Field of the invention

The invention relates to certain substituted quinuclidine-3-one compounds for use in the treatment of hyperproliferative disease, such as cancer, and diseases associated with inflammation. More particularly, the present invention relates to certain substituted 3-quinuclidinones, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and to methods for using such compounds. In this manner, these compounds are of use for treating hyperproliferative diseases and inflammatory diseases.

Background of the invention

The fact that around half of all human tumors carry mutations in TP53, the gene encoding p53, is solid testimony as to the critical role of this protein as tumor suppressor. p53 halts the cell cycle and/or triggers apoptosis in response to various stress stimuli, including DNA damage, hypoxia, and oncogene activation (Ko & Prives (1996), Genes Dev 10:1054-1072; Sherr (1998), Genes Dev 12:2984-2991). Upon activation, p53 initiates the p53- dependent biological responses through transcriptional transactivation of specific target genes carrying p53 DNA binding motifs. In addition, the multifaceted p53 protein may promote apoptosis through transactivation- independent effects; in the nucleus repression of certain genes, and in the cytoplasmic space involving sequestering the anti-apoptotic protein Bcl-xL (Bennett et a/ (1998), Science 282:290-293; Gottlieb & Oren (1998), Semin Cancer Biol 8:359-68; Ko & Prives (1996), supra ; Green etal (2009), Nature 458: 1127-1130). Analyses of a large number of mutant TP53 genes in human tumors have revealed a strong selection for mutations that inactivate the specific DNA binding function of the resulting “mutant” p53; most TP53 mutations in tumors are point mutations clustered in the part encoding the DNA binding core domain of p53 (residues 94-292) (Beroud & Soussi (1998), Nucl Acids Res 26:200-204). Both p53-induced cell cycle arrest and apoptosis could be involved in p53-mediated tumor suppression. While p53-induced cell cycle arrest could conceivably be reversed in different ways, p53-induced apoptosis would have the advantage of being irreversible. There is indeed evidence from animal in vivo models (Symonds et al (1994), Cell 78:703-711 ) and human tumors (Bardeesy et a/ (1995), Cancer Res 55:215-219) indicating that p53- dependent apoptosis plays a major role in the elimination of emerging tumors, particularly in response to oncogenic signaling. Moreover, the ability of p53 to induce apoptosis often determines the efficacy of cancer therapy (Lowe et al (1994), Science 266:807-810). Taking into account the fact that more than 50% of human tumors carry p53 mutations, it appears highly desirable to restore the function of wild type p53-mediated apoptosis to tumors. The advantage of this approach is that it will allow selective elimination of tumor cells carrying mutant p53, since these are particularly sensitive to p53 reactivation, supposedly for two main reasons. Firstly, tumor cells are sensitized to apoptosis due to oncogene activation (reviewed in Evan & Littlewood (1998), Science 281:1317-1322). Secondly, mutant p53 proteins tend to accumulate at high levels in tumor cells. Therefore, restoration of the wild type function to the abundant and presumably ’’activated” mutant p53 should trigger a massive apoptotic response in already sensitized tumor cells, whereas normal cells that harbor low or undetectable levels of p53 should not be affected. The feasibility of p53 reactivation as an anticancer strategy is supported by recent data on quinuclidine-3-one derivatives, suggesting that a therapeutic strategy based on rescuing p53-induced apoptosis may be widely applicable (Bykov et a/ (2016), Front Oncol 6, article 21).

It may be that malfunctioning of the p53 pathway is generally involved in a number of diseases, such as those enumerated above. Indeed, in addition to hyperproliferative diseases such as cancer, various authors have shown the involvement of deficient p53 functioning in a number of other disease states, e.g. autoimmune diseases and cardiac diseases.

Thus, Mountz ef a/ (1994), Arthritis and Rheumatology 10:1415-1420, state that human autoimmune diseases share the common feature of an imbalance between the production and destruction of various cell types including lymphocytes (SLE), synovial cells (Ra), and fibroblasts (scleroderma). Proto-oncogenes which regulate apoptosis, including bcl-2, TP53, and myc, are also expressed abnormally. According to the authors, specific therapies that induce apoptosis without incurring side effects should improve treatment of autoimmune disease.

Okuda et al { 2003), J Neuroimmunol 135:29-37, present results suggesting that p53 may be involved in the regulatory process of experimental autoimmune encephalomyelitis (EAE) through the control of cytokine production and/or the apoptotic elimination of inflammatory cells.

EAE as a model for autoimmune inflammatory diseases of the central nervous system (CNS) is a widely used model for the human disease multiple sclerosis.

In addition to refolding mutant p53, treatment with a 2,2-substituted quinuclidine-3-one has been shown to result in reversible inhibition of thioredoxin reductase (TrxR) 1, and also to deplete the cells of glutathione (Peng et al (2013), Cell Death Dis 4:e881 ; Mohell et al (2015), Cell Death Dis 6:e1794; Liu et al ( 2017), Nat Commun 8:14844). Hence, a 2,2-substituted quinuclidine-3-one derivative leads to suppression of both branches of the cellular defense against oxidative stress, which has been shown to have an anti-cancer effect (Wondrak (2009), Antioxid Redox Signal 11:3015-3069). The redox effects of 2,2-substituted quinuclidine-3-one derivatives suggest that this type of compounds may have a beneficial effect in chronic inflammatory diseases, comprising allergy, asthma, atherosclerosis, coeliac disease, Crohn’s disease, gout, inflammatory bowel disease, rheumatoid arthritis, and transplant rejection.

A number of quinuclidine-3-one derivatives that are able to induce apoptosis of cells carrying mutant p53 are set forth in WO2002/24692, W02003/070250, W02004/084893, W2005/090341 and W02020/058458. Nonetheless, there still remains a general need of compounds having activity in the treatment of disorders and diseases related to p53 malfunctioning and/or oxidative stress. Preferably, such compounds should have improved pharmacokinetic and pharmacodynamic properties. One main objective of the present invention is to provide such compounds. WO201 5/150472 describes a method of treating melanoma using a 2,2-substituted quinuclidine-3-one in a combination therapy with a BRAF inhibitor.

W02007/062030 and CN104860994 describe a series of 2,2- substituted quinuclidine-3-one derivatives for the treatment of cancer by restoring the activity of mutant p53.

The use of quinuclidine-3-one derivatives for inducing apoptosis via p53 in breast cancer cells is described by Malki et al (2017), Bioorg Chem 72:57-63.

Certain 2-substituted 3-quinuclidinones have been described earlier in a biological context, but not in the therapeutic areas mentioned above. Thus, 2-[N'-(0-alkoxyphenyl)piperazinomethyl]-3-quinuclidinones (US3598825) have been described as nervous system depressants. Amine-substituted 2- methylene 3-quinuclidinones have been described as anti-bacterial agents (US3726877) and antidepressants (US3462442). US3384641 describes a method wherein 2-methylene-3-quinuclidinone is reacted with amines to form intermediates which, upon heating, could release the amines. The intermediates thus obtained are used for the purification of amines.

Description of the invention

The present invention provides certain novel compounds, pharmaceutically acceptable salts, hydrates, solvates and combinations thereof and pharmaceutical compositions containing the same, as well as methods and uses for treating disease. The quinuclidine-3-one derivatives of the present invention are useful in the treatment of hyperproliferative diseases, autoimmune diseases, inflammatory diseases and heart diseases.

In particular, they are useful in the treatment of disorders involving malfunctioning of the p53 pathway.

