Novel substituted indole-2-carboxamides as PHGDH inhibitors

Abstract

The present invention encompasses compounds of formula (I), wherein the groups R1 to R8 have the meanings given in the claims and in the specification, their use as inhibitors of PHGDH, pharmaceutical compositions containing such compounds, and their use as medicaments, in particular medicaments for the treatment and / or prevention of neoplastic diseases. JPEG2025540856000051.jpg6693(I)

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I): [ka] (I) (wherein the groups R1 to R8 have the meanings given in the claims and in the specification), their use as inhibitors of PHGDH, pharmaceutical compositions containing such derivatives, and their use as medicaments, in particular as medicaments for the treatment and / or prevention of tumor diseases. [Background technology]

[0002] Numerous studies have demonstrated the essential contribution of the serine synthetic pathway (SSP) to tumorigenesis. Serine (Ser) is a nonessential amino acid that is essential for several cellular processes, particularly those of tumor cells: (i) Ser can be converted to glycine through the action of serine hydroxymethyltransferase (SHMT), providing the carbon unit 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 palmitoyl-CoA to provide sphingosine, which is necessary for the synthesis of sphingolipids that constitute cell membranes (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) Ser plays a very important role in regulating the reducing state due to the fact that serine is involved in the production of NADPH (Tedeschi et al., Cell Death Dis. (2013) 4:e877).(v) Last but not least, PHGDH, a key enzyme of the novel SSP, has been shown to generate the oncometabolite D-2-hydroxyglutarate (D-2HG), which has been linked to epigenetic dysregulation in tumor cells (Mondesir et al., J Blood Med. (2016) 7: 171-180; Fan et al., ACS Chem Biol. (2015) 10: 510-516). SSPs not only provide essential building blocks / metabolites but also the epigenetic regulator, Ser, and its synthetic pathway, which essentially contribute to cell proliferation, tumor homeostasis, and dedifferentiation of cancer cells (Mattaini et al., J Cell Biol. (2016) 214: 249-257; El-Hattab, Mol Genet Metab. (2016) 118: 153-159).

[0003] De novo synthesis of Ser occurs through SSP, which diverts 3-PG from glycolysis to produce Ser and 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, converting 3-phosphohydroxypyruvate (3-PPyr) to the NAD of 3-PG. + 3-PPyr is then converted to phosphoserine by phosphoserine aminotransferase 1 (PSAT-1), which is then converted to serine by phosphoserine phosphatase (PSPH). Finally, Ser can be converted to glycine by SHMT. Increased kinetics of SSPs have been observed in neoplastic tissues of various origins (Snell & Weber, Biochem J. (1986) 233: 617-620; DeBerardinis, Cell Metab. (2011) 14: 285-286) and have been linked to tumorigenesis (DeBerardinis, Cell Metab. (2011) 14: 285-286) and the key enzyme PHGDH, which has been shown to be amplified / overexpressed in malignant 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). In addition, recent studies have identified several activators of SSP in cancer cells, including the general regulatory non-derepressible 2 kinase (GCN2), which induces the expression of activating transcription factor 4 (ATF4) in cancer pathogenesis. Similarly, ATF4 can also be induced by the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) in human non-small cell lung cancer (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, a recent study showed that hypoxia induces the expression of SSP enzymes, and this phenomenon is mediated by HIF-1 and HIF-2 in a panel of multiple breast cancer cell lines (Samanta et al., Cancer Res. (2016) 76: 4430-4442).Finally, it has been reported that the cellular suppressor genes PKC-ζ and p53 suppress PHGDH expression (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). Therefore, deficiency of PKC-ζ or p53 in cancer cells promotes PHGDH activation, leading to SSP.

[0004] Knockdown of PHGDH inhibited the growth of cancer cell lines that harbored PHGDH amplification and / or PHGDH overexpression, but had no effect on lines expressing normal levels of PHGDH (Luo, Breast Cancer Res. (2011) 13: 317; Possemato et al., Nature. (2011) 476: 346-350). To identify novel cancer targets, Possemato et al. developed a negative selection RNAi screening method using a mouse orthotopic human breast cancer xenograft model in 2011 (Possemato et al., Nature. (2011) 476: 346-350). This method revealed that PHGDH is a gene required for tumorigenesis and breast cancer progression in vivo (Samanta et al., Cancer Res. (2016) 76: 4430-4442), and that this gene is localized to a genomic region where copy number gain is recurrent in breast cancer. Subsequently, it was shown that PHGDH is the most abundant SSP enzyme expressed in basal-like TNBC tissues, and that PHGDH expression levels are inversely 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). Furthermore, knockdown of PHGDH in melanoma cells selectively inhibited the growth of cells showing PHGDH gene amplification, but not of cells lacking this 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 colorectal 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, the B-Raf V600E mutation was associated with higher PHGDH expression compared with unmutated cases (Chen et al., Int J Mol Med. (2015) 36: 1607-1614; Sun et al., J Transl Med. (2016) 14: 168). Interestingly, in leukemia, increased oxidative stress due to inhibition of glutamine metabolism was identified as causing PHGDH upregulation. Silencing PHGDH inhibited leukemia cell proliferation, thereby identifying serine as a key pro-survival factor (Polet et al., Oncotarget. (2016) 7: 1765-1776).

[0005] Recently, PHGDH has been shown to catalyze the NADH-dependent reduction of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D-2HG) (Fan et al., ACS Chem Biol. (2015) 10: 510-516). Originally, 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 by mutant isocitrate dehydrogenases 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). Most interestingly, in breast cancer, PHGDH was identified as the enzymatic driver of D-2HG production (Fan et al., ACS Chem Biol. (2015) 10: 510-516). Terunuma et al. performed detailed metabolic profiling of human breast tumors and identified unique metabolic signatures in these tumors using a non-targeted discovery approach and validation of key metabolites. D-2HG accumulated at high levels in breast cancer tumors where MYC pathway activation was observed. Most importantly, MYC-induced D-2HG accumulation is associated with poor prognosis in breast cancer (Terunuma et al., J Clin Invest. (2014) 124: 398-412).Because MYC is known to regulate, among other things, glycolytic enzymes (Stine et al., Cancer Discov. (2015) 5: 1024-39), it is possible that PHGDH amplification and / or overexpression in breast cancer may affect cellular physiology through overproduction of D-2HG in a manner (e.g., DNA methylation) similar to that shown for glioma and AML (see above).

