HK1262051B - [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3- yl](1h-1,2,3-triazol-4-yl)methanones - Google Patents

Description

[8-(Phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl](1H-1,2,3-triazol-4-yl)methanone

The present invention relates to [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl](1H-1,2,3-triazol-4-yl)methanone compounds of the general formula (I) as described and defined herein, processes for preparing said compounds, intermediate compounds for preparing said compounds, pharmaceutical compositions and conjugates comprising said compounds, and uses of said compounds for preparing pharmaceutical compositions for treating or preventing diseases, in particular diseases in mammals, such as, but not limited to, gynecological diseases, hyperproliferative diseases, metabolic diseases or inflammatory diseases.

Background Art

The present invention relates to [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl](1H-1,2,3-triazol-4-yl)methanone compounds of general formula (I), which inhibit the enzyme activity of AKR1C3.

Aldo-keto reductase family 1 member C3 (AKR1C3, also known as type 5 17-β-hydroxysteroid dehydrogenase (17-β-HSD5)) is a member of the aldo-keto reductase (AKR) superfamily of enzymes that reduces the aldehyde/ketone groups in steroid hormones to the corresponding alcohols and thus plays an important role in the metabolism/activation/inactivation of androgens, progesters, and estrogens.

AKR1C3 has 3α-HSD (hydroxysteroid dehydrogenase activity), 17β-HSD, 20α-HSD and prostaglandin (PG) F synthase activity. It catalyzes the conversion of estrone (weak estrogenic activity) to estradiol (potent estrogenic activity), progesterone (strong anti-estrogen activity) to 20-α-hydroxyprogesterone (weak anti-estrogen activity), and androstenedione to testosterone (Labrie et al. Front Neuroendocrinol. 2001, 22(3):185-212). In addition, AKR1C3 catalyzes the conversion of PGH2 to PGF2α and PGD2 to 11β-PGF2, both of which are known to stimulate inflammation and proliferation. In addition, AKR1C3 has been shown to metabolize a broad spectrum of carbonyl compounds and xenobiotics, including clinically used anthracycline antibiotics (Bains et al. J. Pharmacol Exp. Ther. 2010, 335:533-545; Novona et al. Toxicol Lett. 2008, 181:1-6; Hofman et al. Toxicology and Applied Pharmacology 2014, 278:238-248).

AKR1C3 plays a role in several pathological conditions/diseases:

Endometriosis: Endometriosis is a chronic, primarily estrogen-dependent inflammatory disease characterized by the presence of endometrial tissue outside the uterine cavity. The main symptoms of endometriosis are chronic pelvic pain and infertility.

Estrogen (E2) deficiency is a clinically proven concept and a potential primary mechanism of action for pharmacological treatment of endometriosis. In addition to systemic estrogen levels, there is increasing evidence that locally derived estrogen contributes to the growth of endometriotic lesions. High tissue estrogen concentrations in endometriotic lesions have recently been described, suggesting high local estrogen synthesis in endometriosis (Huhtinen et al. J Clin Endocrinol Metab. 2012, 97(11):4228–4235). Therefore, inhibition of local E2 production in endometriotic lesions is considered a highly attractive mechanism of action for the treatment of endometriosis.

AKR1C3 is strongly expressed in endometriotic lesions and is only slightly detectable in the ovaries (Smuc et al. Mol Cell Endocrinol. 2009, 301(1-2):59-64). In synergy with CYP19A1 (aromatase), AKR1C3 is expected to be a key enzyme in local E2 production in endometriotic lesions, creating a pro-estrogenic environment, thereby stimulating the proliferation of estrogen-sensitive endometriotic cells. Therefore, inhibition of AKR1C3 should lead to a decrease in local tissue E2 levels, thereby reducing the proliferation of endometriotic lesions. Since AKR1C3 is only slightly expressed in the ovaries and 17βHSD1 is the major ovarian hydroxysteroid dehydrogenase, it is not expected to affect ovarian estrogen production.

AKR1C3 is also a PGF2a synthase. In addition to the upregulation of AKR1C3 in endometriotic lesions, PGF2a levels have been shown to be significantly higher in normal and ectopic endometrium from patients with intraperitoneal endometriosis than in similar tissues from patients with ovarian endometriomas (Sinreih et al. Chemico-Biological Interactions 2015, 234: 320-331). PGF2a in endometriotic tissue is expected to contribute to inflammation, pain, and proliferation in patients with endometriosis, and AKR1C3 expressed in endometriotic lesions is expected to contribute to the high local PGF2a levels in endometriotic tissue.

AKR1C3 inhibition has the potential to reduce proliferation, pain, and inflammation in patients with endometriosis by locally reducing E2, testosterone, and PGF2a levels in endometriotic tissue.

Polycystic Ovary Syndrome (PCOS):

PCOS is a common endocrine disorder that affects up to 10% of women of childbearing age. Clinically, it is associated with anovulatory infertility, dysfunctional bleeding, hyperandrogenism, hyperinsulinemia and insulin resistance, obesity, and metabolic syndrome (Dunaif et al. Endocrine Rev. 1997, 18: 774-800). The Hyperandrogenism Association has recognized four cardinal features of PCOS: ovulatory and menstrual dysfunction, biochemical hyperandrogenaemia, clinical hyperandrogenaemia (e.g., acne, hirsutism), and polycystic ovaries (Azziz et al. Clin Endocrinol Metab 2006, 91: 4237-45). The vast majority of women with PCOS will experience clinical symptoms of androgen excess, such as acne, hirsutism, or anovulation manifesting as primary infertility or oligomenorrhea (Legro et al. N Engl J Med 2014, 371: 119-129). Women with PCOS are susceptible to glucose intolerance and metabolic syndrome (Taponen et al. J of Clin Endocrinology and Metabolism 2004, 89: 2114-2118), have associated risk factors for cardiovascular disease, and may be at increased risk for future cardiovascular events (Mani et al. Clin Endocrinol 2013, 78: 926-934).

Hyperandrogenism, hirsutism and/or hyperandrogenism are key components of the syndrome and are mandatory for the diagnosis of PCOS (Azziz et al. Clin Endocrinol Metab 2006, 91:4237-45). Although serum testosterone is a key factor in the biochemical assessment of hyperandrogenism, androstenedione has recently been considered to be a more reliable marker of the androgen excess associated with PCOS because androstenedione circulates in high concentrations in PCOS women (Reilly et al. J Clin Endocrinol Metab 2014, jc20133399).

PCOS is traditionally considered an ovarian disease (Franks et al. J Steroid Biochem Molecular Biology 1999, 69: 269-272). However, there is increasing interest in extraovarian and extraadrenal androgen formation in PCOS, highlighting the role of peripheral tissues such as adipose androgen formation (Quinkler et al. J of Endocrinology 2004, 183: 331-342).

AKR1C3 is an androgen-activating enzyme that is known to primarily convert androstenedione to testosterone. Upregulation of AKR1C3 has been documented in adipose tissue of PCOS patients, suggesting that ARK1C3 expression in adipose tissue significantly contributes to androgen formation from androstenedione in PCOS patients. Furthermore, it has been shown that AKR1C3 expression in adipocytes is significantly increased by insulin, suggesting that high insulin levels in PCOS can drive adipose androgen formation by increasing AKR1C3 activity in subcutaneous adipose tissue in women (O'Reilly et al., Lancet 2015, 385 Suppl 1: S16).

AKR1C3 is also a PGF2a synthase that plays an inhibitory role in the formation of endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARγ), the target of insulin-sensitizing drugs (Spiegelman et al. Diabetes 1998, 47:507-514).

Selective AKR1C3 inhibition may provide a new therapeutic target to reduce androgen load and improve the metabolic phenotype of PCOS. (O'Reilly M1, et al. Lancet. 2015 385 Suppl 1: S16.; Du et al. J Clin Endocrinol Metab. 2009, 94(7): 2594-2601.)

Cancer: AKR1C3 is overexpressed in many cancers, including those of the prostate, breast, uterus, blood, lung, brain, and kidney, such as endometrial cancer (T. Rizner et al., Mol Cell Endocrinol 2006 248(1-2), 126-135), lung cancer (Q. Lan et al., Carcinogenesis 2004, 25(11), 2177-2181), non-Hodgkin's lymphoma (Q. Lan et al., Hum Genet 2007, 121(2), 161-168), bladder cancer (J. D. Figueroa, Carcinogenesis 2008, 29(10), 1955-1962), chronic myeloid leukemia (J. Birthwistle, Mutat Res 2009, 662(1-2), 67-74), renal cell carcinoma (J. T. Azzarello, Int J Clin Exp Pathol 2009, 3(2), 147-155), breast cancer (MCByrns, J Steroid Biochem Mol Biol 2010, 118(3), 177-187), and its upregulation is often associated with tumor invasion and invasiveness (Azzarello et al. Int. J. Clin. Exp. Path. 2009, 3: 147-155, Birtwistle et al. Mutat. Res. 2009, 662: 67-74; Miller et al. Int. J. Clin. Exp. Path. 2012, 5: 278-289). AKR1C3 can directly reduce estrone and progesterone to 17β-estradiol and 20α-hydroxyprogesterone, respectively, thereby enhancing this pro-proliferative signal (Smuc and Rizner, Chem Biol Interact. 2009, 178: 228-33). In addition, the prostaglandin F synthase activity of AKR1C3 catalyzes the conversion of PGH2 into PGF2α and PGD2 into 11β-PGF2, both of which are known to stimulate inflammation and proliferation. In the absence of AKR1C3 activity, PGD2 (instead of being converted into PGF2) spontaneously dehydrates and rearranges to form anti-proliferative and anti-inflammatory PGJ2 isomers, including 15d-PGJ2. In short, AKR1C3 increases proliferative PGF2 isomers and reduces anti-proliferative PGJ2 products, so AKR1C3 has the potential to affect hormone-dependent and hormone-independent cancers. In breast cancer, it is assumed that the effect of AKR1C3 can produce prostaglandin F2 (PTGFR) ligands, whose activation leads to cancer cell survival (Yoda T et al., (2015) Mol Cell Endocrinol.15; 413: 236-247).

Prostate cancer: Elevated expression of AKR1C3 is associated with prostate cancer progression and aggressiveness (Stanbrough M et al. Cancer Res 2006, 66:2815–25; Wako K et al. J Clin Pathol. 2008, 61(4):448-54). In hormone-dependent prostate cancer, AKR1C3 converts androstenedione to testosterone, which in turn overactivates the androgen receptor and promotes tumor growth (Penning et al. Mol Cell Endocrinol. 2006, 248(1-2):182-91).

In castration-resistant prostate cancer (CRPC), AKR1C3 is involved in intratumoral androgen biosynthesis - it promotes the conversion of the weak androgens androstenedione (A'-dione) and 5α-androstanedione (5α-dione) into the more active androgens testosterone and DHT, respectively (Liu et al. Cancer Res. 2015, 75(7):1413-22; Fung et al. Endocr Relat Cancer 2006, 13(1), 169-180). Importantly, AKR1C3 expression is increased in CRPC patients compared with primary prostate cancer (Stanbrough et al. Cancer Res 2006, 66:2815-2825; Hamid et al. Mol Med 2012, 18:1449-1455; Pfeiffer et al. Mol Med 2011, 17:657-664). Genetic polymorphisms of the AKR1C3 gene encoding AKR1C3 have also been shown to be independent predictors of prostate cancer (Yu et al. PLoS One 2013, 8(1): e54627). In addition, AKR1C3-dependent de novo androgen synthesis is considered to be a potential mechanism of resistance to CYP17A1 inhibitors (such as abiraterone) (Mostaghel et al. Clin Cancer Res 2011, 17: 5913–5925; Cai et al. Cancer Res 2011, 71: 6503–6513). Therefore, in patients with CRPC, AKR1C3 may be a promising therapeutic agent (Adeniji et al. J Steroid Biochem Mol Biol 2013, 137: 136-149). In a multicenter phase I/II study, AKR1C3 inhibitors were tested in patients with metastatic castration-resistant prostate cancer. However, novel androgen biosynthesis inhibitors have not shown evidence of clinical activity (Loriot et al. Invest New Drugs 2014, 32: 995–1004). Recent data suggest that AKR1C3 activation in CRPC is a key resistance mechanism associated with antiandrogen (enzalutamide) resistance. It has been shown that androgen precursors such as cholesterol, DHEA, and progesterone, as well as androgens, are highly upregulated in enzalutamide-resistant prostate cancer cells compared to parental cells. Data suggest that inhibition of the AKR1C3 pathway in patients with enzalutamide-resistant CRPC can be used as enzalutamide sensitization therapy and restore efficacy (Liu et al. Cancer Res. 2015, 75(7): 1413-22). It is speculated that co-treatment with AKR1C3 inhibitors will overcome enzalutamide resistance and improve survival in patients with advanced prostate cancer (Thoma et al. Nature Reviews Urology 2015, 12: 124).

