Novel substituted indole-2-carboxamides as PHGDH inhibitors

Abstract

The present invention relates to compounds of formula (I) wherein the groups R1 to R8 have the meanings given in the claims and the description, their use as PHGDH inhibitors, pharmaceutical compositions comprising said compounds and their use as medicaments, in particular as medicaments for the treatment and / or prophylaxis of neoplastic diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel indole-2-carboxamides of formula (I):

[0002]

[0003] wherein the groups R1 to R8 have the meanings given in the claims and the description, their use as PHGDH inhibitors, pharmaceutical compositions comprising said derivatives and their use as medicaments, in particular as agents for the treatment and / or prophylaxis of tumour diseases. Background Art

[0004] The important contribution of the serine synthesis pathway (SSP) to tumorigenesis has been demonstrated by numerous studies. Serine (Ser) is a non-essential amino acid that is indispensable for several cellular processes that are particularly important for tumor cells: (i) Ser can be converted to glycine via the action of serine hydroxymethyltransferase (SHMT), thereby providing carbon units for purine nucleotide synthesis (Kalhan & Hanson, J Biol Chem. (2012) 287:19786-19791; Locasale, Nat Rev Cancer. (2013) 13:572-583; Amelio et al., Trends Biochem Sci. (2014) 39:191-198; Mehrmohamadi & Locasale Mol Cell Oncol. (2015) 2:e996418; Tedeschi et al., Cell Death Dis. (2013) 4:e877). (ii) Ser can react with hexadecanoyl-CoA to provide sphingosine required for the generation of sphingolipids that make up the cell membrane (Ravez et al., J. Med. Chem. (2017) 60, 4:1227-1237; Xu et al., J Biol Chem. (1991) 266:2143-2150). (iii) Ser serves as a precursor for several amino acids such as glycine and cysteine (Vazquez et al., Cancer Res. (2013) 73:478-482; Ravez et al., J. Med. Chem. (2017) 60, 4:1227-1237). (iv) Since serine is involved in the production of NADPH, Ser plays a crucial role in the regulation of the redox state (Tedeschi et al., Cell Death Dis. (2013) 4:e877). (v) Last but not least, PHGDH (a key enzyme for de novo synthesis of SSP) has been shown to produce the oncometabolite D-2-hydroxyglutarate (D-2HG), which is associated with epigenetic deregulation in tumor cells (Mondesir et al., J Blood Med. (2016) 7:171-180; Fan et al., ACS Chem Biol. (2015) 10:510-516). SSP not only provides essential building blocks / metabolites, but also epigenetic regulators, and Ser and its synthesis pathway critically contribute to cell proliferation, tumor metastasis, and dedifferentiation of cancer cells (Mattaini et al., J Cell Biol. (2016) 214:249-257; El-Hattab, Mol Genet Metab. (2016) 118:153-159).

[0005] De novo synthesis of Ser is triggered via SSP. SSP diverts 3-PG from glycolysis to generate Ser as well as equimolar amounts of reduced nicotinamide adenine dinucleotide (NADH) and α-ketoglutarate (α-KG). SSP consists of three consecutive enzymatic reactions. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step and produces 3-phosphopyruvate (3-PPyr) by NAD+-coupled oxidation of 3-PG. Subsequently, 3-PPyr is converted to phosphoserine by phosphoserine aminotransferase 1 (PSAT-1) and then to serine by the action of phosphoserine phosphatase (PSPH). Finally, Ser can be converted to glycine by SHMT.

[0006] Elevated rates of SSP have been observed in neoplastic tissues from diverse sources (Snell & Weber, Biochem J. (1986) 233:617 - 620; DeBerardinis, Cell Metab. (2011) 14:285 - 286) and are associated with tumorigenesis in which PHGDH is a key enzyme (DeBerardinis, Cell Metab. (2011) 14:285 - 286). PHGDH has been shown to be amplified / overexpressed in melanoma and breast cancer (Beroukhim et al., Nature. (2010) 463:899 - 8905; Locasale et al., Nat Genet. (2011) 43:869 - 874; Possemato et al., Nature. (2011) 476:346 - 350). Additionally, recent studies have identified several factors that act as activators of SSP in tumor cells and also determine cancer pathogenesis, such as general control non - repressible 2 kinase (GCN2) that leads to the expression of activating transcription factor 4 (ATF4). Similarly, in human non - small cell lung cancer, ATF4 can also be induced by transcription factor nuclear factor erythroid - 2 - related factor 2 (NRF2) (Wang et al., Neoplasia. (2013) 15:989 - 997; DeNicola et al., Nat Genet. (2015) 47:1475 - 1481). MYC also activates SSP by transcriptionally upregulating the expression of SSP enzymes under glucose or glutamine deprivation (Sun et al., Cell Res. (2015) 25:429 - 444). Most importantly, recent studies have shown that hypoxia induces the expression of SSP enzymes and this phenomenon is mediated by HIF - 1 and HIF - 2 in a large panel of breast cancer cell lines (Samanta et al., Cancer Res. (2016) 76:4430 - 4442). Finally, the tumor suppressors PKC - ζ and p53 have been reported to inhibit the expression of PHGDH (Ma et al., Cell. (2013) 152:599 - 611; Ou et al., J Biol Chem. (2015) 290:457 - 466; Maddocks et al., Nature. (2013) 493:542 - 546). Thus, the loss of PKC - ζ or p53 in cancer cells promotes the activity of PHGDH and drives SSP.

[0007] Knockout of PHGDH inhibits the growth of cancer cell lines that include PHGDH amplification and / or PHGDH overexpression, but has no effect on cell lines that express PHGDH at normal levels (Luo, Breast Cancer Res. (2011) 13:317; Possemato et al., Nature. (2011) 476:346-350). Possemato et al. developed a negative selection RNAi screen using a mouse orthotopic human breast cancer xenograft model in 2011 to identify novel cancer targets (Possemato et al., Nature. (2011) 476:346-350). This method highlighted PHGDH as a gene required for tumorigenesis and breast cancer progression in vivo (Samanta et al., Cancer Res. (2016) 76:4430-4442) and this gene is located in a genomic region with recurrent copy number increases in breast cancer. Subsequently, it was found that the SSP enzyme most abundantly expressed in basal-like TNBC tissues is PHGDH, and the PHGDH expression level is negatively correlated with clinical prognostic factors (Noh et al., Tumour Biol. (2014) 35:4457-4468; Ravez et al., J Med Chem. (2017) 60(4):1227-1237). In addition, knockout of PHGDH in melanoma cells selectively inhibits the growth of cells that exhibit the amplification compared to cells lacking PHGDH amplification (Locasale et al., Nat Genet. (2011) 43:869-874; Mullarky et al., Pigment Cell Melanoma Res. (2011) 24:1112-1115). The prognostic significance of PHGDH amplification / overexpression has been clearly demonstrated for colon cancer (Yoon et al., Oncology. (2015) 89:351-359; Jia et al., Transl Oncol. (2016) 9:191-196), glioma (Liu et al., J Neurooncol. (2013) 111:245-255), cervical adenocarcinoma (Jing et al., Cancer Biol Ther. (2015) 16:541-548) and lung adenocarcinoma (DeNicola et al., Nat Genet. (2015) 47:1475-1481; Amelio et al., Oncogene. (2014) 33:5039-5046).In thyroid cancer, a higher ratio of B-Raf V600E mutation to PHGDH expression was demonstrated in comparison with non-mutated cases (Chen et al., Int J Mol Med. (2015) 36:1607-1614; Sun et al., J Transl Med. (2016) 14:168). Interestingly, in leukemia, an increase in oxidative stress upon inhibition of glutamine metabolism was identified as a trigger for PHGDH upregulation. Silencing of PHGDH inhibited leukemia cell growth, thus identifying serine as a key survival factor (Polet et al., Oncotarget. (2016) 7:1765-1776).