The compounds of the present invention have advantageous properties relating to the ability to kill tumor cells, including apoptosis of tumor cells carrying mutant p53. The compounds also display favorable pharmacokinetic and pharmacodynamic properties, a high potency, stability in formulation, low toxicity, and show synergistic effects with other anti-cancer agents. According to a first aspect thereof, the present invention provides a compound of formula (I) wherein R ¹ and R ² are the same or different and selected from the group consisting of H, -CH2-NR ¹⁰ -CS-NR ⁴ R ⁵ , -CH2-O-R ⁴ , -CH2-S-R ⁴ , -CH2-S- R ¹¹ , -CH2-NR ¹⁰ -SO2-R ⁴ , -CH2-NR ⁴ R ⁵ , -CH2-NR ¹⁰ -CO-R ⁴ , -CH2-NR ⁴ -CO- R ¹⁰ , -CH ₂ -NR ⁴ -SO ₂ -R ¹⁰ , -CH ₂ -O-CO-R ⁴ , -CH ₂ -NR ¹⁰ -CO-NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ - CO-OR ⁴ and -CH2-O-CO-NR ⁴ R ⁵ ; or R ¹ and R ² together form =CH2; R ³ is selected from the group consisting of H, halogen, C1-C6 alkyl, C1- C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cyclohaloalkyl, wherein said alkyl, haloalkyl, cycloalkyl, and cyclohaloalkyl may optionally be substituted with one or more C1-C6 alkoxy; R ⁴ and R ⁵ are the same or different and selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, aryl, heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, benzyl, aryl and heteroaryl may optionally be substituted with one to three groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, benzyl and aryl; or R ⁴ and R ⁵ together form a 5- or 6-membered heterocyclyl which may optionally be substituted with one or more halogens; or R ⁴ and R ¹⁰ together form a 5- or 6-membered heterocyclyl which may optionally be substituted with one or more halogens; R ⁶ and R ⁷ are both H or together form a bridging -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - CH2- or -CH2-O-CH2- moiety, wherein each -CH2-group may optionally be substituted with one or two groups selected from halogen, C ₁ -C ₆ alkyl and C ₁ - C ₆ haloalkyl; R ⁸ and R ⁹ are both H or together form a bridging -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - CH ₂ - or -CH ₂ -O-CH ₂ - moiety, wherein each -CH ₂ -group may optionally be substituted with one or two groups selected from halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ haloalkyl; R ¹⁰ is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, benzyl and aryl; R ¹¹ is -CH ₂ -CH(NHAc)-COOH; and provided that all of R ³ , R ⁶ , R ⁷ , R ⁸ and R ⁹ cannot be hydrogen; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -NR ¹⁰ -CS-NR ⁴ R ⁵ , - CH ₂ -S-R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , - CH ₂ -NR ⁴ -CO-R ¹⁰ , -CH ₂ -NR ⁴ -SO ₂ -R ¹⁰ , -CH ₂ -O-CO-R ⁴ , -CH ₂ -NR ¹⁰ -CO-NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-OR ⁴ and -CH ₂ -O-CO-NR ⁴ R ⁵ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -O-R ⁴ , -CH ₂ -S- R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ - NR ⁴ -CO-R ¹⁰ , -CH ₂ -NR ⁴ -SO ₂ -R ¹⁰ and -CH ₂ -O-CO-R ⁴ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-R ⁴ , -CH ₂ -S- R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -NR ⁴ -CO-R ¹⁰ , - CH ₂ -NR ⁴ -SO ₂ -R ¹⁰ and -CH ₂ -O-CO-R ⁴ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -O-R ⁴ , -CH ₂ -S- R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -NR ⁴ -CO-R ¹⁰ and -CH ₂ -NR ⁴ -SO ₂ -R ¹⁰ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-R ⁴ , -CH ₂ -S- R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -NR ⁴ -CO-R ¹⁰ and -CH ₂ -NR ⁴ - SO ₂ -R ¹⁰ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ - S-CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )- CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ ; or R1 and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-CH ₂ -CH(NHAc)- COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ - N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-R ⁴ , -CH ₂ -S- R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -NR ⁴ -CO-R ¹⁰ and -CH ₂ -NR ⁴ - SO ₂ -R ¹⁰ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-CH ₂ -CH(NHAc)- COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ - N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ ; or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ¹ is H. According to one embodiment of formula (I), R ¹ and R ² together form =CH ₂ ; According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ - NR ¹⁰ -CS-NR ⁴ R ⁵ , -CH ₂ -O-R ⁴ , -CH ₂ -S-R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , - CH ₂ -NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -O-CO-R ⁴ , -CH ₂ -NR ¹⁰ -CO-NR ⁴ R ⁵ , -CH ₂ - NR ¹⁰ -CO-OR ⁴ and -CH ₂ -O-CO-NR ⁴ R ⁵ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ - NR ¹⁰ -CS-NR ⁴ R ⁵ , -CH ₂ -S-R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ , -CH ₂ - NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ -CO-R ⁴ , -CH ₂ -O-CO-R ⁴ , -CH ₂ -NR ¹⁰ -CO-NR ⁴ R ⁵ , -CH ₂ -NR ¹⁰ - CO-OR ⁴ and -CH ₂ -O-CO-NR ⁴ R ⁵ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -O- R ⁴ , -CH ₂ -S-R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ and -CH ₂ -NR ¹⁰ -CO-R ⁴ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -S- R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ and -CH ₂ -NR ¹⁰ -CO-R ⁴ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -O- CH ₂ CH ₃ , -CH ₂ -S-CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ - CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ - N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ - NH-CO-CF ₃ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -S- CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )- CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -S- R ⁴ , -CH ₂ -S-R ¹¹ , -CH ₂ -NR ¹⁰ -SO ₂ -R ⁴ and -CH ₂ -NR ¹⁰ -CO-R ⁴ . According to one embodiment of formula (I), R ¹ and R ² are different; R ¹ or R ² is H; and R ¹ or R ² is selected from from the group consisting of -CH ₂ -S- CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )- CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ . According to one embodiment of formula (I), R ¹ is H or R ¹ and R ² together form =CH ₂ . According to one embodiment of formula (I), R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and halogen, said alkyl being optionally substituted with one or more C ₁ -C ₆ alkoxy. According to one embodiment of formula (I), R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and halogen. According to one embodiment of formula (I), R ³ is selected from the group consisting of H, methyl and fluoro. According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ - S-CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )- CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-CH ₂ -CH(NHAc)- COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ - N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ . According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ -S-CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH- SO ₂ -CH ₃ , -CH ₂ -N-CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5- membered ring, -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O- CH ₃ )-CO-CF ₃ and -CH ₂ -NH-CO-CF ₃ ; or R ¹ and R ² together form =CH ₂ ; R ³ is selected from the group consisting of H, methyl and fluoro; R ⁶ and R ⁷ are both H or together form a bridging -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - CH ₂ - or -CH ₂ -O-CH ₂ - moiety; R ⁸ and R ⁹ are both H or together from a bridging -CH ₂ -CH ₂ -; and R ¹⁰ is hydrogen. According to one embodiment of formula (I), R ¹ and R ² are the same or different and selected from the group consisting of H, -CH ₂ -S-CH ₂ -CH(NHAc)-COOH, -CH ₂ -NH-SO ₂ -CH ₃ , -CH ₂ -N- CH ₂ -CH ₂ -CH ₂ -SO ₂ - wherein N and S together form a 5-membered ring, -CH ₂ - N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CHF ₂ , -CH ₂ -N(CH ₂ -CH ₂ -O-CH ₃ )-CO-CF ₃ and -CH ₂ - NH-CO-CF ₃ ; or R ¹ and R ² together form =CH ₂ ; R ³ is selected from the group consisting of H, methyl and fluoro; R ⁶ and R ⁷ are both H or together form a bridging -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ - CH ₂ - or -CH ₂ -O-CH ₂ - moiety; R ⁸ and R ⁹ are both H or together from a bridging -CH ₂ -CH ₂ -; and R ¹⁰ is hydrogen. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: N-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)methanesulfonamid e; N-((7-oxooctahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-6-yl) methyl)- methanesulfonamide; N-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl)methanes ulfon- amide; N-((-4-methyl-3-oxoquinuclidin-2-yl)methyl)methanesulfonamid e; N-acetyl-S-((-4-methyl-3-oxoquinuclidin-2-yl)methyl)-L-cyste ine; N-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)methyl)meth ane- sulfonamide; 4-methyl-2-methylenequinuclidin-3-one; N-acetyl-S-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)-L-cyste ine; N-acetyl-S-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)me thyl)-L- cysteine; 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one; 4-fluoro-2-methylenequinuclidin-3-one; 6-(ethoxymethyl)hexahydro-4,8-methanopyrido[2,1-c][1,4]oxazi n- 7(6H)-one; N-acetyl-S-((7-oxooctahydro-4,8-methanopyrido[2,1-c][1,4]oxa zin-6- yl)methyl)-L-cysteine; 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)- one; N-acetyl-S-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl )-L- cysteine; 3-methylenehexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-o ne; 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one; 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-4-methylquinuclid in-3-one; 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinuclidi n-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2-yl)methyl)ac etamide; N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; 2-((1,1-dioxido-1,2-thiazinan-2-yl)methyl)-4-methylquinuclid in-3-one; 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4-methylquinucl idin-3-one; N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; 2,2,2-trifluoro-N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; 2,2,2-trichloro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; N-cyclopropyl-2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; and 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: N-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)methanesulfonamid e; N-((7-oxooctahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-6-yl) methyl)- methanesulfonamide; N-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl)methanes ulfon- amide; N-((-4-methyl-3-oxoquinuclidin-2-yl)methyl)methanesulfonamid e; N-acetyl-S-((-4-methyl-3-oxoquinuclidin-2-yl)methyl)-L-cyste ine; N-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)methyl)meth ane- sulfonamide; 4-methyl-2-methylenequinuclidin-3-one; N-acetyl-S-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)-L-cyste ine; N-acetyl-S-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)me thyl)-L- cysteine; 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one; 4-fluoro-2-methylenequinuclidin-3-one; N-acetyl-S-((7-oxooctahydro-4,8-methanopyrido[2,1-c][1,4]oxa zin-6- yl)methyl)-L-cysteine; 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)- one; N-acetyl-S-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl )-L- cysteine; 3-methylenehexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-o ne; 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one; 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-4-methylquinuclid in-3-one; 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinuclidi n-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2-yl)methyl)ac etamide; N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; 2-((1,1-dioxido-1,2-thiazinan-2-yl)methyl)-4-methylquinuclid in-3-one; 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4-methylquinucl idin-3-one; N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; 2,2,2-trifluoro-N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; 2,2,2-trichloro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; N-cyclopropyl-2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; and 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: N-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)methanesulfonamid e; N-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl)methanes ulfon- amide; N-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)methyl)meth ane- sulfonamide; 4-methyl-2-methylenequinuclidin-3-one; 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one; 4-fluoro-2-methylenequinuclidin-3-one; 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)- one; 3-methylenehexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-o ne; 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one; 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-4-methylquinuclid in-3-one; 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinuclidi n-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2-yl)methyl)ac etamide; 2-((1,1-dioxido-1,2-thiazinan-2-yl)methyl)-4-methylquinuclid in-3-one; 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4-methylquinucl idin-3-one; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; and N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: 4-methyl-2-methylenequinuclidin-3-one; 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one; 4-fluoro-2-methylenequinuclidin-3-one; 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)-one; 3-methylenehexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-o ne; 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinuclidi n-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2-yl)methyl)ac etamide; 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4-methylquinucl idin-3-one 2,2,2-trifluoro-N-methyl-N-((4-methyl-3-oxoquinuclidin-2-yl) methyl)acetamide; 2,2,2-trichloro-N-(2-methoxyethyl)-N-((4-methyl-3-oxoquinucl idin-2- yl)methyl)acetamide; N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; of N-cyclopropyl-2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: N-acetyl-S-((4-methyl-3-oxoquinuclidin-2-yl)methyl)-L-cystei ne; N-acetyl-S-((4-fluoro-3-oxoquinuclidin-2-yl)methyl)-L-cystei ne; N-acetyl-S-((3-oxooctahydro-2H-2,6-methanoquinolizin-4-yl)me thyl)-L- cysteine; N-acetyl-S-((7-oxooctahydro-4,8-methanopyrido[2,1-c][1,4]oxa zin-6- yl)methyl)-L-cysteine; N-acetyl-S-((6-oxooctahydro-3,7-methanoindolizin-5-yl)methyl )-L-cysteine; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to one embodiment of this aspect of the present invention, there is provided a compound selected from the group consisting of: N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide; N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide; N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide; N-cyclopropyl-2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3-oxoquinuclidin- 2- yl)methyl)acetamide; or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. Racemic and diastereomeric mixtures as well as single stereoisomers of the disclosed and claimed compounds are within the scope of the present invention. According to a second aspect, the present invention provides a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof. According to a third aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, for use in the treatment of a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53. According to a related, fourth aspect, the present invention provides a method of treating a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or combination thereof according to the first aspect, or a pharmaceutical composition according to the second aspect, to a subject in need thereof. As apparent to a person of skill in the art, the embodiments of the first, the second and the third aspects are also applicable here. According to a fifth aspect, the present invention provides a method of preparing a compound according to the first aspect. Throughout the following description of such methods it is understood that, where appropriate, suitable protecting groups may be added and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by the one skilled in the art of organic chemistry. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Greene’s Protective Groups in Organic Synthesis by P.G.M. Wutz and T.W. Greene, 4 ^th Edition, Wiley-Interscience, New York, 2006. Examples of the synthesis of certain compounds of formula (I) are represented in the following reaction schemes: Reaction scheme 1 The fused piperidone (iv) is constructed via a Robinson-Schöpf condensation starting from a masked dialdehyde, acetonedicarboxylic acid and an amine as described by Lowe III et al (1994), J Med Chem 37:2831- 2840. The fused piperidone (ix) is made via a double Mannich reaction from N,N-Bis(methoxymethyl)benzylamine, or an amine and formaldehyde, plus a cyclic ketone as described by Mityuk et al (2010), Synthesis, 3:493-497 and Lowe III et al (1994), supra.

