EA042621B1 - CYCLOPYLAMINES AS LSD1 INHIBITORS - Google Patents

Description

Technical field

The present invention relates to enzyme inhibitors that selectively modulate demethylase and their use. In specific embodiments, compounds and diseases that are indications for their use, treatable by modulation of lysine-specific demethylase-1 (LSD1) are considered.

State of the art

Epigenetic changes can influence genetic diversity, but when dysregulated can also contribute to the development of various diseases (Portela, A. and M. Esteller, Epigenetic modifications and human disease. Nat Biotechnol, 2010. 28(10): p. 1057-68 ; Lund, A. H. and M. van Lohuizen, Epigenetics and cancer Genes Dev, 2004. 18(19): p. 2315-35). In recent in-depth studies of cancer genomics, it has been found that many epigenetic regulatory genes are often mutated or their own expression is abnormal in many cancers. (Dawson, M.A. and T. Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012. 150(1): p. 1227; Waldmann, T. and R. Schneider, Targeting histone modifications-epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2): pp. 184-9 Shen, H. and P. W. Laird, Interplay between the cancer genome and epigenome Cell, 2013. 153(1): pp. 38-55. This suggests that epigenetic regulators act as determinants of cancer or allow tumorigenesis or disease progression. Therefore, deregulated epigenetic regulators represent promising therapeutic targets.

One particular enzyme that has been associated with human disease is lysine-specific demethylase-1 (LSD1), the first histone demethylase to be discovered (Shi, Y., et al., Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004. 119 (7): pp. 941-53). It consists of three large domains: the N-terminal SWIRM, which functions by interacting with nucleosomes, the tower domain, which is involved in protein-protein interaction, for example, a transcription corepressor, a transcription factor corepressor that represses RE1 expression (CoREST), and finally C- a terminal catalytic domain whose sequence and structure is homologous to flavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e., MAO-A and MAO-B) (Forneris F., et al., Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p. 200704; Anand R. and R. Marmorstein, Structure and mechanism of lysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p. 35425-9; Stavropoulos P., G. Blobel and A. Hoelz, Crystal structure and mechanism of human lysine-specific demethylase-1 Nat Struct Mol Biol, 2006. 13(7): pp. 626-32 Chen Y., et al. , Crystal structure of human histone lysine-specific demethylase 1 (LSD1), Proc Natl Acad Sci U S A, 2006. 103(38): p. 13956-61). LSD1 is also somewhat homologous to another lysine-specific demethylase (LSD2) (Karytinos A., et al., A novel mammalian flavin-dependent histone demethylase. J Biol Chem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism of action is conserved in these two isoforms, substrate specificity is thought to differ with relatively little overlap. The enzymatic reactions of LSD1 and LSD2 are dependent on the FAD redox process, and it is hypothesized that the need for a protonated nitrogen atom in methylated lysine limits LSD1/2 activity to mono- and dimethylated at position 4 or 9 of histone 3 (H3K4 or H3K9). Such mechanisms distinguish LSD1/2 from other families of histone demethylases (i.e., the family containing the Jumonji domain), which can demethylate mono-, di-, and trimethylated lysines through alpha-ketoglutarate-dependent reactions (Kooistra S.M. and K. Helin , Mosammaparast, N. and Y. Shi, Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases Annu Rev Biochem, 2010. 79: pp. 155-79).

Methylated histone marks on K3K4 and H3K9 are generally associated with transcriptional activation and repression, respectively. As part of corepressor complexes (eg, CoREST), LSD1 has been reported to demethylate H3K4 and repress transcription, while LSD1, in complex with a nuclear hormone receptor (eg, androgen receptor), can demethylate H3K9 to activate gene expression (Metzger E., et al., Kahl P., et al., Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence Cancer Res, 2006. 66(23): p. 11341-7). This suggests that the substrate specificity of LSD1 may be determined by associated factors, thus regulating alternative gene expression in a context-dependent manner. In addition to histone proteins, LSD1 can demethylate nonhistone proteins. They include p53 (Huang J., et al., p53 is regulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p. 105-8.), E2F (Kontaki H. and I. Talianidis, Lysine methylation regulates E2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang J., et al., Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p. 21499-504), Tat (Sakane N., et al., Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/ KDM1), PLoS Pathog, 2011. 7(8): p. e1002184) and myosin phosphatase target subunit 1 (MYPT1) (Cho H.S., et al., Demethylation of RB regulator