[0008] Recently, it has been demonstrated that PHGDH catalyzes the NADH-dependent reduction of α-ketoesters of glutaric acid to the oncometabolite D-2-hydroxyglutarate (D-2HG) (Fan et al., ACS Chem Biol. (2015) 10:510-516). Initially, D-2HG was identified as an oncometabolite that causes the inhibition of several demethylases, thereby altering the epigenetic landscape in tumor cells (Prensner & Chinnaiyan, Nature Medicine (2011) 17:291–293). D-2HG is produced in large amounts in gliomas (Xu et al., Cancer Cell. (2011) 19:17-30; Rossetto et al., Rev Neurol (Paris) (2011) 167:699-703) and acute myeloid leukemia (Ward et al., Cancer Cell. (2010) 17:225-234; Ward et al., Oncogene. (2012) 31:2491-2498) by mutant isocitrate dehydrogenases. Most interestingly, in breast cancer, PHGDH has been identified as the enzymatic driver of D-2HG production (Fan et al., ACS Chem Biol. (2015) 10:510-516). Terunuma and colleagues performed a detailed metabolic study of human breast tumors and used untargeted discovery methods and validation of key metabolites to identify the intrinsic metabolic signatures of these tumors. D-2HG accumulates at high levels in those breast cancer tumors in which activation of the MYC pathway is observed. Most importantly, MYC-driven D-2HG accumulation is associated with poor prognosis in breast cancer (Terunuma et al., J Clin Invest. (2014) 124:398-412). As shown, MYC particularly regulates the enzymes of the glycolytic pathway (Stine et al., Cancer Discov. (2015) 5:1024-39). PHGDH amplification and / or overexpression in breast cancer may potentially affect cellular physiology through D-2HG overproduction by a pathway similar to that shown in gliomas and AML (see above) (e.g., DNA methylation).

[0009] The mechanisms by which PHGDH supports tumorigenesis may be diverse, but the enzymatic function of PHGDH is a prerequisite that critically contributes to the cell proliferation, invasion, and tumorigenicity of cancer cells. All of these data strongly support PHGDH as an attractive drug target in tumors that overexpress PHGDH or have inhibited PHGDH gene amplification.

[0010] Based on indole-2-carboxamide NAD +- Competitive PHGDH inhibitors were disclosed in 2015 and published in 2016, demonstrating AstraZenca's fragment-based drug discovery (Fuller et al., Drug discovery today (2016), 21(8), 1272 - 83). These compounds lack cellular potency.

[0011] WO 2018 / 167019 discloses compounds based on acetic acid p-toluenesulfonyl ester, which are potent and selective PHGDH inhibitors with nanomolar biomarker modulation ability.

[0012] Weinstabl et al., J. Med. Chem., 2019, 62, 7976 - 7997 reported a carboxylic acid based on acetic acid p-toluenesulfonyl ester (which is a selective and potent PHGDH inhibitor) and its ester prodrugs.

[0013] In WO 2017 / 156179, RAZE THERAPEUTICS INC. described indole-based PHGDH inhibitors.

[0014] However, orally bioavailable PHGDH inhibitors have not been reported. In addition, there are no prior art compounds known to inhibit PHGDH and simultaneously exhibit good permeability properties.

[0015] Therefore, an object of the present invention is to provide novel compounds that can inhibit PHGDH and also have permeability. Detailed Description

[0016] Now, it has surprisingly been found that the compounds of formula (I) as defined below are PHGDH inhibitors and have good oral bioavailability and permeability properties. Accordingly, the compounds according to the present invention can be used, for example, in the treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer.

[0017] Accordingly, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0018]

[0019] Wherein:

[0020] R1, R2 and R3 are each independently selected from the following: hydrogen, C 1-3 alkyl and halogen;

[0021] R4 is C 1-4 alkyl;

[0022] R5 is C 1-3 alkyl or hydroxy-C 1-3 alkyl;

[0023] R6 and R7 together form a heterocyclic ring which contains one or more moieties selected from the group consisting of: -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)- and -S(O)2-, wherein said heterocyclic ring is optionally substituted with one or more substituents each independently selected from -C(O)C 1-3 alkyl and -N(H)COR a ;

[0024] R8 is hydrogen or C 1-3 alkyl;

[0025] R a is selected from the group consisting of: C 1-3 alkyl, -NH2, -N(H)C 1-3 alkyl and -N(C 1-3 alkyl)2.

[0026] The compounds of the present invention have chiral centers. Although not described separately (e.g., in the following examples and tables), all stereoisomers of the compounds are embodiments of the present invention and should be considered specifically disclosed, i.e., the compounds described (e.g., in the schemes and tables), the corresponding enantiomers and / or diastereomers not specifically described in the tables and the racemates of the two enantiomers are separate embodiments of the present invention. Preferred embodiments are the compounds disclosed in the examples.

[0027] In one aspect, the present invention relates to compounds of formula (I'):

[0028]

[0029] It should be understood that formula (I') is a subset of formula (I), and unless otherwise stated, the expression "compounds of formula (I)" or its grammatical variants also and equivalently refers to compounds of formula (I'). In addition, any aspect or embodiment of the present invention described with reference to one or more compounds of formula (I) also and equivalently applies to compounds of formula (I').

[0030] Preferred embodiments

[0031] In another aspect of the present invention, at least one of R1, R2 and / or R3 is a halogen.

[0032] In another aspect, at least one of R1 and / or R2 is a halogen.

[0033] In another aspect, R1 is a halogen.

[0034] In another aspect, R2 is hydrogen or a halogen.

[0035] In another aspect, each of R1 and R2 is independently hydrogen or a halogen.

[0036] In another aspect, each of R1 and R2 is independently selected from the following: hydrogen, fluorine, and chlorine.

[0037] In another aspect, R1 is a halogen and R3 is a C 1-3 alkyl.

[0038] In another aspect:

[0039] - Both R1 and R2 are halogens;

[0040] - R1 is a halogen and R2 is hydrogen;

[0041] - R1 is hydrogen and R2 is a halogen; or

[0042] - Both R1 and R2 are hydrogen.

[0043] In another aspect:

[0044] - R1 and R2 are fluorine;

[0045] - R1 and R2 are chlorine;

[0046] - R1 is fluorine and R2 is chlorine;

[0047] - R1 is chlorine and R2 is fluorine;

[0048] - R1 is chlorine and R2 is hydrogen;

[0049] - R1 is hydrogen and R2 is chlorine;

[0050] - R1 is fluorine and R2 is hydrogen; or

[0051] - R1 is hydrogen and R2 is fluorine.

[0052] In another aspect, R3 is a C 1-3 alkyl.

[0053] In another aspect, R3 is methyl.

[0054] In another aspect, R4 is methyl.

[0055] In another aspect, R5 is methyl or -CH2OH.

[0056] In another aspect, R5 is methyl.