[0006] Although the mechanisms by which PHGDH supports tumorigenesis may be diverse, the enzymatic activity of PHGDH is essential for the cell proliferation, invasion, and tumorigenicity of cancer cells. All these data strongly support PHGDH as an attractive drug target in tumors that overexpress PHGDH or show PHGDH gene amplification. Indole-2-carboxamide NAD + - Competitive PHGDH inhibitors were disclosed in 2015 and published in 2016, describing fragment drug discovery at AstraZeneca (Fuller at al., Drug discovery today (2016), 21(8), 1272-83). These compounds lack cellular potency. WO2018 / 167019 discloses tosylacetate compounds that are potent and selective inhibitors of PHGDH, with nanomolar biomarker modulation. Weinstabl et al. reported a tosylacetate-based carboxylic acid and its ester prodrug as selective and potent inhibitors of PHGDH (J. Med. Chem., 2019, 62, 7976-7997). WO2017 / 156179, RAZE THERAPEUTICS INC., describes indole-based PHGDH inhibitors. However, no orally bioavailable PHGDH inhibitor has been reported, and no prior art compound is known that simultaneously inhibits PHGDH and exhibits an excellent permeability profile. It is therefore an object of the present invention to provide novel compounds that are capable of inhibiting PHGDH and at the same time are permeable.

[0007] Detailed Description of the Invention It has now been surprisingly found that compounds of formula (I), as defined below, act as inhibitors of PHGDH and also have excellent oral bioavailability and permeability profiles. Thus, the compounds of the present invention can be used for the treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer. The present invention therefore relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (I) (In the formula, R1, R2 and R3 are each independently hydrogen, C 1-3 selected from the group consisting of alkyl and halogen; R4 is C 1-4 is alkyl; R5 is C 1-3 Alkyl or hydroxy-C 1-3 is alkyl; R6 and R7 are each independently -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)-, and -S(O)2-, each of said heterocycles optionally independently forming a heterocyclic ring containing one or more moieties selected from the group consisting of -C(O)C 1-3 Alkyl and -N(H)COR a optionally substituted with one or more substituents selected from: R8, hydrogen or C 1-3 is alkyl; R a is C 1-3 Alkyl, -NH2, -N(H)C 1-3 Alkyl and -N(C 1-3 alkyl)2.

[0008] The compounds of the present invention have chiral centers. For example, in the following schemes and tables, all stereoisomers of such compounds, although not specifically listed, are intended to be embodiments of the present invention and are to be considered specifically disclosed. That is, for example, the compounds listed in the schemes and tables, the corresponding enantiomers and / or diastereoisomers not specifically listed in the tables, and the racemates of both enantiomers are individual embodiments of the present invention. Preferred embodiments are the compounds disclosed in the examples. In one aspect, the invention relates to compounds of formula (I'). [ka] (I') Formula (I') is a subgroup (subset) of formula (I), and unless otherwise stated, the expression "compounds of formula (I)" or grammatical variations thereof also equally refer to compounds of formula (I'). Furthermore, any aspect or embodiment of the invention described with reference to one or more compounds of formula (I) is also equally applicable to compounds of formula (I').

[0009] Preferred Embodiments In another aspect of the invention, at least one of R1, R2 and / or R3 is halogen. In another aspect, at least one of R1 and / or R2 is halogen. In another aspect, R1 is halogen. In another aspect, R2 is hydrogen or halogen. In another aspect, R1 and R2 are each independently hydrogen or halogen. In another aspect, R1 and R2 are each independently selected from the group consisting of hydrogen, fluorine, and chlorine. In another aspect, R1 is halogen and R3 is C 1-3 It is alkyl. In another respect: - R1 and R2 are both halogen; - R1 is halogen and R2 is hydrogen; - R1 is hydrogen and R2 is halogen; or - R1 and R2 are both hydrogen. In another respect: - R1 and R2 are fluorine; - R1 and R2 are chlorine; - R1 is fluorine and R2 is chlorine; - R1 is chlorine and R2 is fluorine; - R1 is chlorine and R2 is hydrogen; - R1 is hydrogen and R2 is chlorine; - R1 is fluorine and R2 is hydrogen; or - R1 is hydrogen and R2 is fluorine. In another respect, R3 is C 1-3 It is alkyl. In another aspect, R3 is methyl. In another aspect, R4 is methyl. In another aspect, R5 is methyl or -CH2OH. In another aspect, R5 is methyl. In another aspect, R3, R4 and R5 are methyl.

[0010] In another aspect, the stereocenter at the carbon atom to which R5 is attached is in the (R) configuration. In another aspect, R6 and R7 are each independently selected from -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)-, and -S(O)2-, each of said heterocycles optionally independently forming a heterocyclic ring containing a moiety selected from the group consisting of -C(O)C 1-3 Alkyl and -N(H)COR a may be substituted with one or more substituents selected from: In another aspect, R6 and R7 are each independently selected from -O-, -N(H)-, -N(COR a )-, -N(SO2R a)-, -S-, -S(O)-, and -S(O)2-, each of said heterocycles optionally independently forming a 3- to 7-membered saturated heterocyclic ring containing one or more moieties selected from the group consisting of -C(O)C 1-3 Alkyl and -N(H)COR a may be substituted with one or more substituents selected from: In another aspect of the invention, R6 and R7 together form a heterocycle containing a moiety selected from the group consisting of -O-, -N(H)- and -S-, said heterocycle optionally each independently being selected from the group consisting of -C(O)C 1-3 Alkyl and -N(H)COR a may be substituted with one or more substituents selected from: In another aspect of the invention, R6 and R7 are each independently selected from -O-, -N(H)-, -N(COR a )-, -N(SO2R a )-, -S-, -S(O)-, and -S(O)2-. In another aspect, R6 and R7 together form a 3- to 7-membered saturated heterocyclic ring containing a moiety selected from the group consisting of -O-, -N(H)-, and -S-, and the heterocyclic ring optionally each independently contains -C(O)C 1-3 Alkyl and -N(H)COR a may be substituted with one or more substituents selected from: In another aspect, R6 and R7 together form a 3- to 7-membered saturated heterocycle containing a moiety selected from the group consisting of -O-, -N(H)-, and -S-. In another aspect, R6 and R7 together form a 3- to 7-membered saturated heterocyclic ring containing an oxygen atom, the heterocyclic ring optionally each independently being —C(O)C 1-3 Alkyl and -N(H)COR a may be substituted with one or more substituents selected from: In another aspect, R6 and R7 together form a 3- to 7-membered saturated heterocycle containing an oxygen atom.

[0011] In another aspect, R6 and R7 together form a tetrahydropyran ring. In another aspect, R6 and R7 are each [ka] Form. In this latter respect, and in other respects using the same notation, the dotted lines are understood to represent the points of attachment of R6 and R7 to the remainder of the compound of formula (I). In another aspect, R8 is hydrogen. In another aspect, R3, R4, and R5 are methyl and R6 and R7 together are [ka] Form. In another aspect, R3, R4, and R5 are methyl, R8 is hydrogen, and R6 and R7 together are [ka] Form.

