HK1202550B - Furo [3, 2 - b] - and thieno [3, 2 - b] pyridine derivatives as tbk1 and ikk inhibitors - Google Patents

Description

Furo [3,2-b ] -and thieno [3,2-b ] pyridine derivatives as TBK1 and IKK inhibitors

Background

The object of the present invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to pyridine compounds capable of inhibiting one or more kinases. The compounds find use in the treatment of a variety of disorders including cancer, septic shock, Primary Open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/or neurodegenerative diseases such as alzheimer's disease.

The present invention relates to compounds and to the use of compounds for inhibiting, controlling and/or modulating signal transduction of kinases, in particular receptor tyrosine kinases, the invention further relates to pharmaceutical compositions comprising these compounds and to the use of said compounds for the treatment of kinase-induced diseases.

As protein kinases regulate almost every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are interesting targets for therapeutic intervention in various disease states. Such as, for example, cell cycle regulation and angiogenesis, where protein kinases play a key role in cellular processes associated with a number of disease conditions, such as, but not limited to, cancer, inflammatory diseases, aberrant angiogenesis and diseases associated therewith, atherosclerosis, macular degeneration, diabetes, obesity and pain.

In particular, the invention relates to compounds and to the use of compounds that function in inhibiting, controlling and/or modulating signal transduction through TBK1 and IKK.

One of the main mechanisms by which cell regulation is achieved is through extracellular signal transduction through the membrane, which in turn regulates biochemical pathways within the cell. Protein phosphorylation represents a process by which intracellular signals are propagated from molecule to molecule, ultimately leading to a cellular response. These signal transduction cascades are highly regulated and often overlap, as evidenced by the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly at serine, threonine or tyrosine residues, and protein kinases have therefore been classified according to the specificity of their phosphorylation sites, i.e., serine/threonine kinases and tyrosine kinases. Because phosphorylation is an ubiquitous process within such a cell and because cellular phenotype is largely influenced by the activity of these pathways, it is presently believed that many disease states and/or diseases are attributable to aberrant activation or functional mutations in the molecular components of the kinase cascade. Therefore, considerable attention has been devoted to the characterization of these proteins and compounds capable of modulating their activity (for a review see: Weinstein-Oppenheimer et al, Pharma. &. Therap., 2000, 88, 229-279).

IKK and TBK1 are serine/threonine kinases that are highly homologous to each other and to other IkB kinases. Both kinases play an integral role in the innate immune system. Double stranded RNA viruses are recognized by Toll-like receptors 3 and 4 and RNA helicases RIG-I and MDA-5 and cause activation of the TRIF-TBK1/IKKE-IRF3 signaling cascade, which leads to a type I interferon response.

In 2007, Boehm et al described IKK as a novel oncogene of breast cancer [ j.s. Boehm et al, Cell 129, 1065-1079, 2007 ]. 354 kinases were studied for their ability to recapitulate the Ras-transforming phenotype along with the activated form of the MAPK kinase Mek. IKK is identified herein as a cooperative oncogene. In addition, the authors could show that IKK is amplified and overexpressed in many breast cancer cell lines and tumor samples. Reduction of gene expression by means of RNA interference in breast cancer cells induces apoptosis and attenuates its proliferation. Eddy et al obtained similar results in 2005, which underscores the importance of IKK in breast Cancer disease [ S.F.Eddy et al, Cancer Res. 2005; 65 (24), 11375-.

The protocarcinogenic (protumogenic) effect of TBK1 was first reported in 2006. In the screening of a gene bank containing 251,000 cdnas, korerher et al identified three genes precisely: TRIF, TBK1 and IRF3, which are commonly involved in innate immune defense as proangiogenic factors (C.Korherr et al, PNAS, 103, 4240-. In 2006, Chien et al [ Y.Chien et al, Cell 127, 157-170, 2006] published that TBK 1-/-cells could only be transformed to a limited extent with oncogenic Ras, suggesting the involvement of TBK1 in Ras-mediated transformation. In addition, they could indicate that RNAi-mediated knockdown of TBK1 triggers apoptosis in MCF-7 and Panc-1 cells. Barbie et al recently published that TBKl has essential importance in numerous cancer cell lines with mutant K-Ras, suggesting that intervention of TBK1 may be of therapeutic importance in the corresponding tumor [ D.A. Barbie et al, Nature Letters 1-5,2009 ].

Diseases caused by protein kinases are characterized by abnormal activity or hyperactivity of such protein kinases. Aberrant activity is related to any of the following: (1) expression in cells that do not normally express these protein kinases; (2) increased kinase expression, leading to undesirable cell proliferation such as cancer; (3) increased kinase activity, leading to undesired cell proliferation, such as cancer, and/or to hyperactivity of the corresponding protein kinase. Hyperactivity involves the amplification of a gene encoding a certain protein kinase, or involves the generation of a level of activity that may be associated with a cell proliferative disorder (i.e., the severity of one or more symptoms of a cell proliferative disorder increases with increasing levels of kinase). The bioavailability of a protein kinase may also be affected by the presence or absence of a set of binding proteins for such a kinase.

IKK and TBK1 are highly homologous Ser/Thr kinases that are critically involved in the innate immune response by inducing type 1 interferons and other cytokines. These kinases are stimulated in response to viral/bacterial infections. The immune response to viral and bacterial infections involves the binding of antigens such as bacterial Lipopolysaccharide (LPS), viral double-stranded rns (dsrna) to Toll-like receptors, followed by activation of the TBK1 pathway. Activated TBK1 and IKK phosphorylate IRF3 and IRF7, which trigger dimerization and nuclear translocation of those interferon-regulated transcription factors, ultimately inducing a signaling cascade leading to IFN production.

Recently, IKK and TBK1 have also been implicated in cancer. IKK has been shown to cooperate with activated MEK to transform human cells. In addition, IKK is frequently amplified/overexpressed in breast cancer cell lines and patient-derived tumors. TBK1 is induced under hypoxic conditions and expressed at significant levels in many solid tumors.

In addition, TBK1 is required to support oncogene Ras conversion, whereas TBK1 kinase activity is elevated in transformed cells and is essential for their survival in culture. Similarly, TBK1 and NF-kB signaling have been found to be essential in KRAS mutant tumors. They have identified TBK1 as a synthetic lethal partner of the oncogene KRAS.

The literature:

y. -H.Ou et al, Molecular Cell 41, 458-470, 2011;

D.A. Barbie et al, nature, 1-5, 2009.

Accordingly, a compound according to the invention, or a pharmaceutically acceptable salt thereof, is administered to treat cancer, including solid cancers, for example, such as carcinomas (e.g., lung, pancreatic, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia), or adenomas (e.g., villous colon adenomas).

Tumors also include monocytic leukemia, brain cancer, genitourinary cancer, lymphatic cancer, stomach cancer, laryngeal and lung cancer (including lung adenocarcinoma and small cell lung cancer), pancreatic cancer and/or breast cancer.

The compounds are also suitable for the treatment of immunodeficiency caused by HIV-1 (human immunodeficiency virus type 1).

Cancer-like hyperproliferative diseases are considered to be brain cancer, lung cancer, squamous epithelial cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia. In particular, cancer-like cell growth is a disease that represents a target of the present invention. The present invention therefore relates to compounds according to the invention for use as medicaments and/or pharmaceutical active ingredients in the treatment and/or prophylaxis of said diseases, and to the use of compounds according to the invention for the preparation of medicaments for the treatment and/or prophylaxis of said diseases, and to methods for the treatment of said diseases, which methods comprise administering one or more compounds according to the invention to a patient in need of such administration.

It can be shown that the compounds according to the invention have an antiproliferative effect. The compounds according to the invention are administered to a patient suffering from a hyperproliferative disease, for example to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative diseases, to inhibit transplant rejection or neurological damage due to tissue repair, and the like. The compounds of the invention are suitable for prophylactic or therapeutic purposes. The term "treatment" as used herein is used to refer to both prevention of disease and treatment of an already existing condition. Prevention of proliferation/viability is achieved by administering a compound according to the invention (e.g. to arrest tumour growth) before overt disease has occurred. Alternatively, the compounds are useful for treating an ongoing disease by stabilizing or ameliorating the clinical symptoms of the patient.

The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, which provide models for the treatment of human diseases.

The susceptibility of a particular cell to treatment with a compound according to the invention may be determined by in vitro testing. Typically, cell cultures are incubated with various concentrations of a compound according to the invention for a period of time sufficient to allow the agent to induce cell death or inhibit cell proliferation, cell viability or migration, typically between about I hours and I weeks. In vitro testing can be performed using cultured cells from a biopsy sample. The amount of cells remaining after treatment was then determined. The dosage will vary depending upon the particular compound employed, the particular disease, the patient's condition, and the like. The therapeutic dose is generally sufficient to significantly reduce the undesirable cell population in the target tissue while maintaining the viability of the patient. Treatment is typically continued until a significant reduction is produced, for example at least about 50% reduction in cell load, and treatment may be continued until substantially no more undesired cells are detected in the body.

There are many diseases associated with dysregulation of cell proliferation and cell death (apoptosis). Disorders of interest include, but are not limited to, those as follows. The compounds according to the invention are suitable for the treatment of various conditions in which smooth muscle cells and/or inflammatory cells proliferate and/or migrate into the vascular lining, resulting in a restricted blood flow through the vessel (e.g. in the case of neointimal occlusive lesions). Occlusive graft vascular diseases of interest include atherosclerosis, post-transplant coronary vascular disease, vein graft stenosis, restenosis repaired by peri-anastomosis (restenosis) restenosis following angioplasty or stent placement, and the like.

In addition, the compounds according to the invention may be used in certain existing cancer chemotherapies and radiation therapies to obtain a synergistic or synergistic effect and/or to restore the efficacy of certain existing cancer chemotherapies and radiation therapies.

The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from manners, means, techniques and procedures known to, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.

The term "administering" as used herein refers to a method of bringing together a compound of the invention and a target kinase in such a way that the compound can affect the enzymatic activity of the kinase either directly (i.e., by interacting with the kinase itself) or indirectly (i.e., by interacting with another molecule upon which the catalytic activity of the kinase depends). As used herein, administration can be accomplished in vitro (i.e., in a test tube) or in vivo (i.e., in a cell or tissue of a living organism).

As used herein, the term "treating" includes eliminating, substantially inhibiting, slowing or reversing the progression of the disease or disorder, substantially alleviating the clinical symptoms of the disease or disorder or substantially preventing the appearance of the clinical symptoms of the disease or disorder.

Herein, the term "prevention" refers to a method of protecting an organism from acquiring a condition or disease from the outset.

For any compound used in the present invention, a therapeutically effective amount, also referred to herein as a therapeutically effective dose, can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes IC50 or IC100 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial doses can also be estimated from in vivo data. Using these initial guidelines, one of ordinary skill in the art can determine an effective dose for a human.

Moreover, toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by assaying LD50 and ED 50. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD50 and ED 50. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate dosage ranges that are non-toxic for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that include ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The precise formulation, route of administration and dosage can be selected by The individual physician taking into account The condition of The patient (see, e.g., Fingl et al, 1975, in The pharmacological basis of Therapeutics, Chapter 1, page 1).

The dosage and interval of administration can be adjusted individually to provide plasma levels of the active compound sufficient to maintain a therapeutic effect. Typical patient dosages for oral administration will range from about 50-2000 mg/kg/day, typically about 100-1000 mg/kg/day, preferably about 150-700 mg/kg/day and most preferably about 250-500 mg/kg/day.

Preferably, therapeutically effective serum levels will be obtained by administering multiple doses per day. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration. One skilled in the art will be able to optimize therapeutically effective topical dosages without undue experimentation.

Preferred diseases or conditions for which the compounds described herein are useful for prevention, treatment and/or study are cell proliferative disorders, especially cancers such as, but not limited to, papillomas, blastogliomas (blastogliomas), kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, skin cancer, liver cancer, bladder cancer, breast cancer, lung cancer, uterine cancer, prostate cancer, testicular cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hodgkin's disease and Burkitt's disease.

Prior Art

Other heterocyclic derivatives and their use as antitumor agents have been described in WO 2011/046970 a1 and WO 2007/129044.

The use of other pyridine and pyrazine derivatives in the treatment of cancer has been described in WO 2009/053737, while the use in the treatment of other diseases has been described in WO 2004/055005.

Other heterocyclic derivatives have been disclosed in WO 2009/122180 as IKK inhibitors.

Pyrrolopyrimidines have been disclosed in WO 2010/100431 as IKK and TBK1 inhibitors.

Pyrimidine derivatives have been disclosed in WO 2009/030890 as IKK and TBK1 inhibitors.