Synthesis of compound (xv) from (x) is done via routes described by Lowe III et al (1994), supra and WO1992/12149. Conversion of the ketone (x) to the nitrile, with one extra carbon, is achieved using TosMIC in the Van Leusen reaction. Acidic hydrolysis of the nitrile and esterification of the resulting acid affords the ester (xiii). Removal of the protecting group affords the secondary amine which is subsequently alkylated with ^-halo ethylacetate to give the diester (xv). In an alternative synthesis of compound (xv) the nitrogen of (xvi) is alkylated with α-halo acetonitrile. Subsequently the Van Leusen reaction, followed by hydrolysis and esterification, directly affords the diester according to the example below. 4-substituted piperidones are made via the enolate of (xiii) and a suitable electrophile according to Kong et al (2010), Org Synth 87:137-142. Further transformations analogous to Reaction scheme 2 affords the The quinuclidinone core is constructed via a base promoted Dieckmann condensation followed by an acidic decarboxylation reaction as described by Lowe III et al (1994), supra; Thakore et al (2015), Lett Org Chem 12:277-279; WO1992/12149; Schneider et al (1976), Arch Pharm 309:447-57 and Schneider et al (1966), Tet Lett 7:1585-1586. Compound (xxv) can be made by reacting (xxiv) with N,N,N',N'-tetramethylmethane- diamine and acetic anhydride according to the examples below. Compound (xxv) can also be made by heating (xxiv) with dimethylamine, formalin and a base in an organic solvent, as described by Nielsen (1966), J Org Chem 31:1053-1059. The substituted 2-(dimethylamino)methyl-3-quinuclidinone (xxxviii) can be isolated and used to generate the substituted 2-methylene-3- quinuclidinone (xxv) in situ for subsequent steps, according to below. According to Reaction scheme 6, a substituted 2-methylene-3- quinuclidinone (xxv) can be used as starting material for the synthesis of compounds (xxvi) and (xxvii) and (xxviii). The substituted 2-methylene-3- quinuclidinone (xxv) can be generated in situ from (xxxviii). Compound (xxvi) can be made by reacting a primary sulfonamide (G=SO ₂ ) or primary amide (G=CO) with (xxv) in the presence of an appropriate base according to the examples below. Compound (xxvii) may be made by reacting (xxv) with an amine in organic solvents as described by Malki et al (2017), supra; Singh et al (1969), J Med Chem 12:524-526 and US3726877, or in a mixture of an organic solvent and water in the presence of a phase transfer catalyst as described in WO2005/090341. The synthesis of compound (xxviii) may be performed by methods known to the person skilled in the art by reacting compound (xxvii) with a sulfonyl chloride (G=SO ₂ ) or acid chloride (G=CO) in the presence of an appropriate base. The synthesis of compound (xxviii) from compound (xxvi) may be performed by methods well known to the person skilled in the art by reacting (xxvi) with an alkyl halide and a base in an organic solvent as described by Declerck et al (2004), J Org Chem 69:8372-8381. Alternatively, an alcohol may be used to alkylate the nitrogen under Mitsunobu conditions as described by Lee et al (2016), Org Lett 18:3678-3681. The synthesis of compound (xxviii) from compound (xxv) may be performed by methods well known to the person skilled in the art by reacting (xxv) with a sulfonamide (G=SO ₂ ) or amide (G=CO) and a base in an organic solvent as described below, or by Moriwake et al (1989), J Org Chem 54:4114-20. According to Reaction scheme 7 compound (xxix) can be made by reacting water or an alcohol with (xxv) in the presence of an appropriate acid according to the example below.

According to Reaction scheme 8 compound (xxx) can be made by reacting a thiol with (xxv) in an appropriate solvent according to the examples below. According to Reaction scheme 9 compounds (xxxi), (xxxii), (xxxiii) and (xxxiv) can be made by methods well known to the person skilled in the art from compound (xxvii). Reaction scheme 10 According to Reaction scheme 10 compounds (xxxvi) and (xxxvii) can be made by methods well known to the person skilled in the art from compound (xxxv). Compound (xxxv), in turn, can be made according to Reaction scheme 7, by reacting compound (xxv) with water in the presence of an appropriate acid. Further aspects of the invention are defined by the claims and/or are apparent to a person skilled in the art from the disclosure taken as a whole. As used herein, the term ”C ₁ -C ₆ alkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 6 carbon atoms. Examples of C ₁ -C ₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, t-butyl, n-pentyl, 1-methyl-butyl, n-hexyl and 2-ethyl-butyl groups. Non-limiting examples of unbranched C ₁ -C ₆ alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Non-limiting examples of branched alkyl groups are iso-propyl, iso-butyl, sec-butyl, t-butyl, 1-methyl- butyl and 2-ethyl-butyl groups. As used herein, the term ”C ₁ -C ₃ alkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms. Non- limiting examples of C ₁ -C ₃ alkyl groups include methyl, ethyl, n-propyl and isopropyl groups. As used herein, the term “C ₂ -C ₆ alkenyl” means both linear and branched chain unsaturated hydrocarbon groups with from 2 to 6 carbon atoms. Non-limiting examples of C ₂ -C ₆ alkenyl groups include, ethyleneyl, 1- propene-1-yl, 2-butene-2-yl, 2-methyl-2-butene-1-yl and 3-metyl-2-pentene-2- yl. As used herein, the term “C ₁ -C ₆ alkoxy” means the group O-C ₁ -C ₆ alkyl, where “C ₁ -C ₆ alkyl” is used as described above. Non-limiting examples of C ₁ -C ₆ alkoxy groups are methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, n-hexoxy and 3-methyl-butoxy groups. As used herein, the term “C ₁ -C ₃ alkoxy” means the group O-C ₁ -C ₃ alkyl, where “C ₁ -C ₃ alkyl” is used as described above. Non-limiting examples of C ₁ -C ₃ alkoxy groups are methoxy, ethoxy, isopropoxy and n-propoxy groups. As used herein, the term ”C ₁ -C ₆ haloalkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 6 carbon atoms, having from one to all hydrogens substituted by a halogen of different or same type. Non-limiting examples of C ₁ -C ₆ haloalkyl groups include methyl substituted with from 1 to 3 halogen atoms, ethyl substituted with from 1 to 5 halogen atoms, n-propyl or iso-propyl substituted with from 1 to 7 halogen atoms, n-butyl or iso-butyl substituted with from 1 to 9 halogen atoms, and sec-butyl or t-butyl substituted with from 1 to 9 halogen atoms. As used herein, the term ”C ₁ -C ₃ haloalkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms, having from one to all hydrogens substituted by a halogen of different or same type. Non-limiting examples of C ₁ -C ₃ haloalkyl groups include methyl substituted with from 1 to 3 halogen atoms, ethyl substituted with from 1 to 5 halogen atoms, and n-propyl or iso-propyl substituted with from 1 to 7 halogen atoms. As used herein, the term ”C ₁ -C ₃ haloalkoxy” means both linear and branched chain saturated alkoxy groups with from 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a halogen atom of different or same type. Non-limiting examples of C ₁ -C ₃ haloalkoxy groups include methoxy substituted with from 1 to 3 halogen atoms, ethoxy substituted with from 1 to 5 halogen atoms, and n-propoxy or iso-propoxy substituted with from 1 to 7 halogen atoms. As used herein, the term ”C ₁ -C ₃ fluoroalkyl” means both linear and branched chain saturated hydrocarbon groups with from 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a fluorine atom. Non- limiting examples of C ₁ -C ₃ fluoroalkyl groups include methyl substituted with from 1 to 3 fluorine atoms, ethyl substituted with from 1 to 5 fluorine atoms, and n-propyl or iso-propyl substituted with from 1 to 7 fluorine atoms. As used herein, the term ”C ₁ -C ₃ fluoroalkoxy” means both linear and branched chain saturated alkoxy groups with 1 to 3 carbon atoms, having from one to all hydrogen atoms substituted by a fluorine atom. Non-limiting examples of C ₁ -C ₃ fluoroalkoxy groups include methoxy substituted with from 1 to 3 fluorine atoms, ethoxy substituted with from 1 to 5 fluorine atoms, and n-propoxy or iso-propoxy substituted with from 1 to 7 fluorine atoms. As used herein, the term ”C ₃ -C ₆ cycloalkyl” means a cyclic saturated hydrocarbon group with from 3 to 6 carbon atoms. Non-limiting examples of C ₃ -C ₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term ”C ₁ -C ₃ alkoxy C ₁ -C ₃ alkyl” means both linear and branched chain saturated hydrocarbon groups with 1 to 3 carbon atoms, substituted with an alkoxy group with 1 to 3 carbon atoms. Non-limiting examples of C ₁ -C ₃ alkoxy C ₁ -C ₃ alkyl groups are drawn below. As used herein, the term ”C1-C3 cyanoalkyl” means both linear and branched chain cyano (CN) derivatives with one to three carbon atoms, including the carbon atom that is part of the cyano group. Non-limiting examples of C1-C3 cyanoalkyl groups are drawn below. As used herein, the term “N-C1-C3 alkylamino” means an C1-C3 alkyl substituent attached to the remainder of a molecule via nitrogen. Non-limiting examples of N-C1-C3 alkylamino are drawn below. As used herein, the term “N,N-di C1-C3 alkylamino” means two C1-C3 alkyl substituents attached to the remainder of a molecule via nitrogen. Non- limiting examples of N,N-di C1-C3 alkylamino are drawn below. As used herein, the term “amino-C1-C3 alkyl” means any amino derivative of a C ₁ -C ₃ alkyl radical. Non-limiting examples of amino-C ₁ -C ₃ alkyl are drawn below. As used herein, the term ”halogen” means fluorine, chlorine, bromine or iodine. It is to be understood that when a substituent is halogen (or halo), it is always bound to a carbon atom. As used herein, the term ”aryl” means a monocyclic aromatic carbocyclic group. Non-limiting examples of such groups include phenyl. As used herein, the term ”heteroaryl” means a monocyclic or bicyclic aromatic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. In a bicyclic aryl, one of the rings may be partially saturated. Non-limiting examples of such groups include indolinyl, dihydrobenzofuranyl and 1,3-benzodioxolyl. Non-limiting examples of monocyclic heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl. Non-limiting examples of bicyclic heteroaryl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl, indolyl, indazolyl, benzothiazolyl, pyridopyrimidinyl and isoquinolinyl. As used herein, the term ”heterocyclyl” means a cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include 3- oxoquinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl. As used herein, and as well-known to persons of skill in the art, a “substituent” means an atom or group that replaces another atom or group in a molecule or can be regarded as replacing an atom in a parent compound. As such, in the context of the Markush formula (I) of the compound of the present invention, the substituents R ¹ and R ² are replaced by the various listed alternative options. The compounds of the present invention may form salts, which are within the scope of the present invention. Salts of compounds of formula (I) suitable for use in medicine are for example those wherein a counter ion is pharmaceutically acceptable. Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable acid addition salts according to the present invention include those formed with mineral acids, strong organic carboxylic acids, or with organic alkyl or aryl sulfonic acids, optionally substituted with halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethane- sulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic or glutamic acids, as well as from lysine or arginine. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono- ,di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts of the compounds of the present invention may furthermore be formed. In one embodiment of the second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate or combination thereof, and a pharmaceutically acceptable diluent, carrier and/or excipient. Such compositions may be suitable for oral or parenteral administration. Compositions for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers or other pH-adjusting components, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as polyethylene glycol, ethanol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremophor®. In aspects of the invention the compound according to the first aspect is intended for use in treatment of a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53. In one embodiment, such a disease is cancer, as defined in ICD-10, i.e. the tenth revision of the International Classification of Diseases (ICD) maintained by the World Health Organization (WHO), in the categories C00- C97 (malignant neoplasms) and D37-D48 (neoplasms of uncertain or unknown behavior). Typically, said cancer is selected from malignant neoplasms, stated or presumed to be primary, of the following sites: malignant neoplasms of lip, oral cavity and pharynx including head and neck cancer; malignant neoplasms of digestive organs including esophagus, colon, liver or pancreas cancer; malignant neoplasms of respiratory and intrathoracic organs including lung cancer; malignant neoplasms of bone and articular cartilage including osteosarcoma; melanoma and other malignant neoplasms of skin; malignant neoplasms of mesothelial and soft tissue including sarcoma; malignant neoplasm of breast; malignant neoplasms of female genital organs including ovarian cancer; malignant neoplasms of male genital organs including prostate cancer; malignant neoplasms of urinary tract including bladder cancer; malignant neoplasms of eye, brain and other parts of central nervous system including glioblastoma; malignant neoplasms of thyroid and other endocrine glands including thyroid cancer; malignant neoplasms of ill-defined, secondary and unspecified sites; malignant neoplasms of lymphoid, hematopoietic and related tissue including multiple myeloma, lymphoid leukemia or myeloid leukemia; neoplasms of uncertain or unknown behavior including myelodysplastic syndrome. In one embodiment, said disease associated with a malfunctioning p53 signaling pathway is selected from autoimmune diseases, for example multiple sclerosis, and cardiac diseases, for example myocardial ischemia. In one embodiment, said disease is selected from the group consisting of pre-chronic inflammatory diseases, including allergy, asthma, atherosclerosis, coeliac disease, Crohn’s disease, gout, inflammatory bowel disease, rheumatoid arthritis and transplant rejection. In one aspect of the invention, there is provided a method of treating a disease associated with a malfunctioning p53 signaling pathway, for example associated with mutant p53, comprising administering a therapeutically effective amount of a compound according to the present invention, to a patient in need thereof. The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention will range from about 0.1 to about 1000 mg per kg of body weight per day (mg/kg/day), preferably from 1 to 500 mg/kg/day, and more preferably from 10 to 250 mg/kg/day, for adult humans. For oral administration, compositions may be provided in the form of tablets or other forms, such as capsules, to provide discrete units containing 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 500, 1000, 5000 or 10000 mg of active pharmaceutical ingredient. An oral dosage unit typically contains from about 1 mg to about 5000 mg, preferably from about 1000 mg to about 2500 mg, of active pharmaceutical ingredient.

