Spirocyclopropylamine Derivatives Useful as Inhibitors of Histone Demethylases

KDM1A

Field of the Invention

The present invention relates to spirocyclopropyl derivatives, pharmaceutical compositions containing such compounds and to their use in therapy.

Background of the invention

Alterations in the structural and functional states of chromatin, mainly determined by post- translational modification of histone components, are involved in the pathogenesis of a variety of diseases. These reversible modifications contribute to the dynamicity of chromatin remodeling and are tightly controlled by the opposing activities of enzyme families. The enzymatic processes governing these post-translational modifications on the nucleosomes have become potential targets for the so-called epigenetic therapies (Portela, A. et al. Nat. Biotechnol. 2010, 28, 1057-1068).

The discovery of an increasing number of histone lysine demethylases has highlighted the dynamic nature of the regulation of histone methylation, a key chromatin modification that is involved in eukaryotic genome and gene regulation. Histone lysine demethylases represent attractive targets for epigenetic drugs, since their expression and/or activities are often misregulated in cancer (Varier, R. A. et al. Biochim. Biophys. Acta. 201 1 , 1815, 75-89). A lysine can be mono-, di-, and tri-methylated and each modification, even on the same amino acid, can exert different biological effects.

Histone lysine demethylases can be grouped into two major families with different enzymatic mechanisms (Anand, R. et al. J. Biol. Chem. 2007, 282, 35425-35429; Metzger, E. et al. Nat. Struct. Mol. Biol. 2007, 14, 252-254). On one side, we find the large protein family of Jumonji C (JmjC) domain-containing proteins, where the demethylation reaction is carried out by JmjC domain proteins and where a conserved JmjC domain, the presence of Fe(ll) and a-ketoglutarate is required to generate formaldehyde and succinate and to allow the removal of mono-, di-, and trimethylated lysines. The demethylation reaction of the other class, which includes two proteins, is a flavin dependent oxidative process and is limited to mono- and di-methylated substrates. Mammals contain two flavin dependent amino oxidase histone lysine demethylases: KDM1A (also known as LSD1 ) and KDM1 B (also known as LSD2). KDM1A is a constituent in several chromatin-remodeling complexes and is often associated with the co-repressor protein CoREST. It recruits in this form other histone modifying enzymes such as histone deacetylases 1/2 (HDAC1/2) forming a multienzyme unit typically involved in gene repression regulation (Ballas, N. et al. Neuron 2001 , 31 , 353-365). KDM1A specifically removes the methyl groups from both mono- and di-methyl Lys4 of histone H3, which is a well-characterized gene activation mark.

KDM1 A represents an interesting target for epigenetic drugs as supported by data related to its over-expression in solid and hematological tumors (Schulte, J. H. et al. Cancer Res. 2009, 69, 2065-2071 ; Lim, S. et al. Carcinogenesis 2010, 31 , 512-520; Hayami, S. et al. Int. J. Cancer 201 1 , 128, 574-586; Schildhaus, H. U. et al. Hum. Pathol. 201 1 , 42, 1667- 1675; Bennani-Baiti, I. M. et al. Hum. Pathol. 2012, 43, 1300-1307), to the correlation of its over-expression and tumor recurrence in prostate cancer (Kahl, P. et al. Cancer Res. 2006, 66, 1 1341 -1 1347), to its role in various differentiation processes as adipogenesis (Musri, M. M. et al. J. Biol. Chem. 2010, 285, 30034-30041 ), muscle skeletal differentiation (Choi, J. et al. Biochem. Biophys. Res. Commun. 2010, 401 , 327-332), and hematopoiesis (Hu, X. et al. Proc. Natl. Acad. Sci. USA 2009, 106, 10141 -10146; Li, Y. et al. Oncogene 2012, 31 , 5007-18), to its regulation of cellular energy expenditure (Hino S. Et al. Nat Commun. 2012, doi: 10.1038/ncomms1755), to its involvement in the control of checkpoints of viral gene expression in productive and latent infections (Roizman, B. J. Virol. 201 1 , 85, 7474-7482) and more specifically in the control of herpes virus infection (Gu, H. J. Virol. 2009, 83, 4376-4385) and HIV transcription (Sakane, N. et al. PLoS Pathog. 201 1 , 7(8):e1002184). The role of KDM1A in the regulation of neural stem cell proliferation (Sun, G. et al. Mol. Cell Biol. 2010, 30, 1997-2005) as well as in the control of neuritis morphogenesis (Zibetti, C. et al. J. Neurosci. 2010, 30, 2521 -2532) suggests its possible involvement for neurodegenerative diseases.

Furthermore, there are evidences of the relevance of KDM1A in the control of other important cellular processes, such as DNA methylation (Wang, J. et al. Nat. Genet. 2009, 41 (1 ): 125-129), cell proliferation (Scoumanne, A. et al. J. Biol. Chem. 2007, 282, 15471 - 15475; Cho, H. S. et al. Cancer Res. 201 1 , 71 , 655-660), epithelial mesenchimal transition (Lin, T. et al. Oncogene. 2010, 29, 4896-4904), and chromosome segregation (Lv, S. et al. Eur. J. Cell Biol. 2010, 89, 557-563). Moreover, several inhibitors of KDM1A have been identified in the last years and it was found that KDM1 A inhibitors were able to reactivate silenced tumor suppressor genes (Huang, Y. et al. Proc. Natl. Acad. Sci. U S A. 2007, 104, 8023-8028; Huang, Y. et al. Clin. Cancer Res. 2009, 15, 7217-7228), to target selectively cancer cells with pluripotent stem cells properties (Wang, J. et al. Cancer Res. 201 1 , 71 , 7238-7249), as well as to reactivate the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia (Schenk, T. et al. Nat Med. 2012, 18, 605-61 1 ).

The more recently discovered demethylase KDM1 B (LSD2) displays -similarly to KDM1A- specificity for mono- and di-methylated Lys4 of histone H3. KDM1 B, differently from KDM1A, does not bind CoREST and it has not been found up to now in any of KDM1A- containing protein complex (Karytinos, A. et al. J. Biol. Chem. 2009, 284, 17775-17782). On the contrary, KDM1 B forms active complexes with euchromatic histone methyltransferases G9a and NSD3 as well as with cellular factors involved in transcription elongation. In agreement, KDM1 B has been reported to have a role as regulator of transcription elongation rather than that of a transcriptional repressor as proposed for KDM1A (Fang, R. et al. Mol. Cell 2010, 39, 222-233).

KDM1A and KDM1 B are both flavo amino oxidases dependent proteins sharing a FAD coenzyme-binding motif, a SWIRM domain and an amine oxidase domain, all of which are integral to the enzymatic activity of KDM1 family members. Moreover, both KDM1A and KDM1 B show a structural similarity with the monoamine oxidases MAO-A and MAO-B. Indeed, tranylcypromine, a MAO inhibitor used as antidepressive agent, was found to be also able to inhibit LSD1. The compound acts as an irreversible inhibitor forming a covalent adduct with the FAD cofactor. (Lee, M. G. et al. Chem. Biol. 2006, 13, 563; Schmidt, D. M. Z. et al. Biochemistry 2007, 46, 4408).

MAOs are well known targets for the treatment of diseases of the central nervous system, such as depression or Parkinson's disease. However, inhibition of the MAOs are associated with side effects, among them tyramine-induced hypertensive crisis or the serotonin syndrome, which occurs in situation of concomintant use of MAO inhibitors and other serotoninergic drugs. (Wimbiscus, M. et al. Cleve. Clin. J. Med., 2010, 859-882; Iqbal, M. M. Ann. Clin. Psychiatry, 2012, 24, 310-318).

The synthesis of tranylcypromine analogs and their LSD1 inhibitory activity has been described by Gooden, D. M. et al. in Bioorg. Med. Chem. Lett. 2008, 18, 3047-3051 and by Benelkebir, H. et al. in Bioorg. Med. Chem. 201 1 , 19, 3709-3716. Further arylcyclopropylamine and heteroarylcyclopropylamine derivatives as LSD1 , MAO-A and/or MAO-B enzyme inhibitors are disclosed in US2010/324147, WO2012/013727 and in WO2012/045883.

Oryzon Genomics S.A. disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, and in WO2012/013728, cyclopropylaminoalkylamides, N-heterocyclyl-, aryl-, or heteroarylalkylcyclopropylamines with LSD1 , MAO-A and/or MAO-B inhibitory activity.

Spiro[cyclopropane-2,1 '-indane]-1 -amine (CAS 1250204-62-6, Enamine Cat. Nbr. EN300- 149242), spiro[cyclopropane-2,1 '-tetralin]-1 -amine (CAS 1375474-45-5, Enamine Cat. Nbr. EN300-147284), spiro[chromane-4,2'-cyclopropane]-1 '-amine (CAS 1375474-45-5, Enamine Cat. Nbr. EN300-147140) are commercially available compounds, e.g. provided by Enamine, but no use has been associated to them.

Spiro[cyclopropane-2,1 '-indane]-1 -amines substituted by fluoro, chloro or bromo on positions 4, 5 or 6 (Cat. Nbrs. A13.862.120, A12.751.563, A12.751.564, A15.822.402, A18.546.484, A18.558.783, A18.558.784, A18.615.242 and A18.615.243), spiro[cyclopropane-2,1 '-tetralin]-1 -amines substituted by fluoro, chloro or bromo on positions 5, 6 or 7 (Cat. Nbrs. A18.555.982, A18.555.983, A18.555.984, A18.573.841 , A18.573.842, A18.573.843, A18.625.468, A18.625.469, A18.625.470) and spiro[chromane-4,2'-cyclopropane]-1 '-amine substituted by fluoro, chloro or bromo on positions 6, 7 or 8 (Cat. Nbrs. A18.557.868, A18.557.869, A18.557.870, A18.576.368, A18.576.369, A18.576.370, A18.626.1 18, A18.626.1 19, A18.626.120) are disclosed in the Aurora Screening Library, but no use has been associated to them.

The present invention relates to substituted cyclopropylamine derivatives having highly potent inhibitory activities of the KDM1A enzyme and low inhibitory activity of monoamine oxidases (MAOs), useful in the prevention or therapy of diseases and conditions associated with the activity of the histone demethylases.

Description of the Invention

According to the present invention there are provided spirocyclopropylamine compounds, endowed with a potent KDM1A (LSD1 ) inhibitory activity, of general formula (I)

is a bond, oxygen or CH ₂ ;

is hydrogen, halogen, or R ² -L-;

is hydrogen;

Ci-C ₆ alkyi;

C-i-C-6 alkyi substituted by C-3-C-6 cycloalkyl;

C1-C6 alkyi substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyi, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, OH and NH ₂ ;

C1-C6 alkyi substituted by heterocydyl, wherein the heterocydyl may be optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyi, C-i-C-6 alkyi substituted by aryl, aryl, or (CO)R ³ ;

C ₃ -C ₆ cycloalkyl optionally substituted by NH ₂ ;

heterocydyl optionally substituted by one or more substituents independently selected from the group consisting of Ci-C ₆ alkyi, Ci-C ₆ alkyi substituted by aryl;

or -CH ₂ (CO)NR ⁴ R ⁵ ;

is aryl, wherein the aryl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci- Ce alkyi, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, or Ci-C ₆ haloalkoxy

is a single bond; -(CH ₂ ) _m -Y-(CH ₂ ) _n -; or -(CH ₂ ) _p (CO)NR ⁶ -;

are, independently, zero or an integer from 1 to 6;

is NH; or oxygen;

is C-I-C6 alkyi or aryl; R ⁴ , R ⁵ are, independently, hydrogen; C1 -C6 alkyl; or R ⁴ and R ⁵ together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR ⁷ , O or S and being optionally substituted by NH ₂ ;

R ⁶ , R ⁷ are, independently, hydrogen; or Ci-C ₆ alkyl;

or stereoisomers or pharmaceutically acceptable salts thereof, for use as medicament.

In a preferred embodiment, the invention provides compounds of general formula (I) for the use as a medicament wherein aryl is phenyl.

In a further preferred embodiment, the invention provides compounds of general formula (I)

wherein

X is a bond, oxygen or CH ₂ ;

R is hydrogen, halogen, or R ² -L-;

R is hydrogen;

Ci-C ₆ alkyl;

C1-C-6 alkyl substituted by C ₃ -C ₆ cycloalkyl;

C1 -C6 alkyl substituted by phenyl or benzodioxinyl;

C1 -C6 alkyl substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkyl substituted by phenyl, or

(CO)R ³ ;

C ₃ -C-6 cycloalkyl optionally substituted by NH ₂ ;

heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyl;

or -CH ₂ (CO)NR ⁴ R ⁵ ;

R ² is phenyl, wherein the phenyl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, or Ci-C ₆ haloalkoxy L is a single bond; -(CH ₂ ) _m -Y-(CH ₂ ) _n -; or (CO)NR ⁶ -;

m, n are, independently, zero or 1 ;

Y is oxygen;

R ³ is C1-C-6 alkyl or phenyl; R ⁴ , R ⁵ are, independently, hydrogen; C ₁ -C6 alkyl; or R ⁴ and R ⁵ together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR ⁷ ;

R ⁶ , R ⁷ are, independently, hydrogen; or Ci-C ₆ alkyl;

or stereoisomers or pharmaceutically acceptable salts thereof, for use as medicament. Particularly preferred compounds of general formula (I) for the use as a medicament include:

N-[£rans-2-aminospiro[cyclopropane-1 , 1 '-indane]-5'-yl]benzamide;

A/-[c/s-2-aminospiro[cyclopropane-1 , 1 '-indane]-5'-yl]benzamide;

A/-[irans-2-aminospiro[cyclopropane-1 ,3'-indane]-5'-yl]benzamide;

£rans-spiro[chromane-4,2'-cyclopropane]-1 '-amine;

£rans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine;

c/ ^' s-5'-bromospiro[cyclopropane-2, 1 '-indane]-1 -amine;

c/ ^' s-spiro[cyclopropane-2,1 '-indane]-1 -amine;

£rans-spiro[cyclopropane-2, 1 '-indane]-1 -amine;

£rans-6'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine;

£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

c/ ^' s-spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

A/-[irans-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide;

A/-[c/s-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide;

irans-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

c/ ^' s-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine;

irans-5'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2 , 1 '-indane]-1 -amine;

c/ ^' s-5'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

c/s-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

irans-6'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2 , 1 '-indane]-1 -amine;

£rans-A/-benzylspiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

£rans-A/-benzylspiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-(cyclopropylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-(2,3-dihydro-1 ,4-benzodioxin-6-ylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine; irans-A/-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-indane]-1 -amine;

1 -methyl-N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]pipe din-4-amine;

N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]piperidin-4-amine;

8-methyl-N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]-8-azabicyclo[3.2.1 ]octan-3-amine; £rans-A/4-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]cyclohexane-1 ,4-diamine;

c/s-A/4-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]cyclohexane-1 ,4-diamine;

N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]azetidin-3-amine;

1 -(4-methylpiperazin-1 -yl)-2-[[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]ethanone; 1 -[4-[[[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]-1 -pipe dyl]ethanone; phenyl-[4-[[[trans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]-1 - piperidyl]methanone;

trans-N-[^ -benzyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-[(1 -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]-1 -amine;

trans-N-[^ -isopropyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

trans-N-[^ -phenethyl-4-pipe dyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-N-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

£rans-N4-[£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]cyclohexane-1 ,4-diamine;

c/s-A/4-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]cyclohexane-1 ,4-diamine;

trans-N-[^ -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

trans-N-[^ -phenethyl-4-pipe dyl)methyl]spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

trans-N-[^ -isopropyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

1 -(4-methylpiperazin-1 -yl)-2-[[irans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]amino]ethanone; irans-4'-Bromospiro[cyclopropane-2, 1 '-indane]-1 -amine;

c/s-4'-Bromospiro[cyclopropane-2, 1 '-indane]-1 -amine;

£rans-7'-Bromospiro[cyclopropane-2, 1 '-indane]-1 -amine;

c/ ^' s-7'-Bromospiro[cyclopropane-2, 1 '-indane]-1 -amine;

(-)-irans-Spiro[cyclopropane-2, 1 '-indane]-1 -amine;

(+)-irans-Spiro[cyclopropane-2, 1 '-indane]-1 -amine

or stereoisomers or pharmaceutically acceptable salts thereof. Preferably dihydrochloride, hydrochloride or hydrobromide salts thereof.

In another embodiment, the invention provides the compounds of general formula (I) for use as KDM1 inhibitors. In another embodiment, the invention provides the compounds of general formula (I) for the use in the treatment and/or prevention of cancer, infectious diseases or a disease characterized by aberration of cellular energy metabolism, such as obesity. Preferably, the compounds of general formula (I) are for the use in the treatment and/or prevention of leukemia, non-small cell lung cancer, hepatocellular carcinoma, or glioblastomas. Still preferably the glioblastomas are giant cell glioblastoma or gliosarcoma.

A further embodiment of the invention is a pharmaceutical composition comprising a compound of general formula (I), together with a pharmaceutically acceptable excipient and/or diluent. The pharmaceutical composition may further comprise at least one further therapeutic agent, preferably selected from the group consisting of histone deacetylase inhibitors, retinoid receptor modulators, anti-proliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, anti- angiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors, IGF1/insulin inhibitors or a chemotherapeutic agent.

The invention further provides a combination of the compound as defined above and a calorie restricted diet and/or a caloric restriction mimetic and/or at least one IGF1 /insulin inhibitor.

In the present invention a calorie restricted diet means that the daily caloric intake is reduced by 10 to 100% and lasts for a period of about 24 hours to about 190 hours. The reduction is compared to a regular caloric intake per day. Regular caloric intake per day is between 1200 Kcal and 3000 Kcal. Preferably regular caloric intake per day (the range is based on age, sex and physical activity) is:

Age 4-8 years : 1200-2000 Kcal

Age 9-13 years: 1800-2600 Kcal

Age 19-30 years: 1800-3000 Kcal

Age 31 -50 years: 1800-2600 Kcal

+51 years: 1600-2600 Kcal.

The IGF1/insulin inhibitor may be any known inhibitor, for instance as described in Clemmons DR, Nat. Rev. Drug Discov., 6, 821 -833, 2007, incorporated by reference. In a further embodiment, the invention provides compounds of general formula (I)

(I) wherein X, R and R are as defined above, provided that when R is hydrogen or halogen, then R is other than hydrogen.

In a preferred embodiment, the invention provides compounds of general formula (I) wherein aryl is phenyl.

In a further preferred embodiment, the invention provides compounds of general formula (I)

wherein

X is a bond, oxygen or CH ₂ ;

R is hydrogen, halogen, or R ² -L-;

R is hydrogen;

Ci-C ₆ alkyl;

Ci-C ₆ alkyl substituted by C ₃ -C ₆ cycloalkyl;

Ci-C6 alkyl substituted by phenyl or benzodioxinyl;

C-I -C6 alkyl substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, d-C-6 alkyl substituted by phenyl, or (CO)R ³ ;

C ₃ -C ₆ cycloalkyl optionally substituted by NH ₂ ;

heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyl;

or -CH ₂ (CO)NR ⁴ R ⁵ ;

R ² is phenyl, wherein the phenyl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, or Ci-C ₆ haloalkoxy L is a single bond; -(CH ₂ )m-Y-(CH ₂ )n-; or (CO)NR ⁶ -;

m, n are, independently, zero or 1 ;

Y is oxygen; R ³ is C-i-C-6 alkyl or phenyl;

R ⁴ , R ⁵ are, independently, hydrogen; C ₁ -C6 alkyl; or R ⁴ and R ⁵ together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR ⁷ ;

R ⁶ , R ⁷ are, independently, hydrogen; or Ci-C ₆ alkyl;

or stereoisomers or pharmaceutically acceptable salts thereof.

Particularly preferred compounds of general formula (I) include:

N-[£rans-2-aminospiro[cyclopropane-1 , 1 '-indane]-5'-yl]benzamide;

A/-[c/s-2-aminospiro[cyclopropane-1 , 1 '-indane]-5'-yl]benzamide;

A/-[irans-2-aminospiro[cyclopropane-1 ,3'-indane]-5'-yl]benzamide;

A/-[irans-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide;

A/-[c/s-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide;

irans-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

c/ ^' s-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine;

irans-5'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2 , 1 '-indane]-1 -amine;

c/ ^' s-5'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

c/s-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

irans-6'-bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2 , 1 '-indane]-1 -amine;

£rans-A/-benzylspiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

£rans-A/-benzylspiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-(cyclopropylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine;

£rans-A/-(2,3-dihydro-1 ,4-benzodioxin-6-ylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine; irans-A/-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

1 -methyl-A/-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]piperidin-4-amine;

A/-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]piperidin-4-amine;

8-methyl-A/-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]-8-azabicyclo[3.2.1 ]octan-3-amine; irans-A/4-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]cyclohexane-1 ,4-diamine;

c/s-A/4-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]cyclohexane-1 ,4-diamine;

N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]azetidin-3-amine;

1 -(4-methylpiperazin-1 -yl)-2-[[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]ethanone; 1 -[4-[[[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]-1 -piperidyl]ethanone; phenyl-[4-[[[trans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]-1 - piperidyl]methanone;

trans-N-[^ -benzyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-A/-[(1 -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]-1 -amine;

trans-N-[^ -isopropyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

trans-N-[^ -phenethyl-4-pipe dyl)methyl]spiro[cyclopropane-2, 1 '-indane]-1 -amine;

irans-N-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

£rans-A/4-[£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]cyclohexane-1 ,4-diamine;

c/s-A/4-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]cyclohexane-1 ,4-diamine;

trans-N-[^ -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine;

trans-N-[^ -phenethyl-4-pipe dyl)methyl]spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

trans-N-[^ -isopropyl-4-piperidyl)methyl]spiro[cyclopropane-2, 1 '-tetralin]-1 -amine;

1 -(4-methylpiperazin-1 -yl)-2-[[£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]amino]ethanone or stereoisomers or pharmaceutically acceptable salts thereof. Preferably dihydrochloride, hydrochloride or hydrobromide salts thereof.

In the instant invention, "aryl" represents a mono or bicyclic aromatic ring system of, respectively, 6, 9 or 10 atoms, examples of such an aryl are phenyl, indenyl, indanyl and naphthyl and tetrahydronaphthalenyl.

"Heteroaryl" represents a mono or bicyclic heteroaromatic ring system of, respectively, 5 to 10 members, which contains one, two, three or four heteroatoms selected from nitrogen, oxygen or sulphur and one to nine carbon atoms. Examples of said heteroaryls include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[£>]thienyl, benzopyranyl, indazolyl, benzimidazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, and quinoxalinyl.

"Heterocyclyl" represents a mono or bicyclic saturated or partially saturated non-aromatic ring system of, respectively, 4 to 12 members, which contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and three to eleven carbon atoms. Examples of such heterocycles include, but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxolyl, 2,3- dihydro-benzodioxinyl, benzoxazolyl, azepinyl, diazapinyl and tropinyl.

The "heterocyclic ring" represents a mono or bicyclic saturated or partially saturated non- aromatic ring system of, respectively, 4 to 10 members, which contains one nitrogen and optionally one or more heteroatoms selected from nitrogen, oxygen, and sulphur. Examples of such heterocycles include, but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, azepinyl, diazapinyl and tropinyl.

The term "halogen" refers to fluoro, chloro, bromo, or iodo.

The term "d-C-6 alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms. Suitable examples of Ci-C ₆ alkyl include methyl, ethyl, n-propyl, ispropyl, butyl, te/t-butyl, pentyl, and hexyl.

The term "C-3-6 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms. Suitable examples of C-3-6-cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "C-i-C-6 alkoxy" refers to a straight or branched O-C1 -C6 alkyl, where alkyl is as defined herein. The "C1 -C6 alkoxy" group is preferably a linear or branched Ci-C ₄ alkoxy group, more preferably a C1 -C2 alkoxy group.

The term "C1 -C6 haloalkyi" refers to a straight or branched hydrocarbon chain radical, which is substituted by one or more halogen atoms and having from one to six carbon atoms. The "C1 -C6 haloalkyi" group is preferably a linear or branched Ci-C ₄ haloalkyi group, more preferably a C1 -C2 haloalkyi group, being in particular CF ₃ .

The term "C-i-C-6 haloalkoxy" refers to a straight or branched O-C-i-C-6 haloalkyi, where haloalkyi is as defined herein. The "C-i-C-6 haloalkoxy" group is preferably a linear or branched Ci-C haloalkoxy group, more preferably a C1 -C2 haloalkoxy group, being in particular OCF ₃ , OCHF ₂ or OCH ₂ F.