Anthracycline-resistant cancers: Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy that are derived from the bacterium Streptomyces peucetius var. caesius (Fujiwara et al. Critical Reviews in Biotechnology 1985, 3(2):133). These compounds are used to treat many cancers, including leukemias, lymphomas, breast cancer, gastric cancer, uterine cancer, ovarian cancer, bladder cancer, and lung cancer. Anthracyclines are one of the most effective anticancer treatments ever developed. However, the clinical success of anthracycline-based cancer treatment has been eclipsed by drug resistance. It is generally accepted that increased enzymatic reduction of anthracyclines to their less potent secondary C13-hydroxy metabolites constitutes one of the mechanisms that cause anthracycline resistance in tumors (Gavelova et al. 2008 Chem. Biol. Interact 176, 9-18; Heibein et al. 2012 BMC Cancer 12, 381). Enzymatic metabolism, particularly of doxorubicin, is responsible for the cardiomyopathy observed following doxorubicin chemotherapy. AKR1C3 has been shown to be involved in the metabolism of clinically administered anthracyclines such as doxorubicin and daunorubicin (Novotna et al., Toxicol. Letter 2008, 181: 1-6).

In 2012, an association between AKR1C3 gene variants and doxorubicin pharmacodynamics was shown in Asian breast cancer patients: one genetic variant was associated with longer progression-free and overall survival after doxorubicin-based treatment, suggesting a possible interaction with doxorubicin metabolism (Voon et al. British J of Clin Pharmacology 2012, 75:1497-1505).

Recently it could be demonstrated that AKR1C3 contributes to the resistance of cancer cells to anthracycline treatment, and therefore the simultaneous administration of specific AKR1C3 inhibitors and anthracyclines may be an effective strategy for the successful prevention and treatment of anthracycline-resistant tumors (Hofman et al. Toxicology and Applied Pharmacology 2014, 278:238–248).

Atopic dermatitis: Challenging atopic subjects with antigens results in the release of PGD2 and histamine, indicating that PGD2 has little effect on the immediate allergic response of human skin and that PGD2 is a lipid mediator that promotes skin inflammation in atopic dermatitis (AD) (Barr et al., Br J Pharmacol. 1988, 94: 773–80; Satoh et al. J Immunol. 2006, 177: 2621–9.; Shimura et al. Am J Pathol. 2010; 176: 227–37). PGD2 is a relatively unstable pro-inflammatory mediator that spontaneously converts to the potent anti-inflammatory mediator 15d-PGJ2. This conversion is transferred by AKR1C3, which metabolizes PGD2 to the pro-inflammatory 9α, 11β-PGF2 (Mantel et al. Exp Dermatol. 2016, 25(1): 38-43).

AKR1C3 has been shown to be upregulated in human AD samples, and a role for AKR1C3 in mediating inflammation in skin pathologies, particularly atopic dermatitis and keloids has been postulated (Mantel et al. J Invest Dermatol. 2012, 132(4):1103-1110) Mantel et al. Exp Dermatol. 2016, 25(1):38-43). AKR1C3 inhibition may be a new option for the treatment of AD and keloids.

Inflammation: AKR1C3 is involved in prostaglandin biosynthesis, catalyzing the conversion of PGH2 to PGF2 and PGD2 to 11β-PGF2. It is speculated that the expression and upregulation of AKR1C3 can inhibit inflammation by directly increasing the synthesis rate of 9α,11β-PGF2 and shifting the spontaneous production of the potent anti-inflammatory mediator 15d-PGJ2 (Mantel et al. J Invest Dermatol 2012, 132(4):1103-1110). This function of AKR1C3 has also been implicated in HL-60 cells (Desmond et al. Cancer Res 2003, 63:505-512) and MCF-7 cells (Byrns et al. J Steroid Biochem Mol Biol 2010, 118:177-187). It is hypothesized that inhibition of AKR1C3 increases 15d-PGJ2, an anti-inflammatory lipid that mediates its effects directly by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and/or inhibiting NF-κB signaling in immune cells (Maggi et al. Diabetes 2000, 49: 346-355; Scher et al. Clinical Immunology 2005, 114: 100-109). Previous data have shown that PPAR-γ activation attenuates allergen-induced inflammation in mouse skin and lungs (Ward et al. Carcinogenesis. 2006, 27(5): 1074-80; Dahten et al. J Invest Dermatol. 2008, 128(9): 2211-8). This suggests a role for AKR1C3 inhibition in suppressing inflammation.

Other diseases In addition, AKR1C3 inhibitors have the potential to be used to treat prostate hyperplasia (Roberts et al., Prostate 2006, 66(4), 392-404), hair loss (L. Colombe et al., Exp Dermatol 2007, 16(9), 762-769), obesity (P.A. Svensson et al., Cell Mol Biol Lett 2008, 13(4), 599-613), premature sexual maturation (C. He, Hum Genet 2010, 128(5), 515-527) and chronic obstructive pulmonary disease (S. Pierrou, Am J Respir Crit Care 2007, 175(6), 577-586).

Inhibitors of AKR1C3 are described in the prior art: Flanagan et al. Bioorganic & Medicinal Chemistry 2014, 22:967-977; Jamieson et al. Journal of Medicinal Chemistry 2012, 55:7746-7758; WO 2013/059245; WO 2013/142390; WO 2014/039820; WO 2013/045407; WO 2014/128108 and WO 2014/009274.

Heinrich et al. European Journal of Medicinal Chemistry 2013, 62:738-744 relates to 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-one as an inhibitor of AKR1C3.

WO 2007/111921 (Amgen) relates to 1-phenylsulfonyl-diazacyclic heterocyclic amide compounds and their use in methods for treating conditions or disorders responsive to modulation of hydroxysteroid dehydrogenase (HSD), primarily for the treatment of diabetes or obesity. Endometriosis is specifically mentioned among other diseases. 11βHSD1, 11βHSD2, and 17βHSD3 are explicitly disclosed. The disclosed examples are shown to inhibit 11βHSD1 with _IC50 values ranging from <1 nM to 1000 nM. However, there is no disclosure of inhibition or modulation of the enzymatic activity of AKR1C3 or other HSDs. WO 2007/111921 particularly relates to piperazine compounds, such as Compound No. 4 of Table 1. However, piperazines having an ethylene bridge between the 2- and 6-positions are not disclosed in WO 2007/111921.

WO 2007/103456 (Trimeris) relates to piperazine derivatives and methods of using the same for treating HIV infection and AIDS.

WO 2008/024284 (Merck) relates to sulfonylated piperazines as cannabinoid-1 receptor modulators.

However, the prior art does not describe the [8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl](1H-1,2,3-triazol-4-yl)methanone compounds of the general formula (I) of the present invention as described and defined herein.

It has now been found that the compounds according to the invention have surprising and advantageous properties, which form the basis of the present invention.

In particular, it was surprisingly found that the compounds of the present invention effectively inhibit AKR1C3, where data are given in the biological experimental section, and are therefore useful for treating or preventing AKR1C3-associated disorders, such as gynecological disorders, in particular endometriosis-associated and polycystic ovary syndrome-associated gynecological disorders, conditions and diseases, metabolic disorders, hyperproliferative disorders, conditions and diseases, and inflammatory disorders.

According to a first aspect, the present invention relates to a compound of general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof:

in:

R ¹ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano;

R ² represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ ;

R ³ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or hydroxy;

R ⁴ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ ;

R ⁵ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano;

wherein R ¹ and R ² or R ² and R ³ are optionally linked to each other in such a way that they together form a methylenedioxy group, an ethylenedioxy group, an ethyleneoxy group, a trimethyleneoxy group or a group selected from the following:

definition

When used in this specification, the term "comprising" includes "consisting of".

If any term is referred to herein as "as described herein," it means that it can be referred to anywhere in the document.

The terms used in this document have the following meanings:

The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

The term "C ₁ -C ₃ -alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, for example methyl, ethyl, n-propyl or isopropyl.

The term "C ₁ -C ₃ -haloalkyl" refers to a linear or branched, saturated, monovalent hydrocarbon radical, wherein the term "C ₁ -C ₃ -alkyl" is as defined above and wherein one or more hydrogen atoms are replaced by identical or different halogen atoms. In particular, the halogen atoms are fluorine atoms. The C ₁ -C ₃ -haloalkyl radical is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl.

The term "C ₁ -C ₃ -alkoxy" means a linear or branched saturated monovalent group of the formula (C ₁ -C ₃ -alkyl)-O-, wherein the term "C ₁ -C ₃ -alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy or isopropoxy.

The term "C ₁ -C ₃ -haloalkoxy" means a linear or branched, saturated, monovalent C ₁ -C ₃ -alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by identical or different halogen atoms. In particular, the halogen atoms are fluorine atoms. The C ₁ -C ₃ -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy or trifluoromethoxy.

As used herein, for example in the context of the definition of "C ₁ -C ₃ -alkyl", "C ₁ -C ₃ -haloalkyl", "C ₁ -C ₃ -alkoxy" or "C ₁ -C ₃ -haloalkoxy", the term "C ₁ -C ₃ " means an alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2 or 3 carbon atoms.

When a range of values is given, that range includes every value and sub-range within that range.

For example:

"C ₁ -C ₃ " includes C ₁ , C ₂ , C ₃ , C ₁ -C ₃ , C ₁ -C ₂ and C ₂ -C ₃ .

As used herein, the term "leaving group" means an atom or group of atoms that is replaced in a chemical reaction as a stable form in which the bonding electrons are present. In particular, such leaving groups are selected from the group consisting of: halides, in particular fluorides, chlorides, bromides or iodides, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

The compounds of general formula (I) may exist as isotopic variations. Therefore, the present invention includes one or more isotopic variations of the compounds of general formula (I), in particular deuterated compounds of general formula (I).

The term "isotopic variation" of a compound or agent is defined as a compound that exhibits unnatural proportions of one or more of the isotopes that constitute such compound.

The term "isotopic variation of a compound of formula (I)" is defined as a compound of formula (I) that exhibits unnatural proportions of one or more of the isotopes that constitute such compound.

The expression "unnatural proportion" means that the proportion of such isotopes is higher than their natural abundance. The natural abundance of the isotopes to be used herein is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, 14 C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ^{35 S, 36 S} , ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, and ¹³¹ I, ^respectively .

With respect to the treatment and/or prevention of the conditions described herein, isotopic variations of the compounds of Formula (I) preferably contain deuterium ("deuterated compounds of Formula (I)"). Isotopic variations of the compounds of Formula (I) in which one or more radioactive isotopes such as ³ H or ¹⁴ C are incorporated are useful in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred because they are easy to incorporate and detect. Positron-emitting isotopes such as ¹⁸ F or ¹¹ C can be incorporated into the compounds of Formula (I). These isotopic variations of the compounds of Formula (I) are useful in in vivo imaging applications. Deuterium- and ¹³ C-containing compounds of Formula (I) are useful in mass spectrometry analysis in preclinical or clinical studies.

Isotopic variants of compounds of formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of the reagent, preferably a deuterated reagent. In some cases, depending on the desired deuteration site, deuterium from D ₂ O can be incorporated directly into the compound or into reagents that can be used to synthesize these compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid route to incorporating deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in hydrocarbon-containing functional groups. Various deuterated reagents and synthetic building blocks are commercially available from companies such as C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA, and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term "deuterated compound of formula (I)" is defined as a compound of formula (I) wherein one or more hydrogen atoms are replaced by one or more deuterium atoms, and wherein the abundance of deuterium at each deuterated position of the compound of formula (I) is greater than the natural abundance of deuterium (approximately 0.015%). In particular, in the deuterated compound of formula (I), the abundance of deuterium at each deuterated position of the compound of formula (I) is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably greater than 90%, 95%, 96% or 97%, even more preferably greater than 98% or 99% at said position. It will be understood that the deuterium abundance at each deuterated position is independent of the deuterium abundance at other deuterated positions.