[0057] In another aspect, R3, R4, and R5 are methyl.

[0058] In another aspect, the stereocenter of the carbon atom bonded to R5 has the (R) configuration.

[0059] In another aspect, R6 and R7 together form a heterocyclic ring containing one or more moieties selected from: -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)- and -S(O)2-, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from -C(O)C 1-3 alkyl and -N(H)COR a .

[0060] In another aspect, R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing one or more moieties selected from: -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)- and -S(O)2-, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from -C(O)C 1-3 alkyl and -N(H)COR a .

[0061] In another aspect of the invention, R6 and R7 together form a heterocyclic ring containing moieties selected from: -O-, -N(H)- and -S-, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from -C(O)C 1-3 alkyl and -N(H)COR a .

[0062] In another aspect, R6 and R7 together form a heterocyclic ring containing one or more moieties selected from: -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)- and -S(O)2-.

[0063] In another aspect, R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing moieties selected from: -O-, -N(H)- and -S-, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from -C(O)C 1-3 alkyl and -N(H)COR a .

[0064] In another aspect, R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing moieties selected from: -O-, -N(H)- and -S-.

[0065] In another aspect, R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing an oxygen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents each independently selected from -C(O)C 1-3 alkyl and -N(H)COR a substituted.

[0066] In another aspect, R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing an oxygen atom.

[0067] In another aspect, R6 and R7 together form a tetrahydropyran ring.

[0068] In another aspect, R6 and R7 together form:

[0069]

[0070] In the following aspects and other aspects with the same symbols, it should be understood that the dashed lines depict the points of attachment of R6 and R7 to the remainder of the compound of formula (I).

[0071] In another aspect, R8 is hydrogen.

[0072] In another aspect, R3, R4 and R5 are methyl, and R6 and R7 together form:

[0073]

[0074] In another aspect, R3, R4 and R5 are methyl, R8 is hydrogen, and R6 and R7 together form:

[0075]

[0076] In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is of formula (II):

[0077]

[0078] It should be understood that formula (II) is a subset of formula (I), and unless otherwise stated, the expression "compound of formula (I)" or its grammatical variants also and equivalently refers to the compound of formula (II). Furthermore, any aspect or embodiment of the invention described with reference to one or more compounds of formula (I) also and equivalently applies to the compound of formula (II).

[0079] In one aspect of formula (II), R8 is hydrogen.

[0080] In one embodiment, the compounds of the invention are selected from:

[0081]

[0082] or a pharmaceutically acceptable salt thereof.

[0083] It should be understood that all tautomers of the compounds of formula (I) (including all aspects and embodiments thereof) are disclosed herein and are part of the present invention independent of the compounds described.

[0084] All synthetic intermediates as generally defined herein and specifically disclosed, and their salts, are also part of the present invention.

[0085] All individual synthetic reaction steps as generally defined or specifically disclosed herein, and the reaction sequences including these individual synthetic reaction steps, are also part of the present invention.

[0086] The present invention further relates to hydrates, solvates, polymorphs, co-crystals, metabolites, derivatives, isomers and prodrugs of the compounds of formula (I) (including all aspects and embodiments thereof).

[0087] The present invention further relates to hydrates of the compounds of formula (I) (including all aspects and embodiments thereof).

[0088] The present invention further relates to solvates of the compounds of formula (I) (including all aspects and embodiments thereof).

[0089] The present invention further relates to pharmaceutically acceptable salts of the compounds of formula (I) (including all aspects and embodiments thereof).

[0090] The present invention further relates to pharmaceutically acceptable salts of the compounds of formula (I) (including all aspects and embodiments thereof) with inorganic or organic acids or bases.

[0091] Medical uses and treatment methods

[0092] The present invention relates to PHGDH inhibitors, in particular compounds of formula (I) (including all aspects and embodiments thereof), which can be used for preventing and / or treating diseases and / or conditions in which inhibition of PHGDH can have a therapeutic benefit, including but not limited to treating and / or preventing cancer.

[0093] In another aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.

[0094] In another aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for use in a method for treating a human or animal body.

[0095] In another aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof for treating and / or preventing diseases and / or conditions in which inhibition of PHGDH can have a therapeutic benefit.

[0096] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating and / or preventing cancer, infection, inflammation or autoimmune diseases.

[0097] In another aspect, the present invention relates to a method for treating and / or preventing cancer, infection, inflammation or autoimmune diseases in a human or animal body by using a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating and / or preventing cancer, infection, inflammation or autoimmune diseases.

[0099] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating and / or preventing cancer.

[0100] In another aspect, the present invention relates to a method for treating and / or preventing cancer in a human or animal body by using a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0101] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for preparing a pharmaceutical composition for treating and / or preventing cancer.

[0102] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating and / or preventing hematological cancer.

[0103] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating and / or preventing glioma, breast cancer, melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, cervical cancer, thyroid cancer (preferably BRAF mutant) and leukemia.

[0104] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating and / or preventing p53-mutated cancer, MYC-driven cancer and / or cancer with high D-2-hydroxyglutarate (D-2HG) levels.

[0105] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating and / or preventing hematological cancer.

[0106] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating and / or preventing glioma, breast cancer, melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, cervical cancer, thyroid cancer (preferably BRAF mutant) and leukemia.

[0107] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and / or prevention of p53-mutated cancer, MYC-driven cancer and / or cancer with high D-2HG levels.

[0108] In another aspect, the present invention relates to a method for the treatment and / or prevention of a disease and / or condition in which inhibition of PHGDH may have or has a therapeutic benefit, which comprises administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0109] As used herein, the expression "disease and / or condition in which inhibition of PHGDH may have or has a therapeutic benefit" includes, but is not limited to, any condition of PHGDH overexpression, amplification, mutation or general deregulation.

[0110] In another aspect, the present invention relates to a method for the treatment and / or prevention of a disease or condition selected from the group consisting of: cancer, infection, inflammation and / or autoimmune diseases, wherein the method comprises administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0111] In another aspect, the present invention relates to a method for the treatment and / or prevention of cancer, which comprises administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0112] For example, the compounds of the present invention can be used to treat the following cancers, tumors and other proliferative diseases, without limitation:

[0113] Head and neck cancer / tumor / carcinoma: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar triangle, floor of the mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of the tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including epiglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[0114] Lung cancer / tumor / carcinoma: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell carcinoma, mixed oat cell carcinoma);

[0115] Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma, germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, stromal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);

[0116] Gastrointestinal cancer / tumors / cancers: e.g., esophageal, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (including kidney, e.g., renal pelvis, renal cell carcinoma (RCC), Wilms' tumor, adrenal tumor, Grawitz tumor tumor); ureter; bladder, e.g., ureteral carcinoma, urothelial carcinoma; urethra, e.g., distal, mesial, prostate; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis);

[0117] Testicular cancer / tumor / carcinoma: e.g., seminoma, non-seminomatous carcinoma,

[0118] Gynecological cancers / tumors / cancers: for example, tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[0119] Breast cancer / tumor / cancer: for example, breast cancer (invasive ductal, colloid, invasive lobular, tubular, glandular cystic, papillary, medullary, mucinous), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), Her2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast;

[0120] Endocrine system cancers / tumors / carcinomas: e.g., endocrine glands, thyroid (thyroid carcinoma / tumor; papillary, follicular, anaplastic, medullary), parathyroid (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, paraganglion, pancreatic endocrine tumor (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumor / carcinoma / cancer;

[0121] Soft tissue sarcomas: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small round cell tumor;

[0122] Osteosarcomas: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0123] Mesotheliomas: e.g., pleural mesothelioma, peritoneal mesothelioma;

[0124] Skin cancers: for example, basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, uveal melanoma), actinic keratosis, eyelid cancer;

[0125] Neoplasms of the central nervous system and brain: for example, astrocytoma (brain, cerebellum, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, gemistocytic), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumors, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic), spinal axis tumors;

[0126] Lymphomas and leukemias: for example, B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastic lymphoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphocyte depletion HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myeloid / myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphoblastic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myelogenous leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0127] Cancer of unknown primary origin (CUP).