[0012] In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (II): [ka] (II) Formula (II) is a subgroup of formula (I), and unless otherwise stated, the expression "compounds of formula (I)" or grammatical variations thereof also equally refer to compounds of formula (II). Furthermore, any aspect or embodiment of the invention described with reference to one or more compounds of formula (I) is also equally applicable to compounds of formula (II). In view of formula (II), R8 is hydrogen.

[0013] In an embodiment, the compound of the present invention is [Table 1] or a pharmaceutically acceptable salt thereof.

[0014] It is understood that all tautomers of compounds of formula (I), including all aspects and embodiments thereof, regardless of whether they are depicted, are disclosed herein and are part of the present invention. All synthetic intermediates, generally defined and specifically disclosed herein, and their salts, are also part of the present invention. All individual synthetic reaction steps, both generally defined and specifically disclosed herein, and the reaction sequences comprising these individual synthetic reaction steps, are also part of the present invention. The present invention further relates to hydrates, solvates, polymorphs, co-crystals, metabolites, derivatives, isomers and prodrugs of compounds of formula (I), including all aspects and embodiments thereof. The present invention further relates to hydrates of compounds of formula (I), including all aspects and embodiments thereof. The present invention further relates to solvates of compounds of formula (I), including all aspects and embodiments thereof. The present invention further relates to pharmaceutically acceptable salts of compounds of formula (I), including all aspects and embodiments thereof. The present invention, including all aspects and embodiments thereof, further relates to pharmaceutically acceptable salts of compounds of formula (I) with inorganic or organic acids or bases.

[0015] Pharmaceutical Uses and Methods of Treatment The present invention is directed to PHGDH inhibitors, in particular compounds of formula (I), including all aspects and embodiments thereof, which may be useful in the prevention and / or treatment of diseases and / or conditions in which inhibition of PHGDH is or may be therapeutically beneficial, including, but not limited to, the treatment and / or prevention of cancer. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of diseases and / or conditions in which inhibition of PHGDH is or may be of therapeutic benefit. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylaxis of cancer, an infectious disease, inflammation or an autoimmune disease. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prophylaxis of cancer, infectious diseases, inflammation or autoimmune diseases in the human or animal body. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment and / or prevention of cancer, an infectious disease, an inflammation or an autoimmune disease. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[0016] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for the treatment and / or prophylaxis of cancer in the human or animal body. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment and / or prevention of cancer. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of hematological cancer. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of glioma, breast cancer, malignant melanoma, non-small cell lung cancer (NSCLC), colon cancer, cervical cancer, thyroid cancer, preferably BRAF mutant and leukemia. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of p53 mutant cancers, MYC driven cancers and / or cancers with high levels of D-2-hydroxyglutarate (D-2HG). 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 the treatment and / or prevention of hematological cancer. 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 the treatment and / or prevention of glioma, breast cancer, malignant melanoma, non-small cell lung cancer (NSCLC), colon cancer, cervical cancer, thyroid cancer, preferably BRAF mutation and leukemia.

[0017] 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 the treatment and / or prevention of p53 mutant cancer, MYC-driven cancer and / or cancer with high levels of 2DHG. In another aspect, the present invention relates to a method for the treatment and / or prevention of diseases and / or conditions in which inhibition of PHGDH is or may be therapeutically beneficial, said method comprising administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the phrase "diseases and / or conditions for which inhibition of PHGDH is or may be therapeutically beneficial" includes, but is not limited to, any condition in which PHGDH is overexpressed, amplified, mutated, or generally dysregulated. 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, infectious diseases, inflammation and / or autoimmune diseases, said method comprising administering to a human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] 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. For example, but not limited to, the following cancers, tumors and other proliferative disorders may be treated with the compounds of the present invention: Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, and oral mucosa), oropharynx (including base of tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, and pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, and vocal cords), hypopharynx, and salivary glands (including minor salivary glands); Lung cancer / tumor / carcinoma: e.g. non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma); Mediastinal neoplasms: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, posterior mediastinal gangliocytoma, neuroblastoma, pheochromocytoma, and paraganglioma), germ cell tumors (including seminoma, teratoma, and non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, and thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal cell tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangiomyopericytoma, and lymphangioleiomyoma);

[0019] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., esophagus, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, hybrid 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, and Clark's tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, and ileum) tumors / carcinomas / cancers of the large intestine (including cecum, colon, rectum, anus; including colorectal cancer, gastrointestinal stromal tumor (GIST)); genitourinary system (including kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenal gland tumor, Grawitz tumor; ureter; bladder, e.g., urachal carcinoma, urothelial carcinoma; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); Cancer / tumor / carcinoma of the testis: e.g., seminoma, non-seminoma, Gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, uterine corpus (including endometrium, fundus); Cancers / tumors / carcinomas of the breast: for example, breast adenocarcinoma (invasive ductal, colloid, lobular invasive, tubular, adenoid 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; Cancers / tumors / carcinomas of the endocrine system: for example, endocrine glands, thyroid gland (thyroid carcinoma / tumors; papillary, follicular, undifferentiated, medullary), parathyroid gland (parathyroid carcinoma / tumors), adrenal cortex (adrenocortical carcinoma / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, tumors / carcinomas / cancer of the carotid body, pancreatic islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functioning PET, PP-producing tumors, gastrinoma, insulinoma, VIP-producing tumors, glucagonoma, somatostatin-producing tumors, GRF-producing tumors, ACTH-producing tumors), carcinoid tumors;

[0020] Sarcomas of soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexus sarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal cell tumor, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma-like tumor, desmoplastic small cell tumor; Bone sarcomas: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade superficial, small cell, radiation-induced osteosarcoma, and 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, and chondroblastoma; Mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma; Cancers of the skin: for example, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentigo, nodular, and intraocular melanoma), actinic keratosis, and eyelid cancer; Neoplasms of the central nervous system and brain: for example, astrocytoma (cerebral, cerebellar, diffuse, fibrous, anaplastic, pilocytic, protoplasmic, round cell), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, posterior mediastinal ganglioneuroma, neuroblastoma, retinoblastoma, schwannoma (e.g., acoustic nerve), spinal axis tumor;

[0021] Lymphomas and leukemias: for example, B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), and Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia (ATL)), disease / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastoma 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), skin T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosing HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, and lymphopenic HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / Myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML); Carcinoma of unknown primary site (CUP).

[0022] All of the above cancers / tumors / carcinomas, characterized by their particular location / origin in the body, are intended to include both the primary tumor and metastatic tumors derived therefrom. All of the above cancers / tumors / carcinomas can be further differentiated by their histopathological classification: Epithelial cancers, e.g. squamous cell carcinoma (SCC) (in situ carcinoma, superficially invasive, verrucous carcinoma, pseudosarcoma, undifferentiated, 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, gastric adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumor (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; Non-epithelial carcinomas, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas. The compounds of the invention may be used in treatment regimens in the first line, second line, or any further line of treatment setting. The compounds of the present invention can be used for the prevention, short-term treatment or long-term treatment of the above mentioned diseases, and may also be used in combination with radiation therapy and / or surgery.