The selective incorporation of one or more deuterium atoms into compounds of general formula (I) can change the physicochemical properties of the molecule (e.g., acidity (C.L.Perrin, et al., J.Am.Chem.Soc., 2007, 129, 4490), basicity (C.L.Perrin et al., J.Am.Chem.Soc., 2005, 127, 9641), lipophilicity (B.Testa et al., Int.J.Pharm., 1984, 19(3), 271)) and/or metabolic profile and can lead to changes in the ratio of parent compound to metabolite or the amount of metabolite formed. These changes may give rise to certain therapeutic advantages and may therefore be preferred in certain circumstances. It has been reported that when the ratio of metabolites changes, the metabolic rate and metabolic conversion are reduced (A.E.Mutlib et al., Toxicol.Appl.Pharmacol., 2000, 169, 102). These changes in parent drug and metabolite exposure may have important consequences for the pharmacodynamics, tolerability and efficacy of deuterated compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and increases the formation of desired metabolites (e.g., Nevirapine: A.M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A.E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the systemic clearance rate. Therefore, the biological half-life of the compound is increased. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may result in lower side effects and enhanced efficacy, depending on the pharmacokinetic/pharmacodynamic relationship of the specific compound. ML-337 (C.J.Wenthur et al., J.Med.Chem., 2013, 56, 5208) and Odanacatib (K.Kassahun et al., WO2012/112363) are examples of this deuterium effect. Other cases have also been reported where reduced metabolic rates lead to increased drug exposure without changing systemic clearance rates (e.g., Rofecoxib: F.Schneider et al., Arzneim.Forsch./Drug.Res., 2006, 56, 295; Telaprevir: F.Maltais et al., J.Med.Chem., 2009, 52, 7993). Deuterated drugs showing this efficacy may reduce dosage requirements (e.g., lower dosages or lower doses to achieve the desired effect) and/or may produce a lower metabolite load.

Compounds of general formula (I) may have multiple potential metabolic attack sites. In order to optimize the above-mentioned impact on physicochemical properties and metabolic profiles, deuterated compounds of general formula (I) with specific patterns of one or more deuterium-hydrogen exchanges can be selected. In particular, the deuterium atom of the deuterated compound of general formula (I) is connected to a carbon atom and/or is located at those positions of the compound of general formula (I) that are attack sites for metabolic enzymes, such as cytochrome P ₄₅₀ .

When plural forms of compounds, salts, polymorphs, hydrates, solvates, etc. are used herein, this also means a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

In addition, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention containing a 1,2,3-triazole moiety may exist as a 1H tautomer or a 3H tautomer, or even as a mixture of any amount of both tautomers, i.e.:

The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.

Additionally, the compounds of the present invention may exist as N-oxides, which are defined as compounds of the present invention in which at least one nitrogen atom is oxidized. The present invention includes all such possible N-oxides.

The present invention also encompasses useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts (particularly pharmaceutically acceptable salts) and/or coprecipitates.

The compounds of the present invention may exist as hydrates or solvates, wherein the compounds of the present invention contain polar solvents, particularly water, methanol or ethanol, as structural elements of the compound's crystal lattice. The amount of polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates such as hydrates, these may be hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

Furthermore, the compounds of the present invention may exist in free form, for example as a free base or as a free acid or as a zwitterion, or in the form of a salt. The salt may be any salt, organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt, which is conventionally used in the preparation of pharmaceuticals or for example for the isolation or purification of the compounds of the present invention.

The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention, see, for example, S. M. Berge et al. J. Pharm. Sci. 1977, 66: 1-19.

Suitable pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of compounds of the present invention having a nitrogen atom in the chain or ring with sufficient basicity, for example, acid addition salts with inorganic acids or "mineral acids", such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid, or with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, dihydrogen iodide, benzoic acid, benzoyl benzoate ... Hydroxynaphthoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptose, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium salt, a magnesium salt or a strontium salt; or an aluminum or zinc salt; or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine , arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt of a quaternary ammonium ion containing 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium chloride.

Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base using various known methods.

The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

In this text, in particular in the experimental part, for synthetic intermediates and examples according to the invention, when compounds are mentioned as salt forms with the corresponding bases or acids obtained by the respective preparation and/or purification processes, the exact stoichiometric composition of said salt forms is in most cases not known.

Unless otherwise indicated, suffixes in chemical names or formulas related to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "xHCl", "xCF ₃ COOH", "xNa ⁺ ", refer to the salt form, the stoichiometry of which is unspecified.

This applies analogously to the case in which synthesis intermediates or example compounds or salts thereof are obtained by the preparation and/or purification processes as solvates (eg hydrates) which have, if defined, an unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" herein refers to compounds that may themselves be biologically active or inactive but are converted (eg metabolized or hydrolyzed) to the compounds of the present invention during their residence time in the body.

According to a second embodiment of the first aspect, the present invention relates to compounds of the above-mentioned general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano;

R ² represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ ;

R ³ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or hydroxy;

R ⁴ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ ;

R ⁵ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano.

According to a third embodiment of the first aspect, the present invention relates to compounds of the above-mentioned general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano;

R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano or SF ₅ ;

R ³ represents hydrogen;

R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano or SF ₅ ;

R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano.

According to a fourth embodiment of the first aspect, the present invention relates to compounds of the above-mentioned general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl;

R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or SF ₅ ;

R ³ represents hydrogen;

R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or SF ₅ ;

R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.

Other embodiments of the first aspect of the present invention:

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ² represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ³ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or hydroxy.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ³ represents hydrogen.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁴ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro, cyano or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or SF ₅ .

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁵ represents hydrogen, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy, nitro or cyano.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

^R1 and ^R2 or ^R2 and ^R3 are linked to each other in such a way that they together form a methylenedioxy group, an ethylenedioxy group, an ethyleneoxy group, a trimethyleneoxy group or

A group selected from the following:

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

R ¹ and R ² or R ² and R ³ are linked to each other in such a manner that they together form a methylenedioxy group, an ethylenedioxy group, an ethyleneoxy group or a trimethyleneoxy group.

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

^R1 and ^R2 or ^R2 and ^R3 are linked to each other in such a way that they together form a group selected from the group consisting of:

In another embodiment of the first aspect, the present invention relates to compounds of formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

^R1 and ^R2 or ^R2 and ^R3 are linked to each other in such a way that they together form a group selected from the group consisting of:

In another embodiment of the first aspect, the present invention relates to a compound selected from the group consisting of:

In certain further embodiments of the first aspect, the invention relates to a combination of two or more of the above embodiments under the heading "Further embodiments of the first aspect of the invention".

The present invention includes any subcombination within any embodiment or aspect of the invention of the compounds of formula (I) described above.

The present invention includes any subcombination within any embodiment or aspect of the invention of the intermediate compounds of formula (IV) or (VIII).The present invention includes compounds of formula (I) as disclosed below in the Examples section herein.

The compounds of the general formula (I) of the present invention can be prepared according to the following scheme 1. The schemes and steps described below illustrate the synthetic routes of the compounds of the general formula (I) of the present invention, but are not restrictive. It is clear to those skilled in the art that the conversion sequence illustrated in scheme 1 can be modified in various ways. Therefore, the conversion sequence illustrated in this scheme is not restrictive. In addition, the mutual conversion of any substituent, R ¹ , R ² , R ³ , R ⁴ or R ⁵ can be achieved before and/or after the exemplary conversion. These modifications can be, for example, the introduction of protecting groups, the cleavage of protecting groups, the reduction or oxidation of functional groups, halogenation, metalation, substitution or formation and the cleavage of ethers known to those skilled in the art. These conversions include those that introduce functional groups that allow substituents to further convert to each other. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, Protective Groups in Organic Synthesis by TW Greene and PGM Wuts, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

Two routes to prepare compounds of general formula (I) are described in Scheme 1.

Scheme 1: Route for the preparation of compounds of the general formula (I), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings given above for the general formula (I).

The starting materials required to carry out the synthetic sequence listed in Method 1, i.e. tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Formula (II)) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Formula (V)), are known to those skilled in the art and are commercially available, for example from Arkpharminc, Achemblock or ASM chemicals.

Compounds of general formula (I) can be assembled according to Scheme 1 from tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate of formula (II), which can be reacted with a suitable sulfonyl chloride of general formula (VIII) in a suitable solvent (e.g., NMP or DCM) at a reaction temperature ranging from room temperature to the boiling point of the solvent in the presence of a suitable base (e.g., DIPEA) at a reaction temperature in the range of room temperature to the boiling point of the solvent to form a Boc-protected sulfonamide intermediate of general formula (III). The Boc-protected intermediate (III) can be deprotected in a suitable solvent (e.g., DCM or DCE) in the presence of a suitable acid (e.g., TFA), or with HCl in a suitable solvent (e.g., dioxane) and optionally in the presence of a scavenger such as water to form an intermediate of general formula (IV). The intermediate of general formula (IV) can be converted into the compound of general formula (I) of the present invention by reacting with 1H-1,2,3-triazole-5-carboxylic acid in the presence of a suitable coupling agent (e.g., HATU) in the presence of a suitable base (e.g., DIPEA) in a suitable solvent (e.g., NMP, DMF, DCM or THF) at a reaction temperature ranging from room temperature to the boiling point of the solvent.

Alternatively, the compound of formula (I) can be synthesized from tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Formula (V)), which is reacted with 1H-1,2,3-triazole-5-carboxylic acid in the presence of a suitable coupling agent (e.g., HATU) in the presence of a suitable base (e.g., DIPEA) in a suitable solvent (e.g., NMP, DMF, DCM, or THF) at a reaction temperature ranging from room temperature to the boiling point of the solvent to form intermediate (VI). Deprotection of intermediate (VI) can be carried out with a suitable acid (e.g., TFA) in a suitable solvent (e.g., DCM or DCE), or with HCl in a suitable solvent (e.g., dioxane). Intermediates of general formula (VII) can be converted into compounds of general formula (I) of the present invention by reacting with a suitable sulfonyl chloride of general formula (VIII) in the presence of a suitable base (e.g. DIPEA) in a suitable solvent (e.g. NMP or DCM) at a reaction temperature ranging from room temperature to the boiling point of the solvent.

According to a second aspect, the present invention relates to a process for preparing a compound of general formula (I) as defined above, said process comprising the step of reacting an intermediate compound of general formula (IV) with a compound of formula (IX) to obtain a compound of general formula (I):

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above for the compounds of general formula (I),

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

According to a third aspect, the present invention relates to a process for preparing a compound of general formula (I) as defined above, said process comprising the step of reacting an intermediate compound of formula (VII) with a compound of general formula (VIII) to obtain a compound of general formula (I):

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above for the compounds of general formula (I),

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

The present invention relates to a process for preparing the compounds of general formula (I) of the present invention, said process comprising the steps described in the experimental part herein.

According to a fourth aspect, the present invention relates to compounds of formula (III), (IV) or (VII)

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for the compounds of formula (I) according to any one of claims 1 to 5 , wherein at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is not hydrogen.

According to a fifth aspect, the present invention relates to the use of a compound of formula (III), (IV) or (VII) for the preparation of a compound of formula (I) according to any one of claims 1 to 5

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for the compounds of formula (I) according to any one of claims 1 to 5 , wherein at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is not hydrogen.

The present invention relates to the intermediates disclosed in the Examples section hereinafter.

As described herein, the compound of the general formula (I) of the present invention can be converted into any salt, preferably a pharmaceutically acceptable salt, by any method known to those skilled in the art. Similarly, any salt of the compound of the general formula (I) of the present invention can be converted into a free compound by any method known to those skilled in the art.

Indications

The compounds of the general formula (I) according to the present invention exhibit a promising, unpredictable spectrum of pharmacological action. Surprisingly, the compounds of the present invention have been found to effectively inhibit AKR1C3. For the majority of the claimed structural domains, these substances exhibit potent inhibition of AKR1C3 in vitro ( _IC50 values less than 10 nM), and remarkably, even _IC50 values of approximately <1 nM.

According to another aspect, the present invention relates to a compound of the above general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof for use in treating or preventing diseases.

As used herein, the terms "treating" or "treatment" are used conventionally, e.g., to manage or care for a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a gynecological disease, a hyperproliferative disease, a metabolic disease, or an inflammatory disease. The term "therapy" is understood herein to be synonymous with the term "treatment."

In the context of the present invention, the terms "prevention," "prophylaxis," or "preclusion" are used synonymously and refer to avoiding or reducing the risk of contracting, experiencing, suffering, or having a disease, condition, disorder, injury, or health problem, or the development or progression of such a condition, and/or the symptoms of such a condition.