[0128] All of the above cancers / tumors / carcinomas characterized by their specific location / origin in the body mean including the primary tumor and metastatic tumors derived therefrom.

[0129] All of the above cancers / tumors / carcinomas can be further differentiated by their histopathological classification:

[0130] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic cell carcinoma;

[0131] Nonepithelial cancers, such as sarcoma (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumor, hematological neoplasm, mixed and undifferentiated carcinoma.

[0132] The compounds of the present invention can be used in treatment regimens in the context of first-line, second-line or any further-line treatment.

[0133] The compounds of the present invention can be used for the prevention, short-term or long-term treatment of the above diseases, optionally in combination with radiotherapy and / or surgery.

[0134] Pharmaceutical composition

[0135] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt as defined above, a pharmaceutically acceptable excipient and optionally one or more other pharmacologically active substances.

[0136] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0137] In another aspect, the present invention relates to a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other cell growth inhibitory substance and / or cytotoxic active substance.

[0138] Suitable pharmaceutical compositions for administering the compounds of the present invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions - particularly solutions for injection (s.c., i.v., i.m.) and infusion (injectables) - elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the compounds of the present invention should range from 0.1 to 90 wt.-% of the said composition as a whole, preferably 0.5 to 50 wt.-%, i.e., an amount sufficient to achieve the dosage ranges specified below. The specified dosage can be administered several times a day, if desired.

[0139] Suitable tablets can be obtained, for example, by mixing the compounds of the present invention with known excipients (such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants). The tablets can also comprise several layers.

[0140] Thus, coated tablets can be prepared by coating cores similar to those produced in tablet manufacture with substances and excipients commonly used for tablet coating (such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar). In order to achieve delayed release or prevent incompatibilities, the cores can also consist of several layers. Similarly, the tablet coating can consist of several layers to achieve delayed release, possibly using the above-mentioned excipients for the tablets.

[0141] , Syrups or elixirs containing the compounds of the present invention can additionally contain sweeteners (such as saccharin, cyclamate, glycerol or sugar) and flavoring agents (such as flavorings such as vanillin or citrus extracts). They can also contain excipients such as suspending adjuvants or thickening agents (such as sodium carboxymethylcellulose), wetting agents (such as, for example, condensation products of fatty alcohols with ethylene oxide), or preservatives (such as parabens).

[0142] Solutions for injection and infusion can be prepared in the usual manner, for example, by adding isotonic agents, preservatives such as parabens, or stabilizers such as the alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifying agents and / or dispersing agents (and if water is used as a diluent, for example, organic solvents can optionally be used as solubilizers or for dissolving acids), and transferring them to injection vials or ampoules or infusion bottles.

[0143] Capsules containing one or more compounds of the present invention can be prepared, for example, by mixing the compounds with an inert carrier (such as lactose or sorbitol) and packaging them in gelatin capsules.

[0144] Suitable suppositories can be prepared, for example, by mixing with carriers provided for this purpose (such as neutral fats or polyethylene glycols or their derivatives).

[0145] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as, for example, natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly disperse silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methyl cellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0146] The pharmaceutical composition is administered by conventional methods, preferably by the oral or transdermal route, most preferably by the oral route. For oral administration, in addition to the above carriers, the tablets may of course contain additional additives (such as sodium citrate, calcium carbonate, and dibasic calcium phosphate), and also contain various additives (such as starch, preferably potato starch, gelatin, etc.). In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc can be used simultaneously in the tabletting process. In the case of an aqueous suspension, in addition to the above excipients, the active substance can be combined with various flavoring agents or coloring agents.

[0147] For parenteral use, a solution of the active substance with a suitable liquid carrier can be used.

[0148] The daily dose range of the compound of formula (I) is generally from 1 mg to 2000 mg, preferably from 1 to 1000 mg, preferably from 1 to 100 mg.

[0149] The dose for intravenous use is from 1 mg to 1000 mg at different infusion rates, preferably between 5 mg and 500 mg at different infusion rates.

[0150] Depending on body weight, age, route of administration, severity of the disease, individual response to the drug, nature of the formulation, and time or interval of drug administration (continuous or intermittent treatment with one or more doses per day), it may sometimes be necessary to deviate from the specified amount. Thus, in some cases, using less than the minimum dose given above may be sufficient, while in other cases, it may be necessary to exceed the upper limit. When administering large amounts, it is recommended to divide them into several smaller doses distributed throughout the day.

[0151] The one or more other pharmacologically active substances optionally present in the pharmaceutical composition as described herein can be selected from the combination partners defined, for example, in the following paragraph.

[0152] Combination therapy

[0153] The compounds of the present invention can be used alone or in combination with one or more other pharmacologically active substances (such as state-of-the-art or standard-of-care compounds, such as, for example, cell proliferation inhibitors, anti-angiogenic substances, steroids or immunomodulators / checkpoint inhibitors, etc.).

[0154] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above, wherein the compound is administered before, after or together with at least one other cell growth inhibitory or cytotoxic substance.

[0155] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above, wherein the compound is administered in combination with at least one other pharmacologically active substance (such as a cell growth inhibitory or cytotoxic substance).

[0156] In another aspect, the present invention relates to a cell growth inhibitory or cytotoxic substance for preparation for use before, after or together with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above.

[0157] In another aspect, the present invention relates to a method for treatment and / or prophylaxis as defined above, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof before, after or together with at least one other cell growth inhibitory or cytotoxic substance.

[0158] Pharmacologically active substances (such as cell growth inhibitory substances or cytotoxic active substances) that can be administered in combination with the compounds according to the present invention include, but are not limited to: hormones, hormone analogs, and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, flucloxazole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, luprolide), growth factors and / or their corresponding receptor inhibitors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors such as (anti)-growth factor antibodies, (anti)-growth factor receptor antibodies, and tyrosine kinase inhibitors, such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab, and trastuzumab); antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine, and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylated liposomal doxorubicin), daunomycin, epirubicin, and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, nitrogen mustard, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotics (e.g., vinca alkaloids such as vincaleukoblastine, vindesine, vinorelbine, and vincristine; and taxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., tasquinimod), microtubule inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (such as epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (such as PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, aurora kinase inhibitors), tyrosine kinase inhibitors (such as PTK2 / FAK inhibitors), protein-protein interaction inhibitors (such as IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (such as everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents such as immune checkpoint inhibitors (such as CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (such as anti-CD33 antibody, anti-CD37 antibody, anti-CD20 antibody), T cell engagers (such as bispecific T cell engagers; such as CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMAx CD3), tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastim, interferon, interferon α, folinic acid, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer sodium.