Pharmaceutically acceptable salts comprise conventional non-toxic salts obtained by salification of a compound of formula (I) with inorganic acids (e.g. hydrochloric, hydrobromic, sulphuric, or phosphoric acids), or with organic acids (e.g. acetic, propionic, succinic, benzoic, cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, maleic, malonic, fumaric, tartaric, citric, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or naphthalensulfonic acids). For reviews on suitable pharmaceutical salts see Berge S. M. et al., J. Pharm. Sci. 1977, 66, 1 -19; Gould P. L. Int. J. Pharm 1986, 33, 201 -217; and Bighley et al. Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497. Other salts, which are not pharmaceutically acceptable, for example the trifluoroacetate salt, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).

In addition, the compounds of formula (I) may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, EtOH and the like.

Compounds of formula (I) contain two or more asymmetric carbon atoms. The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.

Likewise, it is understood that compounds of the invention may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³ H or ¹⁴ C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated ³ H, and carbon-14 ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.

Compounds of general formula (I), wherein R is hydrogen may be prepared according to Scheme A:

A5 A6

Scheme A

wherein R and X are as defined above for fomula (I); PG and PG ¹ are protecting groups chosen among those known in the art. Examples of a suitable protecting group for PG may include methyl, ethyl etc. and examples for PG ¹ may include a carbamate, for instance (1 ,3-benzodioxol-5-ylmethylamino)carbamate or (2- trimethylsilylethylamino)carbamate.

Compounds of formula A1 are known compounds or can be prepared by known methods, e.g. in case where R is R ² -L, wherein R ² is as defined above and L is (CH ₂ ) _p (CO)NR ⁶ - with p and R ⁶ as defined above, by reacting a compound of formula A1 , wherein R is NH ₂ with a compound R ² -CO-W, wherein W is a halogen atom, e.g. chloride or bromide in presence of a suitable base, for instance triethylamine (TEA), in an appropriate solvent, for example in tetrahydrofuran (THF) or toluene, at a temperature ranging from 0°C to the boiling point of the solvent.

Compounds of formula A2 can be obtained by reacting triphenylmethylphosphonium bromide with a compound of formula A1 in presence of a suitable base, for instance potassium te/t-butoxide, in a suitable solvent, for instance THF or toluene, at a temperature ranging from 0°C to the boiling point of the solvent. Preferably, the reaction is carried out under nitrogen atmosphere.

A compound of formula A3 can be obtained by treating a compound of formula A2 with ethyl diazoacetate in presence of a suitable catalyst, which can be a Rh(ll) or copper based catalyst such as rhodium acetate, in a suitable solvent, for instance dichloromethane (DCM), at a temperature ranging from RT to the boiling point of the solvent. Preferably, the reaction is carried out under nitrogen atmosphere.

A compound of formula A4 can be obtained according to known methods, e.g. when the compound of formula A3 is a methyl or ethyl ester, by treatment of an ethyl ester with LiOH, NaOH or KOH in a suitable solvent, for example in ethanol/water, in THF ethanol/water, in methanol/water, or in a dioxane/ethanol/water mixture. The hydrolysis may be carried out at a temperature ranging from 0°C to the boiling point of the solvent. The isocyanate compounds of formula A5 can be prepared by reacting a carboxylic acid of formula A4 with [azido(phenoxy)phosphoryl]oxybenzene in presence of a suitable base, for instance TEA, in a suitable solvent, for instance toluene, at a temperature ranging from 0°C to the boiling point of the solvent. Preferably, the reaction is carried out under nitrogen atmosphere.

The isocyanate of formula A5 can be converted into a protected amine A6 by reacting with a suitable alcohol, for instance benzyl alcohol, 1 ,3-benzodioxol-5-ylmethanol or 2- trimethylsilylethanol, in in a suitable solvent, for instance toluene or THF, at a temperature ranging from RT to the boiling point of the solvent, forming a carbamate derivative. Optionally the reaction may be carried out under microwave irradiation and a suitable base, such as TEA, may be added. Preferably, the reaction is carried out under nitrogen atmosphere.

The protected amine A6, wherein X and PG is a defined above, and R is bromide or iodide, can be converted into a protected amine A6, wherein R is R ² -(CH ₂ ) _p (CO)NR ⁶ and R ² , p and R ⁶ as defined above, according to the Ullmann or the Buchwald-Hartwig type reaction. In case of the Ullmann reaction a compound of formula A6 is treated with a compound of formula R ² -(CH ₂ ) _P (CO)NR ⁶ -H in presence of a copper catalyst, for instance Cul, and a base, for example K ₂ CO ₃ , N,W-dimethylethane-1 ,2-diamine or 2-aminoethanol, in a suitable solvent, for example in dimethylacetamide or dioxane, at temperature ranging from room temperature to the boiling point of the solvent. Optionally the reaction may be carried out under microwave irradiation. Preferably, the reaction is carried out under nitrogen atmosphere. In case of the Buchwald-Hartwig type reaction a compound of formula A6 is treated with a compound of formula R ² -(CH ₂ ) _p (CO)NR ⁶ -H in presence of a catalyst, for instance palladium or a palladium salt, for example palladium (II) acetate and tris(dibenzylideneacetone)dipalladium(0), and a phosphine ligand, for instance triphenylphosphine, tri(o-tolyl)phosphine, 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl) (BINAP), and a base, for example C-S2CO3, in a suitable solvent, for example dioxane, toluene or THF, at temperature ranging from room temperature to the boiling point of the solvent. Optionally the reaction may be carried out under microwave irradiation. Preferably, the reaction is carried out under nitrogen atmosphere.

In case the protected amine A6 is a carbamate, the carbamate may be hydrolysed providing a compound of formula (I) by reaction with an acid, for instance hydrobromic acid (HBr) or hydrochloric acid (HCI), in a suitable solvent, for instance acetic acid, THF or diethylether (Et ₂ O), at a temperature ranging from 0°C to the boiling point of the solvent. Alternatively, a compound of formula A5 can be treated with an acid, for instance hydrobromic acid (HBr) or hydrochloric acid (HCI), in a suitable solvent, for instance acetic acid, THF or Et ₂ O, at a temperature ranging from 0°C to the boiling point of the solvent providing a compound of formula (I).

Compounds of general formula (I), wherein R is Ci-C ₆ alkyl; d-C ₆ alkyl substituted by C ₃ - C6 cycloalkyl; C ₁ -C6 alkyl substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, OH and NH ₂ ; C ₁ -C6 alkyl substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkyl substituted by aryl, aryl, or (CO)R ³ _; C ₃ -C ₆ cycloalkyl optionally substituted by NH ₂ ; heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkyl substituted by aryl; or -CH ₂ (CO)NR ⁴ R ⁵ ; and wherein R ³ , R ⁴ and R ⁵ are as defined for formula (I), may be prepared according to Scheme B:

B1 B3 (I)

Scheme B

wherein R and X are as defined above for fomula (I); R ⁸ is d-C-6 alkyi; d-C-6 alkyi substituted by C ₃ -C ₆ cycloalkyl; Ci-C ₆ alkyi substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyi, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, C-I -C6 haloalkoxy, OH and NH ₂ ; C-i-C-6 alkyi substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyi, C-i-C-6 alkyi substituted by aryl, aryl, or COR ³ ; C ₃ -C ₆ cycloalkyl optionally substituted by NH ₂ ; heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C ₁ -C6 alkyi, Ci-C ₆ alkyi substituted by aryl; or -CH ₂ (CO)NR ⁴ R ⁵ ; W is a halogen atom, e.g. chloride or bromide; R ⁹ is C ₁ -C5 alkyi; C ₁ -C5 alkyi substituted by C ₃ -C ₆ cycloalkyl; C ₁ -C5 alkyi substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C ₆ alkyi, Ci-C ₆ alkoxy, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, OH and NH ₂ ; C-i- C5 alkyi substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C ₁ -C6 alkyi, Ci-C ₆ alkyi substituted by aryl, aryl, or COR ³ ; R ⁰ is hydrogen or R ⁹ and R ⁰ form together with the carbon atom to which they are bound a C ₃ -C6 cycloalkyl optionally substituted by NH ₂ ; or R ⁹ and R ⁰ form together with the carbon atom to which they are bound a heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of Ci-C ₆ alkyl, Ci-C ₆ alkyl substituted by aryl.

Reaction of a compound of formula B1 with a compound of formula R ⁸ -W (B2) can be carried in a suitable solvent (e.g. DMF) in the presence of a suitable base (e.g. NaH). The reaction may be carried out at a temperature between 0°C to the boiling point of the solvent. In the case it is necessary to protect the cyclopropylamino group, said chemical group may be protected and deprotected according to known methods (e.g. a protecting group is a te/t-butyloxycarbonyl group). Alternatively, compounds of general formula (I), wherein R is other than hydrogen or -CH ₂ (CO)NR ⁴ R ⁵ may be prepared according to Scheme B by reaction of a compound of formula B1 with a compound of formula R ⁹ -CO- R ⁰ (B3), preferably under nitrogen atmosphere, in a suitable organic solvent (e.g. dichloroethane, CH ₂ CI ₂ , MeOH, EtOH, DMF or tetrahydrofuran) at a temperature between about 0°C and 70°C in the presence of a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. Compounds of formula B1 may be for example prepared according to Scheme A.

In the case it is necessary to protect a chemical group of a compound of the present invention and/or an intermediate thereof, before carrying out one of the aforedescribed reactions, said chemical group may be protected and deprotected according to known methods. A thorough discussion for suitable protecting groups and the means for protection/deprotection steps can be found for example in Greene and Wuts (Greene, T.W.; Wuts, P.G.M. "Protective Groups in Organic Synthesis", John Wiley & Sons Inc., 1991 ) or in Kocienski (Kocienski, P.J. "Protecting Groups", George Thieme Verlag, 1994). Salification of the compounds of formula (I), and preparation of compounds of formula (I), free of their salts, may be carried out by known conventional methods.

In view of the above described mechanisms of action, the compounds of the present invention are useful in the prevention or treatment of tumor type diseases, including but not limited to: acute and chronic myeloid leukaemia, acute and chronic lymphoblastic leukaemia, myelodysplastic syndromes, multiple myeloma, Hodgkin's disease, non- Hodgkin's lymphomas, cutaneous and peripheral T-cell lymphoma, adult T-cell leukemia, large B-cell lymphoma; mammary tumors; pulmonary tumors and pleural mesotheliomas, adenocarcinoma, non-small lung cancer, small-cell lung cancer; skin tumors including basal cell carcinomas (basaliomas), melanomas, squamous cell carcinoma, Kaposi's sarcoma, keratocanthomas; osteosarcomas, fibrosarcomas, rhabdomyosarcomas, neuroblastomas, glioblastomas, cerebral tumors, head and neck cancer, testicular and ovarian tumors, cervical carcinoma, endometrial and prostate tumors (for example advanced prostate cancer), thyroid carcinomas (for example tyroid follicular cancer), colon cancers (for example colon adenocarcinoma, colon adenoma), gastric tumors and gastrointestinal adenocarcinomas, hepatocellular carcinomas, pancreatic carcinomas (for example exocrine pancreatic carcinoma), renal tumors, teratocarcinomas and embryonic carcinomas.

The compounds of the invention are also useful in the prevention or treatment of infections, including, but not limited to, infections caused by protozoa, fungi, phytotoxic agents, viruses and parasites, for example HIV or herpes virus infections.

Considering the role of KDM1A in the regulation of cellular energy expenditure in the adypocites as well as the direct relation between KDM1A function and its target genes in adipose tissue of high fat diet mice, the compounds of the invention are also useful in the prevention or treatment of diseases characterized by aberration of cellular energy metabolism, such as obesity (Hino S. et al. Nat Commun. 2012, doi: 10.1038/ncomms1755).

The compounds of formula (I) can also be used in combination with additional agents, in particular anti-tumor and differentiating agents, either by separate administrations, or by including the two active principles in the same pharmaceutical formulation. Non- exhaustive examples of suitable additional agents include:

a) histone deacetylase inhibitors (for example, but not limited to SAHA, PXD101 , JNJ- 26481585, SB939, ITF-2357, LBH589, PCI-24781 , valproic acid, butyric acid, MS-275, MGCD0103 and FK-228);

b) retinoid receptor modulators such as 13-c/s-retinoic acid, 9-c/s-retinoic acid, bexarotene, alitretinoin, or tretinoin; vitamin D;

c) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example platin derivatives like c/s-platin, carboplatin, oxaliplatin, lobaplatin, satraplatin, nedaplatin, heptaplatin; nitrogen mustard such as chlorambucil, melphalan, chlormethine, cyclophosphamide, ifosfamide, trofosfamide, uramustine, bendamustine, estramustine; busulphan, temozolomide or nitrosoureas); antimetabolites (for example antifolates such as aminopterin, methotrexate, pemetrexed, raltitrexed); purines such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine; pyrimidines like capecitabine, cytarabine, fluorouracil, floxuridine, gemcitabine; azacitidine, decitabine; cytosine arabinoside or hydroxyurea; antitumour antibiotics (for example anthracyclines like aclarubicin, amrubicin, daunomycin, doxorubicin, epirubicin, idarabicin, valrubicin, zorubicine; mitoxantrone; or antibiotics from streptomyces like actinomycin, bleomycin, mitomycin, or plicamycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine or vinorelbine; taxoids like docetaxel, paclitaxel or tesetaxel; epothilones like ixabepilone) and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide; amsacrine, camptothecin, irinotecan, rubitecan, and topotecan);

d) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, liarozole or cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha-reductase such as finasteride;

e) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function);

f) inhibitors of growth factor function, for example growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibodies figitumumab (CP- 751 ,871 ), cixutumumab (IMC-A12), dalotuzumab (MK-0646; h7C10), ganitumab (AMG 479), R1507 and MEDI-573 (IGF1 -IFG2)), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors (for example the tyrosine kinase inhibitors against IGF-1 R linsitinib (OSI-906), BMS-754807, BVP 51004, or XL228) and serine/threonine kinase inhibitors, for example enzastaurin, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib, everolimus, sirolimus or temsirolimus;

g) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab, lenalidomide or thalidomide;

h) cell cycle inhibitors including for example CDK inhibitors (for example but not limited to flavopiridol, roscovitine) and other inhibitors of cell cycle checkpoints; inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation;

i) proteasome inhibitors (for example lactacystin, bortezomib, epoxomicin);

j) HSP90 inhibitors (for example but not limited to AT-13387, KOS-953, KOS-1022, CNF-1010, CNF-2024, SNX 5422, STA-9090, NVP-HSP990, NVP-AUY922, PU-H17 and XL -888)

k) Selective COX-2 inhibitors (for example celecoxib), or non selective NSAIDs (for example diclofenac, flurbiprofen, ibuprofen, ketoprofen, or naproxen).

In another aspect, a compound of general formula (I) can be used in combination with radiation therapy. In yet another aspect, a compound of general formula (I) may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

The invention also provides pharmaceutical compositions comprising one or more compounds of formula (I) and one or more pharmaceutically acceptable excipient and/or diluent. The pharmaceutical compositions can be chosen on the basis of the treatment requirements. Such compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable, or infusible liquid solutions, suspensions, or suppositories.

Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).

The oral solid compositions can be prepared by conventional methods of blending, filling or tableting. The blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers. Such operations are conventional. Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents. Oral formulations also include conventional slow-release formulations such as enterically coated tablets or granules.

Pharmaceutical preparation for administration by inhalation can be delivered from an insufflator or a nebulizer pressurized pack.

For parenteral administration fluid unit dosages can be prepared, containing the compound and a sterile vehicle. The compound can be either suspended or dissolved, depending on the vehicle and concentration. The parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilising by filtration, filling suitable vials and sealing. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle. To increase the stability, the composition can be frozen after having filled the vials and removed the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the invention.

For buccal or sublingual administration the compositions may be tablets, lozenges, pastilles, or gel.

The compounds can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.

Another means of administering the compounds of the invention regards topical treatment. Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres. Examples of ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights. Creams, as known to formulation experts, are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol. Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.

A further method of administering the compounds of the invention regards transdermal delivery. Typical transdermal formulations comprise conventional aqueous and non- aqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches.

A reference for the formulations is the book by Remington ("Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins, 2000).

The compounds of the present invention may be employed alone as a sole therapy or in combination with other therapeutic agents (see the list of additional agents is as indicated previously and comprises also standard chemotherapeutic agents) for the treatment of the above-mentioned conditions. The combination can be administered as separate compositions (simultaneous, sequential) of the individual components of the treatment or as a single dosage form containing both agents. When the compounds of this invention are in combination with others active ingredients, the active ingredients may be separately formulated into single-ingredient preparations of one of the above-described forms and then provided as combined preparations, which are given at the same time or different times, or may be formulated together into a two- or more- ingredient preparation.

Compounds of general formula (I) may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The determination of optimum dosages for a particular patient is well known to one skilled in the art.

As is common practice, the compositions are normally accompanied by written or printed instructions for use in the treatment in question.

The following non limiting examples and biological data are presented and reference to the following figures is made in order to further illustrate the invention.

1. CHEMICAL SYNTHESIS

Unless otherwise indicated, commercially available reagents and solvents (HPLC grade) were used without further purification.

Specifically, the following abbreviations may have been used in the descriptions of the experimental methods:

NMR (Nuclear Magnetic Resonance) ¹ H (proton)

MHz (Megahertz) Hz (Hertz)

HPLC (High Performance Liquid LC-MS (Liquid Chromatography Mass

Chromatography) Spectrum)

s (seconds) min (minutes) h (hours) mg (milligrams)

g (grams) it (microlitres)

ml (millilitres) mmol (millimoles) nm (nanometers) μΜ (micromolar)

M (molarity) r.t. (room temperature)

ACN (acetonitrile) AcOH (acetic acid)

BOC or boc (te/t-butyloxycarbonyl) (BOC) ₂ 0 (di-tert-butyl dicarbonate)

Cul (cuprous iodide) DCE (dichloroethane)

DCM (dichloromethane) D ₂ 0 (deuterium oxide)

DIPEA (A/,A/-diisopropylethylamine) DMF (dimethylformamide)

DMSO-de (deuterated dimethyl

DMSO (dimethyl sulfoxide)

sulfoxide)

Et ₂ 0 (diethyl ether) EtOAc (ethyl acetate)

EtOH (ethanol) HBr (hydrobromic acid)

HCI (hydrochloric acid) iPr ₂ 0 (diisopropyl ether) K ₂ C0 ₃ (potassium carbonate) LiOH (lithium hydroxide)

MAO A (monoamine oxidase A) MAO B (monoamine oxidase B)

MeOH (methanol) NaBH ₄ (sodium borohydride)

NaBH(OAc) ₃ (sodium

NaCI (sodium chloride)

triacetoxyborohydride)

NaH (sodium hydride) NaHCO ₃ (sodium bicarbonate)

NaOH (sodium hydroxide) Na ₂ SO (sodium sulphate)

NH ₄ CI (ammonium chloride) NH ₄ OH (ammonium hydroxide)

NOE (Nuclear Overhauser Effect) TEA (triethylamine)

Xantphos (4,5-bis(diphenylphosphino)-

THF (tetrahydrofuran)

9,9-dimethyl-9H-xanthene)

Except where indicated otherwise, all temperatures are expressed in °C (degrees centigrade).

The ¹ H-NMR spectra were acquired with a Varian 500 MHz instrument. The chemical shifts are expressed in parts per million (ppm, δ units). The coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).

The LC-MS analyses were carried out on a Waters Acquity UPLC or Waters Acquity UPLC H-Class linked to with a SQD Single quadrupole (Waters) using an Acquity UPLC BEH C18 (50 x 2.1 mm, 1.7 μηι) or Acquity UPLC HSS T3 (50 x 2.1 mm, 1 .8 μηι) column. Phase A was composed by either Milli-Q water/CH ₃ CN 95/5 + 0.07% formic acid or Milli-Q water + 0.07% formic acid; Phase B by CH ₃ CN + 0.05% formic acid; flow rate: 0.6 mL/min; UV detection (DIODE array) from 210 to 400 nm; ESI+ detection in the 100-2000 m/z range. The structure of all intermediates and final products was confirmed by NMR and LC-MS analysis. The yields were calculated assuming that products were 100% pure if not stated otherwise.

Intermediate 1 : A -(4-oxotetralin-6-yl)benzamide

2.00 g (1 1.8mmol) of 7-aminotetralin-1 -one (ENAMINE-BB, Cat No. EN300-99961 ) was dissolved in 45 ml of dry THF and 1.8 ml (13 mmol) of TEA was added. The mixture was chilled to 0°C and 1.5 ml (13 mmol) benzoyl chloride was added dropwise with a THF rinse (5 ml). The mixture was stirred at r.t. for 5 h. The mixture was evaporated. The residue was taken up in DCM and extracted with 0.5 M HCI, water, NaHC0 ₃ acq. satd. and brine. The organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was crystallized from EtOH at reflux. The separated solid was filtered, portionwise rinsed with mother liquor then rinsed with EtOH. A light-brown solid was obtained (2.21 g, 70.5%). ¹ H NMR (CDCI ₃ ) δ (ppm): 8.29 (dd, J = 8.31 , 1.96 Hz, 1 H), 8.13 (bs, 1 H), 7.89 - 7.95 (m, 3 H), 7.48 - 7.61 (m, 3 H), 7.32 (d, J = 8.31 Hz, 1 H), 2.97 (m, 2 H), 2.62 - 2.70 (m, 2 H), 2.09 - 2.21 (m, 2 H); MS (ESI): m/z: 266 [M+H] ⁺ Intermediate 2: 1 -methyleneindane

12.39 g (104.9 mmol) of potassium te/t-butoxide in 105 ml of THF was added under nitrogen over 2 h to a suspension of 7.00 g (52.4 mmol) of indan-1 -one and 38.23 g (104.9 mmol) of triphenylmethylphosphonium bromide in 200 ml of THF. The resulting mixture was stirred at r.t. for 3 h after addition. The reaction was concentrated and resuspended in hexane. The mixture was passed through a silica gel plug and rinsed with hexane. Removal of the solvent gave the 1 -methyleneindane as a yellow oil (6.49 g, 95%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.57 - 7.52 (m, 1 H), 7.32 - 7.26 (m, 1 H), 7.26 - 7.16 (m, 2 H), 5.49 (m, 1 H), 5.02 (m, 1 H), 2.96 - 2.88 (m, 2 H), 2.73 (m, 2 H). Intermediate 3: 5-bromo-1 -methylene-indane

4.1 g (85%) of 5-bromo-1 -methylene-indane was prepared according to the procedure described for Intermediate 2, starting from 5.00 g (23.2 mmol) of 5-bromoindan-1 -one (FLUROCHEM, Cat No. 001726). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.28 - 7.43 (m, 3 H), 5.45 (m, 1 H), 5.06 (m, 1 H), 2.92 - 3.02 (m, 2 H), 2.77 - 2.85 (m, 2 H).

Intermediate 4: 6-bromo-1 -methylene-indane

1.56 g (79.0%) of 6-bromo-1 -methylene-indane was prepared according to the procedure described for Intermediate 2, starting from 2.000 g (9.476 mmol) of 6-bromoindan-1 -one (FLUROCHEM, Cat No. 037027). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.61 (m, 1 H), 7.34 - 7.30 (m, 1 H), 7.13 (m, 1 H), 5.44 (m, 1 H), 5.08 (m, 1 H), 2.96 - 2.91 (m, 2 H), 2.85 - 2.80 (m, 2 H). Intermediate s: 1 -methylenetetralin

3.85 g (quantitative) of 1 -methylenetetralin was prepared according to the procedure described for Intermediate 2, starting from 4.00 g (26.54 mmol) of tetralin-1 -one. ¹ H NMR (DMSO-de) δ (ppm): 7.64 - 7.69 (m, 1 H), 7.09 - 7.20 (m, 3 H), 5.52 (s, 1 H), 4.95 (s, 1 H), 2.79 (m, 2 H), 2.45 - 2.53 (m, 2 H), 1.74 - 1.82 (m, 2 H).