[0023] Pharmaceutical Composition The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above, a pharmaceutically acceptable excipient, and optionally further comprising one or more pharmacologically active ingredients. 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. In another aspect, the present invention relates to a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other cytostatic and / or cytotoxic active ingredient. Suitable pharmaceutical compositions for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, particularly injectable solutions (subcutaneous, intravenous, intramuscular), and infusions (injectables), elixirs, syrups, sachets, emulsions, inhalants, or dispersible powders. The content of the compound of the present invention should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage ranges specified below. The specified doses may be administered several times a day as needed. 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 may also comprise several layers. Thus, coated tablets can be prepared by coating a core similar to that of a tablet with substances and excipients commonly used in tablet coatings, such as collidone, or shellac, gum arabic, talc, titanium dioxide, or sugar. The core may also consist of several layers to achieve delayed release or to prevent incompatibilities. Similarly, tablet coatings may consist of several layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[0024] Syrups or elixirs containing the compounds of the present invention may further contain a sweetener such as saccharin, cyclamate, glycerol or sugar, and a flavor enhancer, e.g., a flavoring agent such as vanillin or orange extract. They may also contain excipients such as suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Solutions for injection and infusion are prepared in the usual manner by adding excipients such as an isotonic agent, a preservative such as p-hydroxybenzoate, and a stabilizer such as an alkali metal salt of ethylenediaminetetraacetic acid (emulsifying agents and / or dispersing agents may also be used); however, when water is used as a diluent, an organic solvent may be used as a solubilizing agent or dissolution aid, and the solution may be transferred into an injection vial, an ampoule, or an infusion bottle. Capsules containing one or more compounds of the present invention can be prepared, for example, by mixing the compound with an inert carrier, such as lactose or sorbitol, and filling a gelatin capsule. Suitable suppositories may be prepared, for example, by mixing with carriers which achieve this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. 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 natural inorganic powders (e.g., kaolin, clay, talc, chalk), synthetic inorganic powders (e.g., highly dispersed silicic acid and silicates)), sugars (e.g., cane sugar, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite pulp liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0025] This pharmaceutical composition is administered by conventional methods, preferably by oral or transdermal route, most preferably by oral route.For oral administration, in addition to the above-mentioned carriers, tablets may naturally contain additional additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatin, etc.In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time in the tableting process.For aqueous suspensions, active ingredients may be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients. For parenteral use, a solution of the active ingredient with a suitable liquid carrier may be used. The applicable daily dose range of the compound of formula (I) is usually 1 mg to 2000 mg, preferably 1 to 1000 mg, and preferably 1 to 100 mg. The intravenous dosage is between 1 mg and 1000 mg at various infusion rates, preferably between 5 mg and 500 mg at various infusion rates. However, it may sometimes be necessary to deviate from the specified amount (single or multiple doses per day, continuous or intermittent treatment) depending on the body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation, and the time or interval at which the drug is administered. Thus, in some cases, it may be sufficient to use less than the minimum dose indicated above, while in other cases the upper limit may have to be exceeded. When administering large amounts, it may be advisable to divide them into several smaller doses over the course of a day. The one or more additional pharmacologically active ingredients that may optionally be present in the pharmaceutical compounds described herein may, for example, be selected from among the combination partners defined in the following paragraphs.

[0026] Combination therapy The compounds of the present invention can be used alone or in combination with one or several other pharmacologically active ingredients, such as front-line or standard of care compounds (such as cell proliferation inhibitors, anti-angiogenic agents, steroids or immunomodulatory / checkpoint inhibitors). In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as previously defined, wherein said compound is administered before, after or together with at least one other cytostatic and / or cytotoxic active ingredient. In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as previously defined, wherein said compound is administered in combination with at least one other pharmacologically active ingredient, such as a cytostatic and / or cytotoxic active ingredient. In another aspect, the present invention relates to a cytostatic and / or cytotoxic active ingredient prepared for administration before, after or together with a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as defined above. In another aspect, the present invention relates to a method for the treatment and / or prevention as defined above, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, before, after or together with at least one other cytostatic and / or cytotoxic active ingredient.

[0027] Pharmaceutically active ingredients, e.g., cytostatic and / or cytotoxic active ingredients, that may be administered in combination with the compounds of the 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, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide), inhibitors of growth factors and / or their corresponding receptors (e.g., platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF)), and the like. Growth factors such as 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 include, for example, (anti) growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors (e.g., cetuximab, gefitinib, afatinib, nintedanib, imatinib, , lapatinib, bosutinib, bevacizumab, and trastuzumab); antimetabolites (e.g., antifolates (e.g., methotrexate, raltitrexed), pyrimidine analogs (e.g., 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine), purine and adenosine analogs (e.g., mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine (arabinose), C), fludarabine, etc.); antitumor antibiotics (e.g., anthracyclines (doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride), Myoset (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin, and idarubicin, etc.), mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin, etc.);Platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosamide, temozolomide, nitrosoureas (e.g., carmustine and lomustine, thiotepa, etc.)); antimitotic agents (e.g., vinca alkaloids (e.g., vinblastine, vindesine, vinorelbine, vincristine, etc.); and taxanes (paclitaxel, docetaxel, etc.)); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.)), serine / threonine kinase inhibitors (e.g., PDK1 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, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., 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 (e.g., ErbB receptor inhibitors), verolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents (immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins (e.g., ipilimumab, nivolumab, pembrolizumab, etc.))), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., , anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers (BiTEs®, such as CD3xBCMA, CD3xCD33, CD3xCD19, PSMAxCD3)), tumor vaccines, and various chemotherapeutic agents (such as amifostine, anaglide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer);

[0028] Most preferred is a combination with an IAP activator, a proteasome inhibitor, an immunotherapeutic agent such as an immune checkpoint inhibitor (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecule / immunoglobulin (e.g., ipilimumab, nivolumab, pembrolizumab, etc.)), an ADCC (antibody-dependent cell-mediated cytotoxicity) enhancer (e.g., anti-CD33 antibody, anti-CD37 antibody, anti-CD20 antibody), a T cell engager (e.g., bispecific T cell engagers (BiTEs®), such as CD3×BCMA, CD3×CD33, CD3×CD19, PSMA×CD3)), and a tumor vaccine. When two or more substances or principles are used as part of a combination therapeutic regimen, they can be administered through the same route of administration or different routes of administration, at essentially the same time (i.e., simultaneously, in parallel) or at different times (e.g., sequentially, one after the other, alternatingly, consecutively, or according to any other type of alternating regimen). When substances or principles are administered simultaneously through the same route of administration, they may be administered in different pharmaceutical formulations or compositions or as part of a combined pharmaceutical formulation or composition. Also, when two or more active ingredients or principles are used as part of a combined therapeutic regimen, each of the ingredients or principles may be administered in the same amounts and according to the same regimen as when the compound or principle is used alone, and such a combination may or may not result in a synergistic effect. However, when the combination of two or more active ingredients or principles results in a synergistic effect, it may be possible to reduce the amount of one, more, or all of the substances or principles administered while still achieving the desired therapeutic effect. This may be useful, for example, to avoid, limit, or reduce any undesirable side effects associated with the use of one or more substances or principles when the one or more substances or principles are used in their usual amounts, while still obtaining the desired pharmacological or therapeutic effect. Of course, the above includes formulations and formulation methods of the compounds of the present invention for combination with the above combination partners. Also included are formulations and preparation methods of the above-mentioned combination partners for combination with the compounds of the present invention. Furthermore, the present invention also encompasses a kit comprising at least one compound of the present invention, one or more other components selected from the group consisting of other agents used for the treatment of the above diseases and disorders, and the following device.