[0159] Most preferably in combination with the following: IAP activators, proteasome inhibitors, immunotherapeutic agents such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins such as ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibody, anti-CD37 antibody, anti-CD20 antibody), T-cell engagers (e.g., bispecific T-cell engagers such as e.g., CD3 x BCMA, CD3 x CD33, CD3 x CD19, PSMAx CD3) and tumor vaccines.

[0160] When two or more substances or principles are to be used as part of a combination treatment regimen, they may be administered via the same route of administration or via different routes of administration, either substantially simultaneously (i.e., concurrently) or non-simultaneously (e.g., sequentially, successively, alternately, continuously or according to any other form of alternating regimen).

[0161] When substances or principles are administered simultaneously via the same route of administration, they may be administered as separate pharmaceutical formulations or compositions or as part of a combined pharmaceutical formulation or composition. Additionally, when two or more active substances or principles are to be used as part of a combination treatment regimen, each of the substances or principles may be administered in the same amount and according to the same regimen as when the compound or principle is used alone, and the combined use may or may not result in a synergistic effect. However, when the combination use of two or more active substances or principles results in a synergistic effect, it may also be possible to reduce the amount of one, more or all of the substances or principles to be administered while still achieving the desired therapeutic effect. For example, this may be used to avoid, limit or reduce any unnecessary side effects associated with using one or more substances or principles in their general amounts while still obtaining the desired pharmacological or therapeutic effect.

[0162] Of course, the above includes formulations and preparation methods of the compounds of the present invention for use in combination with the above combination partners. Also included are formulations and preparation methods for preparing the above combination partners for use in combination with the compounds of the present invention.

[0163] Furthermore, the present invention also encompasses kits that contain at least one compound of the present invention and one or more other components selected from other drugs for treating the diseases and disorders described above, and the devices described below.

[0164] Definitions

[0165] Terms not specifically defined herein shall be given the meanings ascribed to them by those skilled in the art in view of the present disclosure and the context. However, as used in the specification, unless otherwise specified, the following terms have the indicated meanings and follow the following conventions.

[0166] All different descriptions of Rx with superscripts or subscripts (such as R x or R x ) shall refer to and be understood as Rx. For example, R1 or R 1 shall refer to R1.

[0167] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group. For example, C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In particular, the prefix C x-y is used, where x and y each represent natural numbers (x < y), indicating that the chain or ring structure or the combination of chain and ring structures specified and mentioned in direct association can consist of a maximum of y and a minimum of x carbon atoms.

[0168] In a group containing one or more heteroatoms (such as a heterocyclic group), the indication of the number of members relates to the total number of all ring members or chain members or all ring and chain members.

[0169] Generally, for a combined group containing two or more subunits (such as hydroxyalkyl), the last-named subunit is the group attachment point. For example, the substituent "aryl-C 1-3 -alkylene" means an aryl group attached to a C 1-3 -alkyl-group, where the latter is bonded to the core or to the group to which the substituent is attached.

[0170] Generally, in a group such as OH, NH2, S(O), S(O)2, CN (cyano), COOH, CF3 or a similar group, those skilled in the art can see the group attachment point to the molecule from the free valence of the group itself.

[0171] In the case where the compounds of the present invention are described in the form of chemical names and as chemical formulas, if there are any differences, the chemical formula shall prevail.

[0172] As will be clear to those skilled in the art, the group attachment point from the free valence of the group itself to the molecule can be indicated, for example, by a dash ("-"), an asterisk ("*") or a dotted line ("…"). An asterisk can be used in a subchemical formula to indicate the bond connecting to the core molecule as defined.

[0173] The term "halogen" means fluorine, chlorine, bromine and iodine. Preferably, "halogen" refers to fluorine or chlorine.

[0174] The term "C 1-n -alkyl", where n is an integer selected from 2, 3, 4, 5 or 6, preferably 3, 4 or 5, alone or in combination with another group represents an acyclic, saturated, branched or linear hydrocarbon group having 1 to n carbon atoms. For example, the term C 1-5 -alkyl includes the groups: H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0175] Preferably, as used herein, "C 1-4 -alkyl" means: methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; i-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3).

[0176] Preferably, as used herein, "C 1-4 -alkyl" means methyl (Me; -CH3).

[0177] Preferably, as used herein, "C 1-3 -alkyl" means methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2).

[0178] Preferably, as used herein, "C 1-3 -alkyl" means methyl (Me; -CH3).

[0179] The terms propyl, butyl, etc. without further definition mean saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0180] If the alkyl group is another (linked) group (such as, for example, hydroxy-C x-y which is part of the alkyl group), the above definition for the alkyl group also applies.

[0181] The term "hydroxy-C 1-3 alkyl" refers to a C 1-3 alkyl group as defined above, in which any one or more hydrogens of the hydrocarbon chain are replaced by -OH.

[0182] The term "heterocyclic group" or "heterocyclic ring" means a saturated or unsaturated mono- or polycyclic ring system optionally including an aromatic ring, which contains one or more heteroatoms such as selected from N, O, S, SO or SO2, consisting of 3 to 14 ring atoms, and in which no heteroatom is part of the aromatic ring. The term "heterocyclic group" is intended to include all possible isomeric forms.

[0183] Thus, the term "heterocyclic group" or "heterocyclic ring" includes the following exemplary structures (not described as groups, since each form is optionally covalently linked to any atom as long as the appropriate valence is maintained):

[0184]

[0185]

[0186]

[0187] By "unsaturated" is meant that there is at least one double bond in the heterocyclic ring system under discussion, but no heteroaromatic system is formed. In a bicyclic heterocyclic ring, the two rings are joined together such that they have at least two identical (hetero)atoms. In a spiro heterocycle, one carbon atom (the spiro atom) belongs to two rings.

[0188] If the heterocyclic group is substituted, the substitution can in each case be carried out independently of one another in mono- or poly-substituted form on all carbon atoms carrying hydrogen and / or on nitrogen atoms. The heterocyclic group itself can be attached to the molecule as a substituent via each suitable position of the ring system.

[0189] Preferably, the heterocyclic group is 3- to 7-membered, monocyclic, saturated and has one heteroatom selected from oxygen, nitrogen and sulfur.

[0190] Preferred heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuryl.

[0191] As used herein, the term "substituted" means that one or more hydrogens on a specified atom are replaced by one or more substituents selected from the defined substituent groups, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Similarly, the term "substituted" can be used for chemical moieties rather than individual atoms, e.g., "substituted alkyl", "substituted aryl", etc.

[0192] Unless explicitly indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates and mixtures of the individual enantiomers in different ratios, mixtures of diastereomers, or any mixture of any of the foregoing forms (where such isomers and enantiomers exist), as well as salts (including their pharmaceutically acceptable salts) and their solvates (such as, for example, hydrates, including solvates and hydrates of the free compound and solvates and hydrates of salts of the compound).

[0193] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, e.g., by separating the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of the racemic form or by synthesis, e.g., starting from optically active starting materials and / or by using chiral reagents.

[0194] The enantiomerically pure compounds or intermediates of the present invention can be prepared via asymmetric synthesis, e.g., by preparing and subsequently separating appropriate diastereomeric compounds or intermediates, which can be separated by known methods (e.g., by chromatographic separation or crystallization) and / or by using chiral reagents (such as chiral starting materials, chiral catalysts or chiral auxiliaries).