Intermediate 6: /V-(4-methylenetetralin-6-yl)benzamide

1.069 g (9.046 mmol) of potassium te/t-butoxide was added portionwise under nitrogen to a suspension of 3.297 g (9.046 mmol) of triphenylmethylphosphonium bromide in 20 ml toluene, and the mixture was stirred at r.t. for 4 h. 1.20 g (4.52 mmol) of N-(4-oxotetralin-6- yl)benzamide (Intermediate 1 ) in 50 ml of toluene was added dropwise to the resulting yellow mixture, which was stirred at r.t overnight, then neutralized with saturated aqueous NH ₄ CI and diluted with Et ₂ 0. The organic phase was separated, and the aqueous layer was extracted with Et.20. The combined organic phases were washed with brine, dried and concentrated under vacuum. The residue was purified by flash chromatography (eluent: hexane/EtOAc 8:2) to afford A/-(4-methylenetetralin-6-yl)benzamide as a white solid (694 mg, 58%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.17 (s, 1 H), 8.06 (m, 1 H), 7.96 (m, 2 H), 7.64 (m, 1 H), 7.58 (m, 1 H), 7.50 - 7.56 (m, 2 H), 7.10 (d, J = 8.31 Hz, 1 H), 5.44 (s, 1 H), 4.99 (s, 1 H), 2.77 (m, 2 H), 1 .72 - 1.84 (m, 2 H); MS (ESI): m/z: 264 [M+H] ⁺ . Intermediate 7: Ethyl spiro[cyclopropane-2,1'-indane]-1 -carboxylate

4.91 ml (37.3 mmol) of ethyl diazoacetate in 5 ml of DCM was added under nitrogen via syringe pump over 5 h ca. to a solution of 3.24 g (24.9 mmol) of 1 -methyleneindane (Intermediate 2) and 0.1 1 g (0.25 mmol) of rhodium acetate dimer in 160 ml of refluxing DCM. The resulting mixture was stirred at 45°C for 1 h and then at r.t. for 1 h and then concentrated, the crude product was purified by flash chromatography (eluent: hexane/EtOAc from 100:1 to 97:3) to afford ethyl spiro[cyclopropane-2,1 '-indane]-1 - carboxylate as a colorless oil (3.51 g, 65%). The obtained ethyl spiro[cyclopropane-2,1 '- indane]-1 -carboxylate is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.25 - 7.10 (m, 7 H), 6.75 - 6.69 (m, 1 H), 4.18 (q, J = 7.3 Hz, 2 H), 4.08 - 3.91 (m, 2 H), 3.17 - 3.09 (m, 1 H), 3.09 - 2.96 (m, 2 H), 2.95 - 2.87 (m, 1 H), 2.43 - 2.35 (m, 1 H), 2.34 - 2.22 (m, 2 H), 2.13 - 2.08 (m, 1 H), 2.06 - 2.01 (m, 1 H), 1 .96 - 1.91 (m, 1 H), 1.90 - 1.87 (m, 1 H), 1 .69 - 1.65 (m, 1 H), 1.46 - 1.39 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.13 (t, 3 H); MS (ESI): m/z: 217 [M+H] ⁺ .

Intermediate 8: Ethyl 5'-bromospiro[cyclopropane-2,1'-indane]-1 -carboxylate

0.614 g (78.5%) of ethyl 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.555 g (2.65 mmol) of 5-bromo-1 -methylene-indane (Intermediate 3). The obtained ethyl 5'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of the two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.37 - 7.33 (m, 2 H), 7.29 - 7.21 (m, 2 H), 7.08 (d, J = 7.8 Hz, 1 H), 6.58 (d, J = 7.8 Hz, 1 H), 4.24 - 4.12 (m, 2 H), 4.09 - 3.91 (m, 2 H), 3.16 - 2.84 (m, 4 H), 2.45 - 2.35 (m, 1 H), 2.34 - 2.22 (m, 2 H), 2.13 - 2.07 (m, 1 H), 2.03 - 1.96 (m, 1 H), 1 .95 - 1.88 (m, 1 H), 1.87 - 1.82 (m, 1 H), 1.69 - 1.64 (m, 1 H), 1.46 - 1.37 (m, 2 H), 1.30 (t, J = 7.3 Hz, 3 H), 1.15 (t, J = 7.1 Hz, 3 H); MS (ESI): m/z: 295 [M+H] ⁺ .

Intermediate 9: Ethyl 6'-bromospiro[cyclopropane-2,1'-indane]-1 -carboxylate

0.972 g (69%) of ethyl 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 1.00 g (4.78 mmol) of 6-bromo-1 -methylene-indane (Intermediate 4). The obtained ethyl 6'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.35 - 7.32 (m, 1 H), 7.30 - 7.25 (m, 2 H), 7.1 1 - 7.05 (m, 2 H), 6.84 - 6.80 (m, 1 H), 4.21 - 4.14 (m, 2 H), 4.1 1 - 3.96 (m, 2 H), 3.09 - 2.90 (m, 3 H), 2.90 - 2.80 (m, 1 H), 2.44 - 2.23 (m, 3 H), 2.14 - 2.10 (m, 1 H), 2.05 - 1.99 (m, 1 H), 1 .94 - 1.90 (m, 1 H), 1.88 - 1.81 (m, 1 H), 1.70 - 1.64 (m, 1 H), 1.46 - 1.38 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H); MS (ESI): m/z: 295 [M+H] ⁺ .

Intermediate 10: Ethyl 7'-benzamidospiro[cyclopropane-2,1'-tetralin]-1 -carboxylate

0.400 g (44%) of ethyl 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.690 g (2.62 mmol) of A/-(4-methylenetetralin-6-yl)benzamide (Intermediate 6). The obtained ethyl 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.92 - 7.79 (m, 5 H), 7.71 (m, 2 H), 7.60 - 7.45 (m, 6 H), 7.30 - 7.23 (m, 1 H), 7.21 - 7.05 (m, 4 H), 4.21 - 4.10 (m, 2 H), 3.95 - 3.82 (m, 2 H), 2.97 - 2.81 (m, 4 H), 2.21 - 1.69 (m, 10 H), 1.68 - 1.54 (m, 2 H), 1.36 - 1.20 (m, 5 H), 1.01 (t, J = 7.1 Hz, 3 H); MS (ESI): m/z: 350 [M+H] ⁺ .

Intermediate 11 : Ethyl frans-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate

1.26 g (39%) of ethyl £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 2.00 g (13.9 mmol) of 1 -methylenetetralin (Intermediate 5). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form. These isomers were separated by flash chromatography (eluent: hexane/EtOAc from 100:1 to 95:5). The cis and trans isomers were determined by NMR (NOE) analysis. ¹ H NMR (CDCI ₃ ) δ (ppm): 7.17 - 7.05 (m, 3 H), 6.77 - 6.69 (m, 1 H), 4.25 - 4.09 (m, 2 H), 2.96 - 2.83 (m, 2 H), 2.03 - 1.92 (m, 2 H), 1.91 - 1.70 (m, 3 H), 1.64 - 1.54 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (ESI): m/z: 231 [M+H] ⁺ .

Intermediate 12: Ethyl c/s-spiro[cyclopropane-2,1'-tetralin]-1 -carboxylate

1.17 g (36%) of ethyl c/s-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 2.00 g (13.9 mmol) of 1 -methylenetetralin (Intermediate 5). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form. These isomers were separated by flash chromatography (eluent: hexane/EtOAc from 100:1 to 95:5). The cis and trans isomers were determined by NMR (NOE) analysis. ¹ H NMR (CDCI ₃ ) δ (ppm): 7.19 - 7.03 (m, 4 H), 3.86 (q, J=J=6.8 Hz, 2 H), 2.99 - 2.82 (m, 2 H), 2.20 - 1.88 (m, 4 H), 1.87 - 1.80 (m, 1 H), 1 .29 - 1.21 (m, 2 H), 0.97 (t, J=J=7A Hz, 3 H); MS (ESI): m/z: 231 [M+H] ⁺ .

Intermediate 13: Spiro[cyclopropane-2,1'-indane]-1 -carboxylic acid

0.934 g (39.0 mmol) of LiOH was added at r.t. to a mixture of 7.028 g (32.49 mmol) of ethyl spiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 7) in H ₂ O/THF/EtOH (120 ml:40 ml: 120 ml), and the reaction mixture was then heated at 65°C and stirred for 18 h. THF was evaporated and the reaction was cooled in an ice bath. 2 M HCI was added dropwise until reaching pH 1 -2. EtOH was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried and evaporated. The product was purified by flash chromatography (eluent: DCM/MeOH from 100:1 to 95:5) to afford spiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid as a light-yellow oil (5.53 g, 90.5%). Spiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid obtained is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.26 - 7.10 (m, 7 H), 6.75 - 6.70 (m, 1 H), 3.18 - 3.09 (m, 1 H), 3.09 - 2.99 (m, 2 H), 2.95 - 2.88 (m, 1 H), 2.46 - 2.38 (m, 1 H), 2.38 - 2.32 (m, 1 H), 2.31 - 2.23 (m, 1 H), 2.13 (m, 1 H), 2.03 (m, 1 H), 1.96 - 1.89 (m, 2 H), 1.71 - 1.66 (m, 1 H), 1.54 - 1.47 (m, 2 H); MS (ESI): m/z: 187 [M-H] ^" .

Intermediate 14: 5'-Bromospiro[cyclopropane-2,1'-indane]-1 -carboxylic acid

0.585 g (81 %) of 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.800 g (2.71 mmol) of ethyl 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 8). The obtained 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.37 (s, 1 H), 7.35 (s, 1 H), 7.25 - 7.32 (m, 1 H), 7.24 (d, J=8.31 Hz, 1 H), 7.04 (d, J=8.31 Hz, 1 H), 6.59 (d, J = 8.31 Hz, 1 H), 3.04 - 3.17 (m, 1 H), 2.95 - 3.1 1 (m, 2 H), 2.88 (m, 1 H), 2.42 (m, 1 H), 2.23 - 2.45 (m, 2 H), 2.07 - 2.15 (m, 1 H), 2.02 (m, 1 H), 1.81 - 1.96 (m, 2 H), 1.71 (m, 1 H), 1.50 (m, 1 H), 1.49 (m, 1 H); MS (ESI): m/z: 265 [M-H] ^" .

Intermediate 15: 6'-Bromospiro[cyclopropane-2,1'-indane]-1 -carboxylic acid

0.712 g (83%) of 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.950 g (3.22 mmol) of ethyl 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 9). The obtained 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 12.36 - 12.19 (m, 1 H), 12.17 - 12.00 (m, 1 H), 7.34 - 7.27 (m, 2 H), 7.24 - 7.20 (m, 1 H), 7.19 - 7.13 (m, 2 H), 7.13 - 7.09 (m, 1 H), 2.98 - 2.79 (m, 4 H), 2.33 - 2.24 (m, 1 H), 2.12 - 2.10 (m, 3 H), 2.00 - 1.95 (m, 2 H), 1 .68 - 1.62 (m, 1 H), 1 .50 - 1.46 (m, 1 H), 1.45 - 1.38 (m, 2 H); MS (ESI): m/z: 265 [M-H] ^" .

Intermediate 16: 7'-Benzamidospiro[cyclopropane-2,1'-tetralin]-1 -carboxylic acid

0.205 g (56%) of 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.397 g (1.14 mmol) of ethyl 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate (Intermediate 10). The obtained 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.80 - 7.91 (m, 4 H), 7.75 (s, 1 H), 7.65 (m, , 1 H), 7.43 - 7.59 (m, 5 H), 7.26 (m, 1 H), 7.05 - 7.19 (m, 4 H), 2.81 - 2.97 (m, 4 H), 1.83 - 2.18 (m, 9 H), 1.67 - 1.83 (m, 2 H), 1.57 (m, 1 H), 1.35 (m, 1 H), 1.20 - 1.29 (m, 1 H); MS (ESI): m/z: 322 [M+H] ⁺ .

Intermediate 17: frans-Spiro[cyclopropane-2,1'-tetralin]-1 -carboxylic acid

0.373 g (88%) of £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.482 g (2.09 mmol) of ethyl £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate (Intermediate 11 ). ¹ H NMR (CDCI3) δ (ppm): 7.06 - 7.18 (m, 3 H), 6.70 - 6.78 (m, 1 H), 2.86 - 2.95 (m, 2 H), 1.95 - 2.1 1 (m, 3 H), 1.75 - 1.95 (m, 2 H), 1.70 (m, 1 H), 1.54 - 1.63 (m, 1 H); MS (ESI): m/z: 201 [M-H]-.

Intermediate 18: c/s-Spiro[cyclopropane-2,1'-tetralin]-1 -carboxylic acid

0.226 g (56%) of c/ ^' s-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.459 g (1.99 mmol) of ethyl c/s-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylate (Intermediate 12). ¹ H NMR (CDCIs) δ (ppm): 7.03 - 7.16 (m, 4 H), 2.83 - 2.99 (m, 2 H), 1.99 - 2.20 (m, 3 H), 1.88 - 1.98 (m, 1 H), 1.82 (m, 1 H), 1.31 (m, 1 H), ppm 1 .22 (m, 1 H); MS (ESI): m/z: 201 [M-H] ^"

Intermediate 19: fra/7S-2-lsocyanatospiro[cyclopropane-1 ,1'-indane] and Intermediate 20: c/s-2-lsocyanatospiro[cyclopropane-1 ,1'-indane]

5.53 g (29.4 mmol) of the spiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 13) was dissolved in 490 ml of dry toluene and cooled to 0°C under nitrogen. 6.1 ml (44 mmol) of TEA and 9.1 ml (41 mmol) of diphenylphosphoryl azide were added and the mixture was warmed to r.t. and stirred for 18 h and then concentrated. The residue was treated with hexane/EtOAc/toluene (350 ml/ 60 ml/ 60 ml ca.), the liquid was poured off, then residue was treated again with hexane/EtOAc 97:3 (200 ml). The liquid was poured off and the combined solutions were evaporated. The resulting residue was purified by flash chromatography (eluent: hexane/EtOAc 98:2) to give two products, the frans-isomer and the c/s-isomer (regarding the cyclopropyl ring) in their racemic form. The c/ ^' s and trans isomers were determined by analogy to Intermediates 21 and 22. The frans-isomer, Intermediate 19, was obtained as a colorless oil (2.95 g, 54%). The c/s-isomer, Intermediate 20, was obtained as a colorless oil (1.90 g, 40%). ¹ H NMR (CDCI ₃ ) δ (ppm), trans: 7.27 - 7.14 (m, 3 H), 6.76 - 6.70 (m, 1 H), 3.1 1 - 2.98 (m, 2 H), 2.36 - 2.25 (m, 2 H), 2.05 - 1 .99 (m, 1 H), 1.82 - 1.78 (m, 1 H), 1.64 - 1.60 (m, 1 H); ¹ H NMR (CDCI ₃ ) δ (ppm), c/ ^' s: 7.26 - 7.14 (m, 4 H), 3.17 - 3.07 (m, 1 H), 2.97 - 2.89 (m, 1 H), 2.48 - 2.40 (m, 1 H), 2.16 - 2.1 1 (m, 1 H), 2.07 - 2.02 (m, 1 H), 1 .96 - 1.90 (m, 1 H), 1.60 - 1.56 (m, 1 H);MS (ESI): m/z: 186 [M+H] ⁺ .

Intermediate 21 : frans-5'-Bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and Intermediate 22: c/s-5'-Bromo 2-isocyanatospiro[cyclopropane-1 ,1'-indane]

0.216 g (30%) of £rans-5'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and 0.222 g (30%) of c/ ^' s-5'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] were prepared according to the procedure described for Intermediates 19 and 20, starting from 0.739 g (2.77 mmol) of 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 14). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form. The c/ ^' s and trans isomers were determined by NMR (NOE) analysis. ¹ H NMR (CDCI ₃ ) δ (ppm), trans: 7.37 (s, 1 H), 7.31 - 7.25 (m, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 3.16 - 2.85 (m, 2 H), 2.49 - 2.40 (m, 1 H), 2.16 - 2.1 1 (m, 1 H), 2.03 - 1.98 (m, 1 H), 1.95 - 1.88 (m, 1 H), 1.61 - 1.55 (m, 1 H); ¹ H NMR (CDCI ₃ ) δ (ppm), c/ ^' s: 7.37 (s, 1 H), 7.31 - 7.24 (m, 1 H), 6.58 (d, J = 8.3 Hz, 1 H), 3.14 - 2.92 (m, 2 H), 2.40 - 2.19 (m, 2 H), 2.03 - 1.94 (m, 1 H), 1.83 - 1.75 (m, 1 H), 1 .62 - 1.52 (m, 1 H); MS (ESI): m/z: 264 [M+H] ⁺ .

Intermediate 23: frans-6'-Bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and Intermediate 24: c/s-6'-Bromo 2-isocyanatospiro[cyclopropane-1 ,1'-indane]

0.175 g (59%) of £rans-6'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and 0.121 g (41 %) of c/ ^' s-6'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] were prepared according to the procedure described for Intermediates 19 and 20, starting from 0.300 g (1.12 mmol) of 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 15). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cydopropyl ring) in their racemic form. The cis and trans isomers were determined by NMR (NOE) analysis. ¹ H NMR (CDCI ₃ ) δ (ppm), trans: 7.30 (dd, J = 1.7, 8.1 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 6.83 (d, J = 2.0 Hz, 1 H), 3.08 - 2.87 (m, 2 H), 2.37 - 2.25 (m, 2 H), 2.04 - 1.97 (m, 1 H), 1.83 - 1.77 (m, 1 H), 1.63 - 1.56 (m, 1 H); ¹ H NMR (CDCI ₃ ) δ (ppm), cis: 7.36 (d, J = 2.0 Hz, 1 H), 7.31 (dd, J = 2.0, 7.8 Hz, 1 H), 7.12 - 7.06 (m, 1 H), 3.07 - 3.02 (m, 1 H), 2.90 - 2.86 (m, 1 H), 2.46 - 2.42 (m, 1 H), 2.16 - 2.12 (m, 1 H), 2.01 - 1.96 (m, 1 H), 1 .94 - 1.88 (m, 1 H), 1.60 - 1.56 (m, 1 H); MS (ESI): m/z: 265 [M+H] ⁺ .

Intermediate 25: A -[fra/7S-2-isocyanatospiro[cyclopropane-1 ,4'-tetralin]-6'- yl]benzamide and Intermediate 26: A -[c/s-2-isocyanatospiro[cyclopropane-1 ,4'- tetralin]-6'-yl]benzamide

0.097 g (49%) of N-[£rans-2-isocyanatospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide and 0.073 g (37%) of A/-[c/ ^' s-2-isocyanatospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide were prepared according to the procedure described for Intermediates 19 and 20, starting from 0.202 g (0.628 mmol) of 7'-benzamidospiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid (Intermediate 16). The reaction gave two products, the c/s-isomer and the trans- isomer (regarding the cyclopropyl ring) in their racemic form. The cis and trans isomers were determined by analogy to Intermediates 27 and 28. ¹ H NMR (CDCI ₃ ) δ (ppm), trans: 7.82 - 7.91 (m, 2 H), 7.47 - 7.60 (m, 3 H), 7.72 (bs, 1 H), 7.20 - 7.26 (m, 2 H), 7.10 (m, 1 H), 2.82 - 2.92 (m, 2 H), 1.87 - 2.07 (m, 4 H), 1.83 (m, 1 H), 1.68 - 1.79 (m, 2 H); ¹ H NMR (CDCI ₃ ) δ (ppm), cis: 7.86 - 7.93 (m, 2 H), 7.80 (bs, 1 H), 7.71 (m, 1 H), 7.46 - 7.59 (m, 3 H), 7.09 - 7.20 (m, 2 H), 2.84 - 3.00 (m, 2 H), 2.12 - 2.24 (m, 2 H), 1.92 - 2.09 (m, 2 H), 1.88 (m, 1 H), 1.44 (m, 1 H), 1.21 - 1.32 (m, 1 H); MS (ESI): m/z: 319 [M+H] ⁺ . Intermediate 27: frans-2-lsocyanatospiro[cyclopropane-1 ,1'-tetralin]

0.491 g (quantitative) of £rans-2-isocyanatospiro[cyclopropane-1 ,1 '-tetralin] was prepared according to the procedure described for Intermediates 19 and 20, starting from 0.495 g (2.45 mmol) of £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid (Intermediate 17). ¹ H NMR (CDCI3) δ (ppm): 7.06 - 7.18 (m, 3 H), 6.68 - 6.76 (m, 1 H) 2.85 - 2.93 (m, 2 H), 1.86 - 2.07 (m, 4 H), 1.67 - 1.80 (m, 3 H); MS (ESI): m/z: 200 [M+H] ⁺ .

Intermediate 28: c/s-2-lsocyanatospiro[cyclopropane-1 ,1'-tetral

0.263 g (97%) of c/ ^' s-2-isocyanatospiro[cyclopropane-1 , 1 -tetralin] was prepared according to the procedure described for Intermediates 19 and 20, starting from 0.276 g (1.37 mmol) of c/s-spiro[cyclopropane-2,1 '-tetralin]-1 -carboxylic acid (Intermediate 18). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.08 - 7.23 (m, 4 H), 2.86 - 3.00 (m, 2 H), 2.13 - 2.27 (m, 2 H), 1.89 - 2.13 (m, 2 H), 1.86 (m, 1 H), 1.41 (m, 1 H), 1.26 (m, 1 H; MS (ESI): m/z: 200 [M+H] ⁺ .

Example 1 : /V-[frans-2-Aminospiro[cyclopropane-1 ,1'-indane]-5'-yl]benzamide hydrobromide

Step 1

1 ,3-benzodioxol-5-ylmethyl N-itrans-5'-bromospiroicvclopropane-2, 1 '-indanel-1- yljcarbamate

0.050 g (0.19 mmol) of £rans-5'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 21 ) and 0.032 g (0.21 mmol) of 1 ,3-benzodioxol-5-ylmethanol were dissolved in 3 ml of dry toluene under nitrogen atmosphere and the solution was heated at 85°C for 5 h and at 1 10°C for 6 h. Then, the reaction mixture was irradiated with microwaves at 120°C for 1 h and at 150°C for 1 h. The reaction mixture was evaporated and the residue was purified by flash chromatography (eluent: DCM/EtOAc from 100:1 to 100% EtOAc) to afford 1 ,3-benzodioxol-5-ylmethyl N-[£rans-5'-bromospiro[cyclopropane- 2,1 '-indane]-1 -yl]carbamate as a white solid (0.038 g, 48%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.55 - 7.64 (m, 1 H), 7.33 - 7.40 (m, 1 H), 7.18 - 7.31 (m, 1 H), 6.79 - 6.94 (m, 3 H), 6.50 - 6.75 (m, 1 H), 6.00 (s, 2 H), 4.82 - 5.00 (m, 2 H), 2.84 - 2.97 (m, 2 H), 2.53 - 2.62 (m, 1 H), 1.89 - 1.97 (m, 2 H), 1.29 - 1.35 (m, 1 H), 0.93 - 0.98 (m, 1 H); MS (ESI): m/z: 438 [M+Na] ⁺ . Step 2

1 ,3-benzodioxol-5-ylmethyl N-[trans-5'-benzamidospiro[cvclopropane-2, 1 '-indane]-1- yllcarbamate A microwave vial was charged with 0.037 g (0.089 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[irans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate, 0.012 g (0.098 mmol) of benzamide, 0.0068 g (0.036 mmol) of Cul and 0.025 g (0.18 mmol) of K ₂ C0 ₃ under nitrogen atmosphere. 1 ml of dioxane and 0.0077 ml (0.071 mmol) of Λ/,Λ/ ¹ - dimethylethane-1 ,2-diamine were added with a syringe under nitrogen and the vial was irradiated with microwaves at 140°C for 3 h. The resulting suspension was allowed to cool down to r.t. and was then filtered through a pad of silica gel eluting with 1 :1 DCM/EtOAc. The filtrate was concentrated and purified by flash chromatography (eluent: hexane/EtOAc from 9:1 to 6:4) to afford 1 ,3-benzodioxol-5-ylmethyl N-[trans-5'- benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate as a yellow solid (8.4 mg, 20%). ¹ H NMR (DMSO-de) δ (ppm): 10.13 (s, 1 H), 7.86 - 8.02 (m, 2 H), 7.26 - 7.69 (m, 6 H), 6.54 - 6.98 (m, 4 H), 5.89 - 6.07 (m, 2 H), 4.78 - 5.05 (m, 2 H), 2.81 - 2.98 (m, 2 H), 2.55 - 2.67 (m, 1 H), 1 .97 (m, 2 H), 1.24 - 1.35 (m, 1 H), 0.88 - 0.99 (m, 1 H); MS (ESI): m/z: 457 [M+H] ⁺ .