Parenteral dosages of the present invention, when used for the indicated effects, will range from about 1 to about 1000 mg/kg/day, preferably from 1 to 500 mg/kg/day, most preferably from 10 to 100 mg/kg/day, for adult humans. For intravenous (i.v.) administrations, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Compounds and compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

The compounds and compositions of the present invention may be used or administered in combination with at least one of the following compounds (active pharmaceutical ingredients): platinum based antineoplastic agents (including cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin), nucleoside analogs and antimetabolites (including cytarabine, fludarabine, gemcitabine, 5FU), DNA intercalators (including danorubicin, doxorubicin, epirubicin and idarubicin, camptothecin), alkylating neoplastic agents (including cyclophosphamide, melphalan, bendamustine, carmustine, lomustine. ifosfamide), topoisomerase inhibitors (including etoposide, topotecan), PARP inhibitors (including olaparib, niraparib, rucaparib), a substance interfering with microtubule dynamics (including combrestatin, eribulin, docetaxel, taxane, vinoblastine, vincristine), a substance blocking the interaction between p53 and MDM2 or MDM4 (including nutlins, idasanutlin, siremadlin (HDM201), milademetan (DS3032b), AMG-232 (CAS no. 1352066-68-2), ALRN-6924), a kinase inhibitor (including BRAF inhibitors vemurafenib, dabrafenib), a PI3K and/or mTOR inhibitor (including LY294002 (CAS no. 154447-36-6), dactolisib, rapamycin and rapamycin analogs temsirolimus, everolimus, ridaforolimus), an MRP1 inhibitor (including indomethacin, meloxicam, sulindac sulfide, GSK1904529A (CAS no.1089283-49-7), verlukast (MK571), verapamil), hypomethylation agents (including azacitidine, decitabine), histone deacetylase inhibitor (including cirtuins, hydroxamates including vorinostat, belinostat, dacinostat, panobinostat, valproic acid, benzamides including entinostat, mocetinostat), proteasome inhibitors (including bortezomib, ritonavir, carfilzomib), an antivascular or antiangiogenic agent (including 2aG4, bevacizumab), tyrosine kinase inhibitor (including lapatinib), EGFR inhibitors (including gefitinib), CDK inhibitors, PLK inhibitors, MEK inhibitors (including pimasertib), immune checkpoint inhibitors (including antibodies against PD-1 (including nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab), PD-L2, CTLA-4 (including ipilimumab, tremelimumab), GITR, IL-40, CD-40, LAG3/CD-223 (including BMS-986016, REGN3767), OX-40 (including pogalizumab, PF-04518600)), antibodies binding protein tyrosine kinase receptors, NFE2L2 inhibitors (including ML385 (Cas no. 846557-71-9), brusatol, trigonelline, luteolin, ascorbic acid, tretinoin (ATRA)), autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognize an extracellular cancer target (including CD19, PSMA, mesothelin), glucocorticoid receptor agonist (including dexamethasone), buthionine sulfoximine, folic acid, metformin, sorafenib, sulfasalazine, bleomycin, erlotinib, tunicamycin, wortmannin, pidilizumab, durvalumab, GSK3174998, tavolixizumab, deazaneplanocin A or piperlongumine.