Summary of The Invention

The invention relates to compounds of formula I

Wherein

X represents O or S, and X represents O or S,

R¹is represented by O (CYY)_nHet¹、NY(CYY)_nHet¹、O(CYY)_nCyc or NY (CYY)_nCyc，

R²Represents H, Hal, A, OY, NYY, O (CYY)_mNYY、O(CYY)_nHet²、NY(CYY)_mNYY、NY(CYY)_nHet²Ar or Het²，

Het¹Represents a dihydropyrrolyl group, a pyrrolidinyl group, a tetrahydroimidazolyl group, a dihydropyrazolyl group, a tetrahydropyranyl group, a dihydropyridinyl group, a tetrahydropyridinyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1, 3] or]Dioxolanyl, 2-oxa-6-aza-spiro [3.3]Heptenyl, azepanyl, diazepanyl, tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, chromanyl, or piperazinyl, each of which is unsubstituted or mono-or di-substituted with: hal, CN, A, COOA, OY, S (O)_nA、S(O)_nAr and/or = O (carbonyl oxygen),

Het²represents a monocyclic, bicyclic or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri-, tetra-or pentasubstituted by: hal, A, (CYY)_p-OY、-(CYY)_p-NYY、(CYY)_p-Het¹、NO₂、CN、(CYY)_p-COOY、CO-NYY、NY-COA、NY-SO₂A、SO₂-NYY、S(O)_nA、-CO-Het¹、O(CYY)_p-NYY、-O(CYY)_p-Het¹、NH-COOA、NH-CO-NYY、NH-COO-(CYY)_p-NYY、NH-COO-(CYY)_p-Het¹、NH-CO-NH-(CYY)_p-NYY、NH-CO-NH(CYY)_p-Het¹、OCO-NH-(CYY)_p-NYY、OCO-NH-(CYY)_p-Het¹CHO, COA, = S, = NY and/or = O,

ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di-or tri-substituted with: hal, A, (CYY)_p-OY、(CYY)_p-NYY、(CYY)_p-Het¹、NO₂、CN、(CYY)_p-COOY、CO(CYY)_pNH₂、CO-NYA、CONY(CYY)_mNYCOOA、NY-COA、NY-SO₂A、SO₂-NYY、S(O)_nA、CO-Het¹、O(CYY)_p-NYY、O(CYY)_p-Het¹、NH-COOA、NH-CO-NYY、NH-COO-(CYY)_p-NYY、NH-COO-(CYY)_p-Het¹、 NH-CO-NH-(CYY)_p-NYY、NH-CO-NH(CYY)_p-Het¹、OCO-NH-(CYY)_p-NYY、OCO-NH-(CYY)_p-Het¹、CHO、CONY(CYY)_pHet¹、CONH(CYY)_pThe combination of NHCOA and/or COA,

y represents H or an alkyl group having 1,2,3 or 4C atoms,

a represents unbranched or branched alkyl having 1 to 10C atoms in which 1 to 7H atoms may be replaced by F and/or Cl and/or one or two non-adjacent CH and/or CH₂The groups may be replaced by O and/or N,

cyc denotes cycloalkyl having 3 to 7C atoms which is unsubstituted or monosubstituted by Hal, CN or A,

hal represents F, Cl, Br or I,

n represents 0,1 or 2,

m represents 1,2 or 3,

p represents 0,1, 2,3 or4,

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

The invention also relates to optically active forms (stereoisomers), salts, enantiomers, racemates, diastereomers and hydrates and solvates of these compounds. By the term solvate of a compound is meant that molecules of the inert solvent formed due to the attractive forces of the molecules of the inert solvent and the compound are adducted to the compound. Solvates are, for example, mono-or dihydrate or alkoxides.

Of course, the invention also relates to solvates of the salts.

The term pharmaceutically acceptable derivatives is taken to mean, for example, salts of the compounds according to the invention and also known as prodrug compounds.

By the term prodrug derivative is meant a compound of formula I which has been modified by e.g. alkyl or acyl groups, sugars or oligopeptides and which rapidly cleaves in vivo to form effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in int.j. Pharm.11561-67 (1995).

The expression "effective amount" means that amount of a pharmaceutical or pharmaceutically active ingredient that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought or desired by, for example, a researcher or physician.

Furthermore, the expression "therapeutically effective amount" denotes an amount with the following results compared to a corresponding subject not receiving this amount:

improving the treatment, curing, preventing or eliminating a disease, syndrome, condition, affliction, disorder or side effect, or also slowing the progression of a disease, condition or disorder.

The expression "therapeutically effective amount" also encompasses an amount effective to enhance normal physiological function.

The invention also relates to the use of mixtures of compounds of formula I, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1: 1000.

These are particularly preferred mixtures of stereoisomeric compounds.

The present invention relates to compounds of the formula I and salts thereof and to a process for the preparation of compounds of the formula I according to claims 1 to 12 and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterized in that

a) Reacting a compound of formula II

Wherein Q represents Cl, Br or I,

x and R²Having the meaning specified in claim 1,

with compounds of the formula III

R¹-L　　　　III

Wherein R is¹Have the meaning specified in claim 1 and

l represents a boronic acid or boronic ester group,

or

b) The group R being obtained by conversion of the COOH group into an amide group²Conversion to another group R²，

And/or converting a base or acid of formula I into one of its salts.

In this context, the radical R¹、R²And X have the meanings indicated for formula I, unless explicitly stated otherwise.

A represents an alkyl group which is unbranched (linear) or branched and has 1,2,3,4, 5,6, 7,8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1,2-, 1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl, with a typical example being trifluoromethyl.

A very particularly preferably represents alkyl having 1,2,3,4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1, 1-trifluoroethyl.

One or two CH and/or CH in A₂The groups may also be replaced by N, O or S atoms. A therefore also represents, for example, 2-methoxyethyl.

More preferably, A represents an unbranched or branched alkyl group having 1 to 10C atoms in which 1 to 7H atoms may be replaced by F and/or one or two non-adjacent CH and/or CH₂The groups may be replaced by O and/or N.

Ar denotes, for example, phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-trifluoromethylphenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p-methoxyphenyl, o-, m-or p-methylsulfonylphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p-methylaminophenyl, o-, m-or p-dimethylaminophenyl, o-, m-or p-aminosulfonylphenyl, o-, m-or p-aminocarbonylphenyl, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, m-or p-bromophenylphenyl, M-or p-acetylphenyl, o-, m-or p-formylphenyl, o-, m-or p-cyanophenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar particularly preferably represents phenyl, which is mono-, di-or trisubstituted by: (CYY)_p-OY、(CYY)_p-NYY、(CYY)_p-Het¹、(CYY)_p-COOY、CO(CYY)_pNH₂、CO-NYA、CONY(CYY)_mNYCOOA、CONY(CYY)_pHet¹、CONH(CYY)_pNHCOA and/or CO-Het¹。

Het¹Preferably represents dihydropyrrolyl, pyrrolidinyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, [1, 3]]Dioxolanyl, 2-oxa-6-aza-spiro [3.3]Heptylalkyl, azepanyl, diazepanyl, tetrahydrofuranyl, pyridinyl, chromanyl, or piperazinyl, each of which is unsubstituted or mono-or di-substituted with: hal, CN, A, COOA, OY, S (O)_nA、S(O)_nAr and/or = O (carbonyl oxygen).

Irrespective of the additional substituents, Het²Preferably represents, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, more preferably 1,2, 3-triazol-1-, -4-or-5-yl, 1,2, 4-triazol-1-, -, -3-or 5-yl, 1-or 5-tetrazolyl, 1,2, 3-oxadiazol-4-or-5-yl, 1,2, 4-oxadiazol-3-or-5-yl, 1,3, 4-thiadiazol-2-or-5-yl, 1,2, 4-thiadiazol-3-or-5-yl, 1,2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, indazolyl, oxazolyl, oxazol, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, or a pharmaceutically acceptable salt thereof, 7-or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, more preferablyDi-1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl, 2,1, 3-benzothiadiazol-4-, -5-yl or 2,1, 3-benzooxadiazol-5-yl, azabicyclo [3.2.1]Octyl or dibenzofuranyl.

The heterocyclic group may also be partially or fully hydrogenated.

Irrespective of the additional substituents, Het²Thus, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1,2,3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4-or 5-yl, hexahydro-1-, -3-or 4-pyridazinyl, hexahydro-1-, -2-, -4-or 5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1,2,3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or 8-quinolinyl, 1,2,3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-oxazinyl, more preferably 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or 6-yl, 2,3- (2-oxomethylenedioxy) phenyl or also 3, 4-dihydro-2H-1, 5-benzodioxepin-6-or-7-yl, more preferably 2, 3-dihydrobenzofuranyl, 2, 3-dihydro-2-oxofuranyl, 3, 4-dihydro-2-oxo-1H-quinazolinyl, 2, 3-dihydrobenzoxazolyl, 2-oxo-2, 3-dihydrobenzoxazolyl, 2, 3-dihydrobenzimidazolyl, 1, 3-dihydroindole, 2-oxo-1, 3-dihydroindole or 2-oxo-2, 3-dihydrobenzimidazolyl.

Het²Preferably furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, 2, 3-dihydro-1H-benzimidazolyl, indazolyl, quinolinyl, 1, 3-benzodioxolyl, benzothienyl, benzofuranyl or imidazopyridinyl, each of which is unsubstituted or mono-or disubstituted by: A. s (O)_nA、(CYY)_p-Het¹And/or = O.

R¹Particularly preferably O (CYY)_nHet¹。

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

Throughout the present invention, all groups appearing more than once may be the same or different, i.e. independent of each other.

The compounds of formula I may have one or more chiral centers and may therefore occur in a variety of stereoisomeric forms. Formula I encompasses all of these forms.

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings specified above. Some preferred groups of the compounds can be represented by the following sub-formulae Ia to Ic, which conform to formula I, and in which the groups not specified in more detail have the meaning indicated for formula I, but in which

In Ia, Het²Represents furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, 2, 3-dihydro-1H-benzimidazolyl, indazolyl, quinolinyl, 1, 3-benzodioxolyl, benzothienyl, benzofuryl or imidazopyridinyl, each of which is unsubstituted or substituted by A, S (O)_nA、(CYY)_p-Het¹And/or = O mono-or di-substituted;

in Ib, Ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: (CYY)_p-OY、(CYY)_p-NYY、(CYY)_p-Het¹、(CYY)_p-COOY、CO(CYY)_pNH₂、CO-NYA、CONY(CYY)_mNYCOOA、CONY(CYY)_pHet¹、CONH(CYY)_pNHCOA and/or CO-Het¹；

In Ic, X represents O or S,

R¹is represented by O (CYY)_nHet¹、NY(CYY)_nHet¹、O(CYY)_nCyc or NY (CYY)_nCyc，

R²Represents Ar or Het²，

Het¹Represents a dihydropyrrolyl group, a pyrrolidinyl group, a tetrahydroimidazolyl group, a dihydropyrazolyl group, a tetrahydropyranyl group, a dihydropyridinyl group, a tetrahydropyridinyl group, a piperidyl group, a morpholinyl group, a hexahydropyridazinyl group, a hexahydropyrimidyl group, [1, 3] or]Dioxolanyl, 2-oxa-6-aza-spiro [3.3]Heptylalkyl, azepanyl, diazepanyl, tetrahydrofuranyl, pyridinyl, chromanyl, or piperazinyl, each of which is unsubstituted or mono-or di-substituted with: hal, CN, A, COOA, OY, S (O)_nA、S(O)_nAr and/or = O (carbonyl oxygen),

Het²represents furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, 2, 3-dihydro-1H-benzimidazolyl, indazolyl, quinolinyl, 1, 3-benzodioxolyl, benzothienyl, benzofuryl or imidazopyridinyl, each of which is unsubstituted or mono-or disubstituted by: A. s (O)_nA、(CYY)_p-Het¹And/or = O and/or is,

ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted by: (CYY)_p-OY、(CYY)_p-NYY、(CYY)_p-Het¹、(CYY)_p-COOY、CO(CYY)_pNH₂、CO-NYA、CONY(CYY)_mNYCOOA、CONY(CYY)_pHet¹、CONH(CYY)_pNHCOA and/or CO-Het¹，

Y represents H or an alkyl group having 1,2,3 or 4C atoms,

a represents unbranched or branched alkyl having 1 to 10C atoms in which 1 to 7H atoms may be replaced by F and/or Cl, and/or one or two non-adjacent CH and/or CH₂The groups may be replaced by O and/or N,

cyc denotes cycloalkyl having 3 to 7C atoms which is unsubstituted or monosubstituted by Hal, CN or A,

hal represents F, Cl, Br or I,

n represents 0,1 or 2,

m represents 1,2 or 3,

p represents 0,1, 2,3 or 4;

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

Furthermore, the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard textbooks, for example Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), in order to carry out precisely under the reaction conditions known and suitable for the reaction in question. Also known per se variants not mentioned in more detail herein can be used here.

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III.

Compounds of formula II and III are well known. However, if they are new, they can be prepared by methods known per se.

The reaction is carried out under standard conditions known to the skilled person as the Suzuki reaction.

In the compounds of formula III, L preferably represents

Or。

Depending on the conditions used, the reaction time is between a few minutes and 14 days and the reaction temperature is between about-30 ° and 140 °, generally between 0 ° and 110 °, in particular between about 60 ° and about 110 °.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

Ethanol, toluene, methoxyethane (ethoxyethane), acetonitrile, dichloromethane, DMF, dioxane and/or water are particularly preferred.

Furthermore, the compounds of the formula I may preferably be asThe following were obtained: the group R is converted into an amide group by conversion of the COOH group into an amide group under standard conditions known to the skilled worker²Conversion to another group R²。

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

The standard method for ether (e.g. methyl ether) cleavage is to use boron tribromide.

The cleavage of the hydrogenolytically removable groups, such as benzyl ethers, can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature between about 0 and 100 ° and a pressure between about 1 and 200 bar, preferably between 20 and 30 ° and 1 and 10 bar.

The ester can be saponified, for example, with acetic acid or with NaOH or KOH in water, water/THF or water/dioxane at a temperature between 0 and 100 °.

Alkylation at nitrogen is carried out under standard conditions, as known to those skilled in the art.

Furthermore, the compounds of formula I can be obtained by solvolysis, in particular hydrolysis or hydrogenolysis, liberating them from their functional derivatives.

Preferred starting materials for solvolysis or hydrogenolysis are those which contain the corresponding protected amino and/or hydroxyl group instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, for example those which conform to formula I but contain a NHR 'group (wherein R' represents an amino-protecting group, e.g. BOC or CBZ) instead of NH₂Those of the group.