Step 3

N-[trans-2-aminospiro[cyclopropane-1, 1 '-indane]-5'-yl]benzamide hydrobromide 0.0073 g (0.016 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[trans-5'- benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate was mixed with 0.080 ml of AcOH and 0.080 ml (0.44 mmol) of 33% HBr/AcOH. The reaction mixture was stirred at r.t. 40 min then diluted with Et ₂ O resulting in the formation of a precipitate. The majority of the liquid was decanted off and the remaining residue concentrated with a nitrogen stream. The residue was treated with Et ₂ O and the majority of the liquid was decanted off. Then, the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give A/-[irans-2-aminospiro[cyclopropane-1 ,1 '-indane]-5'-yl]benzamide hydrobromide as a beige solid (5.6 mg, quantitative). ¹ H NMR (DMSO-de) δ (ppm): 10.18 (s, 1 H), 8.28 (bs, 3 H), 7.88 - 7.99 (m, 2 H), 7.70 (s, 1 H), 7.46 - 7.63 (m, 4 H), 6.82 (d, J = 8.31 Hz, 1 H), 3.05 (m, 2 H), 2.78 - 2.90 (m, 1 H), 2.08 - 2.29 (m, 2 H), 1.32 (m, 1 H), 1.17 - 1.25 (m, 1 H); MS (ESI): m/z: 279 [M+H] ⁺ . Example 2: /V-[c;s-2-Aminospiro[cyclopropane-1 ,1'-indane]-5'-yl]benzamide hydrochloride

2-trimethylsilylethyl N-fcis-5'-bromospirofcvclopropane-2, 1 '-indane]-1 -yljcarbamate

0.218 g (0.825 mmol) of c/ ^' s-(5'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 22) and 0.14 ml (0.99 mmol) of 2-trimethylsilylethanol were dissolved in 8 ml of dry THF under nitrogen atmosphere, 0.060 ml (0.40 mmol) of TEA was added and the solution was irradiated with microwaves at 120°C for 12 h. The reaction mixture was concentrated and the residue was taken-up with EtOAc and evaporated. The residue was purified by flash chromatography (eluent: hexane/EtOAc 85:15) to afford 2- trimethylsilylethyl A/-[c/s-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate as a colorless gummy semi-solid (0.206 g, 65%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.09 - 7.40 (m, 3 H), 6.66 - 6.79 (m, 1 H), 3.43 - 3.89 (m, 2 H), 2.81 - 3.06 (m, 2 H), 2.60 - 2.76 (m, 1 H), 2.03 - 2.24 (m, 1 H), 1 .77 - 1.95 (m, 1 H), 1.07 - 1.23 (m, 2 H), 0.26 - 0.79 (m, 2 H), 0.15 - 0.04 (m, 9 H); MS (ESI): m/z: 404 [M+Na] ⁺ .

Step 2

2-trimethylsilylethyl N-icis-5'-benzamidospiroicvclopropane-2, 1 '-indanel-1 -yllcarbamate

0.050 g (0.131 mmol) of 2-trimethylsilylethyl A/-[c/s-5'-bromospiro[cyclopropane-2,1 '- indane]-1 -yl]carbamate, 0.019 g (0.16 mmol) of benzamide, 0.0015 g (0.0016 mmol) of bis[tris(dibenzylideneacetone)palladium(0)], 0.0029 g (0.0049 mmol) of xantphos and 0.060 g (0.18 mmol) of cesium carbonate were added under nitrogen atmosphere to a microwave vial. The vial was sealed, flushed with nitrogen for 15 min and 1 ml of dioxane was added through the septum. Nitrogen was bubbled through the red solution for 1 min ca. then the reaction was heated to 100°C and stirred for 18 h. The reaction mixture was then cooled down to r.t, diluted with DCM, filtered through a small pad of Celite and the pad washed with DCM. The combined organic solutions were concentrated and the residue was purified by flash chromatography (eluent: DCM/EtOAc 93:7) to afford 2- trimethylsilylethyl A/-[c/s-5'-benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate as a white solid (15 mg, 27%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.09 (bs, 1 H), 7.84 - 7.97 (m, 2 H), 7.04 - 7.79 (m, 6 H), 6.69 - 6.84 (m, 1 H), 3.43 - 3.93 (m, 2 H), 2.79 - 3.08 (m, 2 H), 2.59 - 2.76 (m, 1 H), 2.03 - 2.25 (m, 1 H), 1.77 - 1.98 (m, 1 H), 1 .04 - 1.19 (m, 2 H), 0.33 - 0.80 (m, 2 H), 0.35 - 0.14 (m, 9 H); MS (ESI): m/z: 445 [M+Na] ⁺ .

Step 3

N-icis-2-aminospiroicvclopropane-1, 1 '-indanel-5'-yllbenzamide hydrochloride

0.500 ml (1.00 mmol) of 2 M HCI in Et ₂ 0 was added to 0.014 g (0.033 mmol) of 2- trimethylsilylethyl A/-[c/s-5'-benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate in 1.5 ml of Et ₂ 0 and the mixture was heated at 100°C for 6 h. Further 0.170 ml (0.340 mmol) of 2 M HCI in Et ₂ 0 were added and the mixture was heated at 100°C overnight. The majority of the liquid was decanted off, the remaining residue was treated with Et ₂ 0 and the majority of the liquid was decanted off, then the residue was concentrated with a nitrogen stream. The residue was triturated with Et ₂ 0 and MeOH. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give A/-[c/s-2-aminospiro[cyclopropane-1 ,1 '-indane]-5'- yljbenzamide hydrochloride as a burgundy-brown solid (5.8 mg, 54%). ¹ H NMR (DMSO- d ₆ ) δ (ppm): 10.24 (s, 1 H), 8.21 (bs, 3 H), 7.92 - 7.98 (m, 2 H), 7.76 (s, 1 H), 7.48 - 7.63 (m, 4 H), 7.21 (d, J=8.31 Hz, 1 H), 2.77 - 3.08 (m, 3 H), 2.15 - 2.26 (m, 1 H), 1.92 - 2.01 (m, 1 H), 1.43 - 1.52 (m, 1 H), 1.31 (m, 1 H); MS (ESI): m/z: 279 [M+H] ⁺ . Example 3: A -[fra/7S-2-Aminospiro[cyclopropane-1 ,3'-indane]-5'-yl]benzamide hydrochloride

Step 1

2-trimethylsilylethyl N-itrans-6'-bromospiroicvclopropane-2, 1 '-indanel-1 -viicarbamate

0.156 g (63%) of 2-trimethylsilylethyl N-[£rans-6'-bromospiro[cyclopropane-2,1 '-indane]-1 - yl]carbamate was prepared according to the procedure described for Example 2, Step 1 , in the absence of TEA, starting from 0.170 g (0.644 mmol) of £rans-6'-bromo-2- isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 23). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.50 - 7.37 (bs, 1 H), 7.24 (dd, J = 7.8, 1.5 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 6.97 - 6.94 (m, 1 H), 4.1 1 - 3.95 (m, 2 H), 2.93- 2.85 (m., 2 H), 2.66 - 2.55 (m, 1 H), 1.93 - 2.01 (m, 2 H), 1.43 - 1.30 (m, 1 H), 1.02 - 0.85 (m, 3 H), 0.02 (s, 9 H); MS (ESI): m/z: 404 [M+Na] ⁺ .

Step 2

2-trimethylsilylethyl N-[trans-6'-benzamidospiro[cvclopropane-2, 1 '-indanel-1 -viicarbamate

0.040 g (46%) of 2-trimethylsilylethyl N-[£rans-6'-benzamidospiro[cyclopropane-2,1 '- indane]-1 -yl]carbamate was prepared according to the procedure described for Example

1 , Step 2, starting from 0.078 g (0.20 mmol) of 2-trimethylsilylethyl N-[trans-6'- bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate. ¹ H NMR (CDCI ₃ ) δ (ppm): 10.10 (s,

1 H), 7.95 - 7.89 (m, 2 H), 7.60 - 7.40 (m, 4 H), 7.20 - 7.04 (m, 2 H), 6.52 - 6.19 (m, 1 H), 4.15 - 3.84 (m, 2 H), 2.97 - 2.80 (m, 2 H), 2.62 - 2.52 (m, 1 H), 2.12 - 1.84 (m, 2 H), 1.29 - 1.17 (m, 1 H), 1.07 - 0.75 (m, 3 H), 0.01 (s, 9 H); MS (ESI): m/z: 445 [M+Na] ⁺ . Step 3

N-[trans-2-aminospiro[cvclopropane-1,3'-indanel-5'-yllbenzam ide hvdrochoride 0.022 g (74%) of N-[£rans-2-aminospiro[cyclopropane-1 ,3'-indane]-5'-yl]benzamide hydrochoride was prepared according to the procedure described for Example 2, Step 3, starting from 0.040 g (0.095 mmol) of 2-trimethylsilylethyl N-[trans-6'- benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate. ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.17 (s, 1 H), 8.36 (bs, 3 H), 7.93 (d, J = 7.8 Hz, 2 H), 7.64 - 7.40 (m, 4 H), 7.27 (d, J = 1 Hz, 1 H), 7.20 (d, J=7.8 Hz, 1 H), 3.05 - 2.97 (m, 2 H), 2.84 - 2.71 (m, 1 H), 2.32 - 2.10 (m, 2 H), 1.34 - 1.23 (m, 2 H); MS (ESI): m/z: 279 [M+H] ⁺ .

Example 4: frans-Spiro[chromane-4,2'-cyclopropane]-1'-amine hydrobromide

Step 1

1 ,3-benzodioxol-5-ylmethyl N-itrans-spiroichromane-4,2'-cvclopropanel-1'-yllcarbamate

0.050 g (0.23 mmol) of £rans-spiro[chromane-4,2'-cyclopropane]-1 '-carboxylic acid (ENAMINE-BB, Cat No. EN300-85418) was dissolved in 2.5 ml of dry toluene and cooled to 0°C under nitrogen. 0.049 ml (0.35 mmol) of TEA and 0.067 ml (0.30 mmol) of diphenylphosphoryl azide were added and the mixture was allowed to reach r.t. and stirred for 2 h. The mixture was then cooled to 0°C, 0.036 g (0.23 mmol) of 1 ,3- benzodioxol-5-ylmethanol in 0.5 ml of toluene was added and the mixture was stirred at r.t. for 1 h 30 min. then heated at 85°C for 2 h. After being cooled down to r.t., the solvent was evaporated and the crude product was purified by flash chromatography (eluent: hexane-EtOAc from 0% EtOAc to 70:30) to afford a solid that was further triturated with n- hexane/iPr ₂ 0 (2:1 ) to give 1 ,3-benzodioxol-5-ylmethyl N-[£rans-spiro[chromane-4,2'- cyclopropane]-1 '-yl]carbamate as a white solid (34 mg, 41 %). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.67 (bs, 1 H), 6.98 - 7.08 (m, 1 H), 6.59 - 6.95 (m, 6 H), 5.89 - 6.06 (m, 2 H), 4.91 (m, 2 H), 3.80 - 4.22 (m, 2 H), 2.68 - 2.88 (m, 1 H), 1.58 - 1.94 (m, 2 H), 1 .37 - 1.49 (m, 1 H), 0.90 - 1.01 (m, 1 H); MS (ESI): m/z: 376 [M+Na] ⁺ . Step 2

trans-Spiro[chromane-4,2'-cyclopropanel-1 "-amine hydrobromide 0.01 1 g (76%) of £rans-spiro[chromane-4,2'-cyclopropane]-1 '-amine hydrobromide was prepared according to the procedure described for Example 1 , Step 3, starting from 0.020 g (0.057 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[£rans-spiro[chromane-4,2'- cyclopropane]-1 '-yl]carbamate. ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.33 (bs, 3 H), 7.09 (m, 1 H), 6.71 - 6.88 (m, 3 H), 4.15 - 4.34 (m, 2 H), 2.94 (m, 1 H), 1.95 - 2.1 1 (m, 2 H), 1.49 (m, 1 H), 1.21 (m, 1 H); MS (ESI): m/z: 176 [M+H] ⁺ .

Example 5: frans-5'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide and Example 6: c;s-5'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide

Step 1

1 ,3-benzodioxol-5-ylmethyl N-[trans-5'-bromospiro[cvclopropane-2, 1 '-indanel-1- yllcarbamate and 1 ,3-benzodioxol-5-ylmethyl N-icis-5'-bromospiroicvclopropane-2, 1'- indane]-1 -yl]carbamate

0.013 g (17%) of 1 ,3-benzodioxol-5-ylmethyl N-[£rans-5'-bromospiro[cyclopropane-2,1 '- indane]-1 -yl]carbamate and 0.010 g (13%) of 1 ,3-benzodioxol-5-ylmethyl N-[cis-5'- bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate were prepared according to the procedure described for Example 4, Step 1 , starting from 0.050 g (0.19 mmol) of 5'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 14). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form. The cis and trans isomers were determined by NMR (NOE) analysis. ¹ H NMR (DMSO-de) δ (ppm), trans: 7.55 - 7.64 (m, 1 H), 7.33 - 7.40 (m, 1 H), 7.18 - 7.31 (m, 1 H), 6.79 - 6.94 (m, 3 H), 6.50 - 6.75 (m, 1 H), 6.00 (s, 2 H), 4.82 - 5.00 (m, 2 H), 2.84 - 2.97 (m, 2 H), 2.53 - 2.62 (m, 1 H), 1 .89 - 1 .97 (m, 2 H), 1 .29 - 1.35 (m, 1 H), 0.93 - 0.98 (m, 1 H); ¹ H NMR (DMSO-d ₆ ) δ (ppm), cis: 7.53 - 7.64 (m, 1 H), 6.30 - 7.40 (m, 6 H), 6.00 (s, 2 H), 4.48 - 4.81 (m, 2 H), 2.84 - 3.04 (m, 2 H), 2.70 - 2.81 (m, 1 H), 2.04 - 2.24 (m, 1 H), 1.70 - 1.99 (m, 1 H), 1.04 - 1.29 (m, 2 H); MS (ESI): m/z: 438 [M+Na] ⁺ .

Step 2

trans-5'-bromospiro[cvclopropane-2, 1 '-indanel-1 -amine hydrobromide

0.008 g (87%) of £rans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide was prepared according to the procedure described for Example 1 , Step 3, starting from 0.012 g (0.029 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[£rans-5'-bromospiro[cyclopropane- 2,1 '-indane]-1 -yl]carbamate. ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.29 (bs, 3 H), 7.43 (s, 1 H), 7.33 (dd, J = 7.8 1.0 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 3.04 - 3.07 (m, 2 H), 2.86 (bs, 1 H), 2.28 - 2.04 (m, 2 H), 1.37 - 1.21 (m, 1 H), 1.24 (m, 1 H); MS (ESI): m/z: 238 [M+H] ⁺ .

Step 2

cis-5'-bromospiro[cyclopropane-2, 1 '-indanel-1 -amine hydrobromide

0.005 g (81.5%) of c/ ^' s-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide was prepared according to the procedure described for Example 1 , Step 3, starting from 0.008 g (0.02 mmol) of 1 ,3-benzodioxol-5-ylmethyl A/-[c/s-5'-bromospiro[cyclopropane- 2,1 '-indane]-1 -yl]carbamate. ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.06 (bs, 3 H), 7.51 (s, 1 H), 7.39 (d, J = 8.31 Hz, 1 H), 7.12 (d, J = 7.83 Hz, 1 H), 2.81 - 3.08 (m, 3 H), 2.20 (m, 1 H), 1.89 - 1.99 (m, 1 H), 1.44 (m, 1 H), 1.30 - 1.38 (m, 1 H); MS (ESI): m/z: 238 [M+H] ⁺ .

Example 7: c/s-Spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride

100 mg (0.26mmol) of 2-tri methyls i lylethy I N-[c/s-5'-bromospiro[cyclopropane-2,1 '-indane]- 1 -yl]carbamate (Example 2, Step 1 ) was dissolved in 3 ml of EtOH and submitted to Flow Hydrogenator reactor with Pd/C 10% cartdrige at 70°C, 30 bar, 0.5ml/min. The solvent was then removed and the crude mixture was dissolved in 0.5 ml of Et ₂ O and 0.8 ml of 2 M HCI in Et ₂ 0 and stirred at 100°C overnight. The majority of the liquid was decanted off, the remaining residue was treated with Et ₂ 0 and the majority of the liquid was decanted off, then the residue was concentrated with a nitrogen stream. The residue was triturated with Et ₂ 0 and MeOH. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give cis- spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride as a light yellow solid (27 mg, 54%). ¹ H NMR (DMSO-de) δ (ppm): 8.27 (bs, 3 H), 7.32 - 7.09 (m, 4 H), 3.10 - 2.95 (m, 1 H), 2.95 - 2.89 (m, 1 H), 2.84 (m, 1 H), 2.18 (m, 1 H), 2.02 - 1.86 (m, 1 H), 1.49 (m, 1 H), 1.31 (m, 1 H); MS (ESI): m/z: 160 [M+H] ⁺ .

Example 8: frans-Spiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

2.943 g (15.89 mmol) of £rans-2-isocyanatospiro[cyclopropane-1 ,1 '-indane] (Intermediate 19) was dissolved in 75 ml of THF and 80 ml of 1 M HCI was added. The reaction mixture was heated at 90°C for 5 h. The organic solvent was evaporated and the remaining aqueous mixture was diluted with water and extracted with Et ₂ O. The aqueous phase was brought to basic pH with NaHCO ₃ (pH 7-8, cooling with ice) and extracted with Et ₂ O. The combined organic phases containing the free amine were dried over Na ₂ SO ₄ and the solution was filtered. Et ₂ O solution was cooled with ice, 24 ml (48 mmol) of 2 M HCI in Et ₂ 0 was added dropwise and the mixture was then allowed to reach r.t. overnight. The reaction mixture was filtered, the solid was washed with Et.20 and heated at 40°C under vacuum to afford £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride as a white solid (2.021 g, 65%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.50 (bs, 3 H), 7.24 - 7.10 (m, 3 H), 6.85 - 6.80 (m, 1 H), 3.09 - 2.97 (m, 2 H), 2.82 - 2.77 (m, 1 H), 2.28 - 2.09 (m, 2 H), 1.34 - 1.23 (m, 2 H); MS (ESI): m/z: 160 [M+H] ⁺ .

Example 9: frans-6'-Bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride

0.031 g (60%) of £rans-6'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 8, starting from 0.050 g (0.19 mmol) of irans-6'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 23). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.46 (bs, 3 H), 7.33 (dd, J = 1.5, 7.8 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.1 1 (d, J = 1.5 Hz, 1 H), 3.06 - 2.83 (m, 2 H), 2.29 - 2.07 (m, 2 H), 1 .46 - 1.33 (m, 2 H), 1.26 (m, 1 H); MS (ESI): m/z: 238 [M+H] ⁺ .

Example 10: frans-Spiro[cyclopropane-2,1'-tetralin]-1 -amine hydrochloride

0.163 g (77%) of £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride was prepared according to the procedure described for Example 8, starting from 0.200 g (1 .00 mmol) of £rans-2-isocyanatospiro[cyclopropane-1 ,1 '-tetralin] (Intermediate 27). ¹ H NMR (DMSO-de) δ (ppm): 8.53 (bs, 3 H), 7.14 - 7.01 (m, 3 H), 6.74 - 6.64 (m, 1 H), 2.89 - 2.71 (m, 3 H), 1.98 - 1.70 (m, 4 H), 1.45 - 1.33 (m, 1 H), 1.20 - 1.09 (m, 1 H); MS (ESI): m/z: 174 [M+H] ⁺ .

Example 11 : c/s-Spiro[cyclopropane-2,1'-tetralin]-1 -amine hydrochloride

0.144 g (52%) of c/ ^' s-spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride was prepared according to the procedure described for Example 8, starting from 0.262 g (1 .32 mmol) of c/ ^' s-2-isocyanatospiro[cyclopropane-1 ,1 '-tetralin] (Intermediate 28). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.99 (bs, 3 H), 7.08 - 7.23 (m, 4 H), 2.80 - 2.94 (m, 2 H), 2.53 (m, 1 H), 1.78 - 1.95 (m, 3 H), 1.67 (m, 1 H), 1.24 (m, 1 H), 1.18 (m, 1 H); MS (ESI): m/z: 174 [M+H] ⁺ .

Example 12: /V-[frans-2-Aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide hydrochloride

0.029 g (62%) of A/-[irans-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide hydrochloride was prepared according to the procedure described for Example 8, starting from 0.045 g (0.14 mmol) of A/-[irans-2-isocyanatospiro[cyclopropane-1 ,4'-tetralin]-6'- yl]benzamide (Intermediate 25). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.1 1 (s, 1 H), 8.53 (bs, 3 H), 7.90 - 7.97 (m, 2 H), 7.47 - 7.63 (m, 4 H), 7.02 - 7.14 (m, 2 H), 2.68 - 2.85 (m, 3 H), 1.73 - 1.98 (m, 4 H), 1.33 (m, 1 H), 1.21 (m, 1 H); MS (ESI): m/z: 293 [M+H] ⁺ . Example 13: A -[c/s-2-Aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide hydrochloride

0.015 g (43%) of N-[c/ ^' s-2-aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide hydrochloride was prepared according to the procedure described for Example 8, starting from 0.034 g (0.1 1 mmol) of A/-[c/s-2-isocyanatospiro[cyclopropane-1 ,4'-tetralin]-6'- yl]benzamide (Intermediate 26). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.15 (s, 1 H), 8.02 (m, 5 H), 7.69 (m, 1 H), 7.49 - 7.64 (m, 3 H), 7.16 (m, 1 H), 7.45 (s, 1 H), 2.85 (m, 2 H), 2.57 (m, 1 H), 1.77 - 1.98 (m, 3 H), 1.50 - 1.60 (m, 1 H), 1.19 - 1.32 (m, 2 H); MS (ESI): m/z: 293 [M+H] ⁺ .

Example 14: frans-/V-(4-Piperidylmethyl)spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride

Step 1

tert-Butyl 4-iiitrans-spiroicvclopropane-2, 1 '-indanel-1 -yllaminolmethyllpiperidine-1 - carboxylate

0.214 ml (1.53 mmol) of TEA was added to a solution of 0.300 g (1 .53 mmol) of trans- spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8) in 12 ml of dry MeOH under nitrogen, then 0.434 g (1.99 mmol) of te/t-butyl 4-formylpiperidine-1 -carboxylate was added and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was ice-cooled then 0.091 g (2.3 mmol) of NaBH ₄ was added, and the mixture was stirred at r.t. for 50 min. The reaction was cooled with ice, quenched with water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: hexane/EtOAc from 80:20 to 70:30) to afford te/t-butyl 4-[[[£rans-spiro[cyclopropane-2,1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate as a yellow oil (392 mg, 72%). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.24 - 7.17 (m, 1 H), 7.16 - 7.08 (m, 2 H), 6.67 - 6.60 (m, 1 H), 4.24 - 3.96 (m, 2 H), 3.12 - 2.94 (m, 2 H), 2.79 - 2.63 (m, 2 H), 2.62 - 2.47 (m, 2 H), 2.36 - 2.22 (m, 2 H), 2.16 - 2.07 (m, 1 H), 1.80 - 1 .55 (m, 3 H), 1.46 (s, 9 H), 1 .20 - 1.04 (m, 3 H), 0.86 - 0.77 (m, 1 H); MS (ESI): m/z: 357 [M+H] ⁺ .

Step 2

trans-N-(4-piperidylmethyl)spiro[cvclopropane-2, 1 '-indane]-1 -amine dihvdrochloride

A solution of 0.027 g (0.076 mmol) of 4-[[[£rans-spiro[cyclopropane-2,1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate in Et20/MeOH (2 ml/0.7 ml) was cooled with ice. Then, 1.5 ml (3.0 mmol) 2 M HCI in Et ₂ 0 was added and the mixture was stirred at r.t. overnight. The suspension was filtered and the collected solid was washed with Et ₂ 0 to afford £rans-N-(4-piperidylmethyl)spiro[cyclopropane-2, 1 '-indane]-1 -amine dihydrochloride (18 mg, 72%). ¹ H NMR (DMSO-d ₆ , D ₂ 0) δ (ppm): 7.28 - 7.20 (m, 1 H), 7.19 - 7.10 (m, 2 H), 6.83 - 6.73 (m, 1 H), 3.33 - 2.76 (m, 9 H), 2.26 - 2.15 (m, 2 H), 2.09 - 1.99 (m, 1 H), 1.96 - 1.83 (m, 2 H), 1.44 - 1.27 (m, 4 H); MS (ESI): m/z: 257 [M+H] ⁺ .

Example 15: c/s-/V-(4-Piperidylmethyl)spiro[cyclopropane-2,1'-indane]-1 -amine dihydrochloride

2 HCI

Stepl

tert-Butyl 4-iitert-butoxycarbonyl-icis-spiroicvclopropane-2, 1 '-indanel-1- yllaminolmethyllpiperidine-1-carboxylate

0.040 g (0.202 mmol) of c/s-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 7) and 0.041 g (0.192 mmol) of te/t-butyl 4-formylpiperidine-1 -carboxylate were mixed in 1.4 ml of dry DMF and the solution was stirred at r.t. under nitrogen atmosphere for 1.5 h. The solution was then treated with 0.060 g (0.27 mmol) of NaBH(OAc) ₃ and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was cooled with ice, quenched by adding aqueous saturated NaHC0 ₃ and the product was extracted with DCM. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solution concentrated with nitrogen. The solution was cooled with ice, then 0.034 ml (0.24 mmol) of TEA and 0.050 g (0.23 mmol) of di-te/t-butyl dicarbonate were added under nitrogen. The solution was stirred at r.t overnight. The reaction mixture was diluted with DCM, washed with brine, dried and concentrated. The crude mixture was purified by flash chromatography (eluent: hexane/EtOAc 90:10) to afford te/t-butyl 4-[[te/t-butoxycarbonyl-[c/s-spiro[cyclopropane- 2,1 '-indane]-1 -yl]amino]methyl]piperidine-1 -carboxylate as a yellow oil that solidified on- standing (26 mg, 30%). MS (ESI): m/z: 479 [M+Na] ⁺ .