The disease, condition, disorder, injury or health problem may be treated or prevented, partially or completely.

The present invention relates to methods for treating disorders and diseases in mammals and humans using compounds of the above-mentioned general formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or compounds thereof, including but not limited to:

Gynecological diseases,

Metabolic diseases,

Hyperproliferative disorders, and

Inflammatory diseases

Gynecological disease itself includes any gynecological disease, disorder or condition. The term also includes, but is not limited to, gynecological disorders, conditions and diseases such as endometriosis, polycystic ovary syndrome (PCOS), primary and secondary dysmenorrhea, dyspareunia, premature sexual maturation, uterine fibroids, uterine leiomyoma and uterine bleeding disorders.

Examples of endometriosis-related gynecological disorders, conditions, and diseases include, but are not limited to, endometriosis itself, endometriosis; endometriosis-related pain; endometriosis-related symptoms, wherein the symptoms are particularly dysmenorrhea, dyspareunia, dysuria, or dysfecation; endometriosis-related proliferation; and pelvic hypersensitivity.

Examples of gynecological disorders, conditions and diseases associated with polycystic ovary syndrome (PCOS) include, but are not limited to, polycystic ovary syndrome (PCOS) and symptoms associated with polycystic ovary, wherein the symptoms are particularly hyperandrogenimia, hirsutims, acne, hair loss, metabolic phenotypes such as obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome type II diabetes, obesity in PCOS.

Metabolic diseases include, but are not limited to, for example, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome type II diabetes, and obesity, which are not associated with PCOS.

Hyperproliferative disorders, conditions and diseases include, but are not limited to, for example, benign prostatic hyperplasia (BPH), solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid, parathyroid glands, and their distant metastases. Those diseases also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal and lobular carcinoma in situ.

Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung cancer, as well as bronchial adenocarcinoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brainstem and hypophtalmic gliomas, cerebellar and cerebral astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, testicular cancer and hormone-dependent and hormone-independent prostate cancer, including castration-resistant prostate cancer.

Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancers, and uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal carcinoma.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral cavity cancers and squamous cell carcinoma.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphomas of the central nervous system.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia. Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcoma, and rhabdomyosarcoma.

Inflammatory diseases include, but are not limited to, for example, any inflammatory disease, disorder, or condition per se, any condition having an inflammatory component associated therewith, and/or any condition characterized by inflammation, including, inter alia, acute, chronic, ulcerative, atopic, allergic, infection by pathogens, immune response due to allergic reaction, entry of a foreign body, physical injury, and necrotizing inflammation, as well as other forms of inflammation known to those skilled in the art. Thus, for the purposes of the present invention, the term also includes inflammatory pain, general pain, and/or fever. The compounds of the present invention may also be used to treat fibromyalgia, myofascial diseases, viral infections (e.g., flu, colds, shingles, hepatitis C, and AIDS), bacterial infections, fungal infections, surgical or dental procedures, malignancies (e.g., breast cancer, colon cancer, and prostate cancer), arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, diabetes, autoimmune diseases, allergic diseases, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary artery disease, sarcoidosis, atopic dermatitis, and scarring, as well as any other disease with an inflammatory component. The compounds of the present invention may also have effects unrelated to inflammatory mechanisms, such as reducing bone loss in a subject. Conditions which may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal disease.

Preferably, the present invention relates to a method for treating endometriosis and endometriosis-associated pain and symptoms, polycystic ovary syndrome, atopic dermatitis, keloids and prostate cancer (including castration-resistant prostate cancer (CRPC)) using the compound of the above-mentioned general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof.

According to another aspect, the present invention relates to compounds of the above-mentioned general formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof, for use in treating or preventing diseases, especially gynecological diseases, metabolic diseases, hyperproliferative diseases and inflammatory diseases.

According to another aspect, the present invention relates to the use of the compounds of the above-mentioned general formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof for treating or preventing diseases, especially gynecological diseases, metabolic diseases, hyperproliferative diseases and inflammatory diseases.

According to another aspect, the present invention relates to the use of the compounds of the above-mentioned general formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof in methods for treating or preventing diseases, especially gynecological diseases, metabolic diseases, hyperproliferative diseases and inflammatory diseases.

According to another aspect, the present invention relates to the use of the compound of the above-mentioned general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts) or mixtures thereof for preparing a pharmaceutical composition, preferably a medicament, for preventing or treating diseases, especially gynecological diseases, metabolic diseases, hyperproliferative diseases and inflammatory diseases.

According to another aspect, the present invention relates to a method for treating or preventing diseases, in particular gynecological diseases, metabolic diseases, hyperproliferative diseases and inflammatory diseases, using an effective amount of a compound of the above-mentioned general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (in particular pharmaceutically acceptable salts) or mixtures thereof.

These diseases (particularly gynecological diseases, metabolic diseases, hyperproliferative diseases, and inflammatory diseases) have not only been well characterized in humans, but also exist with similar etiologies in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

Pharmaceutical composition

According to another aspect, the present invention relates to a pharmaceutical composition, in particular a medicament, comprising a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt (in particular a pharmaceutically acceptable salt) or a mixture thereof, and one or more excipients, in particular one or more pharmaceutically acceptable excipients. Conventional methods for preparing such pharmaceutical compositions in suitable dosage forms can be used.

The present invention also comprises a pharmaceutical composition, in particular a medicament, comprising at least one compound of the present invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the above-mentioned purposes.

The present invention also provides a medicament comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the above-mentioned purposes.

The compounds of the present invention can act systemically and/or topically. For this reason, they can be administered in an applicable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, vaginal, dermal, transdermal, conjunctival or ear route administration, or as implants or stents.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

The compounds of the present invention may have systemic or local activity. For this reason, they may be administered in a suitable manner, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration, the compounds of the invention can be formulated into dosage forms known in the art that release the compounds of the invention quickly or in a slow manner, such as tablets (uncoated or coated tablets, for example, with enteric or controlled-release coatings that delay dissolution or do not dissolve), tablets that disintegrate in the mouth, films/wafers, films/lyophilized preparations, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. The compounds of the invention can be incorporated into the dosage forms in crystalline and/or amorphous and/or dissolved form.

Parenteral administration can be accomplished by avoiding an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or by including absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable administration forms for parenteral administration are, in particular, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Examples of suitable other routes of administration are inhalable pharmaceutical forms (especially powder inhalers, sprays), nasal drops, nasal solutions or nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear plugs; vaginal capsules, aqueous suspensions (emulsions, agitated mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. Pharmaceutically suitable excipients include in particular

Fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., lactose, mannitol, starch, calcium phosphate (e.g., Di-)),

ointment bases (e.g. petrolatum, paraffin, triglycerides, waxes, wool wax, wool alcohol, lanolin, hydrophilic ointments, polyethylene glycol),

Suppository bases (e.g. polyethylene glycol, cocoa butter, hard fat),

Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl sulfate, lecithin, phospholipids, fatty alcohols (e.g., ), sorbitan fatty acid esters (e.g., ), polyoxyethylene sorbitan fatty acid esters (e.g., ), polyoxyethylene fatty acid glycerides (e.g., ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g., ));

Buffers and acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine);

Isotonic agents (eg, glucose, sodium chloride);

Adsorbents (e.g., highly dispersed silica);

viscosity-increasing agents, gel-forming agents, thickeners and/or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g., ), alginates, gelatin);

Disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g., ), cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose (e.g., ));

Flow regulators, lubricants, glidants and release agents (e.g., magnesium stearate, stearic acid, talc, highly disperse silicon dioxide (e.g., ));

Coating substances (e.g. sugars, shellac) and film-forming agents for films or diffusion membranes that dissolve rapidly or in a modified manner (e.g. polyvinylpyrrolidone (e.g., ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates (e.g., ));

Capsule material (e.g., gelatin, hydroxypropyl methylcellulose);

synthetic polymers (e.g., polylactide, polyglycolide, polyacrylates, polymethacrylates (e.g., ), polyvinylpyrrolidone (e.g., ), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol, and copolymers and block copolymers thereof),

Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerol, triacetin, triethyl citrate, dibutyl phthalate);

Penetration enhancers;

Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate);

Preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate);

Colorants (e.g., inorganic pigments such as iron oxide, titanium dioxide);

• Flavorings, sweeteners, taste and/or odor masking agents.

The present invention also relates to pharmaceutical compositions comprising at least one compound according to the invention, usually in combination with one or more pharmaceutically suitable excipients, and to their use according to the invention.

dose

Based on known standard laboratory techniques for evaluating compounds for the treatment of, inter alia, gynecological, metabolic, hyperproliferative and inflammatory diseases, the effective dosage of the compounds of the present invention for the treatment of each of the target indications can be readily determined by determining standard toxicity tests and standard pharmacological tests for the treatment of the above-mentioned conditions in mammals and comparing these results with the results of known active ingredients or drugs for the treatment of these conditions. The amount of active ingredient to be administered in the treatment of one of these conditions can vary widely depending on considerations such as the specific compound and dosage unit used, the mode of administration, the course of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

The total amount of active ingredient administered is generally in the range of about 0.001 mg/kg body weight to about 200 mg/kg body weight per day, preferably about 0.01 mg/kg body weight to about 20 mg/kg body weight per day. The dosing schedule used clinically is in the range of one to three doses per day to once every four weeks. In addition, a "drug holiday" in which the patient is not given the drug for a certain period of time can be beneficial to the overall balance between the pharmacological effect and tolerance. The unit dose can contain about 0.5 mg to about 1500 mg of active ingredient and can be administered once or more per day, or less than once per day. The average daily dose for administration by injection (including intravenous, intramuscular, subcutaneous and parenteral injections and the use of infusion techniques) is preferably 0.01 to 200 mg/kg total body weight. Preferably, the average daily rectal dosage regimen is 0.01 to 200 mg/kg total body weight. Preferably, the average daily vaginal dosage regimen is 0.01 to 200 mg/kg total body weight. Preferably, the average daily topical dosage regimen is 0.1 to 200 mg, administered one to four times daily. Preferably, the transdermal concentration requirement maintains a daily dose of 0.01 to 200 mg/kg. Preferably, the average daily inhalation dosage regimen is 0.01 to 100 mg/kg total body weight.

Of course, the specific initial and subsequent dosage regimen for each patient will vary depending on the nature and severity of the condition as determined by the diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, etc. The target mode of treatment and the number of doses of the compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, or composition thereof, can be determined by those skilled in the art using routine therapeutic trials.

Combine

The compounds of the present invention can be used alone or, if desired, in combination with other active compounds.

In the present invention, the term "binding" is used as known to those skilled in the art, and the binding may be immobilized binding, non-immobilized binding or a kit-of-parts.

In the present invention, "fixed binding" is used as known to those skilled in the art and is defined as a binding in which, for example, a first active ingredient (e.g., one or more compounds of formula (I) of the present invention) and the other active ingredient are present together in a unit dosage or a single entity. One example of a "fixed binding" is a pharmaceutical conjugate, in which the first active ingredient and the other active ingredient are present in a mixture for simultaneous administration, for example, in a single formulation. Another example of a "fixed binding" is a pharmaceutical conjugate, in which the first active ingredient and the other active ingredient are present in a single unit, but not as a mixture.

In the present invention, a non-fixed combination or "kit of parts" is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the other active ingredients are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the other active ingredients are present separately. The components of the non-fixed combination or kit of parts can be administered separately, sequentially, simultaneously, in parallel, or staggered.

According to another aspect, the present invention relates to a pharmaceutical combination, in particular a medicament, comprising at least one compound of the general formula (I) according to the invention and at least one or more other active ingredients, which is particularly useful for the treatment and/or prevention of the aforementioned diseases. The compound according to the invention can be administered as the sole pharmaceutical agent or in combination with one or more other active pharmaceutical ingredients, wherein the combination does not cause unacceptable side effects. The present invention also includes such pharmaceutical combinations.

In particular, the present invention relates to a drug conjugate comprising:

one or more first active ingredients, in particular compounds of formula (I) as defined above, and

- One or more other active ingredients as above.

Typically, other active ingredients include, but are not limited to, antibacterial substances (e.g., penicillin, vancomycin, ciprofloxacin), antiviral substances (e.g., aciclovir, oseltamivir), and antifungal substances (e.g., naftifin, nystatin); as well as gamma globulins, immunomodulatory compounds, and immunosuppressive compounds, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, and tacrolimus. mofetil), interferon, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine, and sulfasalazine; acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).