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MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res, 2011. 71(3): p. 655-60). The lists of non-histone substrates are increasing as technical progress is made in the field of functional proteomics research. This suggests that in addition to the regulation of chromatin reconstruction, LSD1 plays an additional role in oncogenesis. LSD1 is also associated with other epigenetic regulators such as DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet, 2009. 41( 1): p. 125-9) and histone deacetylase (HDACs) complexes (Hakimi M.A., et al., A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci USA, 2002. 99(11 ): p. 7420-5; Lee M. G., et al., Functional interplay between histone demethylase and deacetylase enzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al., CoREST is an integral component of the CoREST- human histone deacetylase complex Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Such associations increase DNMT or HDAC activity. Thus, LSD1 inhibitors may potentiate the effects of HDAC or DNMT inhibitors. Indeed, preclinical studies have already demonstrated this potential (Singh M.M., et al., Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han H., et al. ., Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells, PLoS One, 2013. 8(9): p. e75136).

LSD1 has been reported to be involved in various biological processes including cell proliferation, epithelial-mesenchymal transition (EMT) and stem cell biology (both embryonic stem cells and cancer stem cells) or self-renewal and cellular transformation of somatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy, Crit Rev Eukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun G., et al., Histone demethylase LSD1 regulates neural stem cell proliferation Mol Cell Biol, 2010 30(8): p.1997-2005 Adamo A., M.J. Barrero, and J.C. Izpisua Belmonte, LSD1 and pluripotency: a new player in the network Cell Cycle 2011. 10(19): p.3215-6 Adamo A., et al., LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells Nat Cell Biol, 2011. 13(6): p 652-9). In particular, cancer stem cells, or cancer initiating cells, have some of the properties of pluripotent stem cells that promote cancer cell heterogeneity. This feature can make cancer cells more resistant to standard therapies such as chemotherapy or radiation therapy, and they can then cause relapses after treatment (Clevers H., The cancer stem cell: premises, promises and challenges. Nat Med, 2011. 17 (3): pp. 313-9, Beck B. and C. Blanpain Unraveling cancer stem cell potential, Nat Rev Cancer, 2013. 13(10): pp. 727-38. In a number of cancers, LSD1 has been reported to retain an undifferentiated tumor-initiating or cancer stem cell phenotype (Zhang X., et al., Pluripotent Stem Cell Protein Sox2 Confers Sensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2) : p. 445-57; Wang J., et al., Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res, 2011. 71(23): p. 7238-49. Acute myeloid leukemias (AML) are an example of neoplastic cells that retain some of their less differentiated stem cell-like phenotype, or leukemic stem cell (LSC) potential. Analysis of AML cells, including gene expression kits and next-generation chromatin immunoprecipitation sequencing (ChIP-Seq), showed that LSD1 can regulate a subset of genes involved in multiple oncogenic programs to maintain LSC (Harris W.J., et al., The histone Schenk, T., et al., Inhibition of the LSD1 (KDM1A) demethylase reactivates the alltrans -retinoic acid differentiation pathway in acute myeloid leukemia Nat Med, 2012. 18(4): p. 605-11). The findings suggest a potential therapeutic benefit for LSD1 inhibitors in cancers that have stem cell properties, such as AML.

LSD1 overexpression is frequently seen in many cancers, including bladder cancer, non-small cell lung cancer, breast carcinomas, ovarian cancer, glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma, neuroblastoma, prostate cancer, squamous cell carcinoma esophagus and papillary thyroid carcinoma. Notably, studies have found that LSD1 overexpression was significantly associated with clinically aggressive cancers, e.g., recurrent prostate cancer, non-small cell lung cancer, glioma, breast cancer, colon cancer, ovarian cancer, esophageal squamous cell carcinoma, and neuroblastoma. In these studies, knockdown of LSD1 expression or treatment with small molecule inhibitors of LSD1 resulted in a reduction in cancer cell proliferation and/or induction of apoptosis. See, for example, Hayami S., et al., Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p. 574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One, 2012. 7(4): p. e35065; Serce N., et al., Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumor progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive

- 2 042621 biology. Carcinogenesis, 2010. 31(3): p. 512-20; Konovalov S. and I. Garcia-Bassets, Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res, 2013. 6(1): p. 75; Sareddy G.R., et al., KDM1 is a novel therapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1): p. 18-28; Ding J., et al., LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I.M., et al., Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7; Schulte J.H., et al., Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea F., et al., The emerging role of histone lysine demethylases in prostate cancer. Mol Cancer, 2012. 11: p. 52; Suikki H.E., et al., Genetic alterations and changes in expression of histone demethylases in prostate cancer. Prostate, 2010. 70(8): p. 889-98; Yu Y., et al., High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma. Biochem Biophys Res Commun, 2013. 437(2): p. 192-8; Kong L., et al., Immunohistochemical expression of RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol, 2013. 54(3): p. 499-503.