Preference is furthermore given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to formula I but contain RO-phenyl (where R "denotes a hydroxyl-protecting group) instead of hydroxyphenyl.

It is also possible for a plurality of identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from each other, they can be selectively dissociated in many cases.

The expression "amino-protecting group" is known in general terms and relates to a group which is suitable for protecting (blocking) an amino group from a chemical reaction, but which can be easily removed after the desired chemical reaction has taken place elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkyloxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not particularly critical; however, preference is given to those protecting groups having from 1 to 20, in particular from 1 to 8, carbon atoms. The expression "acyl" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl, tolyl; aryloxy alkanoyl such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl groups, such as Mtr, Pbf, Pmc. Preferred amino-protecting groups are BOC and Mtr, in addition to CBZ, Fmoc, benzyl and acetyl.

The expression "hydroxy-protecting group" is also known in general terms and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which can be easily removed after the desired chemical reaction has been completed elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore alkyl groups. The nature and size of the hydroxy-protecting groups are not critical, as they are removed again after the desired chemical reaction or reaction sequence; preference is given to radicals having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of hydroxy-protecting groups are, inter alia, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The COOH groups in aspartic and glutamic acids are preferably protected in the form of their tert-butyl esters (e.g., Asp (OBut)).

Depending on the protecting group used, the compounds of the formula (I) are liberated from their functional derivatives, for example using strong acids, advantageously TFA or perchloric acid, but also other strong inorganic acids, for example hydrochloric acid or sulfuric acid, strong organic carboxylic acids, for example trichloroacetic acid, or sulfonic acids, for example benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid; ethers such as tetrahydrofuran or dioxane; amides, such as DMF; halogenated hydrocarbons such as dichloromethane; also included are alcohols, such as methanol, ethanol or isopropanol, and water. Furthermore, mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without addition of further solvent, perchloric acid preferably being used as a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperature for the decomposition is advantageously between about 0 and about 50 c, preferably between 15 and 30 c (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can be separated, for example, preferably with TFA in dichloromethane or with about 3-5N HCl in dioxane at 15-30 deg.C, and the FMOC group can be cleaved with dimethylamine, diethylamine or piperidine in about 5-50% solution in DMF at 15-30 deg.C.

The hydrogenolytically removable protecting group (e.g. CBZ or benzyl) can be isolated, for example, by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst, such as palladium, advantageously on a support such as carbon). Suitable solvents here are those indicated above, in particular, for example alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature between about 0 and 100 ℃ and at a pressure between about 1 and 200 bar, preferably between 20-30 ℃ and 1-10 bar. Hydrogenolysis of the CBZ group, for example, on 5-10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 deg.C works well.

Pharmaceutically acceptable salts and other forms

The compounds according to the invention can be used in their final non-salt form. In another aspect, the invention also includes the use of these compounds in the form of their pharmaceutically acceptable salts, which salts can be derived from various organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared in large part by conventional methods. If the compounds of formula I contain a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium oxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglucamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating such compounds with: pharmaceutically acceptable organic and inorganic acids, such as hydrohalic acids, e.g., hydrochloric, hydrobromic or hydroiodic acid; other mineral acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc.; and alkylsulfonates and monoarylsulfonates, such as ethanesulfonates, toluenesulfonates and benzenesulfonates; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), sulfite, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (galactarate) (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate (isethionate), isobutyrate, lactate, lactobionate (lactylate), Malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate (palmoate), pectate (pectate), persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not intended to be limiting.

Furthermore, base salts of compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this is not intended to be limiting. Among the above salts, ammonium is preferred; alkali metal sodium and potassium salts, and alkaline earth metal calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) -methylamine (tromethamine), this is not intended to be limiting.

The compounds of the present invention containing basic nitrogen-containing groups may be quaternized using the following agents: for example (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; two (C)₁-C₄) Alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and hexadecyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the invention can be prepared using such salts.

Preferred pharmaceutically acceptable salts mentioned above include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, subsalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.

Acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to cause salt formation in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from the corresponding salt form in some respects (with respect to certain physical properties, such as solubility in polar solvents); however, for the purposes of the present invention, the salts additionally correspond to their respective free base forms.

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

The base addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause the formation of the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from the corresponding salt form in some way (with respect to certain physical properties, such as solubility in polar solvents); however, for the purposes of the present invention, the salts additionally correspond to their respective free acid forms.

If the compounds according to the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, the invention also covers multiple salts. Typical multi-salt forms include, for example, tartrate di-salt (bitartrate), diacetate, fumarate di-salt (difumarate), dimeglumine, diphosphate, disodium, and trihydrochloride, but this is not intended to be limiting.

With regard to the above, it can be seen that the expression "pharmaceutically acceptable salt" is used herein to mean an active ingredient comprising a compound of formula I in the form of one of its salts, in particular if this salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient may also provide for the first time such an active ingredient with desirable pharmacokinetic properties which it did not have before and which may even have a positive impact on the pharmacodynamics of such an active ingredient with respect to its therapeutic effect in vivo.

Isotope of carbon monoxide

Furthermore, it is contemplated that the compounds of formula I include isotopically-labeled forms thereof. The isotopically-labelled forms of the compounds of formula I are identical to such compounds, except for the fact that: one or more atoms of a compound having been substituted with a group consisting of atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in natureOne or more atoms of an atomic mass or mass number of. Examples of isotopes which are readily commercially available and which can be incorporated into compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each being, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and CI. Compounds of formula I, prodrugs thereof, or pharmaceutically acceptable salts thereof, containing one or more of the foregoing isotopes and/or other isotopes of other atoms are contemplated as part of this invention. Isotopically-labelled compounds of formula I can be used in a number of advantageous ways. Has been incorporated, for example, into a radioisotope (e.g. in³H or¹⁴C) The isotopically-labelled compounds of formula I of (a) are suitable for use in drug and/or substrate tissue distribution assays. These radioactive isotopes, i.e. tritium (A)³H) And carbon-14 (¹⁴C) Particularly preferred because of its simplicity of preparation and excellent detectability. Heavier isotopes, e.g. deuterium (²H) Incorporation into the compounds of formula I is of therapeutic advantage due to the higher metabolic stability of such isotopically-labelled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which in most cases will represent a preferred embodiment of the invention. Isotopically-labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and associated descriptions, in the examples section herein and in the preparations section, by substituting a readily available isotopically-labeled reactant for a non-isotopically-labeled reactant.

Deuterium (1)²H) It may also be incorporated into the compounds of formula I in order to manipulate the oxidative metabolism of the compounds by primary kinetic isotope interactions. The primary kinetic isotope effect is to alter the rate of chemical reactions caused by the exchange of isotope nuclei, which in turn is caused by the change in ground state energy necessary for covalent bond formation after such isotope exchange. Exchange of heavier isotopes generally leads to a reduction in the ground-state energy of the chemical bonds and thus to rate-limiting bond scissionThe rate of (rate-limiting bond breakthrough) decreased. Product partitioning rates can vary substantially if bond breakage occurs at or near the saddle point region along the multi-product reaction coordinate. For purposes of explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, k_M/k_DA rate differentiation (rate differences) of = 2-7 is typical. If this ratio differentiation is successfully applied to compounds of formula I which are susceptible to oxidation, the distribution of such compounds in vivo can be greatly altered and lead to improved pharmacokinetic properties.

When discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism. The in vitro liver microsomal assays currently available provide valuable information about the processes of this type of oxidative metabolism, which in turn allows rational design of deuterated compounds of formula I with improved stability by combating such oxidative metabolism. A significant improvement in the pharmacokinetic profile of the compound of formula I is thereby obtained and may be based on an increase in the half-life (t/2) in vivo, at the concentration (C) of maximum therapeutic effect_max) Area under the dose response curve (AUC) and F, and is quantified in terms of reduced clearance, dose, and material cost.

The following is intended to illustrate the above: compounds of formula I having multiple potential sites for attack by oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms such that some, most, or all of these hydrogen atoms have been replaced with deuterium atoms. The half-life determination enables an advantageous and accurate determination of the degree of improvement in resistance to oxidative metabolism improvement. Thus, due to this type of deuterium-hydrogen exchange, it was determined that the half-life of the parent compound could be extended by up to 100%.

Deuterium-hydrogen exchange in the compounds of formula I can also be used to achieve a favorable improvement in the metabolic profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that deuterated analogs will greatly reduce or eliminate the production of undesirable metabolites even if specific oxidation is not a rate-controlling step. Further information on the state of the art involving deuterium-hydrogen exchange can be found, for example, in Hanzlik et al, J. org. chem. 55, 3992-.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

Pharmaceutical formulations may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1 g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and physical condition of the patient, or the pharmaceutical preparations may be administered in the form of dosage units which contain a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or a partial dose as indicated above, or the corresponding fraction of the active ingredient thereof. In addition, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulations may be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared using all methods known in the pharmaceutical art, by, for example, combining the active ingredient with excipients or adjuvants.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units, for example capsules or tablets; powder or granules; a solution or suspension in an aqueous or non-aqueous liquid; edible foams or foamed foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component may be combined with oral, non-toxic and pharmaceutically acceptable inert excipients, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutically acceptable excipient (e.g. an edible carbohydrate such as, for example, starch or mannitol) which is comminuted in a similar manner. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling shaped gelatin shells with it. Glidants and lubricants, such as, for example, highly dispersible silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may also be added to improve the availability of the drug after ingestion of the capsule.

Furthermore, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), sweeteners made from corn, natural and synthetic gums (e.g., such as acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. The tablets were formulated by: for example, a powder mixture is prepared, the mixture is granulated or dry-pressed, a lubricant and a disintegrant are added and the whole mixture is compressed to obtain tablets. The powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or matrix as described above, and optionally with a binder (such as, for example, carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution retardant such as, for example, paraffin, an absorption promoter such as, for example, a quaternary ammonium salt, and/or an absorbent such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder such as syrup, starch paste, gum arabic or a solution of cellulose or polymeric material and pressing it through a sieve. As an alternative to granulation, the powder mixture may be passed through a tablet press to give a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet mould. The lubricated mixture is then compressed to obtain tablets. The compounds according to the invention can also be combined with free-flowing inert excipients and then directly compressed without granulation or dry-pressing steps to give tablets. There may be a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids, such as, for example, solutions, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, and the like, can likewise be added.

If desired, dosage unit formulations for oral administration may be encapsulated in microcapsules. The formulations may also be prepared in a manner such as, for example, by coating or embedding the particulate material in a polymer, wax, or the like, such that the release is extended or delayed.

The compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof can also be administered in the form of liposomal delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as, for example, cholesterol, stearylamine, or phosphatidylcholines.

The compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof can also be delivered using monoclonal antibodies as single carriers to which the compound molecules are coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartyl phenol, or polyethylene oxide polylysine (substituted with palmitoyl). The compounds may further be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, poly-caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or araliphatic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered as a stand-alone paste in long-term, intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the paste by iontophoresis, as described in the general term of Pharmaceutical Research, 3(6), 318 (1986).

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

For treatment of the eye or other external tissues, such as the oral cavity and skin, the formulation is preferably applied as a topical ointment or cream. In the case of administration of an ointment formulation, the active ingredient may be used with a paraffin or water-miscible cream base. Alternatively, the active ingredient may be formulated with an oil-in-water cream base or a water-in-oil base to provide a cream.

Pharmaceutical formulations suitable for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

Pharmaceutical formulations adapted for topical application to the oral cavity include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration, wherein the carrier substance is a solid, comprise a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner of nasal inhalation, i.e. by rapid inhalation through the nasal passage from a container containing the powder held up to the vicinity of the nose. Suitable formulations for administration as nasal sprays or nasal drops with liquid as carrier material comprise solutions of the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation comprise a fine particle dust or mist which may be generated by various types of pressurised dispensers, nebulisers or inhalers with an aerosol.

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

Pharmaceutical formulations adapted for parenteral administration include aqueous or non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending media and thickening agents. The formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, making it necessary to add only the sterile liquid carrier, for example water for injections, immediately prior to use. Injectable solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the components specifically mentioned above, for a particular type of formulation, the formulation may also comprise other agents commonly used in the art; thus, for example, formulations suitable for oral administration may contain flavouring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the physician or veterinarian performing the treatment. However, an effective amount of a compound according to the invention for use in the treatment of neoplastic growth, such as colon or breast cancer, will generally be in the range of from 0.1 to 100mg/kg body weight of the recipient (mammal) per day, and particularly typically in the range of from 1 to 10mg/kg body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, wherein this amount may be administered as a single dose per day or typically in a series of partial doses per day (such as, for example, two, three, four, five or six), such that the total daily dose is the same. An effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound according to the invention per se. It is assumed that similar dosages are also applicable for the treatment of the other conditions mentioned above.

The invention also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

The invention also relates to a pharmaceutical kit (kit) consisting of the following separate packs:

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

and

(b) an effective amount of an additional pharmaceutically active ingredient.

The pharmaceutical kit comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The pharmaceutical kit may, for example, comprise separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of an additional pharmaceutically active ingredient in dissolved or lyophilized form.

Use of

The present invention relates to compounds of formula I for use in the treatment of cancer, septic shock, Primary Open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/or neurodegenerative diseases such as alzheimer's disease.

The present invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of cancer, septic shock, Primary Open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/or neurodegenerative diseases such as alzheimer's disease.

The present invention relates to a method of treating a mammal suffering from a disorder selected from the group consisting of: cancer, septic shock, Primary Open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/or neurodegenerative diseases such as alzheimer's disease, wherein the method comprises administering to a mammal a therapeutically effective amount of a compound of formula I.