Step 2

cis-N-(4-piperidylmethyl)spiroicvclopropane-2, 1 '-indanel-1 -amine dihydrochloride 1.1 ml (2.2 mmol) of 2 M HCI in Et ₂ 0 was added at 0°C to 0.025 g (0.055 mmol) of tert- butyl 4-[[te/t-butoxycarbonyl-[c/s-spiro[cyclopropane-2, 1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate in 1.5 ml of Et20 and the mixture was stirred at r.t. for 24 h. Further, 0.3 ml (1.2 mmol) of 4 M HCI in dioxane and 0.5 ml of MeOH were added obtaining a solution that was stirred at r.t. for 24 h. The resulting suspension was concentrated with a nitrogen stream. The residue was triturated with Et.20 and MeOH. The majority of the liquid was decanted off and the residue was triturated again with Et ₂ O and MeOH. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give cis-N-(4- piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine dihydrochloride as a yellow solid (15 mg, 83%). ¹ H NMR (D ₂ 0) δ (ppm): 6.92 - 7.37 (m, 4 H), 2.14 - 3.27 (m, 10 H), 0.92 - 1.84 (m, 8 H); MS (ESI): m/z: 257 [M+H] ⁺ . Example 16: frans-5'-Bromo-/V-(4-piperidylmethyl)spiro[cyclopropane-2,1' -indane]- 1 -amine dihydrochloride

Stepl

tert-Butyl 4-[[[trans-5'-bromospiro[cvclopropane-2 '-indanel-1-yllaminolm

1-carboxylate

46 mg (0.14 mmol) of £rans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide (Example 5) and 0.020 mg (0.07 mmol) of te/t-butyl 4-formylpiperidine-1 - carboxylate were mixed in 3 ml of DCE, 0.025 ml (0.14 mmol) of DIPEA and 0.008 ml (0.14 mmol) of AcOH were added and the solution was stirred at r.t. under nitrogen atmosphere for 2 h. 0.034 g (0.16 mmol) of NaBH(OAc) ₃ was added and the solution was stirred at r.t. for 4h. The reaction mixture was quenched with aqueous NaHCO ₃ , extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography (eluent: hexane/EtOAc from 95:5 to 60:40) to give te/t-butyl 4- [[[£rans-5'-bromospiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 - carboxylate (12 mg, 12%). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.32 (s, 1 H), 7.25 - 7.20 (m, 1 H), 6.49 (d, J=8.3 Hz, 1 H), 4.21 - 3.99 (m, 2 H), 3.00 (m, 2 H), 2.78 - 2.62 (m, 2 H), 2.61 - 2.45 (m, 2 H), 2.31 (s, 1 H), 2.26 - 2.20 (m, 1 H), 2.14 - 2.06 (m, 1 H), 1.82 - 1.65 (m, 2 H), 1.64 - 1.54 (m, 1 H), 1.46 (s, 9 H), 1 .14 (m, 3 H), 0.86 - 0.78 (m, 1 H); MS (ESI): m/z: 380 [M-tBu] ⁺ .

Step 2

trans-5'-Bromo-N-(4-piperidylmethyl)spiroicvclopropane-2, 1'-indanel-1 -amine

dihydrochloride 0.138 ml (0.276 mmol) of 2 M HCI in Et ₂ 0 was added to a solution of 12 mg (0.028 mmol) of te/t-butyl 4-[[[£rans-5'-bromospiro[cyclopropane-2, 1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate in Et20/MeOH (1 ml/ 0.2 ml) and the mixture was stirred ad room temperature overnight. The precipitated solid was collected, washed with Et ₂ 0 and some drops of MeOH and dried under vacuum to afford £rans-5'-bromo-N-(4- piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine dihydrochloride as a white solid (1 1 mg, 98%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 9.65 - 9.34 (m, 2 H), 8.89 (bs, 1 H), 8.68 (m, 1 H), 7.44 (s, 1 H), 7.38 - 7.28 (m, 1 H), 6.79 (d, J = 8.3 Hz, 1 H), 3.26 (m, 2 H), 3.17 - 2.99 (m, 3 H), 2.94 (bs, 2 H), 2.90 - 2.77 (m, 2 H), 2.43 - 2.22 (m, 2 H), 2.12 (bs, 1 H), 2.03 (m, 1 H), 1 .94 (m, 1 H), 1 .51 (m, 1 H), 1.47 - 1.32 (m, 3 H).

Example 17: c;s-5'-Bromo-/V-(4-piperidylmethyl)spiro[cyclopropane-2,1'-i ndane]-1 - amine dihydrochloride

Stepl

tert-Butyl 4-[[[cis-5'-bromospiro[cvclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 - carboxylate 0.044 g (0.14 mmol) of c/s-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide (Example 6) and 0.028 g (0.13 mmol) of te/t-butyl 4-formylpiperidine-1 - carboxylate were mixed in 1 ml of dry DMF and the solution was stirred at r.t. under nitrogen atmosphere for 1 h. The solution was then treated with 0.041 g (0.18 mmol) of NaBH(OAc)3 and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was cooled with ice, quenched by adding aqueous saturated NaHC0 ₃ and the product was extracted with EtOAc. The EtOAc extract was dried over Na ₂ S0 ₄ , filtered and the solution concentrated. The residue was taken-up with toluene, the solvent was then removed by evaporation, and the product was then purified by flash chromatography (eluent: DCM/EtOAc 80:20) to give te/t-butyl 4-[[[c/ ^' s-5'-bromospiro[cyclopropane-2,1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate as a yellow oil (1 1 mg, 19%). MS (ESI): m/z: 435 [M+H] ⁺ . Step 2

cis-5'-Bromo-N-(4-piperidylmethyl)spiroicvclopropane-2, 1'-indanel-1 -amine

dihydrochloride

0.344 ml (0.688 mmol) of 2 M HCI in Et ₂ 0 was added at 0°C to 0.010 g (0.023 mmol) of te/t-butyl 4-[[[c/ ^' s-5'-bromospiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 - carboxylate in Et ₂ 0/MeOH (1 ml/0.5 ml) and the mixture was stirred at r.t. overnight. The reaction mixture was concentrated with a nitrogen stream. The residue was triturated with and MeOH. The majority of the liquid was decanted off and the residue was triturated again with Et ₂ 0 and MeOH. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give c/s-5'- bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine dihydrochloride as a beige solid (7.0 mg, 74%). ¹ H NMR (D ₂ 0) δ (ppm): 7.45 - 7.51 (m, 1 H), 7.28 - 7.36 (m, 1 H), 6.87 - 6.94 (m, 1 H), 2.58 - 3.26 (m, 9 H), 2.18 - 2.36 (m, 1 H), 0.96 - 1.83 (m, 8 H); MS (ESI): m/z: 335 [M+H] ⁺ .

Example 18: frans-/V-(4-Piperidylmethyl)spiro[cyclopropane-2,1'-tetralin ]-1 -amine dihydrochloride

Stepl

tert-Butyl 4-iiitrans-spiroicvclopropane-2, 1 '-tetralinl-1 -yllaminolmethyllpiperidine-1 - carboxylate

0.044 g (62%) of te/t-butyl 4-[[[£rans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]methyl]piperidine-1 -carboxylate was prepared according to the procedure described for Example 17, Step 1 , starting from 0.042 g (0.20 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.16 - 6.98 (m, 3 H), 6.64 - 6.56 (m, 1 H), 4.23 - 3.98 (m, 2 H), 2.96 - 2.79 (m, 2 H), 2.78 - 2.50 (m, 4 H), 2.45 - 2.29 (m, 1 H), 2.05 - 2.00 (m, 1 H), 1 .98 - 1.89 (m, 1 H), 1.88 - 1.66 (m, 4 H), 1.46 (s, 9 H), 1.25 - 1.18 (m, 1 H), 1.18 - 1.04 (m, 2 H), 0.81 - 0.54 (m, 1 H); MS (ESI): m/z: 371 [M+H] ⁺ .

Step 2

trans-N-(4-piperidylmethyl)spiro[cvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride A solution of 0.042 (0.1 1 mmol) of te/t-butyl 4-[[[£rans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]methyl]piperidine-1 -carboxylate in Et ₂ 0/MeOH (3 ml/1 ml) was cooled with ice. Then 1.134 ml (2 267 mmol) of 2 M HCI in Et ₂ 0 were added and the reaction was stirred at r.t. overnight. The reaction mixture was then concentrated and the residue was triturated with Et ₂ 0. The solid was filtered and heated at 40°C under vacuum to afford irans-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-tetralin]-1 -amine dihydrochloride as a light-yellow solid (33 mg, 84%). ¹ H NMR (D ₂ 0) δ (ppm): 7.09 - 7.00 (m, 3 H), 6.63 - 6.53 (m, 1 H), 3.35 - 3.26 (m, 2 H), 3.14 - 3.06 (m, 1 H), 3.05 - 2.97 (m, 1 H), 2.95 - 2.81 (m, 3 H), 2.78 - 2.67 (m, 2 H), 2.1 1 - 1.97 (m, 1 H), 1.97 - 1.84 (m, 2 H), 1.77 (s, 4 H), 1.44 - 1.29 (m, 3 H), 1.17 - 1.09 (m, 1 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Example 19: c/s-/V-(4-Piperidylmethyl)spiro[cyclopropane-2,1'-tetralin]- 1 -amine dihydrochloride

Stepl

tert-Butyl 4-iitert-butoxycarbonyl-icis-spiroicvclopropane-2, 1'-tetralinl-1- yllaminolmethyllpiperidine-1-carboxylate

0.040 ml (0.29 mmol) of TEA were added to a solution of 0.060 g (0.29 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 11 ) in 3 ml of dry MeOH under nitrogen. Then, 0.061 g (0.29 mmol) of te/t-butyl 4-formylpiperidine-1 -carboxylate was added and the reaction mixture was stirred at r.t. for 3.5 h. 0.017 g (0.43 mmol) of NaBH ₄ was then carefully added, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was solubilised in 7 ml of DCM, the solution was cooled with ice and 0.050 ml (0.36 mmol) of TEA and 0.075 g (0.34 mmol) of di-te/t-butyl dicarbonate were added under nitrogen. The solution was stirred at r.t for 1 h, then kept in the freezer overnight. The reaction mixture was diluted with DCM, washed with brine, dried and concentrated. The residue was purified by flash chromatography (eluent: hexane/EtOAc 90:10) to afford te/t-butyl 4-[[te/t-butoxycarbonyl- [c/ ^' s-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]amino]methyl]piperidine-1 -carboxylate as a colorless oil (45 mg, 33%). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.15 - 6.93 (m, 3 H), 6.58 - 6.46 (m, 1 H), 4.24 - 3.91 (m, 2 H), 3.72 - 3.21 (m, 1 H), 3.01 - 2.78 (m, 3 H), 2.77 - 2.52 (m, 3 H), 2.15 - 1.75 (m, 4 H), 1.73 - 1.37 (m, 13 H), 1 .16 (bs, 12 H); MS (ESI): m/z: 493 [M+Na] ⁺ . Step 2

cis-N-(4-piperidylmethyl)spiroicvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride A solution of 0.043 g (0.091 mmol) of te/t-butyl 4-[[te/t-butoxycarbonyl-[c/ ^' s- spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]amino]methyl]piperidine-1 -carboxylate in Et ₂ 0/MeOH (2.4 ml/0.8 ml) was cooled with ice, then 1.827 ml (3.655 mmol) of 2 M HCI in Et ₂ 0 were added obtaining a colorless solution that was stirred at r.t. for 23 h. The reaction mixture was concentrated to give an oil that was taken up with Et ₂ 0. After evaporation of the solvent, this residue was triturated with Et ₂ 0 and the solid was filtered and heated at 40°C under vacuum to give c/s-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-tetralin]-1 -amine dihydrochloride as a light-yellow solid (23 mg, 73%). ¹ H NMR (D ₂ 0) δ (ppm): 7.24 - 6.86 (m, 4 H), 3.20 - 3.04 (m, 2 H), 2.95 - 2.77 (m, 3 H), 2.73 - 2.53 (m, 3 H), 2.33 - 2.19 (m, 1 H), 2.04 - 1.75 (m, 3 H), 1.74 - 1.67 (m, 1 H), 1 .62 - 1.49 (m, 1 H), 1 .47 - 1.31 (m, 2 H), 1.28 - 1.19 (m, 1 H), 1.18 - 0.93 (m, 2 H), 0.89 - 0.72 (m, 1 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Example 20: fra/7S-6 ^, -Bromo-A -(4-piperidylmethyl)spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride

Stepl

tert-Butyl 4-iiitrans-6'-bromospiroicvclopropane-2, 1 '-indanel-1-yllaminolmeth

1 -carboxylate

0.049 g (56%) of te/t-butyl 4-[[[irans-6'-bromospiro[cyclopropane-2,1 '-indane]-1 - yl]amino]methyl]piperidine-1 -carboxylate was prepared according to the procedure described for Example 14, Step 1 , starting from 0.055 g (0.20 mmol) of trans-6'- bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 9). ¹ H NMR (DMSO-de) δ (ppm): 7.24 - 7.16 (m, 1 H), 7.13 - 7.05 (m, 1 H), 6.90 - 6.80 (m, 1 H), 3.99 - 3.81 (m, 2 H), 2.95 - 2.80 (m, 2 H), 2.77 - 2.54 (m, 3 H), 2.47 - 2.40 (m, 1 H), 2.39 - 2.31 (m, 1 H), 2.29 - 2.20 (m, 1 H), 2.17 - 2.09 (m, 1 H), 1.76 - 1.48 (m, 4 H), 1.37 (s, 9 H), 1.30 - 1.16 (m, 1 H), 1.02 - 0.89 (m, 2 H), 0.75 - 0.66 (m, 1 H); MS (ESI): m/z: 380 [M-tBu] ⁺ .

Step 2

trans-6'-Bromo-N-(4-piperidylmethyl)spiro[cvclopropane-2, 1'-indane]-1 -amine

dihydrochloride

0.031 g (83%) of irans-6'-Bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 - amine dihydrochloride was prepared according to the procedure described for Example 16, Step 2. starting from 0.040 g (0.092 mmol) of te/t-butyl 4-[[[trans-6'- bromospiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 -carboxylate. ¹ H NMR (DMSO-de) δ (ppm): 9.52 (bs, 1 H), 9.44 (bs, 1 H), 8.88 (bs, 1 H), 8.68 (bs, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 7.06 (s, 1 H), 3.32 - 2.76 (m, 9 H), 2.43 - 2.22 (m, 2 H), 2.13 (bs, 1 H), 2.06 - 1.89 (m, 2 H), 1.54 - 1.33 (m, 4 H); MS (ESI): m/z: 335 [M+H] ⁺ . Example 21 : frans-/V-Benzylspiro[cyclopropane-2,1'-tetralin]-1 -amine hydrochloride

0.013 ml (0.095 mmol) of TEA was added to a solution of 0.020 g (0.095 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10) in 1 ml of dry MeOH under nitrogen. Then, 9.7 μΙ (0.095 mmol) of benzaldehyde was added and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was ice-cooled and 0.0056 g (0.14 mmol) of NaBH ₄ was added, and the mixture was stirred at r.t. for further 1 h. The reaction was cooled with ice, quenched with water and extracted with EtOAc. The organic phase was dried over Na ₂ S0 ₄ , filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: hexane/EtOAc 95:5). The resulting oil (18 mg) was solubilized in 1 ml of Et ₂ 0, the solution was cooled with ice, 0.051 ml (0.102 mmol) of 2 M HCI in Et ₂ 0 was added, and the mixture was then allowed to reach r.t. The reaction mixture was concentrated with a nitrogen stream, then the residue was triturated with Et ₂ 0. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to afford trans-N- benzylspiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride as a light-yellow solid (19 mg, 66%). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 9.54 (bs, 2 H), 7.63 - 7.53 (m, 2 H), 7.47 - 7.36 (m, 3 H), 7.14 - 7.03 (m, 3 H), 6.69 - 6.61 (m, 1 H), 4.31 (bs, 2 H), 3.08 - 2.95 (m, 1 H), 2.87 - 2.72 (m, 2 H), 2.02 - 1.71 (m, 4 H), 1.37 - 1.30 (m, 1 H), 1.24 - 1.16 (m, 1 H); MS (ESI): m/z: 264 [M+H] ⁺

Example 22: frans-/V-Benzylspiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.027 g (61 %) £rans-N-benzylspiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 21 , starting from 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8). ¹ H NMR (DMSO-de) δ (ppm): 9.56 (bs, 2 H), 7.59 - 7.50 (m, 2 H), 7.45 - 7.37 (m, 3 H), 7.26 - 7.09 (m, 3 H), 6.83 - 6.75 (m, 1 H), 4.36 - 4.19 (m, 2 H), 3.04 - 2.95 (m, 2 H), 2.91 (bs, 1 H), 2.31 - 2.15 (m, 2 H), 1.41 - 1.26 (m, 2 H); MS (ESI): m/z: 250 [M+H] ⁺ . Example 23: fra/7S-A -(Cyclopropylmethyl)spiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.036 g (56%) of irans-N-(cyclopropylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 21 , starting from 0.050 g (0.26 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 9.24 (bs, 2 H), 7.27 - 6.77 (m, 4 H), 3.13 - 2.96 (m, 3 H), 2.95 - 2.87 (m, 2 H), 2.39 - 2.18 (m, 2 H), 1 .43 - 1.33 (m, 2 H), 1.20 - 1.06 (m, 1 H), 0.64 - 0.31 (m, 4 H); MS (ESI): m/z: 214 [M+H] ⁺ . Example 24: frans-/V-(2,3-Dihydro-1 ,4-benzodioxin-6-ylmethyl)spiro[cyclopropane- 2,1 '-indane]-1 -amine hydrochloride

0.025 g (47%) of £rans-A/-(2,3-dihydro-1 ,4-benzodioxin-6-ylmethyl)spiro[cyclopropane-2,1 '- indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 21 , starting from 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 - amine hydrochloride (Example 8). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 9.51 - 9.26 (m, 2 H), 7.25 - 6.75 (m, 7 H), 4.28 - 4.08 (m, 6 H), 3.04 - 2.95 (m, 2 H), 2.87 (bs, 1 H), 2.29 - 2.14 (m, 2 H), 1.41 - 1.27 (m, 2 H); MS (ESI): m/z: 308 [M+H] ⁺ .

Example 25: fra/7S-A -[2-(4-Piperidyl)ethyl]spiro[cyclopropane-2,1'-indane]-1 -amine dihydrochloride

0.018 g (36%) of irans-N-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-indane]-1 -amine dihydrochloride was prepared according to the procedure described for Example 20, starting from 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8). ¹ H NMR (D ₂ 0) δ (ppm): 7.22 - 7.17 (m, 1 H), 7.15 - 7.05 (m, 2 H), 6.71 - 6.67 (m, 1 H), 3.31 - 3.21 (m, 2 H), 3.19 - 3.05 (m, 2 H), 3.03 - 2.93 (m, 2 H), 2.85 - 2.75 (m, 3 H), 2.19 - 2.05 (m, 2 H), 1.85 - 1.73 (m, 2 H), 1 .65 - 1.53 (m, 3 H), 1.42 - 1.18 (m, 4 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Example 26: 1 -Methyl-/V-[frans-spiro[cyclopropane-2,1'-indane]-1 -yl]piperidin-4- amine dihydrochloride

0.021 ml (0.15 mmol) of TEA and 0.018 ml (0.15 mmol) of 1 -methylpiperidin-4-one were added under nitrogen to a solution of 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane- 2,1 '-indane]-1 -amine hydrochloride (Example 8) in 2 ml of dry MeOH. The mixture was stirred at r.t. for 3 h. The solution was then treated with 0.048 g (0.21 mmol) of NaBH(OAc)3 at 0°C and the mixture was stirred at r.t. overnight. The reaction mixture was cooled with ice, quenched by adding 3 ml of 0.1 M NaOH and the product was extracted with EtOAc. The EtOAc extract was dried over Na ₂ SO ₄ , filtered and the solution concentrated. The crude mixture was purified by flash chromatography (eluent: DCM/MeOH/30% NH ₄ OH aq. 95:5:0.5). The resulting oil (15 mg) was solubilized in Et ₂ O/MeOH (1.5 ml/0.5 ml), the solution was cooled with ice and 2 M HCI in Et ₂ O was added (0.088 ml, 0.18 mmol). A solid separated and the mixture was then allowed to reach r.t. and stirred overnight. The reaction mixture was concentrated, then the residue was triturated with Et ₂ O and MeOH. Finally, the solid was crystallized with MeOH (0.9 ml) and iPr ₂ O (5-6 ml) to give 1 -methyl-N-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]piperidin- 4-amine dihydrochloride as a beige solid (10 mg, 20%). ¹ H NMR (D ₂ 0) δ (ppm): 7.22 - 7.05 (m, 3 H), 6.71 - 6.66 (m, 1 H), 3.57 - 3.41 (m, 3 H), 3.05 - 2.90 (m, 4 H), 2.84 - 2.67 (m, 4 H), 2.46 - 2.36 (m, 1 H), 2.30 - 2.21 (m, 1 H), 2.19 - 2.06 (m, 2 H), 1 .89 - 1.74 (m, 2 H), 1.46 - 1.39 (m, 1 H), 1.24 - 1.17 (m, 1 H); MS (ESI): m/z: 257 [M+H] ⁺ .

Example 27: /V-[frans-Spiro[cyclopropane-2,1'-indane]-1 -yl]piperidin-4-amine dihydrochloride

0.036 g (0.18 mmol) of te/t-butyl 4-oxopiperidine-1 -carboxylate was added under nitrogen to a solution of 0.035 g (0.18 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8) in dry MeOH (2 ml). The solution was treated with 0.080 g (0.36 mmol) of NaBH(OAc) ₃ at 0°C and the mixture was stirred at r.t. for 4 h. The reaction mixture was cooled with ice, quenched by adding NaHCO ₃ aq. and the product was extracted with EtOAc. The combined organic solutions were dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by flash chromatography (eluent: hexane/EtOAc 7:3). The resulting oil (35 mg) was solubilized in Et ₂ O/MeOH (2.7 ml/ 0.9 ml), the solution was cooled with ice, then 1.022 ml (2.044 mmol) of 2 M HCI in Et ₂ O was added obtaining a yellow suspension that was stirred at r.t. overnight. The reaction mixture was concentrated and the residue was triturated with Et ₂ O. Then, the solid was triturated with Et ₂ O and MeOH, filtered and heated at 40°C under vacuum to give Λ/- [irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]piperidin-4-amine dihydrochloride as a light- yellow solid (16 mg, 28%). ¹ H NMR (D ₂ O) δ (ppm): 7.24 - 7.19 (m, 1 H), 7.18 - 7.08 (m, 2 H), 6.74 - 6.68 (m, 1 H), 3.61 - 3.42 (m, 3 H), 3.07 - 2.94 (m, 4 H), 2.88 - 2.81 (m, 1 H), 2.46 - 2.38 (m, 1 H), 2.30 - 2.08 (m, 3 H), 1.89 - 1.75 (m, 2 H), 1 .51 - 1.44 (m, 1 H), 1.30 - 1.24 (m, 1 H); MS (ESI): m/z: 243 [M+H] ⁺ . Example 28: 8-Methyl-A -[fra/7S-spiro[cyclopropane-2,1'-indane]-1 -yl]-8- azabicyclo[3.2.1]octan-3-amine dihydrochloride

0.072 g (0.51 mmol) of 8-methyl-8-azabicyclo[3.2.1]octan-3-one was added under nitrogen to a solution of 0.100 g (0.51 1 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 - amine hydrochloride (Example 8) in 6 ml of dry MeOH and the solution was stirred at r.t. for 5 h. The reaction mixture was then ice-cooled, 0.060 g (1.5 mmol) of NaBH ₄ was added and the mixture was stirred at r.t. for 40 min. The mixture was ice-cooled, 20 ml of an aqueous NaHC03 solution was added and the product was extracted with EtOAc. The extract was washed with brine, dried over Na2S0 ₄ , filtered and the solvent evaporated. The crude product was purified by flash chromatography (eluent: DCM/MeOH/30% NH ₄ OH aq. 90:10:1 ) to afford a mixture of endo and exo derivatives that could not be separated by column chromatography. The obtained oil (67 mg) was solubilized in Et ₂ 0/MeOH (7 ml/0.230 ml), cooled with ice, then 0.356 ml (0.712 mmol) of 2 M HCI in Et ₂ 0 was added obtaining a suspension that was stirred at r.t. for 1 h. The reaction mixture was concentrated then the residue taken up with Et ₂ O and evaporated. The residue was triturated with Et ₂ 0 and MeOH (. The solid was filtered and heated at 40°C under vacuum to give 8-methyl-A/-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]-8- azabicyclo[3.2.1]octan-3-amine dihydrochloride as a yellow solid (56 mg, 31 %). ¹ H NMR (D ₂ O) δ (ppm): 7.23 - 7.03 (m, 3 H), 6.73 - 6.63 (m, 1 H), 3.93 (bs, 1 H), 3.86 - 3.68 (m, 1.5 H), 3.53 - 3.45 (m, 0.5 H), 3.05 - 2.87 (m, 2 H), 2.82 - 2.74 (m, 1 H), 2.70 - 2.58 (m, 3 H), 2.56 - 1.86 (m, 10 H), 1.48 - 1.38 (m, 1 H), 1 .29 - 1.19 (m, 1 H); MS (ESI): m/z: 283 [M+H] ⁺ .