Additionally, for example, the compounds of the present invention may be combined with known hormonal therapeutic agents.

In particular, the compounds of the invention may be administered together with or in combination with hormonal contraceptives. Hormonal contraceptives may be administered orally, subcutaneously, transdermally, intrauterinely or intravaginally, for example as a combined oral contraceptive (COC) or a progestin-only pill (POP) or a hormonal contraceptive device such as an implant, patch or vaginal ring.

COCs include, but are not limited to, birth control pills or methods that contain an estrogen (estradiol) and a progestin (progesterone). The estrogen portion in most COCs is ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.

The COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynediol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.

Birth control pills include, for example, but are not limited to, Yasmin and Yaz, both of which contain ethinyl estradiol and drospirenone; Microgynon or Miranova, which contain levonorgestrel and ethinyl estradiol; Marvelon, which contains ethinyl estradiol and desogestrel; Valette, which contains ethinyl estradiol and dienogest; Belara and Enriqa, which contain ethinyl estradiol and chlormadinon acetate; Qlaira, which contains estradiol valerate and dienogest as active ingredients; and Zoely, which contains estradiol and nomegestrol.

POPs are birth control pills that contain only synthetic progestogen (progesterone) and no estrogen. They are colloquially known as mini-pills.

POPs include, but are not limited to, Cerazette, which contains desogestrel; Microlut, which contains levonorgestrel; and Micronor, which contains norethindrone.

Other progestin-only forms are intrauterine devices (IUDs), such as Mirena Jaydess; Kyleeny, which contains levonorgestrel; injections, such as Depo-Provera, which contains medroxyprogesterone acetate; or implants, such as Implanon, which contains etonogestrel.

Other hormone-containing devices with contraceptive effects suitable for use in combination with the compounds of the present invention are vaginal rings, such as Nuvaring, which contains ethinyl estradiol and etonogestrel, or transdermal systems such as contraceptive patches, for example Ortho-Evra, which contains ethinyl estradiol and norelgestromin, or Apleek (Lisvy), which contains ethinyl estradiol and gestodene.

A preferred embodiment of the present invention is the administration of the compounds of general formula (I) in combination with a COC or POP or other progestin-only form as well as a vaginal ring or contraceptive patch as described above.

In addition to known drugs that have been approved and marketed, the compounds of the present invention can also be administered in combination with P2X purine receptor family (P2X3, P2X4) inhibitors, IRAK4 inhibitors, and prostanoid EP4 receptor antagonists.

In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis agents for the treatment of inflammatory diseases, inflammatory pain or general pain conditions and/or to interfere with endometriotic hyperplasia and endometriosis-related symptoms, namely, in combination with inhibitors of microsomal prostaglandin E synthase (mPGES-1 or PTGES) and functional blocking antibodies of the prolactin receptor and inhibitors of chymase.

For tumor therapy, other active ingredients include, but are not limited to, 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab bemtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alenclavulanic acid, alitretinoin, hexamethylmelamine, amifostine, aminoglutethimide, aminolevulinic acid hexyl ester, amrubicin, amsacrine, anastrozole, anciplostatin, anetholeditholethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, acitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium leucovorin folinate), leucovorin, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, Celebrex, cymoxetine, ceritinib, cetuximab, chlorambucil, chlormadinone acetate, nitrogen mustard, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, inib), copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, daratumumab, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depo-opeptide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride), dehydrated dalutol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, intravascular Etoposide, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alpha, epoetin zeta, epoetin platinum, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, Fentanyl, filgrastim, fluticasone, floxuridine, fludarabine, fluorouracil, flutamide, leucovorin, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadolidol, gadoteric acid dimeglumine, gadoversetamide, gadoxetine, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, carboxypeptidase, glutathione, GM-CSF, goserelin, glancillon, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin (hist relin), hydroxyurea, I-125 particles, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indesitron, incadronic acid, ingenol methylbutyrate, interferon alpha, interferon beta, interferon gamma, iobitril, iodobenzylguanidine (123I), iomeprol, ipilimumab, irinotecan, itrametin Conazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel Norgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprofen, medroxyprogesterone, megestrol, melarsoprol, melphalan, melastrostane, mercaptopurine, mesna, methadone, methotrexate, methoxyfuran, methylaminolevulinate, methylprednisolone, methyltestosterone, methyltyrosine, mifamurtide, miltefosine, miriplatin, dibromomannitol, propionamide, dibromodulanol, mitomycin, mitotane, mitoxantrone, moga mulizumab, molaspritin, mopiridol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentozocin, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab pentetreotide, nilotinib, nilutamide, nimozole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, atezolizumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate), omeprazole, ondansetron, oprelvekin, oguptin, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 particles, palonosetron, Mildronate, panitumumab, panobinostat, pantoprazole, pazopanib, pegaptase, PEG-betaepoetin (methoxy PEG-betaepoetin), pembrolizumab, pegfilgrastim, peginterferon alfa, pemetrexed, pentazocine, pentostatin, peplomycin, perfluorobutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixenolone, plerixafor lerixafor), plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raltitrexed, ramucirumab, ranimustine ), rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romotide, roniciclib, samarium (153Sm), sarcomastim, satumomab, secretin, siltuximab, sipuleucel-T, sizolan, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium [99mTc] thionotumomab, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporphin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab tositumomab), trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine conjugate, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, vatalanib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorinostat, yttrium-90 glass microspheres, nestatin, nestatin aspirin, zoledronic acid, zorubicin.

For the treatment of prostate cancer, the present invention particularly includes drug combinations comprising other active ingredients for the treatment of prostate cancer, including but not limited to:

• Antiandrogens such as Flutamide (Eulexin), Bicalutamide (Casodex), Nilutamide (Nilandron), Enzaluatmide (Xtandi), ODM-201.

CYP17A1 inhibitors, such as abiraterone and abiraterone metabolites,

5-hydroxytryptamine reductase inhibitors, such as finasteride or dutasteride.

Androgen deprivation therapy (ADT), including GNRHa and GNRH antagonists, LHRH agonists such as leuprorelin (Lupron, Eligard), goserelin (Zoladex), triptorelin (Trelstar), histrelin (Vantas), or LHRH agonists such as Degarelix. ADT can be given alone or with antiandrogens, 5-aminobutyric acid reductase inhibitors, or CYP17A1 inhibitors.

For the prevention and treatment of cancers resistant to chemotherapeutic agents, particularly anthracycline antibiotics, the present invention particularly encompasses drug conjugates comprising a chemotherapeutic agent containing an oxo group that can be reduced by the enzymatic activity of AKR1C3 as an additional active ingredient. Examples of such chemotherapeutic agents are anthracycline antibiotics, such as, but not limited to, daunorubicin, doxorubicin, epirubicin, and idarubicin. According to the present invention, the compounds of the present invention are administered concomitantly with the chemotherapeutic agent, particularly an anthracycline antibiotic.

For the prevention and treatment of side effects associated with anthracycline therapy, such as cardiomyopathy, the present invention particularly encompasses drug combinations comprising anthracyclines as further active ingredients.

Experimental part

NMR peak forms are expressed as they appear in the spectrum, without taking into account possible higher order effects.

The ¹ H-NMR data for selected examples are listed in the form of ¹ H-NMR peak lists. For each singlet, the δ value in ppm is given, followed by the signal intensity recorded in parentheses. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, the peak list is described by the following general formula: δ ₁ (intensity ₁ ), δ ₂ (intensity ₂ ), δ _i (intensity _i ), δ _n (intensity _n ).

In printed NMR spectra, the intensity of a peak is related to the signal's height (in cm). When compared to other signals, this data can be correlated with the actual ratio of signal intensities. In the case of broad signals, more than one peak or signal center is shown, along with their relative intensities, compared to the most intense signal displayed in the spectrum. ^1H -NMR peak lists are similar to traditional ^1H -NMR readouts and therefore typically include all peaks listed in traditional NMR translations. Additionally, similar to traditional ^1H -NMR printouts, peak lists may show solvent signals, signals derived from stereoisomers of the target compound (also subject of the present invention), and/or impurity peaks. Stereoisomers' signals and/or impurity peaks typically appear less intense than peaks of the target compound (e.g., >90% purity). Such stereoisomers and/or impurities may be typical for a particular preparation method, and their peaks can therefore help identify the reproducibility of our preparation method based on a "byproduct fingerprint." Experts who calculate the peaks of the target compound using known methods (MestReC, ACD simulation, or by using empirically estimated expectation values) can optionally use additional intensity filters to separate the peaks of the target compound as needed. This operation is similar to peak picking in conventional 1H-NMR interpretation. A detailed description of recording NMR data in peak list format can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see Research Disclosure Database Number 605005, 2014, 01 August 2014, or http://www.researchdisclosure.com/searching-disclosures). During peak picking, as described in Research Disclosure Database Number 605005, the parameter "Minimum Height" can be adjusted between 1% and 4%. Depending on the chemical structure and/or the concentration of the measured compound, it may be reasonable to set the parameter "Minimum Height" to <1%.

Chemical names were generated using ACD/Name software from ACD/Labs. In some cases, generally accepted commercial reagent names were used in place of ACD/Name generated names.

Table 1 below lists the abbreviations used in this paragraph and the Examples section, unless they are explained in the text. Other abbreviations themselves have meanings generally known to those skilled in the art.

Table 1: Abbreviations

Other abbreviations themselves have meanings generally known to those skilled in the art.

Various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

The example test experiments described herein are intended to illustrate the present invention, and the present invention is not limited to the examples given.

Experimental part-Overview part

All reagents whose synthesis is not described in the experimental part are commercially available, are known compounds or can be formed from known compounds by known methods by a person skilled in the art.

The compound and intermediate prepared according to the method of the present invention may need purification. The purification of organic compounds is well known to those skilled in the art, and there are a variety of methods for purifying the same compound. In some cases, purification is not necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be stirred with a suitable solvent. In some cases, the compound can be purified by chromatography (particularly flash column chromatography) using, for example, a pre-installed silica gel column (such as BiotageSNAP column or) in combination with a Biotage automatic purifier system (or Isolera) and an eluent such as a gradient of hexane/ethyl acetate or DCM/methanol. In some cases, the compound can be purified by preparative HPLC using, for example, a Waters automatic purifier equipped with a diode array detector and/or an online electrospray ionization mass spectrometer in combination with a gradient of suitable pre-installed reversed-phase column and eluent such as water and acetonitrile, the gradient can include additives such as trifluoroacetic acid, formic acid or ammonia.

In some cases, the purification methods described above can provide those compounds of the invention having sufficiently basic or acidic functional groups in the form of salts, for example, in the case of sufficiently basic compounds of the invention, such as trifluoroacetate or formate; or in the case of sufficiently acidic compounds of the invention, such as ammonium salts. Such salts can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that the specific form of the compounds of the invention isolated and as described herein (e.g., salt, free base, etc.) is not necessarily the only form in which the compounds can be used in bioassays to quantify specific biological activities.

UPLC-MS standard method

Analytical UPLC-MS was performed as described below. Masses (m/z) were recorded from positive mode electrospray ionization unless negative mode (ESI-) was indicated. In most cases, Method 1 was used. If not, negative mode is indicated.

Method 1:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 x 2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 ml/min; Temperature: 60°C; DAD scan: 210-400 nm.

Method 2:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 x 2.1 mm; Eluent A: water + 0.2 vol% ammonia (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 ml/min; Temperature: 60°C; DAD scan: 210-400 nm.

Method 3:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm 50 x 2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 ml/min; Temperature: 60°C; DAD scan: 210-400 nm.