The compounds of the present invention are suitable as pharmaceutical active ingredients for the treatment and control of cancer diseases and inflammatory diseases in mammals, especially in humans.

The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.

The susceptibility of a particular cell to treatment with a compound according to the invention may be determined by in vitro assays. Typically, cell cultures are combined with various concentrations of a compound according to the invention for a period of time (usually between about 1 hour and 1 week) sufficient for an active agent, such as anti-IgM, to induce a cellular response, such as expression of a surface marker. In vitro tests can be performed using cultured cells from blood or from biopsy samples. The amount of surface marker expressed is assessed by flow cytometry using specific antibodies that recognize the marker.

The dosage will vary depending upon the particular compound used, the particular disease, the patient's condition, and the like. The therapeutic dose is typically sufficient to significantly reduce the undesirable cell population in the target tissue while maintaining the viability of the patient. Treatment generally continues until a significant reduction occurs, e.g., a reduction in cell burden of at least about 50%, and may continue until substantially no more undesired cells are detected in vivo.

In order to identify signal transduction pathways and to detect interactions between various signal transduction pathways, many scientists have developed suitable models or model systems, such as cell culture models (e.g., Khwaja et al, EMBO, 1997, 16,2783-93) and transgenic animal models (e.g., White et al, Oncogene, 2001, 20, 7064-. To determine certain stages in the signal transduction cascade, interacting compounds may be utilized to modulate signals (e.g., Stephens et al, Biochemical j., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in the animal and/or cell culture models mentioned herein or in clinical diseases.

Measurement of kinase activity is a technique well known to those skilled in the art. General test systems for determining kinase activity using substrates, such as histones (e.g.Alessi et al, FEBS Lett. 1996, 399, 3, p. 333-338) or basic myelin proteins, are described in the literature (e.g.Campos-Gonz a lez, R. and Glenney, Jr., J.R. 1992, J.biol. chem. 267, p. 14535).

To identify kinase inhibitors, various assay systems are available. The radioactive phosphorylation of proteins or peptides using gamma ATP as a substrate was detected in scintillation proximity assays (Sorg et al, J.of. Biomolecular Screening, 2002, 7,11-19) and rapid plate assays (flashplate assay). In the presence of the inhibitory compound, a reduced radioactive signal may be detected or not detected at all. Furthermore, homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and Fluorescence Polarization (FP) techniques are suitable for use as assay methods (Sills et al, J. of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA assays employ specific phospho-antibodies (phospho-AB). This phospho-AB binds only to phosphorylated substrates. This binding can be detected by chemiluminescence using peroxidase-conjugated anti-sheep secondary antibodies (Ross et al, 2002, biochem. J.).

The present invention encompasses the use of compounds of formula I and/or physiologically acceptable salts, tautomers and solvates thereof for the preparation of a medicament for the treatment or prevention of cancer. Preferred cancers to be treated are derived from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, lung, intestine. Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma and breast carcinoma.

Also encompassed is the use of a compound of formula I and/or physiologically acceptable salts, tautomers and solvates thereof for the preparation of a medicament for the treatment and/or control of tumor-induced diseases in a mammal, wherein for this method a therapeutically effective amount of a compound according to the invention is administered to a diseased mammal in need of such treatment. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue effort.

Particularly preferred for the treatment of diseases, wherein the cancer disease is a solid tumor.

The solid tumor is preferably selected from the group consisting of: squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and/or lung.

More preferably, the solid tumor is selected from lung adenocarcinoma, small cell lung carcinoma, pancreatic carcinoma, glioblastoma, colon carcinoma and breast carcinoma.

Further preferred is the treatment of tumors of the blood and immune system, preferably tumors selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia and/or chronic lymphoid leukemia.

The invention further relates to the use of a compound according to the invention for the treatment of bone pathologies derived from osteosarcoma, osteoarthritis and chondropathy.

The compounds of formula I may also be administered concurrently with other well-known therapeutic agents selected for their particular usefulness for the condition to be treated.

The present compounds are also suitable in combination with known anticancer agents. Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and additional angiogenesis inhibitors. The present compounds are particularly suitable for administration concurrently with radiation therapy.

"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene (iodoxyfene), LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl ] phenyl 2, 2-dimethylpropionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenylhydrazone, and SH 646.

"androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole, and cyproterone acetate.

"retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethylornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) -retinoamide (retinamide), and N-4-carboxyphenylretinoamide.

"cytotoxic agent" refers to compounds that cause cell death primarily by acting directly on cell function or inhibiting or interfering with cell mitosis (mysis), including alkylating agents, tumor necrosis factors, intercalating agents, tubulin inhibitors, and topoisomerase inhibitors.

Examples of cytotoxic agents include, but are not limited to, prazamine (tirapazimine), serteref, cachectin, ifosfamide, tasloramine, lonidamine, carboplatin, hexamethylmelamine, pomatemustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin (heptaplatin), estramustine, improsulfan tosylate, trofosfamide, nimustine, dibromospiro-ammonium chloride, puripine, lobaplatin, satraplatin, methylmitomycin, cisplatin, elovin, dexifosfamide (dexfosfamide), cis-aminodichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans ) -di-mu- (hexane-1, 6-diamine) -mu- [ diamine-platinum (II) ] bis [ diamine (II (tetrachloro) platinum (II) ] Diarizinilspirmine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, piranhrather, valrubicin, amrubicin, antitumor (antineoplaton), 3 '-deamino-3' -morpholino-13-deoxo-10-hydroxycarminomycin, anamycin, calicheamicin, eletrode, MEN10755 and 4-demethoxy-3-deamino-3-cycloethylimino-4-methylsulfonyldaunorubicin (see WO 00/50032).

Examples of tubulin inhibitors include paclitaxel, vindesine sulfate, 3',4' -didehydro-4 '-deoxy-8' -vinblastine, docetaxel, rhizomycin, dolastatin, mevobulin isethionate, auristatin, cimadrol, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrous vinblastine (anhydrovinblastine), N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butanamide, TDX258 and BMS 188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ',4' -O-exobenzylidene-tebucin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5-kl ] acridine-2- (6H) -propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de ] pyrano [3',4': b,7] indolizino [1,2b ] quinoline-10, 13(9H,15H) dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl ] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzosin, 2 '-dimethylamino-2' -deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl ] -9-hydroxy-5, 6-dimethyl-6H-pyrido [4,3-b ] carbazole-1-carboxamide, asulacrine, (5a,5aB,8aa,9b) -9- [2- [ N- [2- (dimethylamino) ethyl ] -N-methylamino ] ethyl ] -5- [ 4-hydroxy-3, 5-dimethoxyphenyl ] -5,5a,6,8,8a, 9-hexahydrofuro (3',4':6,7) naphtho (2,3-d) -1, 3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenz [ c ] phenanthridinium (phenanthridinium), 6, 9-bis (2-aminoethyl) amino ] benzo [ g ] isoquinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de ] acridin-6-one, N- [1- [2 (diethylamino) ethylamino ] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl ] carboxamide, and pharmaceutically acceptable salts thereof, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) ethyl ] amino ] -3-hydroxy-7H-indeno [2,1-c ] quinolin-7-one, and dimesna.

"antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine octadecyl phosphate (cytarabine ocfosfate), amifostine hydrate (fosetabine hydrate), raltitrexed, patotexed (palitexid), ethimidifluoride, thifluzaline, decitabine, nolatrexed, pemetrexed, nelarabine (nelzabine), 2' -deoxy-2 ' -methylenecytidine, 2' -fluoromethylene-2 ' -deoxycytidine, N- [5- (2, 3-dihydrobenzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [4- [ N- [2- [ 3-2 (2), 4(E) -tetradecadienoyl ] glycylamino ] -L-glycero-B-L-mannose-heptopyranosyl (manno-hepyranosyl) ] adenine, dehydro-phaeosphingosine (aplidine), ecteinascidin, troxacitabine, 4- [ 2-amino-4-oxo-4, 6,7, 8-tetrahydro-3H-pyrimido [5,4-B ] -1, 4-thiazin-6-yl- (S) -ethyl ] -2, 5-thenoyl-L-glutamic acid, aminopterin, 5-fluorouracil, aragonin, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diazepitetracyclo (7.4.1.0.0) -tetradeca-2, 4, 6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane, methioninase, 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl (arabinofuranosyl) cytosine, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (carboxaldehyde thiosemicarbazone). "antiproliferative agents" also include monoclonal antibodies other than those growth factors listed under "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, e.g., U.S. patent No. 6,069,134).

Preferably, the present invention relates to a method wherein the disease is cancer.

Particularly preferably, the invention relates to a method wherein the disease is cancer and wherein the administration is simultaneous, sequential or alternating with the administration of at least one other active agent.

The disclosed compounds of formula I may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anti-cancer agent" relates to any agent that is administered to a patient suffering from cancer for the purpose of treating cancer.

The anti-cancer treatments defined herein may be applied as monotherapy or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Such chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) antiproliferative/antineoplastic/DNA-damaging agents and combinations thereof, such as for medical oncology, for example alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea and gemcitabine); anti-tumor antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and plicamycin); antimitotic agents (e.g. vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxanes like paclitaxel and taxotere); topoisomerase inhibitors (e.g. epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell differentiating agents (e.g. all trans-retinoic acid, 13-cis-retinoic acid and fenretinide);

(ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and idoxifene (iodoxyfene)), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole and imipramine), and 5 a-reductase inhibitors such as finasteride;

(iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasmin activator receptor function);

(iv) inhibitors of growth factor function, e.g., such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2 antibody trastuzumab [ Herceptin ]^TM]And anti-erbbl antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), inhibitors of, for example, the platelet-derived growth factor family; and inhibitors of, for example, the hepatocyte growth factor family;

(v) anti-angiogenic agents, e.g., those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]Compounds such as those disclosed in international patent applications WO 97/22596, WO97/30035, WO 97/32856 and WO 98/13354), and compounds that act by other mechanisms (e.g., linoamine, integrin α v β 3 function inhibitors and angiostatin);

(vi) vascular disrupting agents such as combretastatin a4 and the compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, such as those directed to the above listed targets, e.g., ISIS 2503, anti-Ras antisense drugs;

(viii) gene therapy methods, including, for example, methods of replacing an aberrant gene, such as aberrant p53 or aberrant BRCA1 or BRCA 2; GDEPT (gene-directed enzyme prodrug therapy) methods, such as those with cytosine deamidase, thymidine kinase, or bacterial nitroreductase enzymes, and methods of increasing the tolerance of patients to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(ix) immunotherapy, including for example ex vivo and in vivo methods of increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor; a method of reducing T cell anergy; methods using transfected immune cells such as cytokine-transfected dendritic cells; a method using a cytokine-transfected tumor cell line, and a method using an anti-idiotype antibody.

The medicaments of table 1 below are preferably (but not exclusively) combined with compounds of formula I.

The disclosed compounds of formula I and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, can preferably be administered in combination with an immunomodulator, preferably with anti-PDL-1-or IL-12.

IKK inhibition assay

IKK-kinase assay (IKK)

SUMMARY

Kinase assays are performed as 384-well rapid plate assays (for e.g. Topcount measurements).

1 nM IKK, 800nM biotinylated I κ B α (19-42) peptide (biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) and 10 μ M ATP (spiked with 0.3 μ Ci)³³P-ATP/well) was incubated at 30 ℃ for 2 hours in a total volume of 50 μ l (10mM MOPS, 10mM Mg-acetat, 0.1 mM EGTA, 1 mM dithiothreitol, 0.02% Brij35, 0.1% BSA, 0.1% BioStab, pH7.5) with or without test compound. The reaction was terminated with 25 μ l of 200 mM EDTA. After 30Min at room temperature, the liquid was removed and each well was washed 3 times with 100 μ l of 0.9% sodium chloride solution. Nonspecific reactions were determined in the presence of 3 μ M MSC2119074 (BX-795). Radioactivity was measured by Topcount (PerkinElmer). Computing results (e.g., IC) using procedural tools (e.g., AssayExplorer, Symyx) provided by IT-departments₅₀-value).

Test for inhibition of TBK1

Enzyme assay

SUMMARY

Kinase assays are performed in 384-well rapid plate assay (for e.g. Topcount measurements).

0.6 nM TANK binding kinase (TBK1), 800nM biotinylated MELK-derived peptide (biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR) and 10 μ M ATP (spiked with 0.25 μ Ci)³³P-ATP/well) was incubated at 30 ℃ for 120 Min in a total volume of 50 μ l (10mM MOPS, 10mM Mg-acetat, 0.1 mM EGTA, 1 mM DTT, 0.02% Brij35, 0.1% BSA, pH7.5) with or without test compound. Termination of the reaction with 25 μ l 200 mM EDTA. After 30Min at room temperature, the liquid was removed and each well was washed 3 times with 100 μ l of 0.9% sodium chloride solution. Nonspecific reactions were determined in the presence of 100 nM staurosporine. Radioactivity was measured by Topcount (PerkinElmer). Computing results (e.g., IC) using procedural tools (e.g., AssayExplorer, Symyx) provided by IT-departments₅₀-value).

Cell assay

Dose response inhibition of Phospho-IRF3 @ Ser386 cells/MDAMB 468/INH/PHOS/IMAG/pIRF3

1. Range of

Although the key roles of TBK1 and IKK in innate immune responses are best known, recent results have been directed to the role of TBK1 and IKK in Ras-induced oncogene switching. TBK1 was identified as a RalB effector in the Ras (e.g., (Ral)) -ornithine nucleotide exchange factor (GEF) pathway, which is required for Ras-induced switching. TBK1 directly activates IRF3, which upon phosphorylation, is homodimerized and translocated to the nucleus where it activates processes including inflammation, immune regulation, cell survival and proliferation.