Example 29: frans-/V4-[frans-Spiro[cyclopropane-2,1'-indane]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride and Example 30: c/s-/V4-[frans-Spiro[cyclopropane-2,1'- indane]-1 -yl]cyclohexane-1 ,4-diamine dihydrochloride

2 HCI 2 HCI

Steo1

trans-tert-Butyl N-i4-iitrans-spiroicyclopropane-2, 1 '-indanel-1- yllaminolcvclohexyllcarbamate and cis-tert-butyl N-i4-iitrans-spiroicyclopropane-2, 1'- indanel-1-yllaminolcvclohexyllcarbamate

0.1 15 g (0.51 1 mmol) of te/t-butyl N-(4-oxocyclohexyl)carbamate was added under nitrogen to a solution of 0.100 g (0.51 1 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 - amine hydrochloride (Example 8) in 9 ml of dry MeOH. The solution was treated with 0.228 g (1.02 mmol) of NaBH(OAc) ₃ at 0°C and the mixture was stirred at r.t. for 1 h 15 min. The reaction mixture was cooled with ice, quenched by adding NaHC0 ₃ aq. and the products were extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated. The products were purified by flash chromatography (eluent: hexane/acetone 85:15) to afford c/s-te/t-butyl N-[4-[[trans- spiro[cyclopropane-2,1 '-indane]-1 -yl]amino]cyclohexyl]carbamate as a light-yellow oil that partially solidified on-standing (65 mg, 36%) and frans-te/t-butyl N-[4-[[trans- spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]cyclohexyl]carbamate. trans-tert-B utyl Λ/-[4- [[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]amino]cyclohexyl]carbamate required a further purification (eluent: DCM/MeOH 97:3) and was obtained as a yellow oil that partially solidified on-standing (53 mg, 29%). ¹ H NMR (CDCI ₃ ) δ (ppm), trans: 7.25 - 7.08 (m, 3 H), 6.68 - 6.59 (m, 1 H), 4.43 - 4.28 (m, 1 H), 3.50 - 3.35 (m, 1 H), 3.10 - 2.94 (m, 2 H), 2.64 - 2.27 (m, 3 H), 2.22 - 1.88 (m, 5 H), 1.51 - 1.39 (m, 9 H), 1 .37 - 1.02 (m, 5 H), 0.95 - 0.73 (m, 1 H); ¹ H NMR (CDCI ₃ ) δ (ppm), cis: 7.24 - 7.08 (m, 3 H), 6.68 - 6.59 (m, 1 H), 4.74 - 4.52 (m, 1 H), 3.73 - 3.58 (m, 1 H), 3.12 - 2.94 (m, 2 H), 2.79 - 2.65 (m, 1 H), 2.41 - 2.23 (m, 2 H), 2.21 - 2.08 (m, 1 H), 1.82 - 1.38 (m, 17 H), 1.25 - 1.15 (m, 1 H), 0.95 - 0.68 (m, 1 H); MS (ESI): m/z: 357 [M+H] ⁺ .

Step 2a

trans-N4-itrans-spiroicvclopropane-2, 1 '-indanel-1 -yllcvclohexane-1 ,4-diamine

dihydrochloride

0.050 g (0.14 mmol) of trans-tert-Buty\ N-[4-[[£rans-spiro[cyclopropane-2,1 '-indane]-1 - yl]amino]cyclohexyl]carbamate was solubilized in 24 ml of dry dioxane, the solution was cooled with ice and 1.77 ml (7.08 mmol) of 4 M HCI in dioxane was added. The mixture was allowed to reach r.t. and stirred overnight. Further, 8 ml of dry MeOH was added and the cloudy solution was stirred at 40°C for 7 h then at r.t overnight. The reaction mixture was concentrated then the residue was taken up with Et ₂ O and evaporated. The residue was then triturated with Et ₂ O and MeOH. The solid was filtered and heated at 40°C under vacuum to give irans-N4-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride as a white solid (36 mg, 78%). ¹ H NMR (D ₂ O) δ (ppm): 7.22 - 7.17 (m, 1 H), 7.16 - 7.06 (m, 2 H), 6.72 - 6.67 (m, 1 H), 3.27 - 3.18 (m, 1 H), 3.14 - 2.91 (m, 3 H), 2.83 - 2.76 (m, 1 H), 2.31 - 2.22 (m, 1 H), 2.19 - 1.98 (m, 5 H), 1 .54 - 1.32 (m, 5 H), 1.26 - 1.18 (m, 1 H); MS (ESI): m/z: 257 [M+H] ⁺ . Step 2b

cis-N4-itrans-spiroicyclopropane-2, 1 '-indanel- 1 -yllcyclohexane- 1 , 4-diamine

dihydrochloride

0.059 g (0.17 mmol) of c/s-te/t-Butyl N-[4-[[£rans-spiro[cyclopropane-2,1 '-indane]-1 - yl]amino]cyclohexyl]carbamate was solubilized in 1 ml of dry dioxane, the solution was cooled with ice and 0.621 ml (2.48 mmol) of 4 M HCI in dioxane was added. The solution was then allowed to reach r.t. and stirred for 6.5 h. The reaction mixture was concentrated then the residue was taken up with Et ₂ O and evaporated. The residue was first triturated with Et ₂ O and MeOH, then with acetone and MeOH. The solid was filtered off and heated at 40°C under vacuum to give c/s-A/4-[irans-spiro[cyclopropane-2,1 '-indane]-1 - yl]cyclohexane-1 ,4-diamine dihydrochloride as a yellow solid (37 mg, 67%). ¹ H NMR (D ₂ O) δ (ppm): 7.24 - 7.17 (m, 1 H), 7.16 - 7.07 (m, 2 H), 6.73 - 6.67 (m, 1 H), 3.44 - 3.30 (m, 2 H), 3.06 - 2.91 (m, 2 H), 2.87 - 2.79 (m, 1 H), 2.23 - 2.07 (m, 2 H), 2.04 - 1.87 (m, 2 H), 1.86 - 1.64 (m, 6 H), 1.49 - 1.40 (m, 1 H), 1.28 - 1.21 (m, 1 H); MS (ESI): m/z: 257 [M+H] ⁺ . Example 31 : A -[fra/7S-Spiro[cyclopropane-2,1'-indane]-1 -yl]azetidin-3-amine dihydrochloride

2 HCI Step 1

tert-Butyl 3-itrans-spiroicvclopropane-2, 1 '-indanel-1 -ylliminoazetidine-1 -carboxylate

0.035 g (0.20 mmol) of te/t-butyl 3-oxoazetidine-1 -carboxylate was added under nitrogen to a solution of 0.040 g (0.20 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8) in 4.5 ml of dry MeOH and the solution was stirred at r.t. for 5 h. The mixture was then ice-cooled, 24 mg (0.61 mmol) of NaBH ₄ was added and the mixture was stirred at r.t. for 1 h. Further portions of 72 mg (1.8 mmol) and of 48 mg (1.2 mmol) of NaBH ₄ were added to the reaction at 1 h intervals. Then, the reaction mixture was cooled with ice, quenched by adding NaHC03 aq. and the product was extracted with EtOAc. The EtOAc extract was dried over Na ₂ S0 ₄ , filtered and the solution concentrated. The crude product was purified by flash chromatography (eluent: hexane/EtOAc 75:25) to afford te/t-butyl 3-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]iminoazetidine-1 -carboxylate as a colorless oil (16 mg, 25%). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.25 - 7.08 (m, 3 H), 6.66 - 6.57 (m, 1 H), 4.18 - 4.06 (m, 2 H), 3.73 - 3.57 (m, 3 H), 3.12 - 2.96 (m, 2 H), 2.37 - 2.23 (m, 2 H), 2.16 - 2.07 (m, 1 H), 1 .54 - 1.32 (m, 9 H), 1.19 - 1.12 (m, 1 H), 0.86 - 0.80 (m, 1 H); MS (ESI): m/z: 315 [M+H] ⁺ .

Step 2

N-[trans-spiro[cvclopropane-2, 1 '-indane]-1 -yl]azetidin-3-amine dihydrochloride A solution of 0.014 mg (0.045 mmol) of te/t-butyl 3-[£rans-spiro[cyclopropane-2,1 '-indane]- 1 -yl]iminoazetidine-1 -carboxylate in 1.6 ml of a Et ₂ 0/MeOH (3:1 ) mixture was cooled with ice and 0.445 ml (0.890 mmol) of 2 M HCI in Et ₂ 0 was added obtaining a light-yellow solution that was stirred at r.t. overnight. A solid separated and the reaction mixture was concentrated with a nitrogen stream then the residue was triturated with Et ₂ 0 and MeOH. The majority of the liquid was decanted off. The residue was taken up with Et ₂ 0 and the majority of the liquid was decanted off, then the residue was concentrated with a nitrogen stream. Further, the residue was crystallized with MeOH and Et ₂ O. The majority of the liquid was decanted off and the residue taken up with Et ₂ O. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give N-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]azetidin-3-amine dihydrochloride as a orange solid (8.6 mg, 67%). ¹ H NMR (D ₂ O) δ (ppm): 7.18 (m, 1 H), 7.14 - 7.04 (m, 2 H), 6.67 - 6.62 (m, 1 H), 4.45 - 4.37 (m, 1 H), 4.37 - 4.17 (m, 4 H), 3.05 - 2.90 (m, 2 H), 2.75 - 2.68 (m, 1 H), 2.17 - 2.05 (m, 2 H), 1 .38 - 1.30 (m, 1 H), 1 .22 - 1.15 (m, 1 H); MS (ESI): m/z: 215 [M+H] ⁺ .

Example 32: 1 -(4-Methylpiperazin-1 -yl)-2-[[frans-spiro[cyclopropane-2,1'-indane]-1 - yl]amino]ethanone dihydrochloride

2 HCI

Step 1

tert-Butyl N-itrans-spiroicvclopropane-2, 1 '-indanel-1 -yllcarbamate

0.077 ml (0.55 mmol) of TEA and 0.061 g (0.28 mmol) of di-fert-butyl dicarbonate were added at 0°C to a stirred suspension of 0.050 g (0.26 mmol) of £rans-spiro[cyclopropane- 2,1 '-indane]-1 -amine hydrochloride (Example 8) in 3 ml of DCM . The reaction mixture was warmed to r.t. and stirred for 4 h. DCM and H ₂ O were added to the reaction mixture. The organic phase was separated, washed with H ₂ 0 and dried over Na ₂ S0 ₄ . Evaporation of the solvent provided te/t-butyl A/-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate as a white solid (62 mg, 94%). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.25 - 7.06 (m, 3 H), 6.73 - 6.58 (m, 1 H), 4.75 (bs, 1 H), 3.19 - 2.96 (m, 2 H), 2.77 (bs, 1 H), 2.26 - 2.00 (m, 2 H), 1.54 - 1.27 (m, 10 H), 0.92 (bs, 1 H); MS (ESI): m/z: 204 [M+H-tBu] ⁺ .

Step 2

tert-Butyl N-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyl]-N-[trans-spiro[cv clopropane-2, 1 '- indanel-1 -v II carbarn ate

A solution of 0.060 g (0.23 mmol) of te/t-butyl N-[£rans-spiro[cyclopropane-2,1 '-indane]-1 - yl]carbamate in 2.5 ml of dry DMF was added dropwise at a temperature < 0°C (ice-salt) and under nitrogen atmosphere to a suspension of 0.023 g (0.58 mmol) of NaH in 3.5 ml of dry DMF. After 30 min, 0.074 g (0.35 mmol) of 2-chloro-1 -(4-methylpiperazin-1 - yl)ethanone hydrochloride (CAS 42951 -91 -7; Pharmazie, 1990, vol.45, p. 491 - 492 ) was added and the mixture was allowed to reach r.t overnight. The reaction mixture was poured into ice-water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2S0 ₄ , filtered and evaporated. The residue was taken up with toluene and evaporated. The crude product was purified by flash chromatography (eluent: DCM/MeOH 95:5) to afford te/t-butyl A/-[2-(4-methylpiperazin-1 -yl)-2-oxo-ethyl]-A/-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate as a light-yellow semi-solid (59 mg, 64%). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.23 - 7.06 (m, 3 H), 6.71 - 6.61 (m, 1 H), 4.38 (d, J = 16.1 Hz, 1 H), 3.80 (d, J = 16.1 Hz, 1 H), 3.74 - 3.39 (m, 4 H), 3.15 - 2.90 (m, 3 H), 2.51 - 2.37 (m, 4 H), 2.32 (bs, 3 H), 2.25 - 2.03 (m, 2 H), 1.51 - 1.16 (m, 10 H), 0.94 (bs, 1 H); MS (ESI): m/z: 400 [M+H] ⁺ .

Step 3

1 -(4-Methylpiperazin-1 -yl)-2-iitrans-spiroicyclopropane-2, 1 '-indanel-1 -yllaminolethanone dihydrochloride

0.54 ml (2.2 mmol) of 4 M HCI in dioxane was added dropwise at 0°C to a solution of 0.057g (0.14 mmol) of te/t-butyl A/-[2-(4-methylpiperazin-1 -yl)-2-oxo-ethyl]-A/-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate in 2 ml of dry MeOH and the yellow solution was stirred at r.t. for 4 h. The solution was concentrated and the residue was taken up with Et ₂ O and evaporated. The residue was first triturated with Et ₂ O, then with acetone. The majority of the liquid was decanted off, the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give 1 -(4-methylpiperazin-1 -yl)-2- [[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]amino]ethanone dihydrochloride as a light- yellow solid (32 mg, 61 %). ¹ H NMR (D ₂ 0, DCI) δ (ppm): 7.17 - 6.99 (m, 3 H), 6.67 - 6.60 (m, 1 H), 4.40 - 4.32 (m, 1 H), 4.27 - 4.10 (m, 2 H), 3.83 - 3.74 (m, 1 H), 3.45 - 3.32 (m, 3 H), 3.07 - 2.81 (m, 6 H), 2.75 (m, 3 H), 2.16 - 2.08 (m, 2 H), 1 .37 - 1.30 (m, 1 H), 1.27 - 1.20 (m, 1 H); MS (ESI): m/z: 300 [M+H] ⁺ .

Example 33: 1 -[4-[[[fra/7S-Spiro[cyclopropane-2,1'-indane]-1 -yl]amino]methyl]-1 - piperidyl]ethanone hydrochloride

Step 1

tert-Butyl 4-[[[trans-spiro[cvclopropane-2, 1 '-indane]- 1 -yl]-(2, 2.2- trifluoroacetyl)aminolmethyllpiperidine-1-carboxylate

0.394 ml (2.83 mmol) of TEA followed by 0.17 ml (1 .2 mmol) of trifluoroacetic anhydride was added at 0°C to a stirred solution of 0.336 g (0.942 mmol) of fert-butyl 4-[[[trans- spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 -carboxylate (Example 14, Step 1 ) in 10 ml of DCM . The reaction mixture was stirred at r.t. for 1 h, then diluted with DCM, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford te/t-butyl 4-[[[trans-spiro[cyclopropane- 2, 1 '-indane]-1 -yl]-(2,2,2-trifluoroacetyl)amino]methyl]piperidine-1 -carboxylate as a yellow gum that solidified on-standing (0.418 g, 98%). MS (ESI): m/z: 475 [M+Na] ⁺ . Step 2

2, 2, 2-trifluoro-N-(4-piperidylmeth yl)-N-itrans-spiroicyclopropane-2, 1 '-indanel- 1 - yllacetamide trifluoroacetate

0.699 ml (9.13 mmol) of trifluoroacetic acid was added to a stirred solution of 0.413 g (0.913 mmol) of te/t-butyl 4-[[[trans-spiro[cyclopropane-2,1 '-indane]-1 -yl]-(2,2,2- trifluoroacetyl)amino]methyl]piperidine-1 -carboxylate in 7 ml of dry DCM at 0°C and the reaction mixture was allowed to reach r.t. overnight. The reaction mixture was concentrated, taken up with DCM and evaporated, taken up with Et ₂ 0 and evaporated. The residue was triturated with Et ₂ 0. The beige solid was collected by filtration, washed with Et. ₂ 0 and dried under vacuum at 40°C to give 2,2,2-trifluoro-A/-(4-piperidylmethyl)-N- [irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide trifluoroacetate (352 mg, 83%). ¹ H NMR (D ₂ 0) δ (ppm): 7.22 - 7.04 (m, 3 H), 6.78 - 6.67 (m, 1 H), 3.76 - 2.69 (m, 9 H), 2.20 - 1.20 (m, 9 H); MS (ESI): m/z: 353 [M+H] ⁺ .

Step 3

N-[(1-acetyl-4^iperidyl)methyl]-2,2,2-trifluoro^-[trans-spir o[cyclopropane-2, V

yllacetamide

0.045 ml (0.32 mmol) of TEA followed by 0.01 1 ml (0.16 mmol) of acetyl chloride was added to a solution of 0.050 g (0.1 1 mmol) of 2,2,2-trifluoro-A/-(4-piperidylmethyl)-N- [£rans-spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide trifluoroacetate in 1.5 ml of DCM, cooled with ice. The reaction mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with DCM, a saturated solution of NH ₄ CI was added, and the layers were separated. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: hexane/EtOAc 25:75) to afford A/-[(1 -acetyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide as a colorless oil that solidified on standing (31.5 mg, 74%). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.26 - 7.1 1 (m, 3 H), 6.77 - 6.63 (m, 1 H), 4.77 - 4.58 (m, 1 H), 3.96 - 3.40 (m, 2 H), 3.28 - 2.77 (m, 5 H), 2.66 - 2.46 (m, 1 H), 2.17 - 1.06 (m, 12 H); MS (ESI): m/z: 395 [M+H] ⁺ . Step 4

1 -i4-iiitrans-spiroicyclopropane-2, 1 '-indanel-1 -yllaminolmethyll-1 -piperidvUethanone hydrochloride

0.380 ml (0.380 mmol) of 1 M NaOH was added at 0°C to a solution of 0.030 g (0.076 mmol) of Λ/-[(1 -acetyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans-spiro[ cyclopropane-2, 1 '- indane]-1 -yl]acetamide in 0.6 ml of EtOH and the solution was stirred at r.t. for 5 h. The reaction mixture was concentrated. The concentrated solution was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The obtained oil (20.6 mg) was solubilized in 1.5 ml of Et ₂ O, the solution was cooled with ice, 0.052 ml (0.104 mmol) of 2 M HCI in Et.2O was added and the mixture was then allowed to reach r.t. The reaction mixture was concentrated then the residue was triturated with Et ₂ O. The majority of the liquid was decanted off, the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to afford 1 -[4- [[[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]-1 -piperidyl]ethanone

hydrochloride as an off- white solid (16.1 mg, 63%). ¹ H NMR (D ₂ 0) δ (ppm): 7.23 - 7.05 (m, 3 H), 6.72 - 6.65 (m, 1 H), 4.29 - 4.19 (m, 1 H), 3.85 - 3.75 (m, 1 H), 3.09 - 2.91 (m, 5 H), 2.86 - 2.78 (m, 1 H), 2.61 - 2.51 (m, 1 H), 2.23 - 2.05 (m, 2 H), 2.04 - 1.91 (m, 4 H), 1.78 - 1.62 (m, 2 H), 1.44 - 1.34 (m, 1 H), 1.28 - 0.99 (m, 3 H); MS (ESI): m/z: 299 [M+H] ⁺ .

Example 34: Phenyl-[4-[[[trans-spiro[cyclopropane-2,1'-indane]-1 -yl]amino]methyl]- 1 -piperidyl]methanone hydrochloride

Step 1

N-[( 1 -benzoyl-4-piperidyl)methyl]-2, 2.2-trifluoro-N-[trans-spiro[cvclopropane-2, 1 '-indane]- 1 -yllacetamide

0.060 g (83%) of A/-[(1 -benzoyl-4-piperidyl)methyl]-2,2,2-trifluoro-N-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide was prepared according to the procedure described for Example 33, Step 3, starting from 0.074 g (0.16 mmol) of of 2,2,2-trifluoro- A/-(4-piperidylmethyl)-A/-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]acetamide

trifluoroacetate (Example 33, Step 2). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.49 - 7.34 (m, 5 H), 7.26 - 7.1 1 (m, 3 H), 6.76 - 6.62 (m, 1 H), 4.75 (bs, 1 H), 4.04 - 3.44 (m, 2 H), 3.30 - 2.66 (m, 6 H), 2.17 - 1.96 (m, 3 H), 1.93 - 1.51 (m, 3 H), 1.47 - 1.06 (m, 3 H); MS (ESI): m/z: 457 [M+H] ⁺ .

Step 2

Phenyl-i4-iiitrans-spiroicyclopropane-2, 1 '-indanel-1 ' -yllaminolmethyll-1 - piperidvUmethanone hydrochloride

0.646 ml (0.646 mmol) of 1 M NaOH was added at 0°C to a solution of 0.059 g (0.13 mmol) of Λ/-[(1 -benzoyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans-spiro [cyclopropane-2, 1 '- indane]-1 -yl]acetamide in 1 ml of EtOH and the solution was stirred at r.t. overnight. The reaction mixture was concentrated. The concentrated solution was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The obtained residue (white semi-solid, 47 mg) was solubilized in ACN/MeOH (3 ml/1 ml), the solution was cooled with ice and 0.049 ml (0.20 mmol) of 4 M HCI in dioxane was added. The yellow solution was allowed to reach r.t. and then concentrated. The residue was taken up with Et ₂ 0 and evaporated. The residue was first triturated with Et^O, then with Et^O and MeOH. The majority of the liquid was decanted off, the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give phenyl-[4-[[[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]amino]methyl]-1 - piperidyl]methanone hydrochloride as a yellow solid (42 mg, 82%). ¹ H NMR (D ₂ 0) δ (ppm): 7.43 - 7.32 (m, 3 H), 7.31 - 7.25 (m, 2 H), 7.24 - 7.18 (m, 1 H), 7.17 - 7.07 (m, 2 H), 6.73 - 6.66 (m, 1 H), 4.46 - 4.36 (m, 1 H), 3.67 - 3.58 (m, 1 H), 3.13 - 2.93 (m, 5 H), 2.89 - 2.77 (m, 2 H), 2.24 - 1.99 (m, 3 H), 1.89 - 1.76 (m, 1 H), 1 .67 - 1.54 (m, 1 H), 1 .45 - 1.37 (m, 1 H), 1.32 - 1.10 (m, 3 H); MS (ESI): m/z: 361 [M+H] ⁺ . Example 35: fra/7S-A -[(1 -Benzyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride

Step 1

N-H 1 -benzyl-4-piperidyl)methyll-2, 2, 2-trifluoro-N-itrans-spiroicvclopropane-2, 1 '-indanel-1- yl]acetamide

0.022 ml (0.159 mmol) of TEA and 0.017 ml (0.167 mmol) of benzaldehyde were added under nitrogen to a solution of 0.074 g (0.1587 mmol) of 2,2,2-trifluoro-N-(4- piperidylmethyl)-N-[£rans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]acetamide trifluoroacetate (Example 33, Step 2) in 2 ml of dry MeOH. The reaction was stirred at r.t. for 2 h. The solution was then treated with 0.050 g (0.22 mmol) of NaBH(OAc) ₃ at 0°C and the mixture was stirred at r.t. overnight. A further portion of 0.050 g (0.22 mmol) of NaBH(OAc) ₃ was added to the ice-cooled reaction and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was cooled with ice, quenched by adding water and the product was extracted with EtOAc. The EtOAc extract was dried over Na2SO ₄ , filtered and the solution was concentrated. The crude product was purified by flash chromatography (eluent: hexane/EtOAc 25:75) to afford A/-[(1 -benzyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide as a yellow oil (24 mg, 34%). ¹ H NMR (CDCI ₃ , D ₂ O) δ (ppm): 7.47 - 7.01 (m, 8 H), 6.77 - 6.60 (m, 1 H), 3.84 - 2.76 (m, 9 H), 2.16 - 1.05 (m, 1 1 H); MS (ESI): m/z: 443 [M+H] ⁺ .

