. Subsequently, 20 μΐ supernatant from each well of the transil plate was removed from the pipetting robot and transferred to a separate microtiter plate. In each case, the supernatants of four transil plates in a microtiter plate were pooled ("pooled"), so that at the end of three pooled microtiter plates each with 80μ1 solution and an active compound concentration of 62.5 nM were present per well.

Before the active ingredients can be quantified by means of HPLC-MS, an optimization must be carried out for each active ingredient, in which daughter injection and optimum electrical voltages are determined by a single injection. Da / u made the pipetting robot from the mother plate a dilution of 1 to 10 000 000 in an acetonitrile-water mixture in the ratio 8 + 2 in a separate microtiter plate.

This microtiter plate was measured with the Discovery Quant Optimize software from AB Sciex on the HPLC-MS. The three pooled microtiter plates were measured on the HPLC-MS using the software Discovery Quant Analyze from AB Sciex.

Chromatographic conditions:

HPLC-MS System: Agilent 1200 Rapid Resolution HPLC

Sciex Triple Quad 5500 Mass Spectrometer (AB Sciex Company) PAL Autosampler DLW Option

Software: Analyst 1.4 (company AB Sciex)

Discovery Quant Optimize (AB Sciex company)

Discovery Quant Analyze (AB Sciex company)

Optimization:

Column: capillary

Injection volume: 5 μΐ

Flow rate: 0 min -> 80μ1 / ιηϊη

0.20 - 0.65 min-> 30μ1 / πύη

0.66 0.7 min -> 150μ1 / πύη Plasticizer: A = acetonitrile + 0.05% formic acid

B = water + 0.05% formic acid

Isocratic A: B 8 + 2

Analysis:

Column: Poroshell 120 SB-C18 2.7μm 3 x 30 mm

Injection volume: 2 μΐ

Flow rate: 1 ml / min

Plasticizer: Gradient

A = acetonitrile + 0.05% formic acid

B = water + 0.05% formic acid

0 min -> 95% A, 5% B

0 - 1.0 min -> 5% A, 95% B increasing linearly

1.0 - 2.2 min -> 5% A, 95% B isocratic

2.21 -2.3 min -> 95% A, 5% B isocratic

3.5 Determination of plasma protein binding by equilibrium dialysis The binding of test substances to plasma proteins is determined by equilibrium dialysis with the aid of the Teflon Ht-dialysis apparatus (96well) and a semipermeable membrane (regenerated cellulose, MWCO 12-14K). This separates 150 μΐ each of a plasma and a buffer side (50 mM phosphate buffer). The test substance is added to the plasma side in 2 concentrations (usually 3 and 0.3 μΜ) and binds to plasma proteins. The unbound portion of the test substance passes through the membrane and spreads on both sides until equilibrium is established (about 6-8 h at 37 ° C). The substance concentration on buffer and plasma side determined by LC-MS analysis. For this purpose, both sides are brought to dilution with buffer or plasma on the same matrix (10% plasma) and then precipitated with methanol. From the quotient of the buffer and plasma concentration, the free (unbound) fraction (fu) is calculated. As controls, stability samples and recommen- dation samples are carried. In addition, the substance is dialyzed in buffer against buffer to check the non-specific binding to the apparatus and membrane and the adjustment of the equilibrium. Since dilution of the plasma occurs during incubation due to the osmotic pressure of the plasma proteins (volume shift), this possible error is determined by weighing empty plasma samples and included in the calculation of the fu. The equilibrium and plasma stability should not be less than 80% and at least 30% recovery. A free fraction of <1% is called high, between 1 and 10% as moderate and> 10% as low plasma protein binding. 3.6 Pharmacokinetic parameters

Determination of the pharmacokinetic parameters of a test substance in the rat and dog

For this purpose, the test substances were applied in dissolved form both for intravenous and for intragastric administration, using compatible solubilizers such as PEG400 and / or ethanol in a tolerated amount. Intravenous application:

The test substances were applied at a dose of 0.1 -1 mg kg. The application was in the male rat as bolus Inj ection, in the female dog as an infusion (15 min). At various times after bolus injection or before and after the 15-minute infusion, about 100-150μΕ blood samples were taken via a jugular vein catheter (rat) or from the saphenous vein (dog). The blood samples were treated with lithium heparin as an anticoagulant and kept refrigerated until further processing. After centrifuging the samples for 15 min at 3000 rpm, an aliquot of ΙΟΟμΕ was taken from the supernatant (plasma) and precipitated by addition of 400 μΙ <cold ACN or methanol (absolute). The precipitated samples were frozen overnight at 20 ° C, then centrifuged again for 15 min at 3000 rpm before 150μΙ_ of the clear supernatant was removed for concentration determination. The analysis was carried out by an Agilent 1200 HPLC system with connected LCMS / 'MS detection. Calculation of the PK parameters (via PK calculation software, eg WinNonLin®): CLplasma: total plasma clearance of the test substance (in L * kg / h); CLblood: total blood clearance of the test substance (in L * kg / h), where (CLblood = CLplasma * Cp / Cb); Vss: Apparent volume of distribution in steady state (in L / kg); tl / 2: half-life within a specified interval (here: terminal tl / 2, in h); AUCnorm: Area under the plasma concentration time profile from time zero to infinity extrapolated divided by the body weight normalized dose (in kg * L / h); AUC (0-tn) norm: integrated area under the plasma concentration time profile from time zero to the last time a plasma concentration was measurable, divided by the body weight normalized dose (in kg * L / h); Cmax: maximum concentration of the test chemical in plasma (in μ ^ υ>; Cmax, norm: maximum concentration of test chemical in plasma divided by the kilogram weighted normalized dose (in kg / L); Cb / Cp: ratio of blood to plasma concentration distribution. Intragastric application:

The test substances were intragastrically administered as a bolus to fasting male rats or female dogs at a dose of 0.3-1 mg / kg by means of a probe. 150μΙ _^ blood samples taken via a catheter in the jugular vein (rat) or from the saphenous vein (dog) - at different times after administration were about 100th The blood samples were treated with lithium heparin as an anticoagulant and kept refrigerated until further processing (refrigerator). After centrifugation of the samples at 3000 rpm for 15 min an aliquot of ΙΟΟμΕ was removed from the supernatant (plasma) and cold by the addition of 400μΙ _^ ACN or methanol (absolute) like. The precipitated samples were frozen overnight at -20 ° C, then centrifuged for 15 min at 3000 rpm, before 150 μΕ of the clear supernatant was taken for concentration determination. The analysis was carried out by an Agilent 1200 HPLC system with connected LCMS / MS detection calculation of the PK parameters (via PK calculation software, eg WinNonLin®):

AUCnorm: Area under the plasma concentration time profile from time zero to infinity extrapolated divided by the body weight normalized dose (in kg * L / h); AUC (0-tn) norm: integrated area under the plasma concentration time profile from time zero to the last time a plasma concentration was measurable, divided by the body weight normalized dose (in kg * L / h); Cmax: maximum concentration of the test chemical in plasma (in μg / L); Cmax, norm: maximum concentration of test chemical in plasma divided by body weight normalized dose (in kg / 'L); tl / 2: half-life within a specified interval (here: terminal tl / 2, in h); Fobs%: observed oral bioavailability, AUC (0-tn) norm after i.g. Gabe divided by AUC (0-tn) norm to i.v. Administration, tmax: time, in addition, the maximum concentration of the test substance in the plasma is measured.

To calculate the relative bioavailability of a test substance, the AUC (0-tn) standard after administration of a microcrystalline substance suspension is divided by the AUC (0-tn) norm after administration of a substance solution.