[0029] Definitions Terms not specifically defined herein should be given the meaning that those skilled in the art would ascribe to them, taking into account the disclosure and context. However, when used herein, unless otherwise specified, the following terms have the indicated meanings and the following conventions are observed. All different notations of Rx with superscripts or subscripts, for example, R x or R x shall refer to Rx and be understood as Rx. For example, R1 or R 1 shall refer to R1. In the groups, radicals or moieties defined below, the number of carbon atoms is often specified before the group, for example, C 1-6 -alkyl means an alkyl group or radical having from 1 to 6 carbon atoms. In particular, the use of the prefix C where x and y each represent natural numbers (x < y) is specified in a direct context and indicates that the chain or ring structure, or the combination as a whole of the chain and ring structures, can consist of a maximum of y and a minimum of x carbon atoms. x-y The use of the prefix C where x and y each represent natural numbers (x < y) is specified in a direct context and indicates that the chain or ring structure, or the combination as a whole of the chain and ring structures, can consist of a maximum of y and a minimum of x carbon atoms. The indication of the number of members in a group containing one or more heteroatoms (e.g., heterocyclyl) relates to the total number of all ring members or chain members or all ring and chain members. Generally, for a combined group containing two or more subgroups (e.g., hydroxyalkyl), the last-specified subgroup is the radical bonding point. For example, the substituent "aryl-C 1-3 -alkylene" means that the aryl group is bonded to the C 1-3 -alkyl-group, and the C 1-3It means that the -alkyl- group is attached to the group or nucleus to which the substituent is attached. Generally, for groups such as OH, NH, S(O), S(O), CN (cyano), COOH, CF, etc., one skilled in the art can understand the point of attachment of the radical to the molecule from the free valence of the group itself. When a compound of the invention is described by chemical name and formula, in the event of a conflict, the formula shall prevail. The point of attachment of the radical to a molecule will be apparent to one skilled in the art from the free valence of the group itself and may be indicated, for example, by a dash ("-"), an asterisk ("*"), or a dotted line ("..."). An asterisk may be used in subformulas to indicate the bond that connects to the core molecule being defined.

[0030] The term "halogen" means fluorine, chlorine, bromine and iodine. Preferably, "halogen" refers to fluorine or chlorine. The term “C 1-n "-alkyl" means, alone or in combination with another radical, an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms, where n is an integer selected from 2, 3, 4, 5 or 6, preferably 3, 4 or 5. For example, the term "C 1-5 "-Alkyl" encompasses the radicals HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)- and HC-CH-CH(CHCH)-. Preferably, as used herein, "C 1-4"-Alkyl" refers to methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (iso-butyl; 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). Preferably, as used herein, "C 1-4 -Alkyl" refers to methyl (Me; -CH3). Preferably, as used herein, "C 1-3 "-Alkyl" refers to methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; iso-propyl; -CH(CH3)2). Preferably, as used herein, "C 1-3 -Alkyl" refers to methyl (Me; -CH3).

[0031] The terms "propyl", "butyl", etc., unless further defined, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms. The alkyl may be part of another (combined) group, e.g., hydroxy-C x-y In the case of alkyl, etc., the above definition of alkyl also applies. The term "hydroxy-C 1-3 "Alkyl" means a C alkyl group as defined above. 1-3 It refers to alkyl, in which any one or more hydrogen atoms of the hydrocarbon chain are replaced by -OH. The term "heterocyclyl" or "heterocycle" means a saturated or unsaturated mono- or polycyclic ring system, optionally containing an aromatic ring, containing one or more heteroatoms selected from, for example, N, O, S, SO, or SO, consisting of 3 to 14 ring atoms, wherein the heteroatoms are not part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0032] Thus, the term "heterocyclyl" or "heterocycle" includes the following exemplary structures (not depicted as radicals because each form may optionally be attached to any atom through a covalent bond as long as appropriate valences are maintained): [ka] [ka]

[0033] By unsaturated, it is meant that at least one double bond is present in the heterocyclic ring system, but it does not form a heteroaromatic system. In bicyclic heterocycles, the two rings have at least two common (hetero)atoms to connect them together. In spiro-heterocycles, one carbon atom (spiroatom) belongs to both rings. If a "heterocyclyl" is substituted, the substitution may occur independently of one another on all hydrogen-containing carbon and / or nitrogen atoms, in the form of mono- or polysubstitution in each case. The heterocyclyl itself, as a substituent, may be attached to the molecule through any suitable position of the ring system. Preferably, the heterocyclyl is 3 to 7 membered, monocyclic, saturated and has one heteroatom selected from oxygen, nitrogen and sulfur. Preferred heterocyclyls are piperazinyl, piperidinyl, monophenyl, pyrrolodinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl. As used herein, the term "substituted" means that one or more hydrogens on a specified atom are replaced with one or more groups selected from the defined group of substituents, 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 in connection with a chemical moiety in place of a single atom, such as, for example, "substituted alkyl," "substituted aryl," etc. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, as well as mixtures of separated enantiomers in different ratios, mixtures of diastereomers, or mixtures of such isomers and enantiomers in any of the above forms, where such isomers and enantiomers exist, and pharmaceutically acceptable salts, including solvates thereof (e.g., solvates and hydrates of the free compound or hydrates, including solvates and hydrates of salts of the compound).