Step 2

trans-N-K 1 -benzyl-4-piperidyl)methyllspiro[cvclopropane-2, 1 '-indanel-1 -amine

dihydrochloride 0.256 ml (0.256 mmol) of 1 M NaOH was added at 0°C to a solution of 0.023 g (0.051 mmol) of Λ/-[(1 -benzyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans-spiro[ cyclopropane-2,1 '- indane]-1 -yl]acetamide in 1 ml of EtOH and the solution was stirred at r.t. overnight. The reaction mixture was concentrated. The concentrated solution was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The obtained oil (16 mg) was solubilized in Et ₂ 0/MeOH (1 ml/0.3 ml), the solution was cooled with ice and 0.069 ml (0.138 mmol) of 2 M HCI in Et ₂ 0 was added. The obtained suspension was then allowed to reach r.t. and concentrated with a nitrogen stream. The residue was triturated with Et ₂ 0 and the majority of the liquid was decanted off (twice), then the residue was concentrated with a nitrogen stream. Furthermore, the residue was triturated with Et ₂ 0 and MeOH and the majority of the liquid was decanted off. The residue was taken up with Et ₂ 0 and the majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give irans-A/-[(1 -benzyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '- indane]-1 -amine dihydrochloride as a yellow solid (15 mg, 70%). ¹ H NMR (D ₂ 0) δ (ppm): 7.45 - 7.27 (m, 5 H), 7.26 - 7.04 (m, 3 H), 6.73 - 6.64 (m, 1 H), 4.17 (bs, 2 H), 3.50 - 3.34 (m, 2 H), 3.14 - 2.74 (m, 7 H), 2.23 - 1.78 (m, 5 H), 1.49 - 1.32 (m, 3 H), 1 .30 - 1.20 (m, 1 H); MS (ESI): m/z: 347 [M+H] ⁺ .

Example 36: fra/7S-A -[(1 -Methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride

Step 1

2, 2, 2-trifluoro-N-i( 1 -methyl-4-piperidyl)methyll-N-itrans-spiroicvclopropane-2, 1 '-indanel-1- yllacetamide 0.060 ml (37%, 0.793 mmol) of aqueous formaldehyde was added to a solution of 0.074 g (0.16 mmol) of 2,2,2-trifluoro-A/-(4-piperidylmethyl)-A/-[irans-spiro[cyclo propane-2,1 '- indane]-1 -yl]acetamide trifluoroacetate (Example 33, Step 2) in 3 ml of MeOH . The solution was treated with 0.106 g (0.476 mmol) of NaBH(OAc) ₃ at 0°C and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was cooled with ice, quenched by adding water, the pH of the aqueous layer was adjusted to 7-8 with NaHC0 ₃ and the product was extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na ₂ S0 ₄ , filtered and the solution was concentrated under reduced pressure to give 2,2,2-trifluoro- Λ/-[(1 -methyl-4-piperidyl)methyl]-A/-[irans-spiro[cyclopropane-2, 1 '-indane]-1 -yl]acetamide as a yellow oil (43 mg, 74%). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.26 - 7.09 (m, 3 H), 6.78 - 6.61 (m, 1 H), 3.89 - 2.75 (m, 7 H), 2.44 - 2.21 (m, 3 H), 2.17 - 1.88 (m, 4 H), 1 .87 - 1.06 (m, 7 H); MS (ESI): m/z: 367 [M+H] ⁺ . Step 2

trans-N-K 1 -methyl-4-piperidyl)methyllspiroicvclopropane-2, 1 '-indanel-1 -amine

dihydrochloride

0.017 g (42%) of irans-A/-[(1 -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]-1 - amine dihydrochloride was prepared according to the procedure described for Example 35, Step 2, starting from 0.042 g (0.1 1 mmol) of 2,2,2-trifluoro-A/-[(1 -methyl-4- piperidyl)methyl]-A/-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide. ¹ H NMR (D ₂ 0) δ (ppm): 7.25 - 7.06 (m, 3 H), 6.75 - 6.65 (m, 1 H), 3.48 - 3.37 (m, 2 H), 3.15 - 2.80 (m, 7 H), 2.79 - 2.68 (m, 3 H), 2.24 - 1.89 (m, 5 H), 1 .51 - 1.35 (m, 3 H), 1 .30 - 1.20 (m, 1 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Example 37: frans-/V-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- indane]-1 -amine dihydrochloride

Step 1

2, 2, 2-trifluoro-N-i( 1 -isopropyl-4-piperidyl)methyll-N-itrans-spiroicvclopropane-2 , 1 '-indanel- 1 -yllacetamide

0.024 ml (0.24 mmol) of isopropyl iodide and 0.067 g (0.48 mmol) of K ₂ C0 ₃ were added to a solution of 0.075 g (0.16 mmol) of 2,2,2-trifluoro-N-(4-piperidylmethyl)-A/-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide trifluoroacetate (Example 33, Step 2) in 4 ml of acetonitrile and the mixture was stirred in a sealed tube at 80°C for 7 h and then at r.t. overnight. The reaction mixture was filtered through a sintered glass to eliminate most of the inorganic salts and the solvent was removed under vacuum. The residue was partitioned between EtOAc and water, the pooled organic phases were washed with brine, dried over Na ₂ S0 ₄ , filtered and the solvent removed under vacuum. The residue was purified by flash chromatography (eluent: DCM/MeOH/30% NH ₄ OH aq. 95:5:0.5) to afford 2,2,2-trifluoro-A/-[(1 -isopropyl-4-piperidyl)methyl]-A/-[irans-spiro[cyclopropane- 2,1 '-indane]- 1 -yl]acetamide as a yellow oil that solidified on standing (45 mg, 71 %). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.26 - 7.10 (m, 3 H), 6.78 - 6.60 (m, 1 H), 3.84 - 2.58 (m, 8 H), 2.40 - 1.95 (m, 4 H), 1.91 - 1.23 (m, 7 H), 1.20 - 0.93 (m, 6 H); MS (ESI): m/z: 395 [M+H] ⁺ .

Step 2

trans-N-[(1 -isopropyl-4-piperidyl)methyl]spiro[cvclopropane-2, 1 '-indane]-1 -amine dihydrochloride 0.033 g (80%) of irans-A/-[(1 -isopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]- 1 -amine dihydrochloride was prepared according to the procedure described for Example 35, Step 2, starting from 0.044 g (0.1 1 mmol) of 2,2,2-trifluoro-A/-[(1 -isopropyl-4- piperidyl)methyl]-A/-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide. ¹ H NMR (D ₂ 0) δ (ppm): 7.24 - 7.06 (m, 3 H), 6.73 - 6.65 (m, 1 H), 3.43 - 3.30 (m, 3 H), 3.15 - 2.81 (m, 7 H), 2.23 - 1.92 (m, 5 H), 1.52 - 1.35 (m, 3 H), 1 .31 - 1.23 (m, 1 H), 1 .22 - 1.13 (m, 6 H); MS (ESI): m/z: 299 [M+H] ⁺ . Example 38: fra/7S-A -[(1 -Phenethyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- indane]-1 -amine dihydrochloride

0.008 g (30%) of irans-N-[(1 -phenethyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]- 1 -amine dihydrochloride was prepared according to the procedure described for Example 36, starting from 0.033 g (0.072 mmol) of 2,2,2-trifluoro-N-(4-piperidylmethyl)-N-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide trifluoroacetate (Example 33, Step 2). ¹ H NMR (D ₂ 0) δ (ppm): 7.33 - 7.08 (m, 8 H), 6.74 - 6.68 (m, 1 H), 3.63 - 3.51 (m, 2 H), 3.32 - 2.76 (m, 1 1 H), 2.24 - 1.91 (m, 5 H), 1.53 - 1.37 (m, 3 H), 1 .30 - 1.22 (m, 1 H); MS (ESI): m/z: 361 [M+H] ⁺ .

Example 39: fra/7S-A -[2-(4-Piperidyl)ethyl]spiro[cyclopropane-2,1'-tetralin]-1 -amine dihydrochloride

Stepl

tert-butyl 4-[2-[[trans-spiro[cvclopropane-2, 1 '-tetralin]-1 ' -yl]amino]ethyl]piperidine-1 - carboxylate 0.024 g (26%) of tert-butyl 4-[2-[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]ethyl]piperidine-1 -carboxylate was prepared according to the procedure described for Example 14, Step 1 , starting from 0.050 g (0.24 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10). ¹ H NMR (CDCI3, D ₂ 0) δ (ppm): 7.18 - 6.94 (m, 3 H), 6.72 - 6.54 (m, 1 H), 4.26 - 3.90 (m, 2 H), 3.01 - 2.53 (m, 6 H), 2.44 - 2.29 (m, 1 H), 2.1 1 - 1.37 (m, 18 H), 1.24 - 1.18 (m, 1 H), 1.16 - 1.03 (m, 2 H), 0.75 - 0.63 (m, 1 H); MS (ESI): m/z: 385 [M+H] ⁺ .

Step 2

trans-N-i2-(4-Piperidyl)ethyllspiroicvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride

A solution of 0.022 mg (0.057 mmol) of te/t-butyl 4-[2-[[£rans-spiro[cyclopropane-2,1 '- tetralin]-1 -yl]amino]ethyl]piperidine-1 -carboxylate in 2 ml of a Et ₂ 0/MeOH (3:1 ) mixture was cooled with ice and 0.6 ml (1.14 mmol) of 2 M HCI in Et ₂ 0 was added obtaining a light-yellow solution that was stirred at r.t. overnight. The reaction mixture was concentrated then the residue was taken up with Et ₂ 0 and concentrated (twice). The residue was crystallized from MeOH and Et ₂ 0. The majority of the liquid was decanted off and the residue was treated with acetone. The majority of the liquid was decanted off again and the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give irans-N-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine dihydrochloride as a yellow solid (14 mg, 70%). ¹ H NMR (D ₂ 0) δ (ppm): 7.1 1 - 7.01 (m, 3 H), 6.65 - 6.54 (m, 1 H), 3.34 - 3.02 (m, 4 H), 2.93 - 2.68 (m, 5 H), 1 .89 - 1.71 (m, 6 H), 1.70 - 1.55 (m, 3 H), 1.47 - 1.39 (m, 1 H), 1.38 - 1.19 (m, 2 H), 1.17 - 1.09 (m, 1 H); MS (ESI): m/z: 285 [M+H] ⁺ . Example 40: fra/7S-A 4-[fra/7S-Spiro[cyclopropane-2,1 '-tetralin]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride and Example 41 : c;s-/V4-[irans-Spiro[cyclopropane-2,1'- tetralin]-1 -yl]cyclohexane-1 ,4-diamine dihydrochloride

Steo1

trans-tert-Butyl N-[4-[[trans-spiro[cvclopropane-2, 1 '-tetralin]-1 - yllaminolcvclohexyllcarbamate and cis-tert-butyl N-i4-iitrans-spiroicyclopropane-2, 1'- tetralinl-1 ' -yllaminolcvclohexyllcarbamate

0.058 g (47%) of trans-tert-bu y\ N-[4-[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]cyclohexyl]carbamate and 0.039 g (31 %) of c/ ^' s-te/t-butyl N-[4-[[trans- spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]amino]cyclohexyl]carbamate were prepared according to the procedure described for Example 29 and Example 30, Step 1 , starting from 0.070 g (0.334 mmol) of £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm), trans: 7.15 - 6.99 (m, 3 H), 6.66 - 6.56 (m, 1 H), 3.40 (bs, 1 H), 2.93 - 2.78 (m, 2 H), 2.53 - 2.37 (m, 2 H), 2.08 - 1.85 (m, 6 H), 1.84 - 1.71 (m, 2 H), 1.53 - 1.39 (m, 9 H), 1.24 - 1.03 (m, 5 H), 0.70 - 0.62 (m, 1 H); ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm), cis: 7.15 - 6.99 (m, 3 H), 6.66 - 6.57 (m, 1 H), 3.63 (bs, 1 H), 2.97 - 2.80 (m, 2 H), 2.74 (bs, 1 H), 2.39 (bs, 1 H), 2.04 - 1.88 (m, 2 H), 1 .85 - 1.39 (m, 19 H), 1.24 - 1.19 (m, 1 H), 0.71 (bs, 1 H); MS (ESI): m/z: 371 [M+H] ⁺ .

Step 2a

trans-N4-[trans-spiro[cvclopropane-2, 1 '-tetralinl-1 -yllcyclohexane-1 ,4-diamine

dihydrochloride 0.054 g (0.146 mmol) of frans-te/t-butyl A/-[4-[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]cyclohexyl]carbamate was dissolved in 3 ml of dry dioxane, the solution was cooled with ice and 0.55 ml (2.19 mmol) of 4 M HCI in dioxane was added. The mixture was allowed to reach r.t. and stirred for 2 h 30'. Further, 1 ml of dry MeOH was added and the cloudy solution was stirred at 40°C for 3 h and then at r.t overnight. The reaction mixture was concentrated, then the residue was taken up with Et ₂ 0 and the solvent was evaporated. The remaining residue was triturated with Et.20 and MeOH, filtered and heated at 40°C under vacuum to give irans-N4-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]cyclohexane-1 ,4-diamine dihydrochloride as an off-white solid (37 mg, 74%). ¹ H NMR (D ₂ 0) δ (ppm): 7.13 - 7.03 (m, 3 H), 6.69 - 6.59 (m, 1 H), 3.35 - 3.22 (m, 1 H), 3.18 - 3.06 (m, 1 H), 2.96 - 2.88 (m, 1 H), 2.82 - 2.71 (m, 2 H), 2.38 - 2.00 (m, 4 H), 1 .86 - 1.73 (m, 4 H), 1.61 - 1.33 (m, 5 H), 1.21 - 1.13 (m, 1 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Step 2b

cis-N4-itrans-spiroicyclopropane-2, 1 '-tetralinl- 1 -yllcyclohexane- 1 , 4-diamine

dihydrochloride

0.028 g (82%) of c/ ^' s-A/4-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride was prepared according to the procedure described for Example 30, Step 2b. starting from 0.037 g (0.10 mmol) of c/s-fert-butyl N-[4-[[trans- spiro[cyclopropane-2,1 '-tetralin]-1 -yl]amino]cyclohexyl]carbamate. ¹ H NMR (D ₂ O) δ (ppm): 7.13 - 7.04 (m, 3 H), 6.70 - 6.58 (m, 1 H), 3.49 - 3.36 (m, 2 H), 3.00 - 2.92 (m, 1 H), 2.82 - 2.70 (m, 2 H), 2.1 1 - 1.64 (m, 12 H), 1 .50 - 1.43 (m, 1 H), 1 .23 - 1.16 (m, 1 H); MS (ESI): m/z: 271 [M+H] ⁺ .

Example 42: frans-/V-[(1 -Methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'-tetralin] - 1 -amine dihydrochloride

Step 1

tert-Butyl 4-[[[trans-spiro[cvclopropane-2, 1'-teralin]-1-yl]-(2,2,2- trifluoroacetyl)aminolmethyllpiperidine-1-carboxylate

0.303 g (75%) of tert-butyl 4-[[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]-(2,2,2- trifluoroacetyl)amino]methyl]piperidine-1 -carboxylate was prepared according to the procedure described for Example 33, Step 1 , starting from 0.322 g (0.869 mmol) of tert- butyl 4-[[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]amino]methyl]piperidine-1 -carboxylate (Example 18, Step 1 ). MS (ESI): m/z: 489 [M+Na] ⁺ .

Step 2

2,2,2-trifluoro^-(4-piperidylmethyl)^-itrans-spiroicvclop ropane-2, 1'-tetrali

yllacetamide trifluoroacetate

0.269 g (87%) of 2,2,2-trifluoro-A/-(4-piperidylmethyl)-A/-[irans-spiro[cyclo propane-2,1 '- tetralin]-1 -yl]acetamide trifluoroacetate was prepared according to the procedure described for Example 33, Step 2, starting from 0.301 g (0.645 mmol) of te/t-butyl 4- [[[£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]-(2,2,2- trifluoroacetyl)amino]methyl]piperidine-1 -carboxylate. ¹ H NMR (D ₂ 0) δ (ppm): 7.13 - 6.99 (m, 3 H), 6.74 - 6.63 (m, 1 H), 3.86 - 2.58 (m, 9 H), 2.22 - 1.19 (m, 1 1 H); MS (ESI): m/z: 367 [M+H] ⁺ .

Step 3

2, 2, 2-trifluoro-N-i( 1 -methyl-4-piperidyl)methyll-N-itrans-spiroicvclopropane-2, 1 '-tetralinl-1- yllacetamide 0.069 g (quant.) of 2,2,2-trifluoro-A/-[(1 -methyl-4-piperidyl)methyl]-N-[irans- spiro[cyclopropane-2,1 '-tetralin]-1 -yl]acetamide was prepared according to the procedure described for Example 36, Step 1 , starting from 0.080 g (0.166 mmol) of 2,2,2-trifluoro-/V- (4-piperidylmethyl)-A/-[irans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yl]acetamide

trifluoroacetate. ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.21 - 7.03 (m, 3 H), 6.76 - 6.54 (m, 1 H), 3.96 - 2.73 (m, 7 H), 2.54 - 2.32 (m, 3 H), 2.29 - 1.01 (m, 13 H); MS (ESI): m/z: 381 [M+H] ⁺ . Step 4

trans-N-[( 1 -methyl-4-piperidyl)methyl]spiro[cvclopropane-2, 1 '-tetralin]-1 -amine

dihydrochloride 1.665 ml (1.665 mmol) of 1 M NaOH was added at 0°C to a solution of 0.0630 g (0.167 mmol) of 2,2,2-trifluoro-A/-[(1 -methyl-4-pipe dyl)methyl]-N-[irans-spiro[cyclopropane-2, 1 '- tetralin]-1 -yl]acetamide in 4.2 ml of EtOH and the solution was stirred at r.t. overnight. The reaction mixture was concentrated and partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO ₄ , filtered and evaporated. The obtained oil (45 mg) was solubilized in Et ₂ O/MeOH (3.6 ml/1.2 ml), the solution was cooled with ice and 0.237 ml (0.474 mmol) of 2 M HCI in Et ₂ O was added. The obtained suspension was then allowed to reach r.t. and concentrated. The residue was taken up with Et ₂ O and concentrated (twice). The residue was then crystallized with MeOH and Et ₂ O. The majority of the liquid was decanted off and the residue was taken up with Et ₂ O. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give £rans-A/-[(1 -methyl-4- piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine dihydrochloride as an off-white solid (26 mg, 44%). ¹ H NMR (D ₂ O) δ (ppm): 7.15 - 7.01 (m, 3 H), 6.66 - 6.56 (m, 1 H), 3.48 - 3.40 (m, 2 H), 3.19 - 2.70 (m, 10 H), 2.16 - 1.77 (m, 7 H), 1.54 - 1.38 (m, 3 H), 1 .24 - 1.13 (m, 1 H); MS (ESI): m/z: 285 [M+H] ⁺ .

Example 43: frans-/V-[(1 -Phenethyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- tetralin]-1 -amine dihydrochloride

Step 1

2, 2, 2-trifluoro-N-[( 1 -phenethyl-4-piperidyl)methyl]-N-[trans-spiro[cvclopropane-2 , 1 '- tetralinl-1 -yllacetamide 0.151 ml (1.166 mmol) of 2-phenylacetaldehyde were added to a solution of 0.080 g (0.166 mmol) of 2,2,2-trifluoro-A/-(4-piperidylmethyl)-A/-[irans-spiro[cyclo propane-2,1 '- tetralin]-1 -yl]acetamide trifluoroacetate (Example 42, Step 2) in 3.5 ml of MeOH. The solution was treated with 0.1 1 g (0.50 mmol) of NaBH(OAc)3 at 0°C and the mixture was stirred at r.t. overnight. The reaction mixture was then cooled with ice, quenched by adding water, the pH of the aqueous layer was adjusted to 7-8 with NaHC03 and the product was extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO ₄ , filtered and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: Hexane/ EtOAc 1 :9) to afford 2,2,2-trifluoro- A/-[(1 -phenethyl-4-piperidyl)methyl]-A/-[irans-spiro[cyclopropane- 2,1 '-tetralin]-1 - yl]acetamide as a colorless thick oil (66 mg, 85%). ¹ H NMR (CDCI ₃ , D ₂ O) δ (ppm): 7.43 - 7.00 (m, 8 H), 6.76 - 6.57 (m, 1 H), 3.97 - 2.47 (m, 1 1 H), 2.20 - 0.98 (m, 13 H); MS (ESI): m/z: 471 [M+H] ⁺ .

Step 2

trans-N-K 1 -phenethyl-4-piperidyl)methyllspiroicvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride

1.36 ml (1.36 mmol) of 1 M NaOH was added at 0°C to a solution of 0.0640 g (0.136 mmol) of 2,2,2-trifluoro-A/-[(1 -phenethyl-4-piperidyl)methyl]-A/-[irans-spiro[cyclopropane- 2,1 '-tetralin]-1 -yl]acetamide in 5.5 ml of EtOH and the solution was stirred at r.t. overnight. MeOH (2 ml) was added and the reaction mixture was heated at 40°C overnight. The reaction mixture was concentrated. The concentrated solution was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO ₄ , filtered and evaporated. The residue was purified by flash chromatography (eluent: DCM/ MeOH 96:4) to afford a light-yellow oil that solified on standing (20 mg). The obtained compound (20 mg) was solubilized in Et ₂ O/MeOH (1.5 ml/0.5 ml), the solution was cooled with ice and 0.080 ml (0.16 mmol) of 2 M HCI in Et ₂ O was added. The obtained suspension was then allowed to reach r.t. and concentrated. The residue was taken up with Et ₂ 0 and concentrated (twice). The residue was then crystallized with MeOH and Et ₂ 0. The majority of the liquid was decanted off and the residue was taken up with Et ₂ 0. The majority of the liquid was decanted off then the residue was concentrated with a nitrogen stream and heated at 40°C under vacuum to give £rans-N-[(1 -phenethyl-4- piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 -amine dihydrochloride as a white solid (6 mg, 10%). ¹ H NMR (D ₂ 0) δ (ppm): 7.35 - 6.99 (m, 8 H), 6.65 - 6.54 (m, 1 H), 3.64 - 3.48 (m, 2 H), 3.31 - 2.70 (m, 1 1 H), 2.16 - 1.71 (m, 7 H), 1.54 - 1.34 (m, 3 H), 1.22 - 1.09 (m, 1 H); MS (ESI): m/z: 375 [M+H] ⁺ .

Example 44: frans-/V-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- tetralin]-1 -amine dihydrochloride

Step 1

2, 2, 2-trifluoro-N-i( 1 -isopropyl-4-piperidyl)methyll-N-itrans-spiroicvclopropane-2 , 1 '-tetralinl- 1 -yllacetamide 0.063 g (93%) of 2,2,2-trifluoro-A/-[(1 -isopropyl-4-piperidyl)methyl]-N-[irans- spiro[cyclopropane-2,1 '-tetralin]-1 -yl]acetamide was prepared according to the procedure described for Example 37, Step 1 , starting from 0.080 g (0.166 mmol) of 2,2,2-trifluoro-/V- (4-piperidylmethyl)-A/-[irans-spiro[cyclopropane-2, 1 '-tetralin]-1 -yljacetamide

trifluoroacetate, Example 42, Step 2. ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.19 - 7.00 (m, 3 H), 6.77 - 6.55 (m, 1 H), 3.98 - 2.69 (m, 8 H), 2.40 - 0.97 (m, 19 H); MS (ESI): m/z: 409 [M+H] ⁺ .

Step 2 trans-N-[( 1 -lsopropyl-4-piperidyl)methyllspiro[cvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride

0.033 g (57%) irans-N-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 - amine dihydrochloride was prepared according to the procedure described for Example 42, Step 4. starting from 0.0610 g (0.149 mmol) of 2,2,2-trifluoro-N-[(1 -isopropyl-4- piperidyl)methyl]-N-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]acetamide. ¹ H NMR (D ₂ 0) δ (ppm): 7.14 - 7.03 (m, 3 H), 6.69 - 6.57 (m, 1 H), 3.43 - 3.33 (m, 3 H), 3.19 - 2.69 (m, 7 H), 2.16 - 1.73 (m, 7 H), 1.55 - 1.38 (m, 3 H), 1.25 - 1.10 (m, 7 H); MS (ESI): m/z: 313 [M+H] ⁺ .