This assay has been developed to evaluate the efficacy/potency of TBK1/IKK inhibitor compounds based on immunocytochemical detection of nuclear localised phospho-IRF3, a target downstream of TBK 1.

Molecular patterns associated with viral infection recognized by Toll-like receptor 3 (TLR3) were used to induce TBK1/IKKe activity and IRF3 phosphorylation at Ser386 by treatment with polyinosinic-polycytidylic acid (poly (I: C), a synthetic analog of double stranded rna (dsrna)).

2. Summary of the assays

Day 1: MDA-MB-468 cells were detached with HyQ-Tase, counted and seeded in 384-well clear bottom TC-surface plates at a density of 10,000 cells per well in a total volume of 35ul of complete medium. Or the cells were directly seeded from the cryo-vial.

Day 2: cells were pretreated with inhibitor compound for 1h, followed by Poly (I: C) stimulation. After 2 hours of incubation with Poly (I: C), the cells were fixed to (oligo) formaldehyde (PFA) and permeabilized with methanol (MeOH). The cells were then blocked and incubated overnight at 4 ℃ with anti-pIRF 3 antibody.

Day 3: the primary antibody was washed away, AlexaFluor 488-conjugated secondary antibody was added, and cells were counterstained with propidium iodide followed by image acquisition in an IMX Ultra high capacity reader.

3. Reagents, materials

Cell: ATCC HTB 132, Burger lab (MP-CB 2010-327 or MDA-MB-468/10)

Plate medium = medium:

RPMI 1640, Invitrogen # 31870

10% FCS, Invitrogen # 10270-106

2mM Glutamax, Invitrogen #35050-038

1mM Natrium-Pyruvat, Invitrogen # 11360

1% Pen / Strep

37℃, 5% CO2

plate: black/clear bottom 384-well cell culture plates, Falcon # 353962 or Greiner #781090

Seed transformation: HyQ-Tase, Thermo Scientific (Hyclone) # SV30030.01

Other reagents:

poly (I: C) (LMW), Invivogen # tlrl-picw (20 mg/ml stock solution in sterile PBS was prepared, denatured in 55 ℃ water bath for 30min, slowly cooled to RT, stored as an aliquot at-20 ℃)

Reference inhibitor: MSC2119074A-4 = BX-795 (IC 50: 200 and 800nM)

Inhibition control: 10 mu M MSC2119074A-4 = BX-795

Neutral control: 0.5% DMSO

A 10-point dose-response curve with MSC2119074A-4 = BX-795 was included in each experiment.

Hepes, Merck #1.10110

PBS 1x DPBS , Invitrogen # 14190

Formaldehyde (methanol-free, 16%, ultra pure EM Grade), Polysciences # 18814 (storage at RT), final concentration: 4 percent of

Methanol, Merck # 1.06009.1011 (-20 ℃ Pre-Cooling)

Goat serum, PAA # B15-035 (stored at 4 ℃ C. for long periods at-20 ℃ C.), final concentrations: 10 percent of

BSA (no IgG and protease, 30%), US-Biological # A1317 (stored at 4 ℃ for a long time at-20 ℃), final concentration: 2 percent of

Tween 20 detergent, Calbiochem # 655204 (stock at RT), (10% stock solution in water was prepared; final concentration: 0.1%)

anti-pIRF-3 rabbit mAb, Epitomics # 2526-B (-20 ℃ storage), final concentration: 1:2000 in PBS/2% BSA

Alexa Fluor goat-anti-rabbit-488, Invitrogen # a11034 or # a11008 (stored at 4 ℃ in the dark), final concentration: 1:2000 in PBS/2% BSA/0.1% Tween

Propidium Iodide (PI), Fluka # 81845, 1mg/ml in H2O (stored in the dark at 4 ℃), final concentration: 0.2 microgram/ml

4. Procedure for measuring the movement of a moving object

HPLC/MS conditions:

column: chromolith speedROD RP-18e, 50-4.6

Gradient: a: B = 96:4-0:100

4% B → 100% B: 0 min-2.8 min

100% B: 2.8 min-3.3 min

100%B → 4%B: 3.3 min-4 min

Flow rate: 2.4 ml/min

Eluent A: water + 0.05% formic acid

Eluent B is acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive mode

¹H NMR: coupling constant J [ Hz ]]。

Examples

Synthesis of 7-chloro-2-iodo-furo [3,2-b ] pyridine

Step 1: 2-trimethylsilanyl-furo [3,2-b ]]Pyridine compound

2-Bromopyridin-3-ol (400 g, 2.3 mol) was dissolved in 1, 4-dioxane (4 l, 46.76 mol). Ethynyl-trimethyl-silane (248.37 g, 2.53 mol), copper (I) iodide (43.78 g, 0.23 mol) and bis (triphenylphosphine) palladium (II) chloride (80.68 g,0, 11 mol) were added. The mixture was stirred at 20 ℃ for 15 minutes. Triethylamine (697.90 g, 6.9 mol) was added to the reaction solution over 20 min. The mixture was stirred at 50 ℃ for 4h, cooled to room temperature for 14 h and evaporated. The residue was dissolved in 6 l ethyl acetate, filtered, and the organic layer was extracted with water, washed with brine, separated and washed with Na₂SO₄And (5) drying. The drying agent was filtered and the solvent removed in vacuo. By using a nailChromatographically separating the product of the tert-butyl ether; 268 g of 2-trimethylsilanyl-furo [3,2-b ] were obtained]Pyridine; HPLC/MS 2.60 min, [ M + H ]]= 192；

¹H NMR (400 MHz, DMSO-d₆) [ppm]8.71 (d, J = 5.2 Hz, 1H), 8.58 (d, J= 8.4 Hz, 1H), 7.69 (dt, J = 18.8, 9.4 Hz, 1H), 7.46 (s, 1H), 0.25 (s, 9H)。

Step 2: 2-trimethylsilanyl-furo [3,2-b ] pyridine 4-oxide

Reacting 2-trimethylsilanyl-furo [3,2-b ]]Pyridine (268 g, 0.14 mol) was dissolved in dichloromethane (3 l) and stirred at 0-5 ℃. To this solution was added 3-chloroperbenzoic acid over 30min, stirred for 1h and warmed to room temperature. After 14 h, NaHCO is used₃The solution and water extract the reaction mixture. The organic layer was separated and passed over Na₂SO₄And (5) drying. Filtering the drying agent and removing the solvent in vacuo; 296 g of 2-trimethylsilanyl-furo [3,2-b ] were obtained]Pyridine 4-oxide; HPLC/MS 2.0 min, [ M + H ]]= 208;

¹H NMR (400 MHz, CDCl₃) [ppm]7.97 (d, J = 6.3 Hz, 1H), 7.22 (d, J =8.4 Hz, 1H), 7.18 (s, 1H), 6.92 (dt, J = 8.4, 6.3 Hz, 1H), 0.15 (s, 9H)。

And step 3: 7-chloro-2-trimethylsilanyl-furo [3,2-b ] pyridine

Reacting 2-trimethylsilanyl-furo [3,2-b ] at room temperature]Pyridine 4-oxide (296 g, 0.14 mol) was dissolved in toluene (100 ml, 9.44 mol) and POCl was added dropwise₃. The reaction mixture was stirred at 95 ℃ for 4h, then the solvent was evaporated. The residue was dissolved in methyl tert-butyl ether and NaHCO was used₃Solution and water extraction. The organic layer was separated and passed over Na₂SO₄And (5) drying. After filtration and removal of the solvent in vacuo, 7-chloro-2-trimethylsilyl-furo [3,2-b ] is isolated]Pyridine; 230 g of 7-chloro-2-trimethylsilanyl-furo [3,2-b ] were obtained]Pyridine; HPLC/MS 2.65 min, [ M + H ]]= 226；

¹H NMR (400 MHz, DMSO-d₆) [ppm]8.46 (d, J = 5.2 Hz, 1H), 7.48 (d, J= 5.2 Hz, 1H), 7.46 (s, 1H), 0.37 (s, 9H)。

And 4, step 4: 7-chloro-2-iodo-furo [3,2-b ] pyridines

Reacting 7-chloro-2-trimethylsilyl-furo [3,2-b ] in a nitrogen atmosphere]Pyridine (185 g, 0.23 mol) was dissolved in ACN. KF (47.6 g, 0.82 mol) and iodosuccinimide (553.1 g, 0.25 mol) were then added. The reaction mixture was stirred at 60 ℃ for 14 h and then cooled to room temperature. To the reaction mixture were added ethyl acetate (5 l) and water (5 l). The organic layer was separated, washed with sodium thiosulfate (5 l) solution, then NaHCO₃The solution was extracted and washed with brine. The organic layer was washed with Na₂SO₄And (5) drying. Filtering the drying agent and removing the solvent in vacuo; 133 g of 7-chloro-2-iodo-furo [3,2-b ] are obtained]Pyridine; HPLC/MS 2.34 min, [ M + H ]]= 280；

¹H NMR (400 MHz, DMSO-d₆) [ppm]8.44 (d, J = 5.3 Hz, 1H), 7.55 (s,1H), 7.44 (dd, J = 5.4, 3.1 Hz, 1H)。

Synthesis of 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile

Step 1: 5-bromo-2- (tetrahydro-pyran-4-yloxy) -benzonitrile

To a solution of tetrahydro-pyran-4-ol (3.3 g, 33.0 mmol) in DMF (60 ml) at 0 ℃ was added sodium hydride (1.4 g, 33.0 mmol). 5-bromo-2-fluoro-benzonitrile (5.5 g, 27.5mmol) in DMF (30 ml) was added dropwise at 0 ℃. The reaction was stirred at 45 ℃ for 16 h. The reaction was cooled to room temperature and quenched by pouring the reaction into water (500 ml). The precipitate was filtered and dried under vacuum; 6.8 g of 5-bromo-2- (tetrahydro-pyran-4-yloxy) -benzonitrile are obtained;

HPLC/MS: 2.27 min, [M+H]= 283。

step 2: 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile

To a solution of 5-bromo-2- (tetrahydro-pyran-4-yloxy) -benzonitrile (6.7 g, 19 mmol) in 1, 4-dioxane (70 ml) were added bis (pinacolato) diboron (7.3 g, 28.6 mmol), potassium acetate (5.6 g, 57.2mmol) and Pd (dppf) Cl₂(778.4 mg, 0.95 mmol). The mixture was heated to 90 ℃ for 4h, then quenched with water (50 ml), followed by extraction with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The drying agent was filtered and the solvent removed in vacuo. The product was purified by chromatography (petroleum ether/ethyl acetate); 5.6 g of 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.553min, [ M + H ]]= 330。

5- [2- (4-Morpholin-4-yl-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A1")

Step 1: 7-chloro-2- (4-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine

7-chloro-2-iodo-furo [3,2-b ] pyridine (100 mg, 0.36 mmol) and 4-morpholinophenylboronic acid (77.8 mg, 0.38 mmol) were dissolved in 1,4 dioxane (2 ml). Potassium carbonate (0.15 g) and water (0.25 ml) were added under nitrogen. Dicyclohexyl- (2',6' -dimethoxy-biphenyl-2-yl) -n-phosphane and palladium (II) acetate were added and the mixture was stirred at 100 ℃ for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed by evaporation. Separating the product by chromatography; to yield 92 mg of 7-chloro-2- (4-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine; HPLC/MS: 2.411 min, [ M + H ] = 315.

Similarly, the following compounds were obtained:

7-chloro-2- (3-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 4- [3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] morpholine; HPLC/MS 2.45 min, [ M + H ] = 315;

4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -N-ethyl-N- (2-methoxy-ethyl) -benzamide

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and N-ethyl-N- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide; HPLC/MS 2.18 min, [ M + H ] = 359;

7-chloro-2- (4-methoxy-phenyl) -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 4-methoxyphenylboronic acid; HPLC/MS 2.55 min, [ M + H ] = 260;

7-chloro-2- (2-methoxy-phenyl) -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 2-methoxyphenylboronic acid; HPLC/MS 2.65 min, [ M + H ] = 262;

7-chloro-2- (3-methoxy-phenyl) -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 3-methoxyphenylboronic acid; HPLC/MS 2.70 min, [ M + H ] = 262;

3- (7-chloro-furo [3,2-b ] pyridin-2-yl) -N-ethyl-N- (2-methoxy-ethyl) -benzamide

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and N-ethyl-N- (2-methoxy-ethyl) -3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide; HPLC/MS 2.19 min, [ M + H ] = 359;

4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -benzoic acid ethyl ester

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 4-ethoxycarbonylphenylboronic acid;

HPLC/MS: 2.89 min, [M+H]= 302；

7-chloro-2- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole; HPLC/MS 2.90 min, [ M + H ] = 278;

7-chloro-2- [3- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 1-methyl-4- [3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -piperazine; HPLC/MS 1.57 min, [ M + H ] = 328;

7-chloro-2- [4- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 1-methyl-4- [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -piperazine; HPLC/MS 1.51 min, [ M + H ] = 328;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.72 (1 H, d, J =6.4 Hz), 8.08(2 H, d, J= 9.0Hz), 7.87 (1 H, d, J =6.4Hz), 7.73 (1 H, s), 7.23 (2 H, d, J =9.1Hz), 4.16 (2 H, d, J =11.0 Hz), 3.62 (2 H, d, J =9.1 Hz), 3.26 (4 H, m)；

4- [4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 4- [4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl ] -piperidine-1-carboxylic acid tert-butyl ester; HPLC/MS: 2.507 min, [ M + H ] = 403;