[0034] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. Methods for preparing optically active forms, for example, by resolution of racemic forms or by synthesis beginning with optically active starting materials and / or using chiral reagents, are known in the art. Enantiomerically pure compounds or intermediates of the invention may be prepared through asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates, which may be separated by known methods (e.g., by chromatographic separation or crystallization), and / or by using chiral reagents (e.g., chiral starting materials, chiral catalysts, or chiral auxiliaries). Furthermore, methods for preparing enantiomerically pure compounds from the corresponding racemic mixture are known to those skilled in the art, for example, 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, for example, by forming diastereomeric salts of the racemate with an optically active acid or base, followed by resolution of the salt and liberating the desired compound from the salt, or by derivatization of the corresponding racemate with an optically active chiral auxiliary, followed by diastereomeric separation and removal of the chiral auxiliary, or by kinetic resolution of the racemate (for example, by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomeric crystals under appropriate conditions, or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0035] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds that are modified by making acid or base salts of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts derived 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. Further pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other acid salts than those mentioned above, for example acid salts that are useful for purifying or isolating the compounds of the invention (eg trifluoroacetate salts), also form part of the present invention. Many of the terms given above may be used repeatedly in the definitions of formulae or groups and may at each occurrence have, independently of one of the meanings given above. For purposes of this invention, the term "therapeutically effective amount" refers to that amount of a substance that is capable of eliminating symptoms of a disease, or preventing or alleviating those symptoms, or prolonging the survival of a treated patient.

[0036] List of abbreviations [Table 2] JPEG2025540856000013.jpg104141

[0037] General Considerations for Synthetic Schemes The compounds of the present 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 of the present invention are prepared by the synthetic methods described below, where the substituents of the general formulae have the previously given meanings. These methods are intended to be illustrative of the present invention and do not limit the scope of the subject matter of the present invention and the claimed compounds to these examples. Where the preparation of starting compounds is not described, they are commercially available, their synthesis is described in the prior art, or they can be prepared analogously to known prior art compounds or methods described herein. Materials described in the literature are prepared according to or in analogy with published synthetic methods. It is understood that compounds of a particular formula can be converted to different compounds of the same formula. In some cases, the order in which reaction steps are carried out can be changed. Modifications of reaction methods known to those skilled in the art but not described in detail herein can also be used. Any functional groups in starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved again at an appropriate stage in the reaction sequence using methods well known to those skilled in the art. Unless otherwise stated, all reactions are carried out using commercially available equipment and methods commonly used in chemical laboratories. Air- and / or moisture-sensitive starting materials are stored under protective gas, and the corresponding reactions and accompanying manipulations are carried out under protective gas (nitrogen or argon). The compounds of the present invention are named according to CAS rules using Autonom (Beilstein) software. When a chemical structure is depicted without the exact configuration of a stereocenter (e.g., a stereocenter at an asymmetrically substituted carbon atom), such representation is deemed to include and disclose both configurations. The representation of a stereocenter in a racemic form is always deemed to include and disclose both enantiomers (if there are no other defined stereocenters) or all other possible diastereomers and enantiomers (if there are additional stereocenters, defined or undefined).

[0038] Microwave reactions are carried out in an initiator / reactor from Biotage, or an Explorer from CEM, or a Synthos3000 or Monowave3000 from Anton Paar, in a closed container (preferably 2, 5 or 20 mL), preferably with stirring.

[0039] Chromatography Thin layer chromatography is performed on commercially available Merck silica gel 60 TLC glass plates (using fluorescent indicator F-254). Preparative high pressure chromatography (RP HPLC) of the example compounds of the present invention was carried out using Waters (name: XTerra Prep. MS C18, 5 μm, 30×100 mm or XTerra Prep. MS C18, 5 μm, 50×100 mm OBD or Symmetrie C18, 5 μm, 19×100 mm or Sunfire C18 OBD, 19×100 mm, 5 μm or Sunfire Prep C 10 μm OBD 50×150 mm or X-Bridge Prep C18 5 μm OBD 19×50 mm) or X-Bridge Prep C18 10 μm OBD 50×150 mm), Agilent (name: Zorbax SB-C8 5 μm PrepHT 21.2×50 mm) and Phenomenex (name: Gemini C18 5 μm AXIA 21.2×50 The chromatography is carried out using a column of 10 μm (50 × 150 mm) or Gemini C18 10 μm. Various gradients of HO / acetonitrile or HO / MeOH are used to elute the compounds, with 0.1% HCOOH added to water (acidic conditions). For chromatography under basic conditions, a HO / acetonitrile gradient is used as well, and the water is made alkaline as follows: 5 mL NH4HCO3 solution (158 g in 1 L HO) and 2 mL NH3 (7 M in MeOH) are added and made up to 1 L with HO. Analytical HPLC (reaction control) of intermediate compounds is carried out using columns from Agilent (designation: Zorbax SB-C8, 5 μm, 21.2 × 50 mm or Zorbax SB-C8 3.5 μm, 2.1 × 50 mm), Phenomenex (designation: Gemini C18 3 μm, 2 × 30 mm) and Waters (designation: XBridge™ C18, 3.5 μm, 2.1 × 50 mm, XBridge™ C18, 5 μm, 2.1 × 50 mm, XBridge™ C18, 2.5 μm, 2.1 × 20 mm or Sunfire™ C18, 3.5 μm, 2.1 × 50 mm). The analytical instruments are also in all cases equipped with mass spectrometers. HPLC-mass spectroscopy / UV-spectrometry Retention time / MS-ESI for characterizing example compounds of the present invention + is obtained using an HPLC-MS system (high performance liquid chromatography with a mass spectrometer). Compounds eluting at the injection peak have retention times t Ret. =0.00 is given.

[0040] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0041] General reaction scheme summarizing synthetic routes Scheme 1: [ka] [Example]

[0042] The features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention, without limiting its scope.

[0043] Synthesis of indole carboxylate intermediates via Hemetzberger-Knittel synthesis Scheme 2: [ka] Synthesis of A-1 (Method A) Sodium ethoxide (25% in ethanol, 293.3 g, 906 mmol) and 2-chloro-4-methylbenzaldehyde (35.0 g, 226 mmol) were added to ethyl azidoacetate (116.8 g, 906 mmol) in THF (70 mL) / ethanol (700 mL) at −30° C. and stirred at ambient temperature for 1 h. Ice water was added and the solid was collected by filtration. The following azido esters can be obtained in a similar manner starting from different aldehydes. [Table 9] [Table 10]

[0044] Synthesis of B-1 (Method B) A-1 (26.0 g, 265.7 mmol) in xylene (20 mL) is added to xylene (520 mL) at 160° C. over 20 minutes and stirred at this temperature for 3 hours. The reaction mixture is concentrated in vacuo and triturated with pentane (100 mL). Synthesis of B-3 (Method C) To A-3 (3.27 g, 11.4 mmol) in toluene (250 mL) was added rhodium(II) heptafluorobutyrate dimer (413 mg, 0.63 mmol) and stirred overnight at 70° C. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography. The following indoles are available in a similar manner by applying routine synthetic methods: [Table 11]