[0195] In addition, it is known to those skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase or by resolution of the racemic mixture using a suitable resolving agent, e.g., by formation of diastereomeric salts of the racemic compound with an optically active acid or base, subsequent resolution of the salt and release of the desired compound from the salt or by derivatization of the corresponding racemic compound with an optically active chiral auxiliary, subsequent diastereomeric separation and removal of the chiral auxiliary group, or by kinetic resolution of the racemate (e.g., by enzymatic resolution); by enantioselective crystallization from an aggregate of enantiomorphic crystals under suitable conditions or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0196] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0197] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making its acid addition salts or base addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and the like.

[0198] For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0199] Other pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0200] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile or a mixture thereof).

[0201] Salts of other acids (which can be used, for example, for purifying or isolating the compounds of the present invention, such as trifluoroacetates) other than those described above also form part of the present invention.

[0202] Many of the terms given above may be reused in the definitions of chemical formulas or groups and, in each case, independently have the meanings given above.

[0203] The term "therapeutically effective amount" for the purposes of the present invention refers to the amount of a substance that is capable of eliminating the symptoms of a disease or preventing or alleviating those symptoms, or prolonging the survival period of the patient being treated.

[0204] List of Abbreviations

[0205]

[0206]

[0207]

[0208] General Considerations for the Synthetic Schemes

[0209] The compounds according to the invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compounds according to the invention are prepared by the synthetic methods described below, where the general formula substituents have the meanings given below. These methods are intended to be illustrative of the invention and not to limit the subject matter of the invention and the scope of the compounds claimed in these examples. If the preparation of the starting compounds is not described, they are commercially available or their synthesis is described in the prior art or they can be prepared analogously to known prior art compounds or the methods described herein. Substances described in the literature are prepared according to or analogous to the published synthetic methods. It should be understood that a compound having a certain chemical formula can be transformed into a different compound having the same chemical formula. In some cases, the order of performing the reaction steps can be varied. Variations of the reaction methods known to those skilled in the art but not described in detail herein can also be used. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at appropriate stages within the reaction sequence using methods familiar to those skilled in the art.

[0210] Unless otherwise stated, all reactions are carried out using methods commonly used in a chemical laboratory in commercially available equipment. Starting materials sensitive to air and / or moisture are stored in a protective gas, and the corresponding reactions and operations are carried out under a protective gas (nitrogen or argon).

[0211] The compounds according to the invention are named according to the CAS rules using the software Autonom (Beilstein).

[0212] If the chemical structure does not describe the exact configuration of a stereocenter (e.g., a carbon atom substituted asymmetrically), then both configurations are considered to be included in this representation and are disclosed therein. The representation of a stereocenter in a racemic form should always be considered to include and disclose both enantiomers (if no other defined stereocenters are present) or all other potential diastereomers and enantiomers (if additional, defined or undefined stereocenters are present).

[0213] Microwave reactions are preferably carried out with stirring in an initiator / reactor manufactured by Biotage or in an Explorer manufactured by CEM or in a Synthos 3000 or Monowave 3000 manufactured by Anton Paar in a sealed container (preferably 2, 5 or 20 mL).

[0214] Chromatography

[0215] Thin layer chromatography was carried out on ready-made silica gel 60 TLC plates (with fluorescent indicator F-254) on glass manufactured by Merck.

[0216] Preparative high performance liquid chromatography (RP HPLC) of the example compounds according to the present invention was carried out using columns manufactured by Waters (name: XTerra Prep.MS C18, 5μm, 30x100mm or XTerra Prep.MS C18, 5μm, 50x100mm OBD or Symmetrie C18, 5μm, 19x100mm or Sunfire C18 OBD, 19x100mm, 5μm or Sunfire Prep C 10μm OBD 50x150mm or X-Bridge Prep C18 5μm OBD 19x50mm) or X-Bridge Prep C18 10μm OBD 50x150mm), Agilent (name: Zorbax SB-C8 5μm PrepHT 21.2x50mm), and Phenomenex (name: Gemini C18 5μm AXIA 21.2x50mm or Gemini C18 10μm 50x150mm). The compounds were diluted with different gradients of H2O / acetonitrile or H2O / MeOH, and 0.1% HCOOH (acidic condition) was added to the water. For chromatography under basic conditions, an H2O / acetonitrile gradient was also used, and the water was made basic as follows: 5 mL of NH4HCO3 solution (158 g in 1 L of H2O) and 2 mL of NH3 (7M in MeOH) were made up to 1 L with H2O.

[0217] Analytical HPLC (reaction control) of the intermediate compounds was carried out using columns manufactured by Agilent (name: Zorbax SB-C8, 5μm, 21.2x50mm or Zorbax SB-C8 3.5μm 2.1x50mm), Phenomenex (name: Gemini C18 3μm 2x30mm), and Waters (name: XBridge TM C18, 3.5μm, 2.1x50mm, XBridge TM C18, 5μm, 2.1x50mm, XBridge TM C18, 2.5μm, 2.1x20mm or Sunfire TM C18, 3.5μm, 2.1x50mm). In each case, the analytical equipment was also configured with a mass detector.

[0218] HPLC-MS / UV-Spectroscopy

[0219] For characterizing the retention time / MS-ESI of the compounds according to embodiments of the present invention + Generated using an HPLC-MS device (high performance liquid chromatography with a mass detector). The compound eluting at the injection peak is assigned a retention time t Ret. = 0.00.

[0220] Method 1

[0221]

[0222]

[0223] Method 2

[0224]

[0225] Method 3

[0226]

[0227]

[0228] Method 4

[0229]

[0230] Method 5

[0231]

[0232] Method 6

[0233]

[0234]

[0235] General reaction scheme summarizing the synthetic route

[0236] Scheme 1:

[0237]

[0238] Examples

[0239] The features and advantages of the present invention will become apparent from the following detailed examples, which illustrate the basic principles of the present invention by way of example and not by way of limitation of the scope of the present invention.

[0240] Synthesis of indole carboxylate intermediates via the Hemetsberger-Knittel synthesis

[0241] Scheme 2:

[0242]

[0243] Synthesis of A-1 (Method A)

[0244] To sodium ethoxide (25% in ethanol, 293.3 g, 906 mmol), 2-chloro-4-methylbenzaldehyde (35.0 g, 226 mmol), and ethyl azidoacetate (116.8 g, 906 mmol) in THF (70 mL) / ethanol (700 mL) at -30 °C and stir at ambient temperature for 1 h. Add ice water and collect the solid by filtration.

[0245] The following azido esters can be obtained in a similar manner starting from different aldehydes.

[0246]

[0247]

[0248] Synthesis of B-1 (Method B)

[0249] Add A-1 (26.0 g, 265.7 mmol) in xylene (20 mL) to xylene (520 mL) at 160 °C over 20 min and stir at this temperature for 3 h. Concentrate the reaction mixture in vacuo and wet grind with pentane (100 mL).

[0250] Synthesis of B-3 (Method C)

[0251] Add rhodium(II) heptafluorobutyrate dimer (413 mg, 0.63 mmol) to A-3 (3.27 g, 11.4 mmol) in toluene (250 mL) and stir at 70 °C overnight. Concentrate the reaction mixture in vacuo and purify the residue by column chromatography.

[0252] Using the given synthetic methods, the following indoles can be obtained in a similar manner.