Method 4:

System: UPLC Acquity (Waters) with PDA detector and Waters ZQ mass spectrometer; column: Acquity BEH C18 1.7 μm 2.1 x 50 mm; temperature: 60°C; solvent A: water + 0.1% formic acid; solvent B: acetonitrile; gradient: 99% A to 1% A (1.6 min) to 1% A (0.4 min); flow rate: 0.8 mL/min; injection volume: 1.0 μl (0.1 mg to 1 mg/mL sample concentration); detection: PDA scan area 210-400 nm plus fixed wavelength 254 nm; MS ESI (+), scan area 170-800 m/z

Method 5:

System: Waters Aqcuity UPC2: solvent manager, sample manager, column manager, PDA, QDa MS; column: Viridis BEH 2-EP 5 μm 100x4.6 mm; solvent: A = CO2 B = methanol + 0.5% NH3 (32%) by volume; flow rate: 4.0 mL/min; gradient: 0-7 min 5-55% B; pressure: 100 bar; temperature: 40°C; detector: DAD 254 nm

Preparative chromatography on HLPC systems:

For purification of some intermediates and examples, preparative reverse phase or normal phase systems were used. Available systems are:

Labomatic, Pump: HD-5000, Fraction collector: LABOCOL Vario-4000, UV-detector: Knauer UVD 2.1S; Column: Chromatorex RP C18 10 μm 125x30 mm, Eluent: A: water + 0.1 vol% formic acid (99%), Eluent B: acetonitrile; Detection: UV 254 nm; Software: SCPA PrepCon5.

Waters automated purification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD2424, SQD; column: XBrigde C18 5μm 100x30 mm; eluent A: water + 0.1% by volume formic acid, eluent B: acetonitrile; flow rate: 50 mL/min; temperature: room temperature; detection: DAD scanning range 210–400 nm; MS ESI+, ESI-, scanning range 160-1000 m/z.

Waters automated purification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD2424, SQD; column: XBrigde C18 5μm 100x30 mm; eluent A: water + 0.2 volume% ammonia water (32%), eluent B: acetonitrile; flow rate: 50 mL/min; temperature: room temperature; detection: DAD scanning range 210–400 nm; MS ESI+, ESI-, scanning range 160-1000 m/z.

Silica gel column chromatography:

For the purification of some intermediates and examples, silica gel column chromatography ("flash chromatography") was performed using equipment purchased from Biotage. Cartridges pre-packed with silica gel of various sizes were used, for example, Biotage cartridges, such as 100% silica gel, KP-SILe, or Interchim cartridges, such as 100% silica gel, such as ESI-767, CFO, DAD 2996, EL, from Biotage.

Experimental Part - Intermediates

Intermediate 1

3,8-Diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone

Step 1.1: tert-Butyl 3-(1H-1,2,3-triazol-4-ylcarbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a stirred solution of 500 mg (2.36 mmol) of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 12 mL of NMP was added 532 mg of 1H-1,2,3-triazole-4-carboxylic acid (4.71 mmol, 2 eq), 1.23 mL of DIPEA (7.07 mmol, 3 eq), and 1.791 g of HATU (4.71 mmol, 2 eq). After stirring overnight at room temperature, the solution was subjected to preparative HPLC to give 378 mg (52%) of tert-butyl 3-(1H-1,2,3-triazol-4-ylcarbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

LC-MS (method 3): Rt = 0.91 min; MS (ESIpos): m/z = 308 [M+H] ⁺

¹ H-NMR(500MHz,DMSO-d6)δ[ppm]:1.43(9H),1.53-1.72(2H),1.83(2H),2.92(1 H),3.33(1H),4.14(1H),4.21(1H),4.30(1H),4.40(1H),8.29(1H),15.22(1H).

Step 2: 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone

To a stirred and cooled (ice bath) solution of 272 mg (887 μmol) of tert-butyl 3-(1H-1,2,3-triazol-4-ylcarbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in 6 mL of DCM was added 0.3 mL of water and 3 mL of TFA. After 3 h, the mixture was evaporated under vacuum, triturated with toluene, and re-evaporated to give 376 mg (200%) of crude 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone as a TFA adduct, which was used in the subsequent step without further purification.

SFC-MS (method 5): Rt = 1.74 min; MS (ESIpos): m/z = 208 [M+H] ⁺

¹ H-NMR (500MHz, DMSO-d6) δ [ppm]: 1.67–2.00(4H), 3.19(1H), 3.61(1H), 4.11(2H), 4.40(1H), 4.70(1H), 8.40(1H).

Intermediate 2

8-(Phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane

Step 2.1: tert-Butyl 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a stirred solution of 100 mg (0.47 mmol) of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 2 ml of DCE was added 246 μL of DIPEA (1.41 mmol, 3 eq) and 90 μL of benzenesulfonyl chloride (125 mg, 0.71 mmol, 1.5 eq) at RT and the mixture was stirred overnight at RT. The organic phase was washed three times with aqueous NaHCO ₃ (10%) and twice with water, dried and evaporated to give 168 mg (101%) of the title compound.

LC-MS (method 3): Rt = 1.26 min; MS (ESIpos): m/z = 353 [M+H] ⁺

¹ H-NMR (500MHz, DMSO-d6) δ [ppm]: 1.19 (2H), 1.36 (11H), 2.87 (1H), 3.01 (1H), 3.75 (2H), 4.19 (2H), 7.60 (2H), 7.70 (1H), 7.87 (2H).

Step 2.2: 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane

To a stirred solution of 166 mg (0.47 mmol) of tert-butyl 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 1 mL of DCM was added 0.1 mL of water and 3 mL of TFA at RT. After 3 h, the mixture was evaporated under vacuum, redissolved in tert-butanol, and freeze-dried to yield 171 mg (143%) of crude 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane as a TFA adduct, which was used in the subsequent step without further purification.

LC-MS (method 1): Rt = 0.54 min; MS (ESIpos): m/z = 253 [M+H] ⁺

¹ H-NMR(500MHz, DMSO-d6)δ[ppm]:1.40(2H),1.77(2H),3.19–3.51(4H),4.37(2H),7.55–7.66(2H),7.74(1H),7.90(1H),8.25–9.50(2H).

Intermediate 3

8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane

Step 3.1: tert-Butyl-8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a stirred solution of 4.246 g (20 mmol) of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 100 ml of DCM were added 14 ml of DIPEA (80 mmol, 4 eq) and 9.78 g of 2-(trifluoromethyl)benzenesulfonyl chloride (40.0 mmol, 2 eq), and the mixture was stirred overnight at RT. The organic phase was removed under vacuum and the residue was flash chromatographed (ethyl acetate/hexane) to give 8.18 g (97%) of the title compound.

LC-MS (method 1): Rt = 1.36 min; MS (ESIpos): m/z = 365 [M-tBu+H] ⁺

¹ H-NMR (500MHz, DMSO-d6) δ [ppm]: 1.38 (9H), 1.51–1.71 (4H), 2.83 (1H), 3.01 (1H), 3.76 (2H), 4.23 (2H), 7.91 (2H), 8.05 (1H), 8.27 (1H).

Step 3.2: 8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane

To a stirred solution of 8 g (19.45 mmol) of tert-butyl 8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 64 mL of DCM was added 3.3 mL of water and 64 mL of TFA. After 3 h, the mixture was evaporated under vacuum, triturated with toluene, and re-evaporated. The residue was redissolved in DCM, washed with aqueous _NaHCO₃ (10%) and water, and the organic phase was dried and evaporated to yield 6.20 g (95%) of the title compound, 8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane.

LC-MS (method 1): Rt = 0.69 min; MS (ESIpos): m/z = 321 [M+H] ⁺

¹ H-NMR (500MHz, DMSO-d6) δ [ppm]: 1.54(2H), 1.79(2H), 2.60(2H), 2.71(2H), 4.02(2H), 7.90(2H), 8.03(1H), 8.27(1H).

Intermediate 4

8-[(3,5-Difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1)

Step 4.1: tert-Butyl 8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a stirred solution of 100 mg (0.47 mmol) of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 2 ml of DCE were added 246 μL of DIPEA (1.41 mmol, 3 eq) and 150 mg of 3,5-difluorobenzenesulfonyl chloride (0.71 mmol, 1.5 eq) at RT and the mixture was stirred overnight at RT. The organic phase was washed three times with aqueous NaHCO ₃ (10%) and once with water, dried and evaporated to give 188 mg (103%) of the title compound.

LC-MS (method 1): Rt = 1.34 min; MS (ESIpos): m/z = 389 [M+H] ⁺

¹ H-NMR (500MHz, DMSO-d6) δ [ppm]: 1.30 (2H), 1.38 (9H), 1.45 (2H), 2.89 (1H), 3.03 (1H), 3.76 (2H), 4.29 (2H), 7.68 (3H).

Step 4.2: 8-[(3,5-Difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1)

To a stirred solution of 183 mg (0.47 mmol) of tert-butyl 8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 3 mL of ethanol was added 1.8 mL of 4M HCl in dioxane (7 mmol, 15 eq) under ice cooling, and the mixture was stirred at room temperature for 2 h. After adding an additional 1 mL of 4M HCl in dioxane and stirring at room temperature for 3 h, the mixture was evaporated under vacuum and freeze-dried from tert-butanol to give 157 mg (103%) of the title compound, 8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1).

LC-MS (method 2): R _t =0.64 min; MS (ESIpos): m/z=289 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.54(2H)1.94(2H)3.11(2H)3.18(2H),4.45(2H)7.72(3H),8.87–9.92(2H)

Intermediate 5

8-[(3-Fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1)

Step 5.1: tert-Butyl 8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a stirred solution of 500 mg (2.36 mmol) of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in DCM was added 1.6 ml of DIPEA (9.4 mmol, 4 eq) and 380 μL of 3-fluorobenzenesulfonyl chloride (2.82 mmol, 1.2 eq), and the mixture was stirred at RT overnight. The organic phase was removed under vacuum and the residue was flash chromatographed (ethyl acetate/hexanes) to give 844 mg (97%) of the title compound.

LC-MS (method 2): R _t =1.28 min; MS (ESIpos): m/z=315 M-t-Bu ⁺

¹ H-NMR (400MHz, chlorine FORM-d) δ [ppm]: 7.68 (1H), 7.58 (1H), 7.51 (1H), 7.35-7.28 (1H) ),4.19(2H),3.93(1H),3.77(1H),3.19-2.96(2H),1.69-1.54(4H),1.44(s,9H)

Step 5.2: 8-[(3-Fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1)

To a stirred solution of 840 mg (2.27 mmol) of 8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in 10 mL of ethanol was added 8.5 mL of 4 M HCl in dioxane (34 mmol, 15 eq) and the mixture was stirred at RT for 72 h. The mixture was evaporated under vacuum, triturated with diethyl ether, filtered and dried under vacuum to give 735 mg (105%) of the title compound, 8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane hydrochloride (1:1).

LC-MS (method 2): R _t =0.84 min; MS (ESIpos): m/z=271 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.36-1.54(2H)1.81-1.97(2H)2.98-3.13(2H)3.13 -3.25(2H),4.40(2H)7.57-7.65(1H),7.66-7.73(1H)7.73-7.83(2H),9.10–9.90(1H)

The following intermediates were synthesized in analogy to the procedures given in Intermediates 2 to 5 using the appropriate sulfonyl chlorides.

Experimental Section - Examples

Example 1

[8-(Phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl](1H-1,2,3-triazol-4-yl)methanone

Step 1.1:

To a stirred and cooled solution of 1.87 g (57% purity, 5.11 mmol) of 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone (Intermediate 1) in 25 mL of NMP was added 4.45 mL (5 eq, 25.5 mmol) of DIPEA and 0.63 g (0.7 eq, 3.57 mmol) of benzenesulfonyl chloride at 0° C., and the mixture was stirred at 0° C. for 1 h. After stirring overnight at room temperature, the mixture was subjected to preparative HPLC to give 215 mg (0.61 mmol, 12%) of the title compound, 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone.

LC-MS (method 1): Rt = 0.85 min; MS (ESIpos): m/z = 348 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.193(3.38),1.211(5.65),1.228(4.02),1.262(0.76),1.382(1.39),1.406(3.26),1.427(1.85),1.510(1.94 ),2.323(0.45),2.327(0.62),2.331(0.43),2.518(2.26),2.523(1.43) ,2.665(0.45),2.669(0.63),2.673(0.45),2.963(3.11),2.992(3.35), 3.397(2.90),4.282(3.57),4.337(7.53),4.368(3.35),7.593(6.59),7.597(2.73),7.611(16.00),7.631(11.11),7.690(3.31),7.693(6.32),7.696(3.91),7.707(2.79),7.711(8.65),7.716(2.33),7.727(1.88),7.730(2.99),7.885(11.98),7.889(15.82),7.894(4.11),7.907(12.63).