Such combined administration may be concomitant and/or sequential. The compounds and compositions of the present invention may be administered alone or administered in combination with other compounds (active pharmaceutical ingredients), wherein the administration is also in combination with an external beam irradiation by gamma or neutron radiation or targeted therapy with antibodies labeled with beta or alpha emitting radionuclides, including I-131, Y-90, Lu-177, Bi-213, Ac-225 and Th-227, or radiotherapy with Ra-223. Examples Example 1: Synthesis of N-((-4-fluoro-3-oxoquinuclidin-2-yl)methyl)methane- sulfonamide To a solution of 4-fluoro-2-methylenequinuclidin-3-one (24 mg, 0.15 mmol) in DMF (1 mL), methanesulfonamide (19 mg, 0.20 mmol) and potassium carbonate (17 mg, 0.17 mmol) were added. The reaction mixture was stirred overnight and then diluted with DCM (1 mL) and purified by column chromatography on silica gel with IPA/DCM (0:100 to 10:90). The pure fractions were pooled and heptane (5 mL) was added. The mixture was concentrated on a rotavapor and a white solid precipitated. The material was dried under high vacuum to yield 4.0 mg (10%) of the title compound. MS ESI+ m/z 251 [M+H] ⁺ . Example 2: Synthesis of N-((7-oxooctahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-6-yl)methyl)methanesulfonamide 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)-one (33 mg, 0.18 mmol) was dissolved in DMF (0.5 mL) followed by addition of methanesulfonamide (23 mg, 0.24 mmol) and potassium carbonate (26 mg, 0.19 mmol). The reaction mixture was stirred at room temperature over 4 days. After completion, 1 eq. HCl in dioxane (4 M) (94 µL, 0.38 mmol) was added, the precipitate was filtered and the solvent was evaporated. The residue was redissolved in DCM then the title product was obtained by column chromatography on silica gel with MeOH/DCM (0:100 to 2:8) as an off-white solid (10 mg, 20 %). MS ESI+ m/z 275 [M+H] ⁺ . Example 3: Synthesis of N-((6-oxooctahydro-3,7-methanoindolizin-5- yl)methyl)methanesulfonamide To a solution of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one (22 mg, 0.13 mmol) in DMF (1 mL), methanesulfonamide (17 mg, 0.18 mmol) and potassium carbonate (21 mg, 0.15 mmol) were added. The reaction mixture was stirred for 48 hours whereafter 1 mL of acetonitrile was added and the reaction mixture was filtered and concentrated to give a yellow oil. The crude product was purified by preparative HPLC (XBridge C1819x50 mm; 50 mM NH ₄ HCO ₃ /MeCN; 95:5 to 60:40) to give 12.1 mg of the title compound. After extensive drying under vacuum to remove residual ammonium carbonate the white solid was suspended in DCM and filtered. After concentration of the filtrate the title compound (2.4 mg, 7%) was obtained as a white solid. MS ESI+ m/z 259 [M+H] ⁺ . Example 4: Synthesis of N-((-4-methyl-3-oxoquinuclidin-2-yl)methyl)- methanesulfonamide To a solution of 4-methyl-2-methylenequinuclidin-3-one (20 mg, 0.13 mmol) in DMF (1 mL), methanesulfonamide (16 mg, 0.17 mmol) and potassium carbonate (20 mg, 0.14 mmol) were added. After 54 hours additional methanesulfonamide (5.2 mg, 0.05 mmol) was added and the reaction mixture was stirred for a total of 9 days.1 drop of water was added followed by 4M HCl in dioxane until pH 6-7 (8 drops). The DMF was removed in vacuo and the crude product was dissolved in an acetonitrile/water mixture and purified by preparative HPLC (XBridge C18; 50 mM NH ₄ CO ₃ /MeCN; 95:5 to 65:45). The purest fractions were combined and freeze-dried to give a white solid. To remove residual NH ₄ CO ₃ the white solid was suspended in DCM and filtered. The filtrate was concentrated and dried to give 13 mg (40%) of the title compound as a white solid. MS ESI+ (m/z) 247 [M+H] ⁺ . Example 5: Synthesis of N-acetyl-S-((4-methyl-3-oxoquinuclidin-2-yl)methyl)- L-cysteine 4-methyl-2-methylenequinuclidin-3-one (20.0 mg, 0.13 mmol) and 0.95 eq. of N-acetyl-L-cysteine (20.0 mg, 0.12 mmol) were suspended in DCM (0.50 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and diethyl ether was added to precipitate the product. The solid was washed with DCM and diethyl ether, and the title compound was obtained as an off-white solid (30 mg, 78%). The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 315 [M+H] ⁺ . Example 6: Synthesis of N-((3-oxooctahydro-2H-2,6-methanoquinolizin-4- yl)methyl)methanesulfonamide To a solution of 4-methylenehexahydro-2H-2,6-methanoquinolizin- 3(4H)-one (30 mg, 0.17 mmol) in DMF (2 mL) methanesulfonamide (20.9 mg, 0.22 mmol) and potassium carbonate (23 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 3 days and then solids was removed by filtration. The filtrate was neutralized with 4M HCl in dioxane (5.9 µL, 0.24 mmol). The mixture was concentrated and the residue was dissolved in a few drops of DCM followed by addition of diethyl ether to precipitate the product. The solvent was removed with a Pasteur pipette and the remaining solid was washed with diethyl ether. The product was dried under high vacuum to give the title compound (8 mg, 17% yield). MS ESI+ m/z 273 [M+H] ⁺ . Example 7: Synthesis of 4-methyl-2-methylenequinuclidin-3-one Step 1. Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-4-methylpiperidine-4- carboxylate Ethyl 2-bromoacetate (2.94 mL, 26.5 mmol) dissolved in THF (5 mL), was added dropwise to a suspension of ethyl 4-methylpiperidine-4- carboxylate hydrochloride (5.00 g, 24.07 mmol) and TEA (10 mL, 72 mmol) in THF (75 mL) at 0°C. The reaction mixture was stirred at ambient temperature overnight. EtOAc was added and the organic phase was washed with water, dried over MgSO ₄ , and filtered. The solvent was evaporated to give 6.02 g (97%) of ethyl 1-(2-ethoxy-2-oxoethyl)-4-methylpiperidine-4-carboxylate as an oil. MS ESI+ m/z 258 [M+H] ⁺ . Step 2. Preparation of ethyl 4-methyl-3-oxoquinuclidine-2-carboxylate hydrochloride Potassium tert-pentoxide (1.7 M in toluene, 35.4 mL, 60.2 mmol) was added to toluene (105 mL) and the mixture was heated to 110°C under N ₂ . Ethyl 1-(2-ethoxy-2-oxoethyl)-4-methylpiperidine-4-carboxylate (6.2 g, 24 mmol) dissolved in dry toluene (15 mL) was added dropwise using syringe pump over a period of 1 hour to the hot mixture. After addition the reaction was further stirred at 110°C for 15 min. The reaction mixture was cooled and stirred in an ice bath before concentrated HCl (80 mL) was added. The organic phase was extracted with 12M HCl (3x20 mL). The combined HCl phases were taken to next step as such. MS ESI+ m/z 212 [M+H] ⁺ . Step 3. Preparation of 4-methylquinuclidin-3-one The combined HCl phases from step 2 above were stirred at 90°C for 15 hours. Activated charcoal (3.6 g) was added and the reaction was further stirred at 90°C for 1 hour. The solid was filtered off on celite and the filtrate was concentrated. The acidic residue was neutralized by adding saturated NaHCO ₃ (aq.). The compound was soluble in the salt solution. The mixture was concentrated giving a solid residue. The product was dissolved in EtOH and the solid was filtered off. The filtrate was concentrated and the crude residue was purified by column chromatography on silica gel with NH ₄ /MeOH/DCM (1:5:94) to give the title compound (1.95 g, 58% over two steps) as a white solid. MS ESI+ m/z 140 [M+H] ⁺ . Step 4. Preparation of 4-methyl-2-methylenequinuclidin-3-one To a solution of 4-methylquinuclidin-3-one (237 mg, 1.7 mmol) in DCM (8 mL) was added acetic anhydride (483 µL, 5.11 mmol) followed by dropwise addition of N,N,N',N'-tetramethylmethanediamine (302 µL, 2.21 mmol). The reaction was stirred overnight at room temperature. The solvent was evaporated and the crude residue was purified by column chromatography on silica gel with NEt ₃ /IPA/DCM (0.1:2:98 to 0.1:5:95). The material was purified by a second column with silica gel using NEt ₃ /acetone/DCM (0.1:10:90) to give 67 mg (26%) of the title compound. MS ESI+ m/z 152 [M+H] ⁺ . Example 8: Synthesis of N-acetyl-S-((4-fluoro-3-oxoquinuclidin-2-yl)methyl)-L- cysteine 4-fluoro-2-methylenequinuclidin-3-one (10.0 mg, 0.06 mmol) and N- acetyl-L-cysteine (10.5 mg, 0.06 mmol) was suspended in DCM (0.5 mL) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the title compound was obtained as a white waxy solid residue (20 mg, 98%). The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 319 [M+H] ⁺ . Example 9: Synthesis of N-acetyl-S-((3-oxooctahydro-2H-2,6-methano- quinolizin-4-yl)methyl)-L-cysteine 4-methylenehexahydro-2H-2,6-methanoquinolizin-3(4H)-one (10.0 mg, 0.06 mmol) and N-acetyl-L-cysteine (8.7 mg, 0.053 mmol) were suspended in DCM (0.5 mL) and the reaction mixture was stirred at room temperature for 3 hours. After completion the solvent was evaporated and diethyl ether was added to precipitate the product. The product was isolated by filtration and after a second precipitation the product was obtained as a white solid (15 mg, 83%). The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 341 [M+H] ⁺ . Example 10: Synthesis of 4-methylenehexahydro-2H-2,6-methanoquinolizin- 3(4H)-one Step 1. Preparation of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-carbonitrile Potassium tert-pentoxide (1.7 M in toluene, 34 mL, 48 mmol) was mixed with monoglyme (50 mL) at 0°C. TosMIC (6.86 g, 35.1 mmol) in monoglyme (70 mL) was added slowly (45 min) at 0°C. Then 9-benzyl-9- azabicyclo[3.3.1]nonan-3-one (4.28 g, 18.7 mmol) dissolved in monoglyme (30 mL) and EtOH (1.56 mL, 27.7 mmol) was added slowly over a period of 60 min. After addition the reaction was allowed to reach ambient temperature and stirred at ambient temperature for 2 hours. Approximately 60% product had been formed but reaction had stopped. Additional TosMIC (1.81 g, 9.25 mmol) was added and the reaction was further stirred overnight. Water (100 mL) was added and the reaction mixture was concentrated to give a brown oil which was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous phase was extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL) and dried over MgSO ₄ . The crude product was purified by column chromatography on silica gel with EtOAc/p- ether (1:9 to 2:8) to give 1.71 g (38%) of the title compound. MS ESI+ m/z 241 [M+H] ⁺ . Step 2. Preparation of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-carboxylic acid hydrochloride 9-Benzyl-9-azabicyclo[3.3.1]nonane-3-carbonitrile (2.82 g, 11.7 mmol) was stirred in 12M HCl (48.9 mL, 587 mmol) at 100°C for 2 hours. The reaction mixture was concentrated and the residual water was co-evaporated with toluene twice. The material was finally dried under vacuum to give 3.04 g (100%) of a residue which was used as such in the next step. MS ESI+ m/z 260 [M+H] ⁺ . Step 3. Preparation of ethyl 9-benzyl-9-azabicyclo[3.3.1]nonane-3- carboxylate 9-Benzyl-9-azabicyclo[3.3.1]nonane-3-carboxylic acid hydrochloride (3.04 g, 11.7 mmol) was stirred in a mixture of ethanol (100 mL) and 4M HCl in dioxane (29.3 mL, 117 mmol) at 80°C for 6 hours. The reaction mixture was concentrated and to the residue was added EtOAc. The organic phase was washed with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and the solvent was evaporated to give the title compound (3.21 g, 95%) as a clear light brown oil. MS ESI+ m/z 288 [M+H] ⁺ . Step 4. Preparation of ethyl 9-azabicyclo[3.3.1]nonane-3-carboxylate Ethyl 9-benzyl-9-azabicyclo[3.3.1]nonane-3-carboxylate (3.21 g, 11.2 mmol) was dissolved in ethanol and 10% Pd/C (containing 55% H ₂ O) (539 mg, 2.79 mmol) was added. The mixture was stirred under an atmosphere of hydrogen (1 bar) at 60°C for 2 hours. The reaction mixture was cooled, filtered through a plug of celite and the filtrate was concentrated and used as such. Yield 2.08 g (94%). MS ESI+ m/z 198 [M+H] ⁺ . Step 5. Preparation of ethyl 9-(2-ethoxy-2-oxoethyl)-9-azabicyclo[3.3.1]- nonane-3-carboxylate Ethyl bromoacetate (1.29 mL, 11.7 mmol) in THF (2 mL) was dropwise added to an ice cold solution of ethyl 9-azabicyclo[3.3.1]nonane-3-carboxylate (2.09 g, 10.6 mmol) in THF (20 mL) followed by addition of triethylamine (2.96 mL, 21.