Example 45: 1 -(4-Methylpiperazin-1 -yl)-2-[[fra/7S-spiro[cyclopropane-2,1'-tetralin]-1 - yl]amino]ethanone dihydrochloride

Step 1

tert-Butyl N-itrans-spiroicvclopropane-2, 1 '-tetralinl-1 -vHcarbamate 0.065 g (quant.) of te/t-butyl A/-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]carbamate was prepared according to the procedure described for Example 32, Step 1 , starting from 0.0500 g (0.238 mmol) of £rans-spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.15 - 6.97 (m, 3 H), 6.71 - 6.54 (m, 1 H), 4.84 - 4.63 (m, 1 H), 2.94 - 2.75 (m, 3 H), 1.94 - 1.72 (m, 4 H), 1 .52 - 1.33 (m, 10 H), 0.89 - 0.71 (m, 1 H); MS (ESI): m/z: 218 [M+H-tBu] ⁺ .

Step 2

tert-Butyl N-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyll-N-[trans-spiro[cv clopropane-2, 1 '- tetralinl-1 -yllcarbamate 0.050 g (53%) of te/t-butyl N-[2-(4-methylpiperazin-1 -yl)-2-oxo-ethyl]-N-[irans- spiro[cyclopropane-2,1 '-tetralin]-1 -yl]carbamate was prepared according to the procedure described for Example 32, Step 2. starting from 0.063 g (0.230 mmol) of te/t-butyl N- [irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]carbamate. ¹ H NMR (CDC , D ₂ 0) δ (ppm): 7.16 - 6.98 (m, 3 H), 6.73 - 6.54 (m, 1 H), 4.48 - 4.32 (m, 1 H), 3.88 - 3.19 (m, 6 H), 2.97 - 2.75 (m, 2 H), 2.56 - 2.24 (m, 7 H), 2.06 - 1.56 (m, 4 H), 1.51 - 1.20 (m, 10 H), 1 .03 - 0.79 (m, 1 H); MS (ESI): m/z: 414 [M+H] ⁺ . Step 3

1 -(4-Methylpiperazin-1 -yl)-2-[[trans-spiro[cyclopropane-2, 1 '-tetralinl-1 -yllaminolethanone dihydrochloride

0.042 g (97%) of 1 -(4-methylpiperazin-1 -yl)-2-[[irans-spiro[cyclopropane-2,1 '-tetralin]-1 - yl]amino]ethanone dihydrochloride was prepared according to the procedure described for Example 32, Step 3, starting from 0.047 g (0.1 14 mmol) of te/t-butyl N-[2-{4- methylpiperazin-1 -yl)-2-oxo-ethyl]-N-[£rans-spiro[cyclopropane-2, 1 '-tetralin]-1 - yl]carbamate. ¹ H NMR (D ₂ 0, DCI) δ (ppm): 7.04 - 6.92 (m, 3 H), 6.56 - 6.48 (m, 1 H), 4.39 - 4.30 (m, 1 H), 4.29 - 4.09 (m, 2 H), 3.84 - 3.73 (m, 1 H), 3.46 - 3.28 (m, 3 H), 3.08 - 2.62 (m, 9 H), 1.82 - 1.65 (m, 4 H), 1.39 - 1.29 (m, 1 H), 1.17 - 1.09 (m, 1 H); MS (ESI): m/z: 314 [M+H] ⁺ .

Intermediate 29: 4-bromo-1 -methylene-indane

0.775 g (80%) of 4-bromo-1 -methylene-indane was prepared according to the procedure described for Intermediate 2, starting from 1.00 g (4.64 mmol) of 4-bromoindan-1 -one (FLUOROCHEM, Cat No. 01 1590). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.61 - 7.54 (m, 1 H), 7.48 - 7.42 (m, 1 H), 7.21 - 7.14 (m, 1 H), 5.59 - 5.52 (m, 1 H), 5.1 1 - 5.04 (m, 1 H), 2.96 - 2.73 (m, 4 H).

Intermediate 30: 7-bromo-1 -methylene-indane

0.756 g (78%) of 7-bromo-1 -methylene-indane was prepared according to the procedure described for Intermediate 2, starting from 1.00 g (4.64 mmol) of 7-bromoindan-1 -one (FLUOROCHEM, Cat No. 040613). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 7.49 - 7.39 (m, 1 H), 7.36 - 7.30 (m, 1 H), 7.19 - 7.10 (m, 1 H), 6.18 - 6.09 (m, 1 H), 5.27 - 5.18 (m, 1 H), 2.97 - 2.89 (m, 2 H), 2.84 - 2.73 (m, 2 H).

Intermediate 31 : Ethyl 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate

0.775 g (71 %) of ethyl 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.773 g (3.70 mmol) of 4-bromo-1 -methylene-indane (Intermediate 29). The obtained ethyl 4'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of the two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.36 - 7.29 (m, 2 H), 7.19 - 7.1 1 (m, 1 H), 7.07 - 6.96 (m, 2 H), 6.68 - 6.60 (m, 1 H), 4.18 (m, 2 H), 4.10 - 3.89 (m, 2 H), 3.15 - 2.95 (m, 4 H), 2.46 - 2.36 (m, 1 H), 2.35 - 2.24 (m, 2 H), 2.14 - 2.09 (m, 1 H), 2.05 - 1.98 (m, 1 H), 1 .97 - 1.91 (m, 1 H), 1 .88 - 1.83 (m, 1 H), 1.71 - 1.63 (m, 1 H), 1.48 - 1.38 (m, 2 H), 1.28 (m, 3 H), 1.14 (m, 3 H); MS (ESI): m/z: 295 [M+H] ⁺ .

Intermediate 32: Ethyl 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate

0.770 g (73%) of ethyl 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.748 g (3.58 mmol) of 7-bromo-1 -methylene-indane (Intermediate 30). The obtained ethyl 7'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of the two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ , D ₂ 0) δ (ppm): 7.33 - 7.25 (m, 2 H), 7.22 - 7.1 1 (m, 2 H), 7.05 - 6.93 (m, 2 H), 4.18 (q, J = 7.3 Hz, 2 H), 3.97 (q, J = 7.1 Hz, 2 H), 3.21 - 2.69 (m, 6 H), 2.53 - 2.17 (m, 4 H), 2.08 - 1.93 (m, 1 H), 1.65 - 1.50 (m, 1 H), 1.48 - 1.37 (m, 2 H), 1.28 (t, J = 7.3 Hz, 3 H), 1.07 (t, J = 7.1 Hz, 3 H); MS (ESI): m/z: 295 [M+H] ⁺ .

Intermediate 33: 4'-Bromospiro[cyclopropane-2,1'-indane]-1 -carboxylic acid

0.658 g (95%) of 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.769 g (2.60 mmol) of ethyl 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 31 ). The obtained 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.41 - 7.30 (m, 2 H), 7.17 - 7.10 (m, 1 H), 7.08 - 6.97 (m, 2 H), 6.67 - 6.60 (m, 1 H), 3.17 - 2.94 (m, 4 H), 2.50 - 2.23 (m, 3 H), 2.17 - 2.10 (m, 1 H), 2.05 - 1.98 (m, 1 H), 1.98 - 1.92 (m, 1 H), 1.90 - 1.83 (m, 1 H), 1.72 - 1.65 (m, 1 H), 1.55 - 1.46 (m, 2 H); MS (ESI): m/z: 265 [M-H] ^" . Intermediate 34: 7'-Bromospiro[cyclopropane-2,1'-indane]-1 -carboxylic acid

0.623 g (91 %) of 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.759 g (2.57 mmol) of ethyl 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 32). The obtained 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.32 - 7.26 (m, 2 H), 7.20 - 7.13 (m, 2 H), 7.06 - 6.94 (m, 2 H), 3.21 - 2.73 (m, 6 H), 2.55 - 2.41 (m, 2 H), 2.40 - 2.21 (m, 2 H), 2.09 - 1.96 (m, 1 H), 1 .63 - 1.49 (m, 2 H), 1.48 - 1.39 (m, 1 H); MS (ESI): m/z: 265 [M-H] ^" .

Intermediate 35: 4'-Bromo-2-isocyanato-spiro[cyclopropane-1 ,1'-indane]

0.639 g (98%) of 4'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] was prepared according to the procedure described for Intermediates 19 and 20, starting from 0.656 g (2.46 mmol) of 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 33). The obtained 4'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS). ¹ H NMR (CDCI ₃ ) δ (ppm): 7.36 (m, 2 H), 7.18 - 7.12 (m, 1 H), 7.08 - 7.00 (m, 2 H), 6.68 - 6.59 (m, 1 H), 3.15 - 2.95 (m, 4 H), 2.51 - 2.39 (m, 1 H), 2.38 - 2.26 (m, 2 H), 2.18 - 2.10 (m, 1 H), 2.04 - 1.90 (m, 3 H), 1.84 - 1.76 (m, 1 H), 1.64 - 1.57 (m, 2 H); MS (ESI): m/z: 264 [M+H] ⁺ .

Intermediate 36: 1 ,3-Benzodioxol-5-ylmethyl N-[frans-4'-bromospiro[cyclopropane- 2,1'-indane]-1 -yl]carbamate and Intermediate 37: 1 ,3-Benzodioxol-5-ylmethyl N-[c;s- 4'-bromospiro[cyclopropane-2,1'-indane]-1 -yl]carbamate

0.450 g (1.70 mmol) of 4'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 35) and 0.291 g (1.87 mmol) of 1 ,3-benzodioxol-5-ylmethanol were dissolved in 20 ml of dry toluene under nitrogen atmosphere and then 0.1 19 ml (0.852 mmol) of TEA were added. The reaction mixture was irradiated with microwaves at 120°C for 10 h. The reaction mixture was evaporated and the residue was purified by flash chromatography (eluent: DCM/EtOAc from 100:1 to 95:5) to give two products, the trans- isomer and the c/s-isomer (regarding the cyclopropyl ring) in their racemic form. The cis and trans isomers were determined by analogy to 1 ,3-benzodioxol-5-ylmethyl N-[cis-5'- bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate and 1 ,3-benzodioxol-5-ylmethyl N- [irans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate, Example 5, Step 1. The frans-isomer, Intermediate 36, was obtained as an off-white solid (0.279 g, 39%). The c/s- isomer, Intermediate 37, was obtained as a yellow thick-oil (0.269 g, 38%). ¹ H NMR (DMSO-de) δ (ppm), trans: 7.70 - 7.57 (m, 1 H), 7.44 - 7.23 (m, 1 H), 7.12 - 6.99 (m, 1 H), 6.97 - 6.48 (m, 4 H), 6.01 (s, 2 H), 5.06 - 4.67 (m, 2 H), 3.00 - 2.76 (m, 2 H), 2.67 - 2.55 (m, 1 H), 2.04 - 1.87 (m, 2 H), 1.42 - 1.28 (m, 1 H), 1.03 - 0.86 (m, 1 H); ¹ H NMR (DMSO- de) δ (ppm), cis: 7.66 - 7.56 (m, 1 H), 7.41 - 7.24 (m, 1 H), 7.07 - 6.95 (m, 1 H), 6.87 - 6.30 (m, 4 H), 6.00 (s, 2 H), 4.80 - 4.37 (m, 2 H), 3.02 - 2.58 (m, 3 H), 2.24 - 1.73 (m, 2 H), 1.28 - 1.05 (m, 2 H); MS (ESI): m/z: 438 [M+Na] ⁺ . Intermediate 38: frans-7'-Bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and Intermediate 39: c/s-7'-Bromo 2-isocyanatospiro[cyclopropane-1 ,1'-indane]

0.263 g (43%) of £rans-7'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] and 0.236 g (39%) of c/ ^' s-7'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] were prepared according to the procedure described for Intermediates 19 and 20, starting from 0.619 g (2.32 mmol) of 7'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid (Intermediate 34). The reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form. The cis and trans isomers were identified by NMR (NOE) analysis of the corresponding amino derivatives. ¹ H NMR (CDCI3) δ (ppm), trans: 7.32 - 7.27 (m, 1 H), 7.21 - 7.14 (m, 1 H), 7.07 - 6.96 (m, 1 H), 3.06 - 2.89 (m, 2 H), 2.87 - 2.79 (m, 1 H), 2.61 - 2.52 (m, 1 H), 2.38 - 2.22 (m, 2 H), 1.60 - 1.55 (m, 1 H); ¹ H NMR (CDCI3) δ (ppm), cis: 7.37 - 7.29 (m, 1 H), 7.24 - 7.14 (m, 1 H), 7.08 - 6.95 (m, 1 H), 3.28 - 3.19 (m, 1 H), 3.17 - 3.03 (m, 1 H), 2.93 - 2.72 (m, 1 H), 2.55 - 2.42 (m, 1 H), 2.09 - 1.98 (m, 1 H), 1.66 - 1.57 (m, 2 H); MS (ESI): m/z: 264 [M+H] ⁺ .

Example 46: frans-4'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide

0.177 g (83%) of £rans-4'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide was prepared according to the procedure described for Example 1 , Step 3, starting from 0.276 g (0.663 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[£rans-4'-bromospiro[cyclopropane- 2,1 '-indane]-1 -yl]carbamate (Intermediate 36). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.43 - 8.18 (m, 3 H), 7.44 - 7.31 (m, 1 H), 7.17 - 7.03 (m, 1 H), 6.92 - 6.81 (m, 1 H), 3.09 - 2.94 (m, 2 H), 2.90 - 2.79 (m, 1 H), 2.29 - 2.08 (m, 2 H), 1.43 - 1.17 (m, 2 H); MS (ESI): m/z: 221 [M+H-17] ⁺ . Example 47: c;s-4'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide

0.139 g (68%) of c/ ^' s-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrobromide was prepared according to the procedure described for Example 1 , Step 3, starting from 0.267 g (0.641 mmol) of 1 ,3-benzodioxol-5-ylmethyl N-[c/s-4'-bromospiro[cyclopropane-2,1 '- indane]-1 -yl]carbamate (Intermediate 37). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.24 - 7.92 (m, 3 H), 7.50 - 7.39 (m, 1 H), 7.24 - 7.1 1 (m, 2 H), 3.06 - 2.80 (m, 3 H), 2.30 - 2.15 (m, 1 H), 2.03 - 1.92 (m, 1 H), 1.51 - 1.29 (m, 2 H); MS (ESI): m/z: 221 [M+H-17] ⁺ .

Example 48: frans-7'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.206 g (76%) of £rans-7'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 8, starting from 0.261 g (0.988 mmol) of irans-7'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 38). ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.44 (bs, 3 H), 7.37 - 7.23 (m, 2 H), 7.14 - 7.04 (m, 1 H), 3.60 - 3.48 (m, 1 H), 3.1 1 - 2.94 (m, 2 H), 2.33 - 2.06 (m, 2 H), 2.03 - 1.96 (m, 1 H), 1.21 - 1.12 (m, 1 H); MS (ESI): m/z: 238 [M+H] ⁺ .

Example 49: c;s-7'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.165 g (68%) of c/ ^' s-7'-bromospiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 8, starting from 0.234 g (0.886 mmol) of c/s-7'-bromo-2-isocyanato-spiro[cyclopropane-1 ,1 '-indane] (Intermediate 39). ¹ H NMR (DMSO-de) δ (ppm): 8.1 1 (bs, 3 H), 7.42 - 7.31 (m, 2 H), 7.25 - 7.09 (m, 1 H), 3.10 - 2.94 (m, 1 H), 2.93 - 2.79 (m, 2 H), 2.66 - 2.55 (m, 1 H), 2.32 - 2.14 (m, 1 H), 1.82 - 1.64 (m, 1 H), 1.32 - 1.17 (m, 1 H); MS (ESI): m/z: 238 [M+H] ⁺ . Intermediate 40: (-)-(2R)-2-methoxy-2-phenyl-N-[fra/7S-spiro[cyclopropane-2,1 '- indane]-1 -yl]acetamide and Intermediate 41 : (+)-(2R)-2-methoxy-2-phenyl-N-[fra/7S- spiro[cyclopropane-2,1'-indane]-1 -yl]acetamide

To a one-neck round-bottom flask was added 0.950 g (4.85 mmol) of trans- spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8), EtOH (25 ml), 4- methylmorpholine (1.7 ml, 16 mmol), (2R)-2-methoxy-2-phenyl-acetic acid (0.839 g, 5.0 mmol) and 1 -hydroxybenzotriazole hydrate (0.1 1 g, 0.73 mmol). The obtained solution was then cooled with ice, and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.13 g, 5.83 mmol) was added. The reaction was stirred at r.t. for 4 h. Water was added (150-200 ml) and the reaction mixture was filtered to collect the products. The products were washed with water and then dried. The diastereomeric amides were separated by flash chromatography (eluent: Hexane/AcOEt from 95:5 to 70:30). The less polar diastereomer, Intermediate 40, was obtained as a white solid (0.635 g, 43%); [a] _D = - 30.8 (c = 0.493, MeOH); ¹ H NMR (CDCI ₃ ) δ (ppm): 7.45 - 7.29 (m, 5 H), 7.24 - 7.08 (m, 3 H), 6.83 (bs, 1 H), 6.71 - 6.61 (m, 1 H), 4.67 (s, 1 H), 3.41 (s, 3 H), 3.19 - 3.01 (m, 2 H), 2.98 - 2.90 (m, 1 H), 2.23 - 2.02 (m, 2 H), 1.44 (m, 1 H), 0.98 (m, 1 H); MS (ESI): m/z: 308 [M+H] ⁺ . The more polar diastereomer, Intermediate 41 , was obtained as a white solid (0.626 g, 42%); [a] _D = + 26.1 (c = 0.507, MeOH); ¹ H NMR (CDCIs) δ (ppm): 7.45 - 7.29 (m, 5 H), 7.18 - 7.07 (m, 3 H), 6.80 (bs, 1 H), 6.72 - 6.59 (m, 1 H), 4.66 (s, 1 H), 3.40 (s, 3 H), 3.07 - 2.86 (m, 3 H), 2.05 - 1.87 (m, 2 H), 1.44 (m, 1 H), 1.02 (m, 1 H); MS (ESI): m/z: 308 [M+H] ⁺ .

Example 50: (-)-frans-Spiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.603 g (1.96 mmol) of (-)-(2R)-2-methoxy-2-phenyl-N-[irans-spiro[cyclopropane-2,1 '- indane]-1 -yl]acetamide (Intermediate 40) in a mixture of EtOH/-4 M HCI (2:1 ; 18 ml) was stirred at 100°C in a sealed tube for 23 h. The organic solvent was evaporated and the remaining aqueous mixture was diluted with water (70 ml) and extracted with Et ₂ 0 (60 ml x 3). The aqueous layer was ice-cooled, brought to a basic pH of about 9 with 1 N NaOH, and extracted with Et ₂ O (60 ml x 3). The combined organic phases containing the free amine were washed with brine, dried over Na ₂ S0 ₄ and the solution was filtered The organic phase was cooled with ice and 2 N HCI in Et ₂ 0 (2.93 ml) was added dropwise. A white solid along with a yellow oil separated and the mixture was then allowed to reach r.t. The mixture was evaporated, the residue was taken up with Et ₂ 0 and concentrated again. The residue was then triturated with Et ₂ 0 (80 ml) and MeOH (2 ml). The {-)-trans- spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was filtered, washed with Et ₂ O and heated at 40°C under vacuum (beige solid, 287 mg, 75%). [a] _D = - 50.7 (c = 0.513, MeOH); ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.46 (bs, 3 H), 7.26 - 7.08 (m, 3 H), 6.86 - 6.79 (m, 1 H), 3.10 - 2.96 (m, 2 H), 2.84 - 2.76 (m, 1 H), 2.29 - 2.08 (m, 2 H), 1.34 - 1.22 (m, 2 H); MS (ESI): m/z: 160 [M+H] ⁺ . Example 51 : (+)-frans-Spiro[cyclopropane-2,1'-indane]-1 -amine hydrochloride

0.294 g (78%) of (+)-irans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 50, starting from 0.594 g (1.93 mmol) of (+)-(2R)-2-methoxy-2-phenyl-N-[irans-spiro[cyclopropane-2,1 '-indane]-1 - yl]acetamide (Intermediate 41 ). [a] _D = + 52.8 (c = 0.517, MeOH); ¹ H NMR (DMSO-d ₆ ) δ (ppm): 8.46 (bs, 3 H), 7.26 - 7.08 (m, 3 H), 6.86 - 6.79 (m, 1 H), 3.10 - 2.96 (m, 2 H), 2.84 - 2.76 (m, 1 H), 2.29 - 2.08 (m, 2 H), 1.34 - 1.22 (m, 2 H); MS (ESI): m/z: 160 [M+H] ⁺ .

2. BIOLOGICAL TESTING

2.1 Assay of enzyme inhibition of KDM1A (LSD1)

The complex of human recombinant KDM1A (LSD1 )/CoRest protein was produced in E. coli as separate proteins and co-purified following previously reported procedures (Forneris F. et al. Trends Biochem. Sci. 2008, 33, 181 -189; Forneris F. et al. J.Biol.Chem. 2007, 282, 20070-20074). The experiments were performed using a mono-methylated H3-K4 peptide containing 21 amino acids (custom synthesis done by Thermo Scientific) as substrate and in a 50 mM TRIS, pH 8, 0.05 mg/ml BSA buffer. The peptide purity was >90% as checked by analytical high-pressure liquid chromatography and mass spectrometry.

The demethylase activity was estimated under aerobic conditions and at RT by measuring the release of H ₂ O ₂ produced during the catalytic process by the Amplex® UltraRed detection system coupled with peroxidase assay. Briefly, a fixed amount of KDM1A/CoRest complex was incubated at RT for 15 minutes in the absence and/or the presence of various concentrations of inhibitor (e.g. from 0 to 100 μΜ, depending on the inhibitor strength) and of Amplex® UltraRed detection system coupled with peroxidase assay. The inhibitors were tested twice in duplicates at each concentration. Tranylcypromine (Sigma) was used as control. After preincubation of the enzyme with the inhibitor, 4.5 μΜ of mono-methylated H3-K4 peptide was added and the experiment was left for additional 12 min. The conversion of the Amplex® Ultra Red reagent to resorufin was monitored in continuous by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure the level of H ₂ O ₂ produced in the absence and/or in the presence of inhibition. The maximum demethylase activity of KDM1 A/Co Rest was obtained in the absence of inhibitors and corrected for background fluorescence in the absence of KDM1A/CoRest. The IC ₅₀ was calculated using GraphPad Software. Compounds 1 , 3, 4, 6, 7, 10, 21 , 45, 47 and 49 exhibit IC ₅₀ values of less than 10 μΜ, compounds 5, 8, 15, 17-19, 22-24, 26-28, 30, 31 , 34, 39-44, 46 and 48 exhibit IC ₅₀ values of less than 1 μΜ, compounds 9, 14, 16, 20, 25, 29, 32, 33, 35-38 exhibit an IC50 value of less than 0.1 μΜ.

Tranylcypromine exhibits an IC ₅₀ value of 12.9±3.2 μΜ.

2.2 Bioluminescent-Coupled Assay for Monoamine oxidases (MAO-Glo Assay)

The MAO Glo Assay from Promega (cat. V1402, Promega, Madison, Wl) was used to measure the effect of inhibitors on MAO A and MAO B activity. Human recombinant MAO A and MAO B were expressed in Pichia pastoris and purified as published (Binda C. et al. Proc. Natl. Acad. Sci. USA, 2003, 9750-9755). The assay was performed at RT in 50 μΙ_ (25 μΙ_ reaction solution + 25 μΙ_ detection reagent) in 96 well half area white plates (cat. 3693, Corning, Corning, NY). Luminescence was measured after 20 min incubation in the dark using a microplate reader (Infinite F200, Tecan Group, Switzerland) with an integration time of 0.25 s per well. 50 nM MAO A or 125 nM MAO B were incubated with five different inhibitor concentrations (from 0.004 μΜ to 100 μΜ) for 15 min at RT in Promega MAO Buffer or Promega MAO B Buffer (MAO Glo Assay kit, catalogue number V1402, Promega, Madison, Wl). After 30 min of incubation the reaction was stopped with the Promega detection reagent. All compounds were tested twice and IC ₅₀ values were calculated using GraphPad Prism version 4.0 (GraphPad Software, San Diego, CA).

Compounds 14, 15, 18-20, 29, 30, 32, 33, 36 and 37 were at least 10 times more active against KDM1A (LSD1) compared to both MAO A and MAO B.