[0045] Synthesis of carboxylic acid intermediates Scheme 3: [ka] Synthesis of C-1 (Method D) To B-1 (12.0 g, 50.5 mmol) and K2CO3 (13.96 g, 101 mmol) in DMF (120 mL) was added iodomethane (14.34 g, 101 mmol) at 0 °C and stirred at ambient temperature for 4 h. Ice water was added. The formed solid was collected by filtration and then triturated with water and pentane. The following indoles are prepared in a similar manner starting from the corresponding indole carboxylate intermediate of formula B: [Table 12] [Table 13]

[0046] Synthesis of D-1 (Method E) To C-1 (12.0 g, 47.7 mmol) in THF (70 mL) / water (25 mL) was added lithium hydroxide monohydrate (8.01 g, 191 mmol) at 0 °C and stirred at ambient temperature for 2 h. 4 N HCl (10 mL) was added and the mixture was exhaustively extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO), filtered, and concentrated in vacuo. The residue was triturated with ether and pentane. The following indole carboxylic acids are prepared in a similar manner starting from their respective ester precursors of formula C: [Table 14] Compounds D-5 and D-6 can be prepared starting from the corresponding halogen-substituted benzaldehyde using methods similar to those described above for D-1, D-2, D-3 and D-4. [Table 15]

[0047] Synthesis of benzylamine building blocks Scheme 4: [ka] Synthesis of E-1 To a stirred solution of [(R)-1-(4-iodophenyl)ethyl]carbamic acid tert.-butyl ester (100.0 g, 288.0 mmol, which can be prepared by the procedure given in WO2011076786) in MeOH (900 mL) is added triethylamine (101 mL, 720.0 mmol) under an argon atmosphere. 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (16.5 g, 20 mmol) is added, and the reaction mixture is stirred under a CO atmosphere (250 psi) at 120 °C for 16 h. The mixture is filtered through a Celite bed and concentrated in vacuo. The crude product is purified by column chromatography (SiO2, 30% EtOAc in hexane). [Table 16]

[0048] Synthesis of E-2 To E-1 (63.0 g, 225.6 mmol) in dry THF (700 mL) was added lithium aluminum hydride (1 M in THF, 338.3 mL, 338.3 mmol) at 0 °C and stirred at room temperature for 2 h. Saturated aqueous NaSO was added and the mixture was filtered through a Celite bed. The aqueous layer was exhaustively extracted with EtOAc. The combined organic layers were dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, 0–25% EtOAc in hexanes). [Table 17]

[0049] Synthesis of E-3 To E-2 (50.0 g, 199.0 mmol) in dry CHCl (500 mL) were added triphenylphosphine (78.3 g, 298.5 mmol) and CBr (99.0 g, 298.5 mmol) at 0° C. and stirred at room temperature for 5 h. Water was added and the aqueous layer was thoroughly extracted with CHCl. The combined organic layers are dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified by column chromatography (SiO2, 10% EtOAc in hexanes). [Table 18]

[0050] Synthesis of E-4 To E-3 (35.0 g; 111.4 mmol) in DMF (350 mL) was added NaCN (10.92 g, 222.8 mmol) and stirred at room temperature for 16 h. The mixture was treated with water and the precipitate was collected by filtration and dried in vacuo. [Table 19]

[0051] Synthesis of E-5 To E-4 (6.0 g, 23.0 mmol) in dry THF (80 mL) was added 60% sodium hydride (1.38 g, 34.5 mmol) at 0 °C and 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 in hexanes). [Table 20]

[0052] Synthesis of E-6 To E-5 (3.0 g, 9.09 mmol) in EtOH (20 mL) / water (20 mL) was added KOH (5.08 g, 90.9 mmol) and stirred under reflux for 24 h. The mixture was treated with 2 N HCl, and the precipitate was collected by filtration and triturated with water. The resulting solid was dried under vacuum. [Table 21]

[0053] Synthesis of E-7 To E-6 (2.00 g, 5.73 mmol) in MeOH (30 mL) is added HSO (1.52 ml) at 0 °C. The reaction mixture is stirred under reflux for 24 h. Water is added and the mixture is neutralized with NaHCO. The aqueous layer is exhaustively extracted with DCM and the combined organic layers are dried (NaSO), filtered and concentrated in vacuo. [Table 22]

[0054] Synthesis of Examples Scheme 5: [ka]

[0055] Synthesis of F-1 (Method F) To D-3 (8.0 g, 31.0 mmol) in dry DMF (80 mL) was added triethylamine (9.39 g, 93.0 mmol), HATU (11.78 g, 31.0 mmol), and HOAT (4.22 g, 31.0 mmol) and stirred at 0 °C for 5 min. E-7 (8.98 g, 34.1 mmol) was added and stirred at room temperature for 16 h. The mixture was treated with water, and the precipitate was collected by filtration and triturated with water. The crude product was dried in vacuo, triturated with diethyl ether, and dried in vacuo. The following substituted indoles are prepared in a similar manner using the corresponding carboxylic acid intermediate of formula D: [Table 23]

[0056] Synthesis of Example 1 (Method G) To F-1 (8.20 g, 16.3 mmol) in MeOH (32 mL) / THF (32 mL) / water (32 mL) was added LiOH monohydrate (6.84 g, 162.6 mmol) and stirred at room temperature for 48 h. The mixture was treated with 4 N HCl, and the precipitate was collected by filtration and triturated with water. The crude product was purified by preparative HPLC-MS. [Table 24]

[0057] Biological Examples The invention will now be described by reference to the following non-limiting examples which illustrate the physiological activity and properties of the compounds of the invention.

[0058] 3-Phosphoglycerate dehydrogenase (PHGDH) fluorescence intensity assay This assay is used to identify compounds that inhibit the enzymatic activity of PHGDH, which catalyzes the reaction of 3-phosphoglycerate (3-PG) and NAD to 3-phosphohydroxypyruvate and NADH. The generated NADH is used in a coupled reaction for the diaphorase-mediated reduction of resazurin to resorufin, which can be measured by fluorescence intensity reading. The full-length version of the PHGDH enzyme was expressed in BL21(DE3) Escherichia coli via transformation with a plasmid containing PHGDH cDNA with an N-terminal HIS tag and a TEV cleavage 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 and used in biochemical assays. 3-Phosphoglycerate substrate was purchased from Sigma. NAD, diaphorase and resazurin were purchased from Sigma Aldrich. Compounds are dispensed from DMSO solution into assay plates (black, low volume, flat-bottom 384-well, Corning) using the Access Labcyte Workstation and Labcyte Echo 55x. For a selected maximum assay concentration of 100 μM, 150 nl of compound solution is transferred from a 10 mM DMSO compound stock solution. A series of 11 concentrations (10 1:5 steps) is transferred for each compound. DMSO is added so that each well contains a total of 150 nl of compound solution.