4- [4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -2-methoxy-benzoyl ] -piperazine-1-carboxylic acid tert-butyl ester

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoyl ] -piperazine-1-carboxylic acid tert-butyl ester; HPLC/MS 2.40 min, [ M + H ] = 472;

4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -2-methoxy-benzoic acid methyl ester

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 3-methoxy-4-methoxycarbonylphenylboronic acid, pinacol ester; HPLC/MS: 2.425 min, [ M + H ] = 318;

2- (1H-benzimidazol-4-yl) -7-chloro-furo [3,2-b ] pyridine

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 1H-benzimidazol-4-ylboronic acid;

HPLC/MS: 1.843 min, [M+H]= 270；

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]9.82 (1 H, s), 8.72 (1 H, d, J5.6), 8.26 (1 H, d, J 7.0), 8.15 (1 H, s), 8.08 (1 H, dd, J 8.3, 0.8), 7.79(2 H, m)；

5- (7-chloro-furo [3,2-b ] pyridin-2-yl) -1, 3-dihydro-benzimidazol-2-one

From 7-chloro-2-iodo-furo [3,2-b ] pyridine and 2, 3-dihydro-2-oxo-1H-benzimidazole-5-boronic acid, pinacol ester; HPLC/MS 1.755 min, [ M + H ] = 286;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.73 (1 H, d, J 6.3), 7.90 (1H, d, J 6.3), 7.84 (2 H, m), 7.72 (1 H, d, J 1.6), 7.18 (1 H, d, J 7.7, 4.0)。

step 2: 5- [2- (4-Morpholin-4-yl-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A1")

The title compound was obtained from 7-chloro-2- (4-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile using the same method described for 7-chloro-2- (4-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine in step 1; 67 mg5- [2- (4-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile was obtained; HPLC/MS 2.26 min, [ M + H ] = 482;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.74 (d, J= 6.4 Hz, 1H), 8.64(d, J= 2.4 Hz, 1H), 8.58 (dd, J= 9.0, 2.4 Hz, 1H), 8.09 (t, J =5.9 Hz, 1H),8.06 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 10.6 Hz, 2H), 7.17 (d, J= 9.1 Hz, 2H),5.08 – 4.98 (m, 1H), 3.99 – 3.92 (m, 2H), 3.83 – 3.78 (m, 4 H), 3.67 – 3.58(m, 2 H), 3.43 – 3.35 (m, 4 H), 2.18 – 2.09 (m, 2 H), 1.86 – 1.77 (m, 2 H)。

the following compounds were obtained analogously:

5- [2- (3-Morpholin-4-yl-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A2")

From 7-chloro-2- (3-morpholin-4-yl-phenyl) -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile;

HPLC/MS: 2.45 min, [M+H]= 482；

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.88 (d, J =6.4 Hz, 1H), 8.76(d, J =2.4 Hz, 1H), 8.59 (dd, J =9.0, 2.4 Hz, 1H), 8.25 (d, J =6.4 Hz, 1H),8.01 (s, 1H), 7.88 (d, J =8.0 Hz, 1H), 7.75 (d, J =7.8 Hz, 1H), 7.68 (d, J =9.2 Hz, 1H), 7.58 – 7.52 (m, 1H), 7.37 – 7.31 (m, 1H), 5.10 – 4.97 (m, 1H),4.01 – 3.93 (m, 2H), 3.92 – 3.87 (m, 4H), 3.67 – 3.59 (m, 2H), 3.42 – 3.35(m, 4H), 2.16 – 2.09 (m, 2H), 1.87 – 1.77 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N-ethyl-N- (2-methoxy-ethyl) -benzamide ("A3")

From 4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -N-ethyl-N- (2-methoxy-ethyl) -benzamide and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.20 min, [ M + H ] = 526;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.91 (d, J= 6.3 Hz, 1H), 8.68(d, J= 2.4 Hz, 1H), 8.64 (dd, J= 9.0, 2.4 Hz, 1H), 8.29 – 8.23 (m, 3H), 8.04(s, 1H), 7.69 (t, J= 8.5 Hz, 1H), 7.64 (d, J= 7.6 Hz, 2H), 5.10 – 4.98 (m, 1H), 4.00 – 3.91 (m, 2 H), 3.70 – 3.59 (m, 4H), 3.58 – 3.17 (m, 7H), 2.20 –2.07 (m, 2H), 1.86 – 1.75 (m, 2H), 1.16 (d, J =57.6Hz, 3H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid ethyl ester ("A4")

From 4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -benzoic acid ethyl ester and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.64 min, [ M + H ] = 369;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.94 (d, J = 6.3 Hz, 1H), 8.69(d, J = 2.4 Hz, 1H), 8.64 (dd, J = 9.0, 2.4 Hz, 1H), 8.34 (d, 2H), 8.28 (d,1H), 8.21 (d, J = 1.7 Hz, 2H), 8.13 (s, 1H), 7.71 (d, J = 9.2 Hz, 1H), 5.09 –5.00 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.99 – 3.92 (m, 2H), 3.66 – 3.58 (m,2H), 2.17 – 2.09 (m, 2H), 1.85 – 1.77 (m, 2H), 1.43 – 1.35 (m, 3H)；

5- [2- (2-methoxy-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A5")

From 7-chloro-2- (2-methoxy-phenyl) -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.33 min, [ M + H ] = 427;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.89 (d, J = 6.3 Hz, 1H), 8.70(d, J = 2.3 Hz, 1H), 8.64 (dd, J = 9.0, 2.4 Hz, 1H), 8.24 (d, J = 6.4 Hz,1H), 8.13 (dd, J = 7.8, 1.5 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H),7.67 – 7.62 (m, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.25 (t,J = 7.6 Hz, 1H), 5.09– 5.01 (m, 1H), 4.10 (s, 3H), 3.95 – 3.89 (m, 2H), 3.65 – 3.57 (m, 2H), 2.15– 2.09 (m, 2H), 1.82 – 1.73 (m, 2H)；

5- [2- (3-methoxy-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A6")

From 7-chloro-2- (3-methoxy-phenyl) -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS: 2.48 min, [ M + H ] = 427;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.90 (d, J = 6.3 Hz, 1H), 8.72(d, J = 2.4 Hz, 1H), 8.62 (dd, J = 9.0, 2.4 Hz, 1H), 8.25 (d, J = 6.3 Hz,1H), 8.04 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.58(t, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.2, 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz,1H), 5.10 – 4.99 (m, 1H), 3.96 – 3.94 (m, 1H), 3.93 (s, 3H), 3.65 (s, 1H),3.64 – 3.58 (m, 2H), 2.15 – 2.08 (m, 2H), 1.82 – 1.75 (m, 2H)；

5- [2- (4-methoxy-phenyl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A7")

From 7-chloro-2- (4-methoxy-phenyl) -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.23 min, [ M + H ] = 427;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.83 (d, J = 6.3 Hz, 1H), 8.67(d, J = 2.4 Hz, 1H), 8.61 (dd, J = 9.0, 2.4 Hz, 1H), 8.19 – 8.12 (m, 3H),7.83 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.21 (d, 2H), 5.09 – 4.98 (m, 1H),3.96 – 3.92 (m, 1H), 3.91 (s, 3H), 3.64 (s, 2H), 3.62 – 3.58 (m, 1H), 2.15 –2.08 (m, 2H), 1.81 – 1.75 (m, 2H)；

5- {2- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A8")

From 7-chloro-2- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 1.89 min, [ M + H ] = 445;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.78 (d, J = 6.4 Hz, 1H), 8.67– 8.63 (m, 2H), 8.59 (dd, 1H), 8.31 (s, 1H), 8.14 (d, J = 6.5 Hz, 1H), 7.66(d, J = 9.1 Hz, 1H), 7.57 (s, 1H), 5.08 – 4.98 (m, 1H), 4.44 (t, J = 5.1 Hz,2H), 4.01 – 3.89 (m, 2H), 3.80 (t, J = 5.1 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.29(s, 3H), 2.19 – 2.07 (m, 2H), 1.87 – 1.74 (m, 2H)。

5- {2- [3- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A9")

From 7-chloro-2- [3- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 1.65 min, [ M + H ] = 495;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.81 (d, J = 6.4 Hz, 1H), 8.71(d, J = 2.4 Hz, 1H), 8.50 (dd, J = 9.1, 2.4 Hz, 1H), 8.17 (d, J = 6.4 Hz,1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 9.3Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.3, 2.1 Hz, 1H), 5.03 –4.89 (m, 1H), 4.01 (d, J = 13.0 Hz, 2H), 3.93 – 3.80 (m, 2H), 3.64 – 3.48 (m,4H), 3.29 – 3.06 (m, 4H), 2.88 (s, 3H), 2.12 – 1.99 (m, 2H), 1.80 – 1.67 (m,2H)；

5- {2- [4- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A10")

From 7-chloro-2- [4- (4-methyl-piperazin-1-yl) -phenyl ] -furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 1.59 min, [ M + H ] = 495;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.77 (1 H, d, J 6.3), 8.65 (1H, d, J 2.4), 8.57 (1 H, dd, J 9.0, 2.4), 8.09 (3 H, dd, J 19.1, 7.7), 7.73(2 H, m), 7.24 (2 H, d, J 9.1), 5.04 (1 H, tt, J 7.8, 3.8), 4.14 (2 H, t, J23.6), 3.93 (2 H, m), 3.61 (4 H, ddd, J 11.3, 8.5, 2.9), 3.21 (4 H, d, J9.2), 2.92 (3 H, s), 2.11 (2 H, m), 1.77 (2 H, dtd, J 12.4, 8.2, 3.9)；

4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoyl) -piperazine-1-carboxylic acid tert-butyl ester ("A11")

From 4- [4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -2-methoxy-benzoyl ] -piperazine-1-carboxylic acid tert-butyl ester and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 2.44 min, [ M + H ] = 639;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.59 (1 H, d, J 5.1), 8.55 (1H, d, J 2.4), 8.44 (1 H, dd, J 9.0, 2.4), 7.87 (1 H, s), 7.66 (4 H, m), 7.39(1 H, d, J 7.8), 4.97 (1 H, m), 3.96 (3 H, s), 3.89 (2 H, m), 3.58 (4 H, m),3.43 (4 H, s), 3.17 (2 H, m), 2.07 (2 H, m), 1.72 (2 H, m), 1.41 (9 H, s)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid methyl ester ("A12")

From 4- (7-chloro-furo [3,2-b ] pyridin-2-yl) -2-methoxy-benzoic acid methyl ester and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS:2.413 min, [ M + H ] = 485;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.93 (1 H, d, J 6.3), 8.73 (1H, d, J 2.4), 8.59 (1 H, dd), 8.28 (1 H, d, J 6.4), 8.17 (1 H, s), 7.88 (2 H,m), 7.82 (1 H, dd, J 8.0, 1.4), 7.65 (1 H, d, J 9.2), 5.03 (1 H, m), 4.04 (3H, s), 3.96 (2 H, m), 3.87 (3 H, s), 3.63 (2 H, m), 2.13 (2 H, m), 1.82 (2 H,m)；

5- [2- (1H-benzimidazol-4-yl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A13")

From 2- (1H-benzimidazol-4-yl) -7-chloro-furo [3,2-b ] pyridine and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile;

HPLC/MS: 1.975 min, [M+H]= 437；

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]9.73 (1 H, s), 8.91 (1 H, d, J6.2), 8.65 (1 H, d, J 2.4), 8.56 (1 H, dd, J 9.0, 2.4), 8.24 (2 H, dd, J 7.0,3.2), 8.20 (1 H, s), 8.06 (1 H, d, J 8.2), 7.74 (1 H, dd, J 13.6, 5.6), 7.59(1 H, d, J 9.2), 4.95 (1 H, tt, J 7.7, 3.8), 3.88 (2 H, m), 3.55 (2 H, m),2.05 (2 H, m), 1.74 (2 H, m)；

5- [2- (2-oxo-2, 3-dihydro-1H-benzimidazol-5-yl) -furo [3,2-b ] pyridin-7-yl ] -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A14")

From 5- (7-chloro-furo [3,2-b ] pyridin-2-yl) -1, 3-dihydro-benzimidazol-2-one and 2- (tetrahydro-pyran-4-yloxy) -5- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzonitrile; HPLC/MS 1.811 min, [ M + H ] = 453;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.79 (1 H, d, J 6.4), 8.64 (1H, d, J 2.3), 8.58 (1 H, dd, J 9.0, 2.4), 8.13 (1 H, d, J 6.4), 7.86 (1 H,dd, J 8.2, 1.6), 7.83 (1 H, s), 7.76 (1 H, d, J 1.5), 7.69 (1 H, dd, J 5.4,3.9), 7.21 (1 H, t, J 6.6), 5.04 (1 H, tt, J 7.8, 3.8), 3.96 (2 H, m), 3.64(2 H, m), 2.14 (2 H, m), 1.82 (2 H, m)。

synthesis of 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-methylamino-ethyl) -benzamide ("A15")

Step 1: 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl]-furo [3,2-b]Pyridin-2-yl } -benzoic acid ("A16a")

A solution of 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid ethyl ester (1.6 g, 3.42 mmol) in 50 mL ethanol and 1M NaOH (20 mL, 40.0 mmol) was stirred at room temperature for 14 h. The ethanol was removed in vacuo and the mixture was acidified with 1M hydrochloric acid. Filtering to remove the generated precipitate, washing with water and drying for 16 h; to give 1.4 g of 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid;

HPLC/MS: 2.12 min, [M+H]= 441；

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.84 (d, J = 6.3 Hz, 1H), 8.58(d, J = 2.4 Hz, 1H), 8.55 (dd, J = 9.0, 2.4 Hz, 1H), 8.22 (d, J = 8.6 Hz,2H), 8.19 (d, J = 6.4 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 8.01 (s, 1H), 7.61(d, J = 9.2 Hz, 1H), 5.01 – 4.91 (m, 1H), 3.94 – 3.84 (m, 2H), 3.61 – 3.50(m, 2H), 2.13 – 2.00 (m, 2H), 1.80 – 1.66 (m, 2H)。

the following compounds were obtained analogously

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid methyl ester; HPLC/MS: 2.136 min, [ M + H ] = 471.