3.7. in vivo efficacy

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 daily a defined dose of the test substance over a period of 3 weeks observed daily for mortality and body weight. The highest administered dose was defined as the MTD, during which no animal died during the treatment phase and there was no more than 10% decrease in body weight compared to baseline. To determine the antitumoral efficacy, xenograft models were then used in which the test substances were added to their MTD or, if this had not previously been determined, at the highest formulation that can be formulated in the standard vehicle and, in some cases, also at lower dosages. A prostate carcinoma model with hormone-independent human PC-3 cells in male nude mice (NMRI-nude (numu) mice, Taconic M & B A / S) was used primarily. For this purpose, 3 million tumor cells (suspended in medium + Matrigel) 1: 1, final 0.1 ml) were injected subcutaneously into the flank per animal. When the tumors reached 20-30 mm ^{2 of} tumor area, the mice were randomized into therapy groups and therapy started. Therapy was then followed by 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 130-160 mm ² . At this time, the experiment was stopped in all groups and the prepared tumors were weighed.

As a primary parameter of success, the T / C value was calculated based on the effect on the final tumor weight: mean value of the tumor weights in the treatment group divided by the mean value of the tumor weights in the vehicle group. 4, results:

4.1. enzyme assay

Table 2 summarizes the results with respect to the experimental and comparative examples from the enzyme assays. For accurate determination of selectivity, measurements of inhibition of ACCl and ACC2 (IC50 determinations) were compared in pairs using copies of the same series of dilutions in both assays. If either the ACCl or the ACC2 -IC50-B mood was not evaluated due to poor data quality, both measurements were left unconsidered and were not listed in the table. The selectivity of the inhibition of ACCl versus the inhibition of ACC2 was then determined as the average of the selectivities observed in the individual measurements.

Tab. 2

These data show that the compounds without trans-methoxy group have a significantly poorer selectivity against human ACC2. Some related structures of the prior art trans-methoxy group at position 8 of the azaspiro [4.5] dec-3-en-2-one ring system also strongly inhibit ACCl and are selective against ACC2. This feature of the prior art structures was unknown, unobvious, and could not be found without undue burden.

4.2 Zeü assays

Table 3 summarizes the results relating to the experimental and comparative examples from the cell assays.

Tab. 3

4.3 ACCl expression in tumor and normal tissues

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. 4.4 Octanol NVasscr partition coefficients (logP / D), membrane affinity (logMA) and protein binding to human serum albumin (K _d USA)

Table 4 shows the determined logP / D, logMA and Kd HSA values.

The evaluation of the HPLC peaks was carried out via Discovery Quant Analyze. The calculation of the results (logMA or binding constant to USA Kd) took place via an Excelworkbook provided by Sovicell. Tab. 4

Example logP / D pH7.4 logMA Kd HSA [μmol / l]

1-1 2.44 (2.4-2.5, n = 5) 1.78 (1.6-1.9, n = 5) 1.73 (1.32-2.16, n = 5)

V. l-a 2.51 (2.4-2.6, n = 7) 1.4 (0.9-1.7, n = 7) 4.84 (3.66-6.18, n = 7)

V.l -b 2.23 (1.8-2.5, n = 3) 2.38 (2.0-2.7, n = 4) 3.07 (2.38-2.8, n = 3)

V. l-c 1.6 (n = 1) 2.1 (n = 1) 6.9 (n = 1)

1 -2 2.45 (2.4-2.5, n = 2) 1.8 (n = 1) 1.79 (n = 1)

V.2-a 2.52 (2.5-2.6, n = 8) 1.67 (1.2-1.9, n = 6) 2.8 (2.42-3.67, n = 6)

V.2-b 2.55 (2.4-2.7, n = 2) 2.55 (2.4-2.7, n = 2) 1.43 (1.16-1.7, n = 2)

V.2 1.3 (n = 1) 2.3 (n = 1) 1.38 (n = 1)

1-3 2.3 (n = 1) <1.0 (n = 1) 4.8 (n = 1)

V.3-a 2.51 (2.4-2.6, n = 7) 1.4 (0.9-1.7, n = 7) 4.84 (3.66-6.18, n = 7)