Step 1.2:

To a stirred solution of 504 mg (2 mmol) of 8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]octane (Intermediate 2) in 6 mL of NMP was added 452 mg (2 eq, 4 mmol) of 1H-1,2,3-triazole-5-carboxylic acid, 1045 μL (3 eq, 6 mmol) of DIPEA, and 1.52 g (2 eq, 4 mmol) of HATU at room temperature, and the mixture was stirred for 6 h. The mixture was poured into ethyl acetate, washed with water, dried over sodium sulfate, evaporated, and the residue was flash chromatographed using ethyl acetate and hexanes to give 787 mg (1.93 mmol, 96%) of the title compound, 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone.

Step 1.3:

To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.3 mmol, 750 μL, 0.4 M) in DCE was added benzenesulfonyl chloride (0.45 mmol, 900 μL, 0.5 M, 1.5 eq) and 0.9 mmol DIPEA (156 μL, 3 eq) in DCE and the mixture was shaken overnight at RT. 2 mL of TFA/DCE 3:1 was added and the mixture was shaken at RT for 3 h. After evaporation of the solvent, 1H-1,2,3-triazole-5-carboxylic acid (0.6 mmol, 1.2 mL, 2 eq, 0.5 M) in NMP, 928 μL of DIPEA (3.6 mmol, 12 eq; adjust the pH to 8) and HATU (0.6 mmol, 1.2 mL, 2 eq, 0.5 M) in NMP were added, and the mixture was shaken overnight to give, after preparative HPLC, 26 mg (25%) of the title compound, 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone.

Example 2

1H-1,2,3-Triazol-4-yl[8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone

Analogously to Example 1, step 1.2, 1.92 g (50% purity, 3.00 mmol) of 8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octane (intermediate 3) was reacted with 0.678 g (6 mmol, 2 eq) of 1H-1,2,3-triazole-5-carboxylic acid to give, after workup and purification, 792 mg (62%) of the title compound 1H-1,2,3-triazol-4-yl[(8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone.

LC-MS (method 1): Rt = 0.96 min; MS (ESIpos): m/z = 416 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.602(2.82),1.629(2.52),1.689(12.16),1.980(0.53),2.073(1.54),2.327(1.17),2. 669(1.20),2.673(0.87),2.934(3.84),2.964(4.10),3.379(5.16),4.293(5.08),4.355(9.64),4.386(4.07),4.519(0.72 ),7.890(1.47),7.908(5.87),7.913(7.23),7.920(16.00),7.927(6.81),7.932(7.53),7.936(7.64),7.950(2.37),7.955(1.54),8.018(0.79),8.030(7.57),8.037(6.89),8.053(5.61),8.295(7.27),8.311(6.51),8.317(6.21),15.524(0.53).

Example 3

{8-[(3,5-Difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}(1H-1,2,3-triazol-5-yl)methanone

Analogously to Example 1, step 1.2, 3.46 g (12.00 mmol) of 8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane (intermediate 4) was reacted with 2.714 g (12 mmol, 2 eq) of 1H-1,2,3-triazole-5-carboxylic acid to give, after workup and purification, 1.93 g (42%) of the title compound {8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}(1H-1,2,3-triazol-5-yl)methanone.

LC-MS (method 1): Rt = 0.93 min; MS (ESIpos): m/z = 384 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.106(1.26),1.153(0.74),1.171(1.48),1.188(0.74),1 .317(4.22),1.336(6.93),1.352(4.93),1.384(1.15),1.452(1.67),1.475(4.11),1.496(2 .26),1.539(1.26),1.561(1.63),1.619(1.48),1.979(1.26),1.986(2.74),2.322(1.07),2.326(1.48),2.331(1.04),2.518(6.26),2.522(4.19),2.664(1.07),2.668(1.52),2.673( 1.07),2.685(0.59),2.692(1.00),2.982(3.59),3.014(3.67),3.282(0.52),3.301(1.00),3.382(3.74),3.412(3.81),4.016(0.63),4.034(0.59),4.345(6.04),4.374(8.00),4.432 (4.74),4.739(1.33),4.770(1.26),7.678(12.00),7.694(15.93),7.698(16.00),7.716(4.00),7.722(3.56),7.727(1.59),8.084(3.89),8.541(4.07),15.373(1.67),15.690(1.00).

Example 4

{8-[(3-Fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}(1H-1,2,3-triazol-5-yl)methanone

Analogously to Example 1, step 1.2, 3.24 g (12.00 mmol) of 8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octane (intermediate 5) was reacted with 2.714 g (12 mmol, 2 eq) of 1H-1,2,3-triazole-5-carboxylic acid to give, after workup and purification, 1.15 g (26%) of the title compound {8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}(1H-1,2,3-triazol-5-yl)methanone.

LC-MS (method 1): Rt = 0.89 min; MS (ESIpos): m/z = 366 [M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(1.28),1.172(2.67),1.189(3.43),1.205(2.55),1.217(0.78 ),1.248(4.37),1.269(6.76),1.284(4.95),1.316(1.10),1.419(1.60),1.442(3.75),1.463(2.05), 1.532(2.35),1.552(3.45),1.578(1.30),1.987(4.67),2.074(0.74),2.323(0.84),2.327(1.16),2.331(0.86),2.523(3.65),2.665(0.90),2.669(1.20),2.673(0.90),2.686(2.75),2.972(3.99),3.003 (4.11),3.376(4.95),3.409(4.43),4.016(1.08),4.034(1.00),4.342(7.38),4.377(7.64),4.524(1.96),4.552(1.84),7.563(1.84),7.568(2.49),7.573(2.29),7.587(4.79),7.591(5.25),7.606(2.93 ),7.609(3.27),7.612(3.43),7.615(3.09),7.650(2.65),7.666(3.73),7.671(5.97),7.685(5.69),7.692(3.89),7.705(3.25),7.749(16.00),7.752(13.33),7.758(4.71),7.769(11.91),8.307(5.49).

The following examples were prepared analogously to Example 1, step 1.1, using 3,8-diazabicyclo[3.2.1]octan-3-yl(1H-1,2,3-triazol-4-yl)methanone (Intermediate 1):

Analogously to Example 1, step 1.2, the following examples were prepared using the given intermediates:

Analogously to Example 1, step 1.3, the following example was prepared using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate:

Example 75

Sodium 5-({8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-yl

To a stirred solution of 6.16 g (16 mmol) of {8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}(1H-1,2,3-triazol-5-yl)methanone in 170 mL of MeOH and 70 mL of THF was added a solution of sodium methoxide (16 mmol, 1 eq, 30% in MeOH) at room temperature. After stirring at room temperature for 2 h, 250 mL of diethyl ether was added to precipitate the product. After cooling and filtering, the solid was dried under vacuum to yield 4.88 g (13 mmol, 87%) of the title compound, 5-({8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}carbonyl)-1,2,3-triazol-1-ylsodium.

LC-MS (method 1): Rt = 0.93 min; MS (ESIpos): m/z = 384 [M-Na ⁺ +H] ⁺

¹ H-NMR(500MHz,DMSO-d6)δ[ppm]:1.088(0.43),1.255(3.70),1.426(0.96),1.623(0.98),2.361(0.88),2.634(0.81),2.838(0.93),3.172(0.95 ),3.373(0.48),4.349(7.53),5.654(0.91),7.582(16.00),7.655(1.88 ),7.660(1.72),7.673(3.97),7.677(4.37),7.690(7.92),7.699(8.03).

Example 76

Sodium 5-({8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-yl

Analogously to Example 75, a stirred solution of 4.99 g (13.7 mmol) of {8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methanone was reacted with sodium methoxide to give 4.89 g (12.5 mmol, 92%) of the title compound 5-({8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-ylsodium.

LC-MS: R _t =0.88 min; MS (ESIpos): m/z = 365 [M-Na ⁺ +H] ⁺

¹ H-NMR(600MHz,METHANOL-d4)δ[ppm]:-0.005(1.50),0.006(1.47),1.177(0.54),1.442(3.45),1. 450(3.48),1.614(2.20),1.628(3.21),1.635(3.51),1.648(1.93),3.055(1.86),3.077(1.92),3. 481(0.45),3.493(0.93),3.502(1.89),3.523(1.92),4.253(2.38),4.363(2.38),4.537(1.86),4.558(2.10),4.586(2.10),4.607(1.77),7.409(1.86),7.410(2.05),7.414(2.17),7.415(2.18),7. 424(4.26),7.428(4.51),7.429(4.41),7.439(2.31),7.442(2.45),7.443(2.31),7.593(3.06),7.602(3.24),7.607(5.51),7.616(5.57),7.621(3.33),7.630(3.16),7.671(3.28),7.675(4.38),7. 678(3.52),7.685(3.35),7.687(4.35),7.692(3.33),7.749(5.52),7.751(6.36),7.754(5.22),7.762(4.66),7.764(5.38),7.765(5.31),7.766(4.19),7.802(15.79),7.803(16.00),7.892(1.93).

Experimental part – Biological tests

Examples were tested one or more times in the selected biological assays. When tested more than once, data are reported as means or medians, where

The average, also called the arithmetic mean, represents the sum of the values obtained divided by the number of tests, and

The median represents the middle number of a set of values arranged in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

The embodiments syntheses were performed one or more times. When synthesized more than once, the data from the bioassays represent the average or median values calculated using a set of data obtained from testing of one or more synthesis batches.

The in vitro activity of the compounds of the present invention can be demonstrated in the following tests:

AKR1C3-inhibitory activity test

The AKR1C3-inhibitory activity of the substances according to the invention was measured in the AKR1C3 assay described in the following paragraphs.

Essentially, enzyme activity is determined by quantifying the amount of coumarin produced from coumarone (Halim et al. J. AM. CHEM. SOC. 2008, 130: 14123–14128 and Yee et al. Proc. Natl. Acad. Sci. USA 2006, 103: 13304–13309). In this assay, the increase in highly fluorescent coumarin is measured by the NADPH- (nicotinamide adenine dinucleotide phosphate)-dependent reduction of non-fluorescent coumarone using AKR1C3.

The enzyme used was recombinant human AKR1C3 (aldo-keto reductase family 1 member C3; GenBank accession number NM_003739). It was expressed in Escherichia coli (E. coli) as a GST (glutathione S-transferase) fusion protein and purified by glutathione-agarose affinity chromatography. GST was removed by digestion with thrombin and subsequent size exclusion chromatography (Dufort, I., Rheault, P., Huang, X. F., Soucy, P., and Luu-The, V., Endocrinology 140, 568-574 (1999)).

For this assay, 50 nl of a 100-fold concentrated solution of the test substance in DMSO was pipetted into a black, small-volume, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2.5 μl of AKR1C3 in assay buffer [50 mM potassium phosphate buffer, pH 7, 1 mM DTT, 0.0022% (w/v) Pluronic F-127, 0.01% BSA (w/v), and a protease inhibitor cocktail (complete, EDTA-free protease inhibitor cocktail from Roche)] were added, and the mixture was incubated for 15 minutes to allow the enzyme to pre-bind to the enzyme prior to the enzymatic reaction. The enzymatic reaction was then initiated by adding 2.5 μl of a solution of NADPH in assay buffer (20 μM → final concentration of 10 μM in a 5 μl assay volume) and Coumberone (0.6 μMv in a 5 μl assay volume, final concentration of 0.3 μM). The resulting mixture was incubated at 22°C for a typical reaction time of 90 minutes. The AKR1C3 concentration and reaction time were tailored to the activity of the respective enzyme preparation and adjusted so that the assay was within the linear range. The AKR1C3 concentration was typically 1 nM. The reaction was terminated by adding 2.5 μl of a stop solution consisting of 3 μM EM-1404 (US Pat. No. 6,541,463) as an inhibitor in 50 mM HEPES, pH 7.5 (3 μM EM-1404 → a final concentration of 1 μM in a 7.5 μl assay volume). Coumarin fluorescence was then measured at 520 nm (excitation at 380 nm) using a suitable measuring instrument (Pherastar from BMG Labtechnologies). The fluorescence intensity was used as a measure of the amount of coumarin formed, and therefore, of AKR1C3 enzyme activity. The data were normalized (enzyme reaction without inhibitor = 0% inhibition; all other assay components, but no enzyme = 100% inhibition). Typically, the test substances were assayed in duplicate on the same microtiter plate at 11 different concentrations ranging from 20 μM to 73 pM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 10.9 nM, 3.1 nM, 0.9 nM, 0.25 nM and 73 pM, a dilution series was prepared at the level of a 100-fold concentrated solution by serial 1:3 dilution with 100% DMSO before the assay), each concentration, and the IC ₅₀ values were calculated using a 4-parameter fit.