Step 2: [2- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] furo [3,2b ] pyridin-2-yl } -benzoylamino) -ethyl ] -methyl-carbamic acid tert-butyl ester ("A16")

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid (100 mg, 0.23 mmol) and N- (2-aminoethyl) -N-methyl-carbamic acid tert-butyl ester (47.5 mg,0.27 mmol) were dissolved in DMSO (2 ml). N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (DAPECI) (87.0 mg, 0.45 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (34.8 mg, 0.15 mmol) and N-methylmorpholine (49.9. mu.l, 0.45 mmol) were added to the solution. The mixture was stirred at rt for 16 h. Evaporating the DMSO and subjecting the product to chromatographic separation; to yield 61 mg of [2- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoylamino) -ethyl ] -methyl-carbamic acid tert-butyl ester; HPLC/MS 2.37 min, [ M + H ] = 597;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.84 (d, J = 6.5 Hz, 1H), 8.62(d, J = 2.3 Hz, 1H), 8.55 (dd, J = 9.0, 2.3 Hz, 1H), 8.25 – 8.17 (m, 3H),8.11 – 7.97 (m, 3H), 7.62 (d, J = 9.2 Hz, 1H), 5.02 – 4.87 (m, 1H), 3.96 –3.81 (m, 2H), 3.65 – 3.49 (m, 3H), 3.47 – 3.29 (m, 4H), 2.80 (s, 3H), 2.10 –2.02 (m, 2H), 1.79 – 1.70 (m, 2H), 1.28 (s, 9H)。

the following compounds were obtained analogously:

5- {2- [4- (4-methyl-piperazine-1-carbonyl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A17")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and 1-methyl-piperazine; HPLC/MS 1.60 min, [ M + H ] = 523;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.91 (dd, J = 6.3, 2.9 Hz, 1H),8.67 (t, J = 2.5 Hz, 1H), 8.61 (dd, 1H), 8.30 (dd, J = 8.4, 2.0 Hz, 2H), 8.26(dd, J = 6.3, 2.6 Hz, 1H), 8.05 (d, J = 3.5 Hz, 1H), 7.78 – 7.73 (m, 2H),7.66 (dd, J = 9.1, 3.8 Hz, 1H), 5.09 – 4.96 (m, 1H), 4.55 (d, J = 119.7 Hz,1H), 4.03 – 3.77 (m, 3H), 3.70 – 3.33 (m, 6H), 3.21 (t, J = 11.2 Hz, 2H),2.91 (s, 3H), 2.17 – 2.07 (m, 2H), 1.88 – 1.76 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzamide ("A18")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and ammonia; HPLC/MS 1.96 min, [ M + H ] = 440;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.92 – 8.88 (m, 1H), 8.68 (d,1H), 8.62 (dd, 1H), 8.32 – 8.23 (m, 3H), 8.18 (d, 2H), 8.06 (dd, 1H), 7.68(dd, J = 7.3 Hz, 1H), 5.07 – 4.97 (m, 1H), 4.02 – 3.91 (m, 2H), 3.69 – 3.57(m, 2H), 2.19 – 2.09 (m, 2H), 1.89 – 1.77 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N-methyl-benzamide ("A19")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and methylamine; HPLC/MS 2.04 min, [ M + H ] = 454;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.89 (dd, J = 6.3, 1.6 Hz, 1H),8.68 (t, 1H), 8.62 (dd, 1H), 8.28 (d, 2H), 8.24 (dd, 1H), 8.13 (d, J = 8.4Hz, 2H), 8.04 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 9.2, 1.8 Hz, 1H), 5.07 –4.99 (m, 1H), 4.01 – 3.90 (m, 2H), 3.68 – 3.59 (m, 2H), 2.90 (s, 3H), 2.18 –2.08 (m, 2H), 1.89 – 1.74 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N-ethyl-benzamide ("A20")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and ethylamine; HPLC/MS 2.13 min, [ M + H ] = 468;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.87 (dd, J = 6.3, 2.0Hz, 1H),8.66 (t, J = 1.9 Hz, 1H), 8.60 (dd, 1H), 8.27 (d, 2H), 8.23 (dd, J = 6.4, 2.0Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.64 (dd, J =9.2, 2.2 Hz, 1H), 5.07 – 4.97 (m, 1H), 4.03 – 3.93 (m, 2H), 3.67 – 3.58 (m,2H), 3.41 (q, J = 7.2 Hz, 2H), 2.17 – 2.09 (m, 2H), 1.90 – 1.76 (m, 2H), 1.22(t, J = 7.2 Hz, 3H)；

n- (2-tert-butoxy-ethyl) -4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzamide ("A21")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and 2-tert-butoxyethylamine; HPLC/MS 2.34 min, [ M + H ] = 540;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.90 (dd, J = 6.3, 1.9 Hz, 1H),8.68 (t, J = 2.0 Hz, 1H), 8.62 (dd, 1H), 8.29 (d, J = 8.5, 1.4 Hz, 2H), 8.25(dd, J = 6.4, 1.8 Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 2.2 Hz,1H), 7.68 (dd, J = 9.2, 2.3 Hz, 1H), 5.07 – 5.00 (m, 1H), 4.00 – 3.92 (m,2H), 3.70 – 3.59 (m, 3H), 3.56 – 3.49 (m, 2H), 3.49 – 3.41 (m, 2H), 2.17 –2.07 (m, 2H), 1.88 – 1.77 (m, 2H), 1.18 (s, 9H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-methoxy-ethyl) -benzamide ("A22")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and 2-methoxy-ethylamine; HPLC/MS 2.08 min, [ M + H ] = 498;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.88 (dd, J = 6.3, 1.3 Hz, 1H),8.67 (s, 1H), 8.61 (dd, J = 9.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 2H), 8.24 (dd,J = 6.4, 1.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 1.6 Hz, 1H),7.66 (dd, 1H), 5.02 (d, J = 3.7 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.69 – 3.61 (m,2H), 3.56 (s, 4H), 3.34 (s, 3H), 2.20 – 2.08 (m, 2H), 1.88 – 1.79 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N, N-dimethyl-benzamide ("A23")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and dimethyl-amine; HPLC/MS 2.08 min, [ M + H ] = 468;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.89 (dd, J = 6.3, 1.4 Hz, 1H),8.66 (s, 1H), 8.63 (dd, 1H), 8.30 – 8.21 (m, 3H), 8.01 (d, J = 1.5 Hz, 1H),7.71 – 7.64 (m, 3H), 5.07 – 4.98 (m, 1H), 4.03 – 3.93 (m, 2H), 3.68 – 3.60(m, 2H), 3.08 (s, 3H), 2.99 (s, 3H), 2.19 – 2.08 (m, 2H), 1.88 – 1.77 (m,2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N-ethyl-N-methyl-benzamide ("A24")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and ethyl-methyl-amine; HPLC/MS 2.17 min, [ M + H ] = 482;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.90 (dd, J = 6.3, 1.6 Hz, 1H),8.67 (s, 1H), 8.64 (d, J = 9.1 Hz, 1H), 8.31 – 8.23 (m, 3H), 8.03 (d, 1H),7.72 – 7.61 (m, 3H), 5.12 – 4.98 (m, 1H), 4.00 – 3.92 (m, 2H), 3.67 – 3.58(m, 2H), 3.42 (d, J = 130.1 Hz, 2H), 3.04 (s, 3H), 2.19 – 2.09 (m, 2H), 1.88– 1.75 (m, 2H), 1.17 (t, J = 40.6 Hz, 3H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-hydroxy-ethyl) -N-methyl-benzamide ("A25")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and 2-methylamino-ethanol; HPLC/MS 1.89 min, [ M + H ] = 498;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.80 (dd, J = 6.2, 3.1 Hz, 1H),8.62 – 8.51 (m, 2H), 8.22 – 8.12 (m, 3H), 7.92 (s, 1H), 7.65 – 7.52 (m, 3H),5.00 – 4.89 (m, 1H), 3.94 – 3.82 (m, 2H), 3.65 (s, 1H), 3.59 – 3.46 (m, 4H),3.28 (s, 1H), 2.97 (d, J = 26.3 Hz, 3H), 2.10 – 1.99 (m, 2H), 1.79 – 1.68 (m,2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-methoxy-ethyl) -N-methyl-benzamide ("A26")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and (2-methoxy-ethyl) -methyl-amine; HPLC/MS 2.11 min, [ M + H ] = 512;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.90 (dd, J = 6.3, 2.7 Hz, 1H),8.67 (dd, J = 2.2 Hz, 1H), 8.63 (dd, J = 9.0, 2.2 Hz, 1H), 8.32 – 8.22 (m,3H), 8.02 (s, 1H), 7.71 – 7.63 (m, 3H), 4.04 – 3.88 (m, 2H), 3.77 – 3.59 (m,5H), 3.56 – 3.42 (m, 2H), 3.31 (s, 3H), 3.05 (s, 3H), 2.21 – 2.06 (m, 2H),1.92 – 1.75 (m, 2H)；

3- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N-ethyl-N- (2-methoxy-ethyl) -benzamide ("A26a")

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.92 (d, J = 6.3 Hz, 1H), 8.70(d, J = 2.4 Hz, 1H), 8.61 (dd, J = 9.0, 2.4 Hz, 1H), 8.26 (d, J = 6.3 Hz,2H), 8.22 (s, 1H), 8.12 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 6.9Hz, 1H), 5.09 – 5.00 (m, 1H), 3.99 – 3.91 (m, 2H), 3.66 – 3.13 (m, 11H), 2.16– 2.08 (m, 2H), 1.85 – 1.73 (m, 2H), 1.25 – 1.07 (m, 3H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-dimethylamino-ethyl) -benzamide ("A27")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and N1, N1-dimethyl-ethane-1, 2-diamine; HPLC/MS 1.66 min, [ M + H ] = 511;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.91 (dd, J = 6.3, 2.9 Hz, 1H),8.69 (d, J = 2.3 Hz, 1H), 8.61 (dd, 1H), 8.33 (dd, J = 8.5, 1.9 Hz, 2H), 8.26(dd, J = 6.3, 2.6 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 2.2 Hz,1H), 8.07 (d, J = 3.5 Hz, 1H), 7.66 (dd, J = 9.1, 3.5 Hz, 1H), 5.07 – 4.99(m, 1H), 4.02 – 3.93 (m, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.69 – 3.60 (m, 2H),3.39 (t, J = 5.8 Hz, 2H), 2.94 (d, J = 7.8 Hz, 6H), 2.20 – 2.07 (m, 2H), 1.88– 1.77 (m, 2H)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-dimethylamino-ethyl) -N-methyl-benzamide ("A28")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and N, N' -trimethyl-ethane-1, 2-diamine; HPLC/MS 1.62 min, [ M + H ] = 525;

¹H NMR (500 MHz, DMSO-d₆)[ppm]8.91 (1 H, d, J 6.3), 8.68 (1 H, d, J2.0), 8.61 (1 H, dd, J 9.0, 2.3), 8.28 (3 H, dd, J 17.0, 7.4), 8.10 (1 H, s),8.04 (1 H, d, J 7.4), 7.77 (2 H, d, J 7.9), 7.67 (1 H, d, J 9.1), 5.03 (1 H,m), 3.95 (4 H, m), 3.64 (2 H, m), 3.47 (2 H, s), 3.02 (8 H, d, J 27.5), 2.14(2 H, m), 1.84 (2 H, m)；

4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoyl) -piperazine-1-carboxylic acid tert-butyl ester ("A29")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoic acid and piperazine-1-carboxylic acid tert-butyl ester; HPLC/MS 2.41 min, [ M + H ] = 609;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.88 (d, J = 6.3 Hz, 1H), 8.65(d, J = 2.2 Hz, 1H), 8.61 (dd, J = 9.0, 2.3 Hz, 1H), 8.27 (d, J = 8.3 Hz,2H), 8.23 (d, J = 6.4 Hz, 1H), 8.00 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.63(d, 1H), 5.07 – 4.97 (m, 1H), 4.02 – 3.89 (m, 2H), 3.73 – 3.59 (m, 4H), 3.58– 3.33 (m, 6H), 2.19 – 2.08 (m, 2H), 1.89 – 1.81 (m, 2H), 1.45 (s, 9H)；

5- {2- [ 3-methoxy-4- (2-oxa-6-aza-spiro [3.3] heptane-6-carbonyl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile ("A30")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid and 2-oxa-6-azaspiro [3.3] heptane oxalate; HPLC/MS 2.041 min, [ M + H ] = 552;

¹H NMR (500 MHz, DMSO-d₆)[ppm]8.58 (1 H, d, J 5.5), 8.56 (1 H, d, J2.4), 8.44 (1 H, dd, J 9.0, 2.4), 7.89 (1 H, s), 7.70 (2 H, dd, J 5.8, 3.2),7.63 (2 H, d, J 9.2), 7.46 (1 H, d, J 7.8), 4.98 (1 H, tt, J 7.8, 3.8), 4.69(4 H, dd, J 24.5, 6.9), 4.20 (2 H, s), 4.11 (2 H, d, J 8.0), 3.98 (3 H, s),3.89 (2 H, m), 3.58 (2 H, ddd, J 11.5, 8.4, 3.1), 2.08 (2 H, m), 1.72 (2 H,dtd, J 12.4, 8.2, 3.8)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-dimethylamino-ethyl) -N-ethyl-2-methoxy-benzamide ("A31")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid and N, N-dimethyl-N' -ethylethylenediamine; 1,728 min, [ M + H ] =569 HPLC/MS;