V.3-b 2.5 (2.5, n = 4) 2.08 (1.9-2.3, n = 4) 4.2 (3.41-4.89, n = 4)

1-4 2.38 (2.3-2.4, n = 5) 1.14 (0.9-1.3, n = 5) 2.85 (1.96-3.4, n = 5)

V.4-a 2.52 (2.5-2.6, n = 8) 1.67 (1.2-1.9, n = 6) 2.8 (2.42-3.67, n = 6)

V.4-b 2.57 (2.5-2.6, n = 3) 2.13 (2.1-2.2, n = 3) 3.64 (2.48-5.18, n = 3) 4.5 Plasma proteinosis by equilibrium dialysis

Table 5 shows the equilibrium analysis of binding to human, murine, and rat plasma proteins.

Tab.5

Example fu [%] (human) fu [%] (mouse) fu [%] (rat) fu (mouse) / fu (human)

0.2 0.82

i-i - 4

(0.18-0.23, n = 2) (0.75-0.88, n = 2)

0.38 2.49 0.23

V. l-a 7

(0.33-0.44, n = 2) (2.35-2.62, n = 2) (n = l)

0.07 2.41

V.l-b - 34

(n = i) (n = 1)

V. l-c - - - -

0.26 1.4

1-2 - 5

(n = 1) (1.29-1.51, n = 2)

0.39 2.8 0.23

V.2-a 7

(n = 1) (n = 1) (0.22-0.25, n = 2)

0.05 1.9

V.2-b - 39

(n = 1) (n = 1)

V.2 - - - -

0.41 3.8

1-3 - 9

(0.40-0.42, n = 2) (3.57-4.02, n = 2)

0.38 2.49 0.23

V.3-a 7

(0.33-0.44, n = 2) (2.35-2.62, n = 2) (n = l)

0.36 10.87 7.79

V.3-b 30

(0.35-0.38, n = 2) (10.4-11.3, n = 2) 7.25-8.33 (n = 2)

0.37 2.17 0.21

1 -4 6

(0.37-0.38, n = 2) (2.06-2.28, n = 2) (n = 2)

0.39 2.8 0.23

V.4-a 7

(n = i) (n = 1) (0.22-0.25, n = 2)

1.41 1.76 0.11

V.4-b 1

(n = 1) (n = 1) (n = 1)

4.6 Pharmacokinetic parameters

Pharmacokinetic parameters in the rat. Table 6 shows the pharmacokinetic parameters from the rat.

Tab. 6

4.7 in vivo efficacy

Maximai tolerable dose (MTD) in the mouse

Examples 1-1, V. l-a / V.3-a, V.2-a V.4-a and 1 -4 were administered to female nude mice (NMRI nu / 'nu):

Dose: s. Tab. 7

Application type: per os

Vehicle: PEG400 / ethanol / solutol HS15 (70/5/25, v / v / v)

(Solutol HS15: polyoxyethylene ester of 12-hydroxy-steric acid) Application volume: 10 ml / kg

Scheme: s. Tab. 7 The treatment phase was followed by a 21-day observation period. The resulting deaths and the effect on body weight are summarized in Table 7.

Tab. 7

Thus, the MTD for a 21-day treatment is once daily for the examples

1-1: whether it is 100 mg / kg

V. l-a / V.3-a: above 100 mg / kg

V.2-a / V.4-a: above 80 mg / kg

1-4: above 100 mg / kg

As a result, the MTD for a 21-day treatment with twice daily administration of Example 1-4 is above 100 mg / kg. In vivo efficacy in the mouse PC3 xenograft model

Examples 1-1, V.1-a / V.3-a, i-2, V.2-a / V.4-a and 1-4 were subsequently described in PC-3

Prostate carcinoma xenograft model of male nude mice (M R! Nu / 'nu) applied:

Dose: s. Tab. 8 Application type: per os

Vehicle: PEG400 / ethanol / solutol HS15 (70/5/25, v / v / v)

Application volume: 10ml / kg

Scheme: s. Tab. 8

Number of mice: s. Tab. Tab. 8

Therapeutic efficacy was defined as T / C of <= 0.50. Good compatibility was defined as maximum body weight change of <= minus 10% and 100%

Survival of the experimental animals.