[0253]

[0254] Synthesis of carboxylic acid intermediates

[0255] Scheme 3:

[0256]

[0257] Synthesis of C-1 (Method D)

[0258] To B-1 (12.0 g, 50.5 mmol) and K2CO3 (13.96 g, 101 mmol) in DMF (120 mL) at 0 °C was added methyl iodide (14.34 g, 101 mmol) and the mixture was stirred at ambient temperature for 4 h. Ice water was added. The formed solid was collected by filtration and then wet milled with water and heptane.

[0259] The following indoles were prepared in a similar manner starting from the corresponding B-indole carboxylate intermediates.

[0260]

[0261]

[0262] Synthesis of D-1 (Method E)

[0263] To C-1 (12.0 g, 47.7 mmol) in THF (70 mL) / water (25 mL) at 0 °C was added lithium hydroxide monohydrate (8.01 g, 191 mmol) and the mixture was stirred at ambient temperature for 2 h. 4N HCl (10 mL) was added and the mixture was exhaustively extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was wet milled with ether and pentane.

[0264] The following indole carboxylic acids were prepared in a similar manner starting from their respective C-ester precursors.

[0265]

[0266] Compounds D-5 and D-6 can be prepared from the corresponding halogen-substituted benzaldehydes using methods similar to those described above for D-1, D-2, D-3 and D-4.

[0267]

[0268] Synthesis of benzylamine building blocks

[0269] Scheme 4:

[0270]

[0271] Synthesis of E-1

[0272] Under an argon atmosphere, triethylamine (101 mL, 720.0 mmol) was added to a stirred solution of tert-butyl [(R)-1-(4-iodophenyl)ethyl]carbamate (100.0 g, 288.0 mmol, produced by the method given in WO2011076786) in MeOH (900 mL). A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (16.5 g, 20 mmol) was added, and the reaction mixture was stirred at 120 °C for 16 h under a CO atmosphere (250 psi). The mixture was filtered through a Celite pad and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 30% EtOAc / hexane).

[0273]

[0274] Synthesis of E-2

[0275] At 0 °C, lithium aluminum hydride (1 M in THF, 338.3 mL, 338.3 mmol) was added to E-1 (63.0 g, 225.6 mmol) in dry THF (700 mL), and the mixture was stirred at room temperature for 2 h. Saturated aqueous Na2SO4 was added, and the mixture was filtered through a Celite pad. The aqueous layer was exhaustively extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 0 - 25% EtOAc / hexane).

[0276]

[0277] Synthesis of E-3

[0278] At 0 °C, triphenylphosphine (78.3 g, 298.5 mmol) and CBr4 (99.0 g, 298.5 mmol) were added to E-2 (50.0 g, 199.0 mmol) in dry CH2Cl2 (500 mL), and the mixture was stirred at room temperature for 5 h. Water was added, and the aqueous layer was exhaustively extracted with CH2Cl2.

[0279] The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10% EtOAc / hexane).

[0280]

[0281] Synthesis of E-4

[0282] NaCN (10.92 g, 222.8 mmol) was added to E-3 (35.0 g, 111.4 mmol) in DMF (350 mL), and the mixture was stirred at room temperature for 16 h. The mixture was treated with water, and the precipitate was collected by filtration and dried in vacuo.

[0283]

[0284] Synthesis of E-5

[0285] Sodium hydride (60%, 1.38 g, 34.5 mmol) was added to E-4 (6.0 g, 23.0 mmol) in dry THF (80 mL) at 0 °C, and the mixture was stirred at this temperature for 30 min. Bis(2-bromoethyl) ether (4.81 g, 20.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. Water was added, and the aqueous layer was exhaustively extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10–30% EtOAc / hexane).

[0286]

[0287] Synthesis of E-6

[0288] KOH (5.08 g, 90.9 mmol) was added to E-5 (3.0 g, 9.09 mmol) in EtOH (20 mL) / water (20 mL), and the mixture was stirred under reflux for 24 h. The mixture was treated with 2N HCl, and the precipitate was collected by filtration and wet-milled with water. The resulting solid was dried in vacuo.

[0289]

[0290] Synthesis of E-7

[0291] H2SO4 (1.52 ml) was added to E-6 (2.00 g, 5.73 mmol) in MeOH (30 mL) at 0 °C. The reaction mixture was stirred under reflux for 24 h. Water was added, and the mixture was neutralized with NaHCO3. The aqueous layer was exhaustively extracted with DCM, and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo.

[0292]

[0293] Synthesis Examples

[0294] Scheme 5:

[0295]

[0296] Synthesis of F-1 (Method F)

[0297] At 0 °C, triethylamine (9.39 g, 93.0 mmol), HATU (11.78 g, 31.0 mmol), and HOAT (4.22 g, 31.0 mmol) were added to D-3 (8.0 g, 31.0 mmol) in dry DMF (80 mL), and the mixture was stirred for 5 min. At room temperature, E-7 (8.98 g, 34.1 mmol) was added and the mixture was stirred for 16 h. The mixture was treated with water, the precipitate was collected by filtration and wet-milled with water. The crude product was dried in vacuo, wet-milled with diethyl ether, and dried in vacuo.

[0298] The following substituted indoles were prepared in a similar manner using the corresponding formula D carboxylic acid intermediate.

[0299]

[0300] Synthesis Example 1 (Method G)

[0301] At room temperature, LiOH monohydrate (6.84 g, 162.6 mmol) was added to F-1 (8.20 g, 16.3 mmol) in MeOH (32 mL) / THF (32 mL) / water (32 mL), and the mixture was stirred for 48 h. The mixture was treated with 4N HCl, the precipitate was collected by filtration and wet-milled with water. The crude product was purified by preparative HPLC-MS.

[0302]

[0303] Biological Example

[0304] The present invention will now be illustrated with reference to the following non-limiting examples that describe the biological activities and properties of the compounds of the present invention.

[0305] 3-Phosphoglycerate Dehydrogenase (PHGDH) Fluorescence Intensity Assay

[0306] This assay is used to identify compounds that inhibit the activity of the PHGDH enzyme, which catalyzes the reaction of 3-phosphoglycerate (3-PG) and NAD to 3-phosphohydroxypyruvate and NADH.

[0307] The NADH produced is used in a coupled reaction mediated by diaphorase that converts resazurin to resorufin, which can be measured in a fluorescence intensity reading.

[0308] The full-length version of the PHGDH enzyme was expressed in BL21(DE3) Escherichia coli transfected with a plasmid containing PHGDH cDNA with an N-terminal HIS-tag and a TEV-cleavable site. The recombinant protein was then isolated with Ni-NTA beads and eluted on a MONO Q ion-exchange chromatography column. The fractions corresponding to PHGDH were desalted and concentrated for biological assays.

[0309] The 3-phosphoglycerate substrate was purchased from Sigma. NAD, resazurin, and luciferin were purchased from Sigma Aldrich.

[0310] Compounds were dispensed from DMSO solutions into assay plates (black, low volume, flat-bottom 384-well, Corning) using an Access Labcyte workstation with a Labcyte Echo 55x. For the highest assay concentration of 100 μM selected, 150 nl of the compound solution was transferred from a 10 mM DMSO compound stock solution. For each compound, a series of 11 concentrations (101:5 steps) were transferred.

[0311] DMSO was added such that each well had a total of 150 nl of the compound solution.

[0312] Assays were performed using 500 μM NAD and 500 μM 3-PG (final assay concentration).