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. Additional ethyl bromoacetate (117.5 µL, 1.06 mmol) was added and the reaction was stirred overnight. The reaction mixture was concentrated and to the residue was added water. The product was extracted with EtOAc (x3) and the combined organics were dried over MgSO ₄ and filtered. The solvent was concentrated and the crude product was purified by column chromatography on silica gel with EtOAc/hexane (2:8) to give the title compound (2.4 g, 80%). MS ESI+ m/z 284 [M+H] ⁺ . Step 6. preparation of ethyl 3-oxooctahydro-2H-2,6-methanoquinolizine-4- carboxylate hydrochloride Potassium tert-pentoxide (1.7 M in toluene, 12.5 mL, 21.2 mmol) was added to toluene (24 mL) and heated to 110°C under N ₂ . Ethyl 9-(2-ethoxy-2- oxoethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (2.4 g, 8.5 mmol) dissolved in dry toluene (24 mL) was added dropwise using a syringe pump over a period of 1 hour to the hot mixture. After addition, the reaction was further stirred at 110°C for 15 min. The reaction was cooled in an ice bath and 12M HCl (40 mL) was added. The organic phase was extracted with 12M HCl (2x15 mL). The combined HCl phases were taken to the next step as such. MS ESI+ m/z 238 [M+H] ⁺ . Step 7. Preparation of hexahydro-2H-2,6-methanoquinolizin-3(4H)-one The combined HCl phases were stirred at 90°C for 15 h. Activated charcoal (2 g) was added and the reaction was further stirred at 90°C for 1 hour. The solution was allowed to cool and was then filtered through a pad of celite. The filtrate was cooled and potassium carbonate was carefully added until basic pH. The aqueous solution was extracted with DCM and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give a solid (1.05 g, 75% over two steps) which was used as such in the next step. MS ESI+ m/z 166 [M+H] ⁺ . Step 8. Preparation of 4-methylenehexahydro-2H-2,6-methanoquinolizin- 3(4H)-one To a solution of hexahydro-2H-2,6-methanoquinolizin-3(4H)-one (400 mg, 2.4 mmol) in DCM (10 mL) was added acetic anhydride (686 µL, 7.26 mmol) followed by dropwise addition of N,N,N',N'-tetramethylmethanediamine (429 µL, 3.15 mmol) in DCM (2 mL). The reaction mixture was stirred overnight and concentrated. The crude product was purified by column chromatography on silica gel with NEt ₃ /IPA/DCM (0.1:2:97.9 to 0.1:3:96.9) followed by a second column using NEt ₃ /acetone/DCM (0.1:10:89.9) to give 275 mg (64%) of the title compound. MS ESI+ m/z 178 [M+H] ⁺ . Example 11: Synthesis of 4-fluoro-2-methylenequinuclidin-3-one Step 1. Preparation of ethyl 1-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-4- carboxylate Ethyl 2-bromoacetate (1.15 mL, 10.4 mmol) was dissolved in THF (2 mL) and cooled to 0°C and added dropwise to a suspension of ethyl 4- fluoropiperidine-4-carboxylate hydrochloride (2.00 g, 9.45 mmol) and triethylamine (3.96 mL, 28 mmol) in THF (20 mL). The reaction mixture was allowed to reach room temperature and stirred at ambient temperature overnight. EtOAc was added and the organic phase was washed with water and dried over MgSO ₄ . The solvent was removed in vacuo to give the title compound (2.34 g, 95%) as an oil. MS ESI+ m/z 262 [M+H] ⁺ . Step 2. Preparation of ethyl 4-fluoro-3-oxoquinuclidine-2-carboxylate hydrochloride Potassium tert-pentoxide (2.81 mL, 4.78 mmol) was added to toluene (5 mL) and the reaction mixture was heated to 110°C under N ₂ . Ethyl 1-(2- ethoxy-2-oxoethyl)-4-fluoropiperidine-4- carboxylate (500 mg, 1.91 mmol) dissolved in dry toluene (5 mL) was added dropwise, using syringe pump over a period of 1 hour to the hot mixture. After addition the reaction was further stirred at 110°C for 15 min. and cooled in an ice batch. Conc. HCl (10 mL) was added and the phases were separated. The organic phase was extracted with conc. HCl (2x10 mL) and the combined HCl phases were taken to next step as such. MS ESI+ m/z 216 [M+H] ⁺ . Step 3. Preparation of 4-fluoroquinuclidin-3-one The crude material of ethyl 4-fluoro-3-oxoquinuclidine-2-carboxylate in HCl was heated at 90°C for 15 hours. Activated charcoal (300 mg) was added and the reaction was further stirred at 90°C for 1 hour. At room temperature the solid was filtered off on celite. The filtrate was cooled and potassium carbonate was carefully added until basic pH. The aqueous solution was extracted with DCM and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 204 mg (74% over two steps) of the title compound. The crude product was used as such in the next step. MS ESI+ m/z 144 [M+H] ⁺ . Step 4. Preparation of 4-fluoro-2-methylenequinuclidin-3-one To a solution of 4-fluoroquinuclidin-3-one (200 mg, 1.40 mmol) in DCM (5 mL) was added acetic anhydride (277 µL, 2.93 mmol) followed by dropwise addition of N,N,N',N' tetramethylmethanediamine (190 µL, 1.40 mmol) in DCM (3 mL). The reaction mixture was stirred overnight and was then transferred to a separation funnel containing 10 mL sat. NaHCO ₃ (aq.). The mixture was extracted with DCM (2x) and the combined organics were dried (MgSO ₄ ) and concentrated. The crude product was purified by column chromatography on silica gel with IPA/DCM (2:98 to 5:95) to give title compound (95 mg, 44%). MS ESI+ m/z 156 [M+H] ⁺ . Example 12: Synthesis of 6-(ethoxymethyl)hexahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-7(6H)-one 6-methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6 H)-one (5.8 mg, 0.03 mmol) was dissolved in a mixture of EtOH (0.50 mL) and 4M hydrochloric acid in 1,4-dioxane (16.2 µL, 0.06 mmol). After stirring the reaction mixture at room temperature for 5 min. the solvent was concentrated and the white solid was redissolved in EtOH (1 mL) and stirred at 30°C for 3 hours. The reaction mixture was concentrated and dried under vacuum to give 6.8 mg (93%) of the title compound. MS ESI+ m/z 226 [M+H] ⁺ . Example 13: Synthesis of N-acetyl-S-((7-oxooctahydro-4,8-methanopyrido- [2,1-c][1,4]oxazin-6-yl)methyl)-L-cysteine N-Acetyl-L-cysteine (30.6 mg, 0.19 mmol) was added to a solution of 6- methylenehexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H) -one (21 mg, 0.12 mmol) in DCM (1 mL). The reaction mixture was stirred for 3 hours and then concentrated. The crude product was purified by preparative HPLC (XBridge C1819x50 mm; water/MeCN; 100:0 to 99.9:0.1) to give the title compound. The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 343 [M+H] ⁺ . Example 14. Synthesis of 6-methylenehexahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-7(6H)-one Step 1. Preparation of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7- carbonitrile Potassium tert-pentoxide (1.7 M in toluene, 40.1 mL, 56.2 mmol) was mixed with monoglyme (60 mL) at 0°C. TosMIC (8.02 g, 41.07 mmol) in monoglyme (85 mL) was added slowly over a period of 50 minutes at 0°C. EtOH (1.82 mL, 32.4 mmol) and monoglyme (36 mL) was added followed by addition of dry powder of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (5.00 g, 21.6 mmol) in portions over 1 hour. Additional monoglyme (100 mL) was added and the reaction was removed from ice bath and further stirred at ambient temperature overnight. The reaction mixture was concentrated to give a brown oil which was partitioned between water (200 mL) and EtOAc (200 mL) and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organics were pooled, dried over MgSO ₄ and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/DCM (0:100 to 35:65) to give the title compound (1.49 g, 28%). MS ESI+ m/z 243 [M+H] ⁺ . Step 2. Preparation of 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid hydrochloride 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carbonitrile (3.50 g, 14.4 mmol) was stirred in 12M HCl (60.2 mL, 722 mmol) at 100°C overnight. The reaction mixture was then concentrated on a rotavapor and residual water was co-evaporated with toluene twice. The material was dried under vacuum to give the title compound (1.71 g, 40%). MS ESI+ m/z 262 [M+H] ⁺ . Step 3. Preparation of ethyl 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7- carboxylate 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid hydrochloride (3.77 g, 12.7 mmol) was stirred in a mixture of ethanol (100 mL) and 4M HCl in dioxane (36 mL, 144 mmol) at reflux for 6 hours. The reaction mixture was concentrated and to the residue was added EtOAc. The organic phase was washed with saturated NaHCO ₃ , dried over MgSO ₄ and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexane (20:80) to give the title compound as an oil (3.69 g, 101%). MS ESI+ m/z 290 [M+H] ⁺ . Step 4. Preparation of ethyl 3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylate Ethyl 9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylate (3.69 g, 12.8 mmol) was dissolved in ethanol (100 mL) containing 10% Pd/C (617 mg, 3.19 mmol). The reaction mixture was heated at 60°C under an atmosphere of hydrogen (1 bar) for 2 hours. The reaction mixture was filtered through a plug of celite and concentrated on a rotavapor to give the title compound (2.59 g, 103%). MS ESI+ m/z 200 [M+H] ⁺ . Step 5. Preparation of ethyl 9-(2-ethoxy-2-oxoethyl)-3-oxa-9-azabicyclo- [3.3.1]nonane-7-carboxylate Ethyl bromoacetate (1.63 mL, 14.7 mmol) in THF (2 mL) was dropwise added to an ice cold solution of ethyl 3-oxa-9-azabicyclo[3.3.1]nonane-7- carboxylate (2.54 g, 12.7 mmol) in THF (20 mL) followed by addition of triethylamine (3.56 mL, 25.5 mmol). The reaction mixture was stirred at room temperature for 3 hours. Additional ethyl bromoacetate (212 µL, 1.91mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated on a rotavapor and to the residue was added water followed by extraction with EtOAc (x3). The combined organics were dried (MgSO ₄ ) and the mixture was concentrated in vacuo. The crude product was purified by column chromatography on silica gel with EtOAc/hexane (20:80) to give the title compound (3.37 g, 93%). MS ESI+ m/z 286 [M+H] ⁺ . Step 6. Preparation of ethyl 7-oxooctahydro-4,8-methanopyrido[2,1- c][1,4]oxazine-6-carboxylate hydrochloride Potassium tert-pentoxide (1.7 M in toluene ,17 mL, 28.9 mmol) was added to toluene (80 mL) and the reaction mixture was heated to 110°C under N ₂ before ethyl 9-(2-ethoxy-2-oxoethyl)-3-oxa-9- azabicyclo[3.3.1]nonane-7-carboxylate (3.35 g, 11.7 mmol) dissolved in dry toluene (25 mL) was added dropwise, using a syringe pump, over a period of 1 hour. After complete addition the reaction mixture was stirred at 110°C for 15 minutes. The reaction mixture was cooled in an ice bath and acidified with 12M HCl (40 mL). The organic phase was extracted with 12M HCl (2x15 mL) and the combined aqueous phases was used as such. MS ESI+ m/z 240 [M+H] ⁺ . Step 7. Preparation of hexahydro-4,8-methanopyrido[2,1-c][1,4]oxazin-7(6H)- one The combined HCl phases from step 6 above were heated at 90°C for 15 hours before activated charcoal (2 g) was added and the reaction mixture was further stirred at 90ºC for 1 hour. The mixture was cooled to room temperature and filtered through at plug of celite. The filtrate was concentrated in vacuo to give the title compound as the HCl salt. The HCl salt was treated with sat NaHCO ₃ (aq.) until bubbling ceased and the water was removed on a rotavapor. The product was dissolved in EtOH and the mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel with NH ₄ OH/MeOH/DCM (1:5:94) to give the title compound (1.35 g, 69% over two steps). MS ESI+ m/z 168 [M+H] ⁺ . Step 8. Preparation of 6-methylenehexahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-7(6H)-one N,N,N',N'-Tetramethylmethanediamine (90 µL, 0.67 mmol) in DCM (1 mL) was added dropwise to a mixture of hexahydro-4,8-methanopyrido[2,1- c][1,4]oxazin-7(6H)-one (112 mg, 0.67 mmol) and acetic anhydride (0.13 mL, 1.34 mmol) in DCM (2 mL) and the reaction mixture was stirred for 2 days. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel with NEt ₃ /IPA/DCM (0.01:20:80) to give the title compound (77 mg, 64%) as a white solid. MS ESI+ m/z 180 [M+H] ⁺ . Example 15: Synthesis of N-acetyl-S-((6-oxooctahydro-3,7-methanoindolizin- 5-yl)methyl)-L-cysteine N-Acetyl-L-cysteine (30 mg, 0.18 mmol) in DCM (0.5 mL) was added to a mixture of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)-one (20 mg, 0.12 mmol) in DCM (1 mL). The obtained reaction mixture was stirred for 2 hours. The crude product was purified by preparative HPLC (Xbridge C18 19x50 mm, water/MeCN, 100:0 to 95:5) to yield 8 mg (20%) of the title compound. The title compound was isolated as a mixture of diastereomers. MS ESI+ m/z 327 [M+H] ⁺ . Example 16. Synthesis of 3-methylenehexahydro-2,5-methanocyclopenta pyridin-4(3H)-one Step 1. Preparation of 2-(8-oxo-3-azabicyclo[3.2.1]octan-3-yl)acetonitrile 3-azabicyclo[3.2.1]octan-8-one hydrochloride (1.00 g, 6.18 mmol) was suspended in dry THF (20 mL) and potassium carbonate (2.56 g, 18.6 mmol) and bromoacetonitrile (1.14 g, 9.5 mmol) was added. After the mixture had been stirred at room temperature for 3 days it was filtered and the filtrate was concentrated and washed with acetonitrile. The dark brown crude product (1.07 g) was used as such in the next step. MS ESI+ m/z 165 [M+H] ⁺ . Step 2. Preparation of 3-(cyanomethyl)-3-azabicyclo[3.2.1]octane-8- carbonitrile 1 M Potassium tert-butoxide in tert-butanol (15.3 mL, 15.3 mmol) was added dropwise at 0°C to a mixture of 2-(8-oxo-3-azabicyclo[3.2.1]octan-3- yl)acetonitrile (1.01 g, 6.15 mmol) and TosMIC (1.56 g, 8.00 mmol) in monoglyme (20 mL). The reaction mixture was stirred overnight and then the reaction mixture was slowly allowed to reach room temperature. The solids was filtered off and rinsed with acetonitrile. The filtrate was concentrated under reduced pressure and the dark brown product was purified by column chromatography on silica gel with MeOH/DCM (5:95 to 2:8) to give the title compound (845 mg, 78%). MS ESI+ m/z 176 [M+H] ⁺ . Step 3. Preparation of 3-(carboxymethyl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid hydrochloride A solution of 3-(cyanomethyl)-3-azabicyclo[3.2.1]octane-8-carbonitrile (845 mg, 4.82 mmol) in 37 % hydrochloric acid (20 mL) was refluxed for 4 hours. The reaction mixture was concentrated, co-evaporated with toluene (2x10 mL) and dried under vacuum. The crude product (845 mg, 70%) was used as such in the next step. MS ESI+ m/z 214 [M+H] ⁺ . Step 4. Preparation of ethyl 3-(2-ethoxy-2-oxoethyl)-3- azabicyclo[3.2.1]octane-8-carboxylate hydrochloride Thionyl chloride (0.88 mL, 10.2 mmol) was added dropwise to a mixture of 3-(carboxymethyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid hydrochloride (845 mg, 3.38 mmol) in ethanol (20 mL). The obtained mixture was refluxed for 3 hours and then concentrated at reduced pressure. The dark brown residue was rinsed with ethyl acetate to give 645 mg (62%) of the title compound. MS ESI m/z 270 [M+H] ⁺ . Step 5. Preparation of hexahydro-2,5-methanocyclopenta[c]pyridin-4(3H)-one A mixture of 1.7 M potassium tert-pentoxide in toluene (2.07 mL, 3.52 mmol) in toluene (3 mL) was heated to reflux. Ethyl 3-(2-ethoxy-2-oxoethyl)-3- azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (384 mg, 1.26 mmol) in toluene (2 mL) was added dropwise over a period of 2 hours and the reaction mixture was then refluxed for 3 hours. The reaction mixture was cooled to 0°C and concentrated. HCl (10 mL) was added. The organic layer was extracted with 12M HCl (2x5 mL). The combined HCl layers were refluxed overnight and activated charcoal (300 mg) was added and the mixture was refluxed for an additional 30 min. The mixture was then cooled, filtered through a pad of celite and the pad was rinsed with warm water. To the ice cold aqueous filtrate potassium carbonate was carefully added until basic pH. The aqueous solution was extracted with DCM (2x10 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated at reduced pressure to give the product as a colourless oil that solidified upon standing. Yield 33 mg (17%). MS ESI m/z 152 [M+H] ⁺ . Step 6. Preparation of 3-methylenehexahydro-2,5-methanocyclopenta[c]- pyridin-4(3H)-one A solution of N,N,N',N'-tetramethylmethanediamine (30 µL, 0.22 mmol) in DCM (0.5 mL) was added dropwise to a mixture of hexahydro-2,5- methanocyclopenta[c]pyridin-4(3H)-one (33 mg, 0.22 mmol) and acetic anhydride (41 µL, 0.44 mmol) in DCM (0.7 mL). The obtained reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with DCM (2 mL), and 1 mL sat. NaHCO ₃ (aq.) was added and the obtained two-phase mixture was stirred for 5 min. The DCM layer was separated using a phase separator (IST) and the organic layer was concentrated at reduced pressure. The crude residue was purified by column chromatography on silica gel with IPA/DCM (1:18). The material was further purified by preparative HPLC (XBridge C1819x50 mm; 50 mM NH ₄ HCO ₃ /MeCN; 99:1 to 80:20) to give 3.2 mg of the title compound (9%). MS ESI+ m/z 164 [M+H] ⁺ . Example 17: Synthesis of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one Step 1. Preparation of 8-benzyl-8-azabicyclo[3.2.1]octane-3-carbonitrile 1.7 M Potassium tert-pentoxide in toluene (9.45 mL, 16.1 mmol) was added dropwise at 0°C to a mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3- one (1.38 g, 6.41 mmol) and TosMIC (1.63 g, 8.35 mmol) in diglyme/ethanol (54 mL / 1.6 mL). The reaction mixture was slowly allowed to reach room temperature. After standing at room temperature for 3 days the solid was filtered off and the solid residue was rinsed with 1,2-dimethoxyethane. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with gradient elution using EtOAc/pet. ether to give 823 mg (57%) of the title compound. MS ESI+ m/z 227 [M+H] ⁺ . Step 2. Preparation of 8-benzyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid hydrochloride A suspension of 8-benzyl-8-azabicyclo[3.2.1]octane-3-carbonitrile (823 mg, 3.64 mmol) in 37 % hydrochloric acid (50 mL) was refluxed for 20 hours. The reaction mixture was concentrated, co-evaporated with toluene (2x10 mL) and dried under reduced pressure to give 1025 mg (100%) of the title compound. The crude product was used in the next step. MS ESI+ m/z 246 [M+H] ⁺ . Step 3. Preparation of ethyl 8-benzyl-8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride 4M HCl in 1,4-dioxane (10 mL, 40 mmol) was added to a mixture of 8- benzyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid hydrochloride (1025 mg, 3.64 mmol) in ethanol (60 mL). The reaction mixture was refluxed for 20 hours and then concentrated under reduced pressure. Co-evaporation with toluene afforded 1126 mg (99%) of the title compound. MS ESI m/z 274 [M+H] ⁺ . Step 4. Preparation of ethyl 8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride 10% Pd/C (213 mg) was added to a mixture of ethyl 8-benzyl-8- azabicyclo[3.2.1]octane-3-carboxylate hydrochloride (1276 mg, 4.12 mmol) in ethanol (40 mL). The mixture was subjected to hydrogenation using H ₂ gas at (1 bar) for a period of 20 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 905 mg (100%) of the title compound. MS ESI+ m/z 184 [M+H] ⁺ . Step 5. Preparation of ethyl 8-(2-ethoxy-2-oxoethyl)-8-azabicyclo[3.2.1]- octane-3-carboxylate Ethyl 2-bromoacetate (0.47 mL, 4.24 mmol) in ethanol (1 mL) was added to a suspension of ethyl 8-azabicyclo[3.2.1]octane-3-carboxylate hydrochloride (905 mg, 4.12 mmol) and triethylamine (1.43 mL, 10.3 mmol) in ethanol (40 mL). The obtained reaction mixture was stirred for 20 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM and sat. NaHCO ₃ (aq.). The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography on silica gel gradient with 0.01% NEt3/EtOAc/p-eter to give 750 mg (68%) of the title compound. MS ESI m/z 270 [M+H] ⁺ . Step 6. Preparation of ethyl 6-oxooctahydro-3,7-methanoindolizine-5- carboxylate hydrochloride A mixture of 1.7 M potassium tert-pentoxide in toluene (2.72 mL, 4.62 mmol) was dissolved in toluene (15 mL) and heated to reflux. Ethyl 8-(2- ethoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylate (622 mg, 2.31 mmol) in toluene (24 mL) was added dropwise and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to 0°C and 20 mL 12M aq. HCl (37%) was added (pH acidic). The organic layer was extracted with 12M HCl (2x5 mL). The combined HCl layers were used in the next step. MS ESI m/z 224 [M+H] ⁺ . Step 7. Preparation of hexahydro-3,7-methanoindolizin-6(5H)-one The HCl solution of ethyl 6-oxooctahydro-3,7-methanoindolizine-5- carboxylate hydrochloride from above was refluxed for 6 hours. Active charcoal was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through a pad of celite and the pad was rinsed with warm water. The filtrate was cooled and potassium carbonate was carefully added until basic pH. The aqueous solution was extracted with DCM (2x10 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 175 mg (50% over two steps) of the title compound. MS m/z 152 [M+H] ⁺ . Step 8. Preparation of 5-methylenehexahydro-3,7-methanoindolizin-6(5H)- one A solution of N,N,N',N'-tetramethylmethanediamine (100 µL, 0.71 mmol) in DCM (0.6 mL) was added dropwise to a mixture of hexahydro-3,7- methanoindolizin-6(5H)-one (107 mg, 0.71 mmol) and acetic anhydride (134 µL, 1.42 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with DCM (5 mL), NaHCO ₃ (1 mL, aq., sat.) was added and the obtained two-phase mixture was stirred for 10 min. The DCM layer was separated using a phase separator (IST) and concentrated. The product was purified using column chromatography on silica gel with DCM/IPA (18:1) to give 78 mg (68%) of the title compound. MS ESI+ m/z 164 [M+H] ⁺ . Example 18: Synthesis of 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-4- methylquinuclidin-3-one A mixture of 2-((dimethylamino)methyl)-4-methylquinuclidin-3-one (89.0 mg, 0.453 mmol), isothiazolidine 1,1-dioxide (165 mg, 1.36 mmol) and cesium carbonate (443 mg, 1.36 mmol) in DMF (3 mL) was stirred under nitrogen at 50°C for 48 hours. After addition of 15 mL DCM the mixture was filtered and evaporated to dryness. Purification by preparative HPLC (Gemini 5µm NX-C18150 x 21; 50 mM NH ₄ OAc/MeCN; 98:2 to 50:50) afforded the title compound (11 mg, 8.9%). MS ESI+ m/z 273 [M+H] ⁺ . Example 19: Synthesis of 2,2-difluoro-N-(2-methoxyethyl)- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide hydrochloride Step 1. Preparation of 22-(((2-methoxyethyl)amino)methyl)-4- methylquinuclidin-3-one 2-((Dimethylamino)methyl)-4-methylquinuclidin-3-one (82 mg, 0.54 mmol) was dissolved in 5 ml THF followed by addition of 2- methoxyethylamine (470 μl, 5.41 mmol) and K ₂ CO ₃ (150 mg, 1.09 mmol). The reaction mixture was stirred over night at ambient temperature. The mixture was diluted with 10 ml DCM, filtered and concentrated under reduced pressure to give 22-(((2-methoxyethyl)amino)methyl)-4-methylquinuclidin-3- one as a crude product that was used in next step without any further purification. Step 2. Preparation of 2,2-difluoro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide hydrochloride The crude product from the previous step was dissolved in 15 ml DCM. Molecular sieves were added followed by difluoroacetyl chloride (55 μl, 0.53 mmol). The solution was stirred over night. The mixture was filtered and concentrated under reduced pressure. The crude product was mixed with triethylamine (80 μl) in DCM (3 ml) and purified by flash chromatography (spherical silica gel (10 g); DCM/MeOH; 100:0 to 72:28). The pure product was then dissolved in cyclopentyl methyl ether and precipitated as the hydrochloride salt with 2 eq. HCl (3M in cyclopentyl methyl ether). The solid material was isolated to give the title compound (10 mg, 2%). MS ESI+ m/z 305 [M+H] ⁺ . Example 20: Synthesis of 2,2,2-trifluoro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide trifluoroacetate 2-((Dimethylamino)methyl)-4-methylquinuclidin-3-one (82 mg, 0.54 mmol) was dissolved in 5 ml THF followed by addition of 2- methoxyethylamine (470 μl, 5.41 mmol) and K ₂ CO ₃ (150 mg, 1.09 mmol). The mixture was stirred over night at ambient temperature. The mixture was diluted with 10 ml DCM, filtered and concentrated under reduced pressure. The crude product was dissolved in 5 ml DCM. Molecular sieves were added followed by trifluoroacetic acid anhydride (90 μl, 0,65 mmol). The solution was stirred over night at ambient temperature. The mixture was filtered and concentrated under reduced pressure. Analysis by LCMS showed substantial amounts of unreacted 4-methyl-2-methylenequinuclidin-3-one, so the procedure above was repeated on the crude material. The mixture was filtered and concentrated under reduced pressure. Purification by flash chromatography (spherical C18 (12 g); 0.1% TFA/MeCN; 97:3 to 60:40) gave the title compound (55 mg, 7%). MS ESI+ m/z 323 [M+H] ⁺ . Example 21: Synthesis of 2,2,2-trifluoro-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)acetamide A mixture of 2-((dimethylamino)methyl)-4-methylquinuclidin-3-one (112 mg, 0.571 mmol), 2,2,2-trifluoroacetamide (645 mg, 5.71 mmol) and cesium carbonate (930 mg, 2.85 mmol) in MeCN (22.4 mL) was stirred for 1,5 days under nitrogen at ambient temperature. The