¹H NMR (400 MHz, DMSO-d₆)[ppm]8.58 (1 H, d, J 5.1), 8.55 (1 H, d, J2.4), 8.44 (1 H, dd, J 8.9, 2.4), 7.85 (1 H, d, J 3.3), 7.69 (2 H, d, J 5.1),7.64 (2 H, ddd, J 8.7, 5.0, 3.7), 7.33 (1 H, dd, J 7.8, 4.8), 4.97 (1 H, m),3.91 (5 H, m), 3.56 (6 H, m), 3.16 (2 H, dd, J 16.0, 9.0), 2.30 (4 H, m),2.07 (2 H, m), 1.97 (2 H, s), 1.72 (2 H, dtd, J 12.3, 8.2, 3.8), 1.07 (3 H,dt, J 63.3, 7.1)；

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-dimethylamino-ethyl) -2-methoxy-benzamide ("A32")

From 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoic acid and N, N-dimethylethylenediamine; HPLC/MS 1,713 min, [ M + H ] = 541;

¹H NMR (400 MHz, DMSO-d₆)[ppm]8.59 (1 H, d, J 5.1), 8.55 (1 H, d, J2.4), 8.43 (1 H, dd, J 9.0, 2.4), 8.36 (1 H, t, J 5.3), 7.96 (1 H, d, J 8.1),7.90 (1 H, s), 7.70 (3 H, ddd, J 11.5, 8.5, 1.4), 7.62 (1 H, d, J 9.1), 4.97(1 H, tt, J 7.8, 3.8), 4.05 (3 H, s), 3.90 (2 H, m), 3.58 (2 H, m), 3.42 (2H, m), 2.52 (2 H, m), 2.28 (6 H, s), 2.08 (2 H, m), 1.73 (2 H, m)。

and step 3: 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N (2-methylamino-ethyl) -benzamide ("A15")

Tert-butyl [2- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } benzoyl-amino) -ethyl ] -methyl-carbamate (59.0 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml). Trifluoro-acetic acid (1 ml, 12.98 mmol) was added to the solution. The mixture was stirred at rt for 16 h. The solvent was removed in vacuo; this gave 20mg of 4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-methyl-amino-ethyl) -benzamide trifluoroacetate; HPLC/MS 1.61 min, [ M + H ] = 497;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.91 (dd, 1H), 8.69 (d, 1H),8.60 (dd, J = 10.7, 5.6 Hz, 1H), 8.32 (d, J = 6.5 Hz,2H), 8.26 (dd, 1H),8.18 (dd, J = 8.4, 1.8 Hz, 2H), 8.06 (dd, 1H), 7.67 (dd, J = 8.6, 3.0 Hz,1H), 5.12 – 4.97 (m, 1H), 4.01 – 3.92 (m, 2H), 3.73 – 3.60 (m, 4H), 3.21 (t,J = 5.3 Hz, 2H), 2.68 (s, 3H), 2.18 – 2.10 (m, 2H), 1.88 – 1.76 (m, 2H)。

the following compounds were obtained analogously:

4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -N- (2-hydroxy-ethyl) -benzamide ("A33")

From N- (2-tert-butoxy-ethyl) -4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzamide; HPLC/MS 1.90 min, [ M + H ] = 484;

¹H NMR (500 MHz, DMSO-d₆)[ppm]8.57 (1 H, m), 8.47 (1 H, m), 8.11 (1H, d, J 8.5), 8.03 (1 H, d, J 8.5), 7.85 (1 H, s), 7.69 (1 H, d, J 5.1), 7.65(1 H, d, J 9.0), 4.98 (1 H, tt, J 7.9, 3.8), 4.73 (1 H, t, J 5.6), 3.90 (1 H,m), 3.57 (2 H, m), 3.37 (1 H, q, J 6.0), 2.08 (1 H, m), 1.73 (1 H, m)；

5- {2- [4- (piperazine-1-carbonyl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile x TFA ("A34")

From 4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -benzoyl) -piperazine-1-carboxylic acid tert-butyl ester; HPLC/MS 1.60 min, [ M + H ] = 509;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.89 (dd, J = 6.1, 4.1 Hz, 1H),8.66 (d, 1H), 8.61 (dd, 1H), 8.28 (dd, J = 8.3, 2.6 Hz, 2H), 8.24 (dd, J =6.1, 3.7 Hz, 1H), 8.03 (d, 1H), 7.75 (dd, J = 8.3, 2.0 Hz, 2H), 7.65 (dd, J =8.1, 5.8 Hz, 1H), 5.08 – 4.93 (m, 1H), 4.02 – 3.56 (m, 8H), 3.27 (s, 4H),2.21 – 2.05 (m, 2H), 1.87 – 1.77 (m, 2H)；

5- {2- [ 3-methoxy-4- (piperazine-1-carbonyl) -phenyl ] -furo [3,2-b ] pyridin-7-yl } -2- (tetrahydro-pyran-4-yloxy) -benzonitrile x TFA ("A35")

From 4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -2-methoxy-benzoyl) -piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid; HPLC/MS 1.63 min, [ M + H ] = 539;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁)[ppm]8.89 (1 H, d, J 6.3), 8.72 (1H, d, J 2.4), 8.58 (1 H, dd, J 9.0, 2.4), 8.25 (1 H, d, J 6.4), 8.10 (1 H,s), 7.87 (2 H, d, J 5.1), 7.62 (1 H, d, J 9.2), 7.55 (1 H, d), 5.02 (1 H, m),4.06 (3 H, s), 3.97 (4 H, m), 3.64 (2 H, m), 3.50 (2 H, m), 3.24 (4 H, m),2.13 (2 H, m), 1.84 (2 H, m)；

4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -pyrazol-1-yl) -piperidine xTFA ("A36")

From 4- (4- {7- [ 3-cyano-4- (tetrahydro-pyran-4-yloxy) -phenyl ] -furo [3,2-b ] pyridin-2-yl } -pyrazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester; HPLC/MS 1.50 min, [ M + H ] = 470;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁)[ppm]8.77 (1 H, d, J 6.4), 8.70 (1H, s), 8.61 (1 H, d, J 2.4), 8.57 (1 H, dd, J 9.0, 2.4), 8.34 (1 H, s), 8.12(1 H, d, J 6.5), 7.62 (1 H, d, J 9.2), 7.56 (1 H, s), 5.01 (1 H, tt, J 7.6,3.7), 4.73 (1 H, m), 3.97 (2 H, m), 3.63 (2 H, ddd, J 11.6, 7.4, 3.3), 3.53(2 H, d, J 13.0), 3.20 (2 H, td, J 13.0, 8.4), 2.33 (4 H, m), 2.13 (2 H, m),1.83 (2 H, dtd, J 12.1, 8.1, 3.8)。

synthesis of N-ethyl-N- (2-methoxy-ethyl) -3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide

Step 1: N-ethyl-N- (2-methoxy-ethyl) -3-boronic acid-2-yl) -benzamide

3-carboxyphenylboronic acid (500 mg, 3.01 mmol) and ethyl- (2-methoxy-ethyl) -amine (373 mg,3.62 mmol) were dissolved in 5 ml DMSO. 2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate methylammonium (HATU) (1718 mg, 4.52 mmol) and N-methylmorpholine (457 mg, 4.52 mmol) were added to the solution. The mixture was stirred at room temperature for 2 h. After vacuum concentration, the product is separated by chromatography; to yield 700mg of N-ethyl-N- (2-methoxy-ethyl) -3-boronic acid-2-yl) -benzamide; HPLC/MS: 1.394 min, [ M + H ] = 252.

The following compounds were obtained analogously:

3-methoxy-4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenylboronic acid

From 3-methoxy-4-carboxyphenylboronic acid and 1-piperazinecarboxylic acid tert-butyl ester; HPLC/MS 1.765 min, [ M + H ] = 365.

Step 2: N-ethyl-N- (2-methoxy-ethyl) -3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide

Reacting 3- [ ethyl- (2-methoxy-ethyl) -carbamoyl in 200 ml of dry toluene]Boronic acid (700mg, 2.79 mmol), 2, 3-dimethyl-butane-2, 3-diol (329 mg, 2.79 mmol) and 48 mg toluene-4-sulfonic acid were refluxed in a Dean-Stark appatus (Dean-Stark appaatus) 3. After cooling to room temperature, the mixture was washed with aqueous bicarbonate solution. With Na₂SO₄After drying the organic layer, filtering and removing the solvent in vacuo, the product was isolated; 880 mg of N-ethyl-N- (2-methoxy-ethyl) -3- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxa-borolan-2-yl) benzamide; HPLC/MS 2.23 min, [ M + H ]]= 334。

The following compounds were obtained analogously:

4- [ 2-methoxy-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoyl ] -piperazine-1-carboxylic acid tert-butyl ester

From 3-methoxy-4- (4- (tert-butoxycarbonyl) piperazin-1-yl) phenylboronic acid and pinacol; HPLC/MS 2.46 min, [ M + H ] = 447;

¹H NMR (400 MHz, DMSO-d₆)[ppm]7.31 (1 H, dd, J 7.3, 0.8), 7.24 (1 H,s), 7.20 (1 H, d, J 7.3), 3.81 (3 H, s), 3.58 (2 H, m), 3.37 (2 H, m), 3.25(2 H, m), 3.07 (2 H, m), 1.40 (9 H, s), 1.31 (12 H, s)。

synthesis of 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole

4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (19.4 g,0.10 mol), 1-bromo-2-methoxy-ethane (14.18 ml, 0.15 mol) and cesium carbonate (32.58 g,0.1 mol) were dissolved in DMF (200 ml). The suspension was stirred at 80 ℃ for 16 h, filtered and the solvent removed in vacuo. The residue was treated with tert-butyl methyl ether (200 ml), filtered through Celite (Celite), and the solvent removed in vacuo; to give 25.4 g of 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole; HPLC/MS: 1.82min, [ M + H ] = 253.

Synthesis of 1-methyl-4- [3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -piperazine

Step 1: 1- (3-bromo-phenyl) -4-methyl-piperazine

1-methyl-piperazine (1 ml, 8.99 mmol) and 1, 3-dibromo-benzene (3 ml, 24.82 mmol) were heated to 200 ℃ under microwave irradiation in a sealed tube for 300 min (150W, 9 bar). The residue was diluted with tert-butyl methyl ether (50 ml) and extracted with 1M HCl. The aqueous layer was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate (150 ml). The organic layer was separated and MgSO₄And (5) drying. Filtering the drying agent and removing the solvent in vacuo; obtained 700mg1- (3-bromo-phenyl) -4-methyl-piperazine; HPLC/MS 1.24 min, [ M + H ]]= 255。

Step 2: 1-methyl-4- [3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl ] -piperazine

To 1- (3-bromo-phenyl) -4-methyl-piperazine (0.7 g, 2.73mmol) in 1,4 dioxane (100 ml) was added bis (pinacolato) diboron (1.04 g, 4.09 mmol), KOAc (0.80 g, 8.19 mmol) and Pd (dppf) Cl₂(111 mg, 0.14 mmol). The mixture was heated to 90 ℃ for 3h, quenched with water (100 ml) and then extracted with EtOAc. The organic layer was separated, washed with brine and over Na₂SO₄And (5) drying. The drying agent was filtered and the solvent removed in vacuo. The product was isolated by chromatography (DCM/EtOH); 198 mg of 1-methyl-4- [3- (4,4,5, 5-tetramethyl- [1,3,2] are obtained]Dioxa-borolan-2-yl) -phenyl]-piperazine; HPLC/MS 1.48 min, [ M + H ]]= 303。

The following compounds were obtained analogously

Compounds according to the invention inhibit IC of TBK1 and IKK₅₀Value of

IC₅₀：<0.3 M = A 0.3- 3 M = B 3-50 M = C

The following examples relate to medicaments:

example A injection vial

A solution of 100g of the active ingredient of the formula I and 5g of disodium hydrogen phosphate in 3l of bidistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active ingredient.

Example B suppository

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

Example C: solutions of

Comprises 1 g of active ingredient of formula I, 9.38 g of NaH₂PO₄∙2 H₂O、28.48g Na₂HPO₄∙12 H₂A solution of O and 0.1 g benzalkonium chloride in 940ml double distilled water was prepared. The pH was adjusted to 6.8 and the solution was made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D: ointment formulation

500mg of the active ingredient of the formula I are mixed with 99.5g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets, each tablet obtained in this manner containing 10mg of active ingredient.

Example F: sugar-coated pill

Tablets were compressed analogously to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G capsules

2 kg of active ingredient of the formula I are introduced into hard gelatin capsules in a conventional manner, each capsule obtained in such a way containing 20mg of active ingredient.

Example H: ampoule (CN)

A solution of 1 kg of the active ingredient of the formula I in 60 l of bidistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Claims (3)

1. A compound selected from

And pharmaceutically acceptable salts thereof.

2. A medicament comprising at least one compound of formula I according to claim 1 and/or a pharmaceutically acceptable salt thereof, and optionally excipients and/or auxiliaries.

3. Use of a compound according to claim 1, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of cancer, septic shock, Primary Open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/or neurodegenerative diseases.