[0313] To 150 nl of the compound, 5 μl of PHGDH protein (final assay concentration 100 ng / ml) in assay buffer (125 mM Tris-HCl, pH 7.5; 56.25 mM hydrazine sulfate pH 9.0; 2.5 mM EDTA; assay-specific NAD concentration; 0.0125% Tween 20) was added.

[0314] A 10 μl mixture containing the assay-specific 3-PG concentration (500 μM), resazurin (25 μM final assay concentration), and phenazine methosulfate (35 μg / ml final assay concentration) was added. The plate was kept at room temperature and after incubation for 240 minutes, the fluorescence signal was measured in a PerkinElmer Envision HTS multimode plate reader with an excitation wavelength of 530 - 560 nm and an emission wavelength of 590 nm.

[0315] Each plate contained a negative control (diluted DMSO instead of the test compound; reacted with PHGDH protein as described) and a positive control (diluted DMSO instead of the test compound; reacted with buffer instead of PHGDH protein as described). The negative and positive control values were used for normalization.

[0316] A known PHGDH activity inhibitor was used as an internal control.

[0317] In the MEGALAB IC 50 application software, use the 4-parameter logic model to calculate and analyze the IC 50 value.

[0318] Table 1:

[0319] Example <![CDATA[IC 50 PHGDH]]> 1 6 nM 2 27 nM 3 10 nM 4 31 nM 5 25 nM 6 943 nM

[0320] Drug transport across human Caco-2 cells is used to estimate human intestinal drug absorption

[0321] This assay provides information on the potential of a compound to cross cell membranes, the extent of oral absorption, and whether the compound is actively transported by uptake and / or efflux transporters. An in vitro absorption model is used with an assay of the permeability of a polarized, confluent monolayer of Caco-2 cells grown on a permeable filter support. The apparent permeability coefficient (PE) of a compound across the Caco-2 monolayer is measured in the apical-to-basolateral (AB) (absorption) and basolateral-to-apical (BA) (secretion) transport directions (pH 7.2, 37 °C). AB permeability (PEAB) represents drug absorption from the small intestine into the blood and BA permeability (PEBA) represents drug secretion from the blood back into the small intestine via passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed on Caco-2 cells. Compounds are classified into permeability / absorption classes by comparing the AB permeability of the compound with the AB permeability of a reference compound with known in vivo permeability and human oral absorption. Permeabilities that are the same or similar in both transport directions indicate passive permeability, and vectorial permeability indicates additional active transport mechanisms. A higher PEBA compared to PEAB indicates the involvement of apical efflux transporters (such as P-gp) and / or basolateral uptake transporters; a higher PEAB compared to PEBA indicates the involvement of apical uptake transporters (such as PepT1) and / or basolateral efflux transporters (such as MRP3). Active transport is concentration-dependent and saturable.

[0322] From Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures GmbH (1 - 2x10 5 cells / 1 cm 2Caco-2 cells obtained by (area) were seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days. The compound was dissolved in a suitable solvent (such as DMSO, 1 - 20 mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4x7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, pH 7.2) containing 0.25% BSA to prepare the transport solution (0.1 - 300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) was applied to the apical or basolateral donor side respectively for measuring A - B or B - A permeability (3 filters were repeated). The acceptor side contained HTP-4 buffer supplemented with 0.25% BSA. Samples were collected from the donor at the start and end of the experiment and also from the acceptor side at different time intervals (0, 30, 60, and 90 minutes) up to 2 hours for measuring the concentration by HPLC - MS / MS or scintillation counting. The sampled acceptor volume was replaced with fresh acceptor solution.

[0323] Compounds were classified into the following permeability / oral absorption categories:

[0324] - Very low: 1x10 -7 cm / sec < PEAB

[0325] - Low: 1x10 -7 cm / s < PEAB < 6x10 -7 cm / sec

[0326] - Medium: 6x10 -7 cm / sec < PEAB < 5x10 -6 cm / sec

[0327] - Good: 5x10 -6 cm / s < PEAB < 1x10 -5 cm / sec

[0328] - Excellent: PEAB < 1x10 -5 cm / sec

[0329] Compounds were classified according to the (permeability) efflux ratio (PEBA / PEAB) given below, regardless of whether they might be actively transported:

[0330] - No: 0.67 <= ratio <= 1.5

[0331] - Possible (active efflux): 1.5 < ratio <= 2

[0332] - Possible (active uptake): 0.67 < ratio <= 0.5

[0333] - Yes (active efflux): 2 < ratio

[0334] - Yes (active uptake): ratio < 0.5

[0335] Table 2:

[0336]

[0337] Table 3:

[0338]

[0339]

[0340] The following formulation examples illustrate the present invention without limiting its scope:

[0341] Example of pharmaceutical preparation

[0342] A)

[0343] Mix some of the finely ground active substance, lactose and corn starch together. Sieve the mixture, then moisten, knead, granulate wet and dry with polyvinylpyrrolidone / aqueous solution. Sieve the granules, the remaining corn starch and magnesium stearate and mix them together. Press the mixture into tablets of suitable shape and size.

[0344] B)

[0345] Mix the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone together. Sieve the mixture and mix it with the remaining corn starch and water to form dry and sieved granules. Add sodium carboxymethyl starch and magnesium stearate and mix, and press the mixture into tablets of suitable size.

[0346] C)

[0347] Mix the active substance, lactose and cellulose together. Sieve the mixture, then moisten with water, knead, granulate wet and dry or granulate dry or directly mix with magnesium stearate finally and press into tablets of suitable shape and size. When granulating wet, add additional lactose or cellulose and magnesium stearate and press the mixture into tablets of suitable shape and size.

[0348] D) Ampoule solution

[0349] 50 mg of the active substance according to formula (I)

[0350] 50 mg of sodium chloride

[0351] 5 mL of water for injection

[0352] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The resulting solution is filtered for pyrogens and the filtrate is transferred to ampoules under aseptic conditions, which are then sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of the active substance.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: R1, R2, and R3 are each independently selected from the following: hydrogen, C 1-3 alkyl, and halogen; R4 is C 1-4 alkyl; R5 is C 1-3 alkyl or hydroxy-C 1-3 alkyl; R6 and R7 together form a heterocyclic ring which contains one or more moieties selected from the group consisting of: -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)- and -S(O)2-, wherein said heterocyclic ring is optionally substituted by one or more substituents each independently selected from -C(O)C 1-3 alkyl and -N(H)COR a ; R8 is hydrogen or C 1-3 alkyl; R a selected from the following: C 1-3 alkyl, -NH2, -N(H)C 1-3 alkyl and -N(C 1-3 alkyl)2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is halogen and / or R3 is C 1-3 alkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R2 is hydrogen or halogen.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein at least one of R1, R2 and / or R3 is halogen.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R3 is methyl.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R4 is methyl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R5 is methyl.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R6 and R7 together form a 3-7 membered saturated heterocyclic ring containing moieties selected from: -O-, -N(H)- and -S-.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R6 and R7 together form a tetrahydropyran ring.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R6 and R7 together form:

11. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R8 is hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, selected from: or a pharmaceutically acceptable salt thereof.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, for use as a medicament.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, for the treatment and / or prevention of cancer, infection, inflammation and / or autoimmune diseases.

15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12 and a pharmaceutically acceptable excipient and optionally one or more other pharmacologically active substances.

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