As a result, Example 1-1 showed therapeutic efficacy and good tolerability at 80 mg / kg and twice daily dosing.

As a result, Example V.i-a / V.3-a showed therapeutic efficacy and good tolerability at 100 mg / kg and once daily, whereas 100 mg kg and twice daily administration showed therapeutic efficacy but no good tolerability.

As a result, Example 1 -2 showed therapeutic efficacy and good tolerability at 40 mg / kg and 80 mg / kg (twice daily).

Accordingly, Example V.2-a / V.4-a showed therapeutic efficacy and good tolerability at 80 mg kg once daily, while no therapeutic efficacy was given at 40 mg / kg and once daily, and no good at 80 mg and twice daily Compatibility showed.

Thus, at 80 mg / kg and twice daily, Example 1-4 showed therapeutic efficacy and good tolerability. Prediction of human pharmacokinetic parameters and human therapeutic dose

The prediction of the human pharmacokinetic (PK) parameters (Table 9) was based on the in vivo PK parameters, which were collected for the rat (single species scaling), taking into account species differences in the free fraction (fu) in the plasma. The effective AUC (area under curve) was determined based on the measured plasma concentration time profile when tested in vivo in the mouse PC3 mouse model (nu / 'nu mouse). The therapeutic human dose was determined by means of predicted human clearance (CL), the assumption of 100% bioavailability (F = 1) and the effective AUC in the animal model according to the following formula:

Dose = A UC X x- ^.

f ^U

Tab. 9

ther. = therapeutic

calculated = calculated

prev. = predicted (fu-corrected) Characters:

Fig. 1: ACCl expression in tumor and corresponding normal tissue

Claims

Patcntansprüche

1. Compounds according to formula (I)

in the

R ^{l is} a trifluoromethyl or methoxymethyl group and

R ^{2 is} hydrogen or fluorine,

and their salts.

2. Connections

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

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

3. A compound according to claim 1 or 2 for use as a medicament.

4. A compound according to claim 3 for the prophylaxis and / or therapy of

Tumor diseases.

5. A compound according to claim 4 for the prophylaxis and / or therapy of breast cancers, colorectal carcinomas, prostate carcinomas or non-small cell bronchial carcinomas.

6. A compound according to claim 5 for the prophylaxis and / or therapy of hormone receptor-positive breast carcinoma or androgen receptor-negative prostate cancer.

7. Use of a compound of formula (I) according to claim 1 for the preparation of a

drug

Use of a compound of the formula (I) according to Claim 7 for the preparation of a medicament for the prophylaxis and / or therapy of tumor diseases.

9. Use according to claim 8 for the manufacture of a medicament for the prophylaxis and / or therapy of breast, colorectal, prostate or non-small cell lung carcinoma.

10. Use according to claim 9 for the manufacture of a medicament for the prophylaxis and / or therapy of hormone receptor-positive breast carcinomas or androgen receptor-negative prostate carcinomas. 11. Use of a compound of formula (I) according to claim 1 for the prophylaxis and / or therapy of diseases of humans or other mammals.

Use according to claim 11 for the prophylaxis and / or therapy

Tumor diseases.

13. Use according to claim 12 for the prophylaxis and / or therapy of

Breast cancer, colorectal carcinoma, prostate cancer or non-small cell lung carcinoma.

Use according to claim 13 for the prophylaxis and / or therapy of hormone receptor positive breast carcinomas or androgen receptor negative prostate carcinomas.

A compound of formula (I) according to claim 1 in combination with another

Active ingredient.

16. A pharmaceutical formulation comprising a compound of the formula (I) according to

Claim 1.