As described above, the claimed pharmacological substances were examined for their inhibitory activity against the AKR1C3 enzyme (see Table 2). For the majority of the claimed structural regions, these substances showed strong inhibition of AKR1C3 in vitro with _IC50 values of less than 10 nM and, remarkably, even _IC50 values of about 1 nM.

Table 2: AKR1C3-inhibitory activity: _IC50 values of the examples

Compound No. 4 in Table 1 of WO 2007/111921 (Comparative Example) was analyzed in the same assay to determine the AKR1C3-inhibitory activity of the compound. The IC ₅₀ of Compound No. 4 in Table 1 of WO 2007/111921 was 1810 nM.

Inhibition of testosterone formation from androstenedione in primary human adipocytes

Human primary preadipocytes from 2 donors with a body mass index (BMI) of 26 and 30 were differentiated into mature adipocytes (ordered by ZenBio, Cat#SA-1012-2 12 well Platte; Cat#SA-1012-3 12 well Platte). Adipocytes were incubated for 48 hours in adipocyte basal medium (Fa.ZenBio, Cat#BM-1) + 1% FCS + 2.5io, Ca amphotericin B (Fa.Sigog, Cat#A2942) supplemented with 1 μM androstenedione and 1 μM, 10 μM compound 76 or vehicle. Androstenedione was used as a substrate for the formation of testosterone. After incubation, adipocytes were collected and testosterone and androstenedione concentrations were determined by LC/MS at "Biological Analytical Services and Research Provider Pharm-Analyt". The inhibitory effect of compound 76 on the conversion of androstenedione to testosterone was determined as the testosterone/androstenedione ratio [%]. This indicates that compound 76 inhibits the formation of testosterone from androstenedione in primary human adipocytes (see Figure 1).

Marmoset (Callithrix jacchus) Endometriosis Model

The in vivo efficacy of Compound 76 was tested in a non-human primate endometriosis model in marmosets.

Marmosets (Callithrix jacchus) are non-menstrual species in which endometriosis is induced by injecting endometrial tissue into the peritoneal cavity (Einspanier, Lieder et al., 2006). Female common marmosets aged 6-12 years (weighing between 358 g and 520 g) with established endometriosis were used and divided into two groups of n=5 animals each. Before the actual start of treatment, the animals underwent laparotomy and were examined for the presence of endometriotic lesions on the bladder, uterus, and ovaries to measure the area of each lesion. Based on the initial lesion status at the time of the first laparotomy, the animals were randomly divided into two treatment groups. The severity of endometriosis based on the total lesion area of each animal was similarly distributed in each group.

For the treatment group (5 mg/kg compound 76) and the vehicle-treated group, the sum of the total lesion area/size [ ^cm2 ] of each animal was determined based on the lesion area and the number of lesions, and was defined as the pre-treatment state. Treatment was initiated after 6 weeks. The test compound was administered orally once a day in the form of capsules (PC capsules, Capsugel). To adapt to the expected dose, a grind of the active compound and lactose was prepared and the exact dose was filled into each capsule. Each capsule was coated with an anti-salvia coating (Eudragit EPO; Evonik). After the 6-week treatment period, a second laparotomy was performed, and the number and size of lesions on the uterus, ovaries, and bladder were determined based on the total lesion size/area, and defined as the post-treatment state.

Total lesion size/area before and after treatment is shown in Figure 2A. In the vehicle group, total lesion size [ ^cm2 ] increased during the study period, whereas after 6 weeks of treatment with 5 mg/kg Compound 76, total lesion size was significantly reduced in all animals.

The reduction in total lesion size after treatment can be visually assessed as the ratio of total lesion size/area after treatment to that before treatment in both groups (vehicle, 5 mg/kg Example 76). A ratio of 1 corresponds to a stable lesion size. A ratio above 1 indicates an increase in total lesion size over the course of the experiment, while a ratio below 1 indicates a decrease in total lesion size. The results shown in Figure 2A are reflected in Figure 2B: all vehicle animals had ratios above 1, while all animals treated with Compound 76 had ratios below 1. The average reduction in total lesion size in animals treated with Compound 76 compared to baseline was 68.9%, while the total lesion size in vehicle-treated animals increased compared to baseline.

Interference with anthracycline resistance in cancer cells through AKR1C3 inhibition

A549 lung cancer cells express AKR1C3. A549 cells were inoculated 24 hours before the start of the experiment. After 24 hours, the culture medium was replaced with fresh culture medium containing 1, 10, 50, 100, 200, 500 and 1000nM daunorubicin, doxorubicin and idarubicin, with or without 1μM, 10μM, and 30μM compound 76. Cell viability was determined after incubation for 72 hours under standard conditions (37°C, 5% _CO2 ). Cell viability was measured by adding MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Sigma-Aldrich) in PBS to the cells to a final concentration of 1mg/ml, and then the cells were incubated under standard conditions for 4h. The culture medium was aspirated and the cells were lysed with dimethyl sulfoxide on an automatic shaker for 15min. The absorbance was measured at 570nm and 690nm using a microplate reader.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Conversion of 1 μM androstenedione to testosterone in human primary adipocytes from donors with a BMI of 26 (Figure 1A) and 30 (Figure 1B) after incubation with vehicle (white bars), 1 μM compound 76 (grey bars) or 10 μM compound 76 (black bars). The testosterone/androstenedione ratio [%] is shown.

Figure 2:

(FIG. 2A) Shown are the total lesion sizes before and after treatment in the bladder, ovaries, and uterus of individual marmosets (n=5) with established endometriosis in the vehicle-treated (left frame) and compound (5 mg/kg, Example 76)-treated (right frame) groups.

( FIG. 2B ) shows the ratio of post-treatment/pre-treatment total lesion size of the bladder, ovary, and uterus in marmosets with established endometriosis treated with vehicle (left frame) or 5 mg/kg Example 76 (right frame). The dotted line indicates the status at the beginning of the study (first laparotomy).

Claims (9)

1. A compound of general formula (I) or its stereoisomers, tautomers, salts, or mixtures thereof: in: ^R1 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, or cyano; ^R2 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, cyano, or _SF5 ; R ³ represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro or hydroxyl; ^R4 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, cyano, or _SF5 ; R ⁵ represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, or cyano; ^R1 and ^R2 or ^R2 and ^R3 are optionally connected to each other in such a way that they together form a methylenedioxy, ethylenedioxy, ethylenedioxy, trimethyleneoxy, or a group selected from the following: 2. The compound of claim 1 or its stereoisomers, tautomers, salts, or mixtures thereof, wherein: ^R1 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, or cyano; ^R2 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, cyano, or _SF5 ; R ³ represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro or hydroxyl; ^R4 represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, cyano, or _SF5 ; R ⁵ represents hydrogen, halogen, _C1 - _C3 -alkyl, _C1 - _C3 -haloalkyl, _C1 - _C3 -alkoxy, _C1 - _C3 -haloalkoxy, nitro, or cyano. 3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or salts, or mixtures thereof, wherein: R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano; R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, or _SF5 ; R ³ represents hydrogen; R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, or _SF5 ; R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano. 4. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or salts, or mixtures thereof, wherein: R ¹ represents hydrogen, fluorine, chlorine, bromine, methyl, or trifluoromethyl; R ² represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, or _SF5 ; R ³ represents hydrogen; R ⁴ represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, or _SF5 ; R ⁵ represents hydrogen, fluorine, chlorine, bromine, methyl, or trifluoromethyl. 5. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or salts, or mixtures thereof, selected from: 1[8-(phenylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-4-yl)methyl ketone 2 1H-1,2,3-triazol-4-yl[8-{[2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 3{8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 4{8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 5{8-[(3-chlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 6{8-[(2-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-4-yl)methyl ketone 7{8-[(2-chlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-4-yl)methyl ketone 8[8-{[3-(pentafluoro-λ-thioalkyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-4-yl) methyl ketone 9{8-[(3,5-dichlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-4-yl)methyl ketone 10[8-{[3,5-bis(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl)methyl ketone 12{8-[(2,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-4-yl)methyl ketone 13{8-[(3-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 14{8-[(4-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 15{8-[(2-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 16{8-[(4-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 17 3-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 18{8-[(3,5-dimethylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 19{8-[(2,5-dimethylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 20{8-[(3-methoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 21{8-[(4-methoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 22{8-[(4-chlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 23{8-[(3,4-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 24{8-[(2,6-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 25{8-[(2,4-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 26{8-[(3-chloro-2-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 27{8-[(3-chloro-2-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 28{8-[(3-chloro-4-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 29 1H-1,2,3-triazol-5-yl[8-{[3-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 30{8-[(2,5-dichlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 31{8-[(3-bromophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 32{8-[(2-bromophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 33 1H-1,2,3-triazol-5-yl[8-{[3-(trifluoromethoxy)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 34[8-{[5-chloro-2-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl)methyl ketone 35 2-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 36 1H-1,2,3-triazol-5-yl[8-{[4-(trifluoromethyl)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 37{8-[(4-hydroxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 38{8-[(4-bromophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 39[8-(naphthyl-1-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 40[8-(quinoline-8-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 41 1H-1,2,3-triazol-5-yl[8-{[4-(trifluoromethoxy)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 42 1H-1,2,3-triazol-5-yl[8-{[2-(trifluoromethoxy)phenyl]sulfonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl ketone 43{8-[(4-nitrophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 44{8-[(3-nitrophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 45 1H-1,2,3-triazol-5-yl{8-[(2,4,6-trimethylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl} methyl ketone 46{8-[(2-nitrophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 47{8-[(2,5-dimethoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 48{8-[(3,4-dichlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 49{8-[(4-ethylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 50{8-[(2-chloro-4-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 51{8-[(2-chloro-6-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 52{8-[(3,4-dimethoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 53{8-[(2,3-dichlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 54[8-(2,1,3-benzothiadiazole-4-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 55[8-(2,1,3-benzoxadiazol-4-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 56 1H-1,2,3-triazol-5-yl{8-[(2,4,6-trichlorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl} methyl ketone 57{8-[(5-chloro-2-methoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 58[8-(2,1,3-benzothiadiazole-5-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 59 1H-1,2,3-triazol-5-yl{8-[(2,3,4-trifluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl} methyl ketone 60 2-Fluoro-5-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 61{8-[(5-chloro-2-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 62 1H-1,2,3-triazol-5-yl{8-[(2,4,5-trifluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl} methyl ketone 63{8-[(5-chloro-2-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 64{8-[(2-methoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 65{8-[(5-bromo-2-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 66[8-(1,3-benzodioxolane-5-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 67{8-[(2-methoxy-4-methylphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 68 2-Chloro-6-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 69[8-(2,3-dihydro-1-benzofuran-7-ylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl](1H-1,2,3-triazol-5-yl) methyl ketone 70{8-[(2-chloro-5-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 71{8-[(2-chloro-3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl)methyl ketone 72{8-[(4-fluoro-2-methoxyphenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}(1H-1,2,3-triazol-5-yl) methyl ketone 73 4-Methoxy-3-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 74 4-Chloro-3-{[3-(1H-1,2,3-triazol-5-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}benzylnitrile 75 5-({8-[(3,5-difluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-yl sodium 76 5-({8-[(3-fluorophenyl)sulfonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}carbonyl)-1,2,3-triazol-1-yl sodium. 6. A method for preparing a compound of general formula (I) according to any one of claims 1 to 5, the method comprising the step of reacting an intermediate compound of general formula (IV) with a compound of formula (IX) to obtain a compound of general formula (I): Wherein ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) according to any one of claims 1 to 5. ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) of any one of claims 1 to 5. 7. A method for preparing a compound of general formula (I) according to any one of claims 1 to 5, the method comprising the step of reacting an intermediate compound of formula (VII) with a compound of general formula (VIII) to obtain a compound of general formula (I): Wherein ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) according to any one of claims 1 to 5. ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) of any one of claims 1 to 5. 8. Compounds of general formula (III), (IV) or (VII) ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) according to any one of claims 1 to 5, wherein at least one of ^R1 , ^R2 , ^R3 , ^R4 and ^R5 is not hydrogen. 9. Use of compounds of general formula (III), (IV) or (VII) for the preparation of compounds of general formula (I) according to any one of claims 1 to 5, ^R1 , ^R2 , ^R3 , ^R4 and ^R5 are as defined for compounds of general formula (I) according to any one of claims 1 to 5, wherein at least one of ^R1 , ^R2 , ^R3 , ^R4 and ^R5 is not hydrogen.