[0059] Assays were performed using 500 μM NAD and 500 μM 3-PG (final assay concentrations). 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) is added to 150 nl of compound. Add 10 μl of a mixture containing the assay-specific 3-PG concentration (500 μM), resazurin (25 μM final assay concentration), and diaphorase (35 μg / ml final assay concentration). Keep the plate at room temperature. After a 240-minute incubation period, measure the fluorescent signal using a PerkinElmer Envision HTS Multilabel Reader at an excitation wavelength of 530-560 nm and an emission wavelength of 590 nm. Each plate contains a negative control (DMSO diluted in place of test compound; reaction with PHGDH protein as indicated) and a positive control (DMSO diluted in place of test compound; reaction with buffer as indicated in place of PHGDH protein). The negative and positive control values ​​are used for normalization. A known inhibitor of PHGDH activity is used as an internal control. I C 50 The values ​​were analyzed using a four-parameter logistic model with the MEGALAB IC 50 The application performs calculations and analysis.

[0060] [Table 25]

[0061] Drug transport in human Caco-2 cells for estimation of intestinal drug absorption in humans The assay provides information on the compound's ability to cross cell membranes, the extent of oral absorption, and whether the compound is actively transported by uptake and / or efflux transporters. Permeability measurements on polarized, confluent Caco-2 cell monolayers grown on permeable filter supports are used as an in vitro absorption model. The apparent permeability coefficient (PE) of a compound across Caco-2 monolayers 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) indicates drug absorption from the intestine into the blood, while BA permeability (PEBA) indicates secretion from the blood back into the intestine through both passive and active transport mechanisms mediated by efflux and uptake transporters expressed on Caco-2 cells. Compounds are classified into permeability / absorption classes by comparing their AB permeability with that of reference compounds with known in vitro permeability and oral absorption in humans. Identical or similar permeabilities in both transport directions indicate passive transport, while vectorial permeability indicates an additional active transport mechanism. PEBA higher than PEAB suggests the involvement of apical efflux transporters (e.g., P-gp) and / or basal uptake transporters; PEAB higher than PEBA permeability suggests the involvement of apical uptake transporters (e.g., PepT1) and / or basal efflux transporters (e.g., MRP3). Active transport is concentration-dependently saturable. Caco-2 cells (1–2 × 10 ) were obtained from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH. 5 cells / 1cm 2Cells (approximately 100 μM in area) are seeded onto filter inserts (Costar Transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (in DMEM) for 10 to 25 days. Compounds are dissolved in an appropriate solvent (e.g., DMSO, 1-20 mM stock solution). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO × 7H2O, 0.41 mM NaHPO × 7H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) containing 0.25% BSA to prepare transport solution (0.1-300 μM compound, final DMSO ≤ 0.5%). Transport solution (TL) is applied to the apical or basal donor side (filter triplicate measurements) to measure AB or BA permeability, respectively. The receiver side contains HTP-4 buffer formulated with 0.25% BSA. Samples are collected from the donor at the beginning and end of the experiment and from the receiver side at various time intervals (0, 30, 60, and 90 min) for up to 2 h for concentration measurement by HPLC-MS / MS or scintillation counter. The collected receiver volume is replenished with fresh receiver solution.

[0062] The compounds are divided into the following permeability / oral absorption classes: -Very low: 1×10 -7 cm / sec <PEAB -Low: 1×10 -7 cm / s <PEAB<6×10 -7 cm / sec -Medium: 6×10 -7 cm / sec <PEAB<5×10 -6 cm / sec -Good: 5×10 -6 cm / s <PEAB<1×10 -5 cm / sec - Very good: PEAB<1×10 -5 cm / sec Compounds are classified with respect to the (permeability) efflux ratio (PEBA / PEAB), indicating whether they can be actively transported: - None: 0.67<= ratio<=1.5 - Possibly (active discharge): 1.5<= ratio<=2 - Possibly (active uptake): 0.67<ratio<=0.5 -Yes (active discharge): 2< ratio -Yes (active uptake): ratio <0.5

[0063] [Table 26]

[0064] [Table 27]

[0065] The following formulation examples illustrate the invention without limiting its scope: Examples of Pharmaceutical Formulations [Table 28] The finely ground active ingredient, lactose and a portion of the cornstarch are mixed together. The mixture is sieved, then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining cornstarch and magnesium stearate are sieved and mixed together. The mixture is compressed to produce tablets of the desired shape and size.

[0066] [Table 29] The finely ground active ingredient, a portion of cornstarch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved, the remaining cornstarch and water are added to form granules, the granules are dried and sieved, sodium starch glycolate and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of the desired size.

[0067] [Table 30] The active ingredient, lactose and cellulose are mixed together. The mixture is sieved, then moistened with water, kneaded, wet-granulated, dried, or dry-granulated or directly final mixed with magnesium stearate and compressed into tablets of desired shape and size. In the case of wet-granulation, additional lactose or cellulose and magnesium stearate are added, and the mixture is compressed to produce tablets of desired shape and size.

[0068] [Table 31] The active ingredient 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 to make it pyrogen-free, and the filtrate is transferred under aseptic conditions into ampoules, which are then sterilized and sealed by melting. The ampoules contain 5 mg, 25 mg, and 50 mg of the active ingredient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (I) (In the formula, R1, R2 and R3 are each independently hydrogen, C 1-3 selected from the group consisting of alkyl and halogen; R4 is C 1-4 is alkyl; R5 is C 1-3 Alkyl or hydroxy-C 1-3 is alkyl; R6 and R7 are each independently —O—, —N(H)—, or —N(COR a ) -, -N(SO 2 R a )-, -S-, -S(O)- and -S(O) 2 -, wherein the heterocycle optionally includes one or more moieties selected from the group consisting of -C(O)C 1-3 Alkyl and —N(H)COR a optionally substituted with one or more substituents selected from R8, hydrogen or C 1-3 is alkyl; R a is C 1-3 Alkyl, —NH 2 , -N(H)C 1-3 Alkyl and -N(C 1-3 alkyl) 2 is selected from the group consisting of

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

3. 3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein R2 is hydrogen or halogen.

4. 4. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein at least one of R1, R2 and / or R3 is halogen.

5. 5. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein R3 is methyl.

6. 6. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein R4 is methyl.

7. 7. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein R5 is methyl.

8. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein R6 and R7 together form a 3- to 7-membered saturated heterocycle containing a moiety selected from the group consisting of -O-, -N(H)-, and -S-.

9. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein R6 and R7 together form a tetrahydropyran ring.

10. R6 and R7 are mutually 【Chemistry 2】 10. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, which forms:

11. 11. The compound or pharmaceutically acceptable salt of any one of claims 1 to 10, wherein R8 is hydrogen. 【Request Item 12】 【Table 1】 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from:

13. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 12 for use as a pharmaceutical.

14. 13. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 12 for use in the treatment and / or prevention of cancer, infectious diseases, inflammation and / or autoimmune diseases.

15. 13. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and a pharmaceutically acceptable excipient, and optionally further comprising one or more pharmacologically active ingredients.

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