solids were removed by centrifuging the mixture in a 50 mL Falcon tube and drawing off the liquid. The solids were washed/centrifuged with 10 mL MeCN three times. The MeCN solutions were combined and concentrated. The crude mixture was dissolved in 2 mL DCM and purified by flash chromatography on spherical silica gel (10 g) using acetonitrile to give the title compound (52.7 mg, 35%). MS ESI+ m/z 265 [M+H] ⁺ . Example 22: Synthesis of N-cyclopropyl- ((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide N-Cyclopropylmethanesulfonamide (89.4 mg, 661 μmol) was added to a mixture of 4-methyl-2-methylenequinuclidin-3-one (50.0 mg, 331 μmol) and cesium carbonate (108 mg, 331 μmol) in acetonitrile (4.0 mL). and the reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure. Purification by preparative HPLC (Gemini®, 5 µm NX-C18110Å (150x21,2 mm), MeCN:H ₂ O; 5:95 to 50:50) afforded the title compound as a transparent oil (14.3 mg, 15 %). MS ESI+ m/z 287 [M+H] ⁺ . Example 23: Synthesis of 2-((1,1-dioxido-1,2-thiazinan-2-yl)methyl)-4- methylquinuclidin-3-one A mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 μmol), 1,2-thiazinane 1,1-dioxide (53.6 mg, 397 μmol) and cesium carbonate (323 mg, 992 μmol) in acetonitrile (12 mL) was stirred at room temperature for 3 days. The solution was filtered and concentrated under reduced pressure. Purification by preparative HPLC (Gemini®, 5 µm NX-C18110Å (150x21,2 mm), MeCN:H ₂ O; 5:95 to 40:60) afforded the title compound as a white solid (14.7 mg, 10 %). MS ESI+ m/z 287 [M+H] ⁺ . Example 24: Synthesis of 2-((3,3-difluoro-2-oxopiperidin-1-yl)methyl)-4- methylquinuclidin-3-one A mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 μmol), 3,3-difluoropiperidin-2-one (53.6 mg, 397 μmol) and cesium carbonate (323 mg, 992 μmol) in acetonitrile (12 mL) was stirred at room temperature for 3 days.The solution was filtered and concentrated under reduced pressure. Purification by preparative HPLC (Gemini®, 5 µm NX-C18110Å (150x21,2 mm), MeCN:H ₂ O; 5:95 to 40:60) afforded the title compound as a white solid (41.5 mg, 37 %). MS ESI+ m/z 287 [M+H] ⁺ . Example 25: Synthesis of N-cyclopropyl- ((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide A mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 μmol), N-cyclopropylcyclopropanesulfonamide (64.0 mg, 397 μmol) and cesium carbonate (323 mg, 992 μmol) in acetonitrile (12 mL) was stirred at room temperature for 3 days. The solution was filtered and concentrated under reduced pressure. Purification by preparative HPLC (Gemini®, 5 µm NX-C18 110Å (150x21,2 mm), MeCN:H ₂ O; 5:95 to 40:60) afforded the title compound as a light yellow gummy solid (16 mg, 13 %). MS ESI+ m/z 313 [M+H] ⁺ . Example 26: Synthesis of N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)cyclopropanesulfonamide A mixture of N-Cyclopropylmethanesulfonamide (60.0 mg, 397 μmol), N-methylcyclopropanesulfonamide (53.6 mg, 397 μmol) and cesium carbonate (323 mg, 992 μmol) in acetonitrile (12 mL) was stirred at room temperature for 3 days.The solution was filtered and concentrated under reduced pressure. Purification by preparative HPLC (Gemini®, 5 µm NX-C18 110Å (150x21,2 mm), MeCN:H ₂ O; 5:95 to 40:60) afforded the title compound as a light yellow solid (8.6 mg, 8 %). MS ESI+ m/z 287 [M+H] ⁺ . Example 27: Synthesis of N-methyl-N-((4-methyl-3-oxoquinuclidin-2- yl)methyl)methanesulfonamide To a cooled solution (-20°C) of 2-((dimethylamino)methyl)-4- methylquinuclidin-3-one (76.0 mg, 417 μmol) and N,N-diisopropylethylamine (363 μL, 2.08 mmol) in DCM (8.3 mL) methanesulfonyl chloride (38.7 μL, 500 μmol) in DCM was added. The cooling bath was removed and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified on Biotage spherical silica gel column (10 g) using 100% of acetonitrile, then on by preparative HPLC (Gemini®, 5 µm NX-C18110Å (150x21,2 mm), MeCN:H ₂ O; 3:97 to 50:50) to afford the title compound as a colorless gummy solid (6.5 mg, 6%). MS ESI+ m/z 261 [M+H] ⁺ . Example 28: Synthesis of 2,2,2-trifluoro-N-methyl- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide To a cooled solution (-20°C) of 2-((dimethylamino)methyl)-4- methylquinuclidin-3-one (76.0 mg, 417 μmol) and N,N-diisopropylethylamine (363 μL, 2.08 mmol) in DCM (8.3 mL), trifluoroacetic anhydride (70 μL, 500 μmol) in DCM was added. The cooling bath was removed and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified on Biotage spherical silica gel column (10 g) using 100% of acetonitrile, then on by preparative HPLC (Gemini®, 5 µm NX-C18110Å (150x21,2 mm), MeCN:H ₂ O; 3:97 to 50:50) to afford the title compound as a colorless gummy solid (3.5 mg, 3%). MS ESI+ m/z 279 [M+H] ⁺ . Example 29: Synthesis of 2,2,2-trichloro-N-(2-methoxyethyl)- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate Step 1. Preparation of 2-(((2-methoxyethyl)amino)methyl)-4- methylquinuclidin-3-one 2-methoxyethylamine (470 µl, 5.41 mmol) and potassium carbonate (150 mg, 1.08 mmol) was added to a crude solution of 4-methyl-2- methylenequinuclidin-3-one (82.0 mg, 540 µmol) in THF (5.0 mL). The reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure to give an oil that was used without any purification in next step. Step 2. Preparation of 2,2,2-trichloro-N-(2-methoxyethyl)-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate To a cooled solution (0°C) of 2-(((2-methoxyethyl)amino)methyl)-4- methylquinuclidin-3-one (63.0 mg, 278 μmol) and triethylamine (194 μL, 1.39 mmol) in DCM (5.6 mL) trichloroacetic anhydride (47 μL, 420 μmol) in DCM was added. The cooling bath was removed and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified on Biotage spherical C18 column (12 g, MeCN:TFA (0.1% aq.); 3:97 to 50:50) to afford the title compound as a light yellow oil (4.7 mg, 3%). MS ESI+ m/z 371, 373 [M+H] ⁺ . Example 30: Synthesis of N-cyclopropyl-2,2-difluoro-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate Step 1. Preparation of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one Cyclopropylamine (422 µl, 6.08 mmol) was added to a solution of 4- methyl-2-methylenequinuclidin-3-one (230 mg, 1.52 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure to give an oil that was used without any purification in next step. Step 2. Preparation N-cyclopropyl-2,2-difluoro-N-((4-methyl-3-oxoquinuclidin- 2-yl)methyl)acetamide 2,2,2-trifluoroacetate To a solution of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one (75.0 mg, 360 μmol) in DCM (6 mL) was added 2,2-difluoroacetyl chloride (56 μL, 540 μmol) and 5 pieces of molecular sieves. The mixture was stirred at room temperature for 3 days and the concentrated under reduced pressure. Purification on Biotage spherical C18 column (12 g, MeCN:TFA (0.1% aq.); 3:97 to 60:40) to afford the title compound (18 mg, 18%). MS ESI+ m/z 287 [M+H] ⁺ . Example 31: Synthesis of N-cyclopropyl-2,2,2-trifluoro- ((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate Step 1. Preparation of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one. Cyclopropylamine (422 µl, 6.08 mmol) was added to a solution of 4- methyl-2-methylenequinuclidin-3-one (230.0 mg, 1.52 mmol) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure to give an oil that was used without any purification in next step. Step 2. Preparation of N-cyclopropyl-2,2,2-trifluoro-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate To a solution of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one (75.0 mg, 360 μmol) in DCM (6 mL) was added trifluoroacetic anhydride (76 μL, 540 μmol) and 5 pieces of molecular sieves. The mixture was stirred at room temperature for 3 days and the concentrated under reduced pressure. Purification on Biotage spherical C18 column (12 g, MeCN:TFA (0.1% aq.); 3:97 to 60:40) to afford the title compound (31 mg, 28%). MS ESI+ m/z 305 [M+H] ⁺ . Example 32: Synthesis of 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate Step 1. Preparation of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one. Cyclopropylamine (422 µl, 6.08 mmol) was added to a solution of 4- methyl-2-methylenequinuclidin-3-one (230.0 mg, 1.52 mmol) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight. The solution was filtered and concentrated under reduced pressure to give an oil that was used without any purification in next step. Step 2. Preparation of 2,2,2-trichloro-N-cyclopropyl-N-((4-methyl-3- oxoquinuclidin-2-yl)methyl)acetamide 2,2,2-trifluoroacetate To a solution of 2-((cyclopropylamino)methyl)-4-methylquinuclidin-3- one (75.0 mg, 360 μmol) in DCM (6 mL) was added trichloroacetyl chloride (60 μL, 540 μmol) and 5 pieces of molecular sieves. The mixture was stirred at room temperature for 3 days and the concentrated under reduced pressure. Purification on Biotage spherical C18 column (12 g, MeCN:TFA (0.1% aq.); 3:97 to 60:40) to afford the title compound (27 mg, 21%). MS ESI+ m/z 353, 355 [M+H] ⁺ . Example 33: Synthesis of 2-((dimethylamino)methyl)-4-methylquinuclidin-3- one To a suspension of 4-methyl-3-oxoquinuclidin-1-ium chloride (320 mg, 1.82 mmol) in 10 mL water/EtOH (3:7) was added NaHCO ₃ at room temperature. When bubbling ceased dimethylamine (40% aq., 345 μl, 2.73 mmol) was added followed by formaldehyde (37% aq., 203 μl, 2.73 mmol). The reaction mixture was heated to 70°C and was left over night with stirring. After cooling, 15 mL EtOH were added to the reaction mixture and the solid NaCl was filtered off. The solution was concentrated under reduced pressure. The product was dissolved in DCM and the solid material was filtered off. The yellow solution was concentrated under reduced pressure to give 350 mg of 2-((dimethylamino)methyl)-4-methylquinuclidin-3-one as a crude product which was used in subsequent steps without any further purification. MS ESI+ m/z 197 [M+H] ⁺ . The exemplified compounds of Examples 1-32 above were synthesized, isolated and tested as a racemic mixture, unless stated otherwise. Example 34: In vitro efficacy study using the SaOS-2 His273 protocol SaOS-2 His273 mtp53 is a human osteosarcoma cell line which has been genetically engineered at OnkPat CCK to express His273 mutated p53. 3000 cells/well (50μl) were seeded into masked (black or white with clear bottom) 96-well cell culture plates using Iscove’s Modified Dulbecco’s Medium supplemented with 10% heat inactivated (56°C for 60 min) fetal calf serum. The plates were then incubated for 4 hours, allowing the cells to attach. The test compounds were dissolved in DMSO or water to a concentration of 0.01 M and then further diluted to desired concentrations using the cell medium.50 μl of freshly diluted test compound from fresh stock was added to the wells. The plates were then incubated for 72 hours. For viability detection, CellTiter-Glo® Luminescent Cell Viability Assay (CTG) was used. CTG is a homogeneous ”add-mix-measure” format method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. The luminescence was measured using the PerkinElmer Victorx4 instrument. The average of the signal values for the untreated cells was calculated for each plate. The % of growth suppression was calculated as: 100 - ((Signal sample / Signal untreated cells) x 100). The results of the SaOs-2 His273 analyses were expressed as IC50 values, i.e. concentration that suppresses growth of at least 50% of the cells. The IC50 values of various compounds according to the invention are shown in Table 1. Table 1: Cell based activity in SaOS-2 His273 Example 35: In vivo efficacy study A compound of Table 1 is administered intraperitoneally twice daily at approximately 25 or 75 mg/kg to NSG mice (NOD.Cg-Prkdcscid Il2rgtm1WjI/SzJ) ortotopically xenografted with the acute myeloid leukemia cell line SKM-1- Luc, carrying mutant p53 (R248Q). To make SKM-1-Luc, the cell line SKM-1 is stably transfected with a synthetic gene for firefly luciferase, Luc2 (pGL4, Promega). Thereby, the tumor load is externally monitored by luminescence measurement (radiance values; photon/second/cm ² /steradian).1 x 10 ⁷ SKM- 1-Luc cells are injected, and six days later the animals are stratified into treatment groups and control, 6 animals in each group, based on luminescence measurement. Treatment is started on day 7 and done in 3 cycles of 5 days each, with 2 days recovery. Tumor progression is evaluated by non-invasive in vivo imaging at the end of each treatment cycle (day 11, 18 and 25).