Induction of CD86 expression by inhibition of LSD1 activity has recently been reported (Lynch J.T., et al., CD86 expression as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1): p 104-6). Expression of CD86 is a marker of maturation of dendritic cells (DCs), which are involved in the antitumor immune response. Notably, CD86 acts as a co-stimulatory factor to activate T cell proliferation (Greaves, P. and J.G. Gribben, The role of B7 family molecules in hematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D. B. Flies, Molecular mechanisms of T cell costimulation and co-inhibition Nat Rev Immunol, 2013. 13(4): pp. 227-42.

In addition to being involved in cancer, LSD1 activity is also associated with viral pathogenesis. In particular, LSD1 activity appears to be associated with viral replication and viral gene expression. For example, LSD1 acts as a co-activator to trigger gene expression from the immediate-early genes of various herpesvirus types, including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human herpesvirus cytomegalovirus β3 (Liang, Y., et al. al., Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency Sci Transl Med, 2013 5(167): p.167ra5 Liang, Y., et al., Inhibition of the histone demethylase LSD1 blocks alphaherpesvirus lytic replication and reactivation from latency, Nat Med, 2009, 15(11): p.1312-7. In these aspects, the LSD1 inhibitor has demonstrated antiviral activity by blocking viral replication and altering virus-associated gene expression.

Recent studies have also shown that LSD1 inhibition by gene depletion or pharmacological intervention increased fetal globin gene expression in erythroid cells (Shi, L., et al., Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med, 2013 19(3): p.291-4 Xu, J., et al., Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A Proc Natl Acad Sci USA, 2013 110(16): p.6518-23 ). Induction of the fetal globin gene would have potential therapeutic benefit for diseases of β-globinopathies, including β-thalassemia and sickle cell anemia, in which production of normal β-globin, a component of mature hemoglobin, is impaired (Sankaran, V.G. and S.H. Orkin, The switch from fetal to adult hemoglobin Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643; Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood, 2012. 120( 15): pp. 2945-53). Moreover, LSD1 inhibition may enhance the effects of other clinically used drugs such as hydroxyurea and azacitidine. Such agents may act, at least in part, by increasing γ-globin gene expression through various mechanisms.

Thus, LSD1 plays a role in tumor development by altering epigenetic marks on histones and non-histone proteins. Accumulating evidence supports the notion that genetic depletion or pharmacological action of LSD1 normalizes altered gene expression, thus inducing differentiation programs into mature cell types, reducing cell proliferation, and stimulating apoptosis in cancer cells. Therefore, LSD1 inhibitors alone or in combination with established drugs will be effective in the treatment of diseases associated with LSD1 activity.

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Brief description of the invention

The present invention relates in particular to a compound of formula (IVa) or formula (IVb)

or its pharmaceutically acceptable salt, where the structural constituent variables are defined in this application.

The present invention further relates to a pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), comprising a compound of formula (IVa) or formula (IVb) and at least one pharmaceutically acceptable carrier.

The present invention further relates to a method for inhibiting LSD1, comprising contacting LSD1 in vitro with a compound of formula (IVa) or formula (IVb).

The present invention further relates to a method of treating an LSD1 mediated disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of formula (IVa) or formula (IVb).

Detailed description of the invention

The present invention provides, in particular, LSD1 inhibitory compounds such as a compound of formula (IVa) or formula (IVb)

or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl;

ring C is a monocyclic 4-7 membered heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 heteroatoms selected from N, O and S;

each R ¹ is halogen;

each R ² is independently selected from halogen, C1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , NR ^c1 R ^d1 , S(O) R ^b1 , S(O)NR ^c1 R ^d1 , S(O)2R ^b1 and S(O)2NR ^c1 R ^d1 , wherein said C1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O)2R ^b1 , NR ^c1 S(O)2NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S( O)2R ^b1 and S(O)2NR ^c1 R ^d1 ;

where each R ² is substituted on any ring-forming atom of ring B, except for the ring-forming atom of ring B to which R ^z is bonded;

each R ³ is independently selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogen

- 4 042621 kila, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, (5-10-membered heteroaryl)-C _1-4 alkyl, (4-10-membered heterocycloalkyl)-C1-4 alkyl, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ⁴² , NR ^c2 C(O)R ^b2 , NR ^c2 C (O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O) R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 where each is Cb6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3 -10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1 -4 alkyl and (4-10 membered heterocycloalkyl)-C1-4 alkyl- optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2 , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ;

R ⁴ is C _1-4 alkyl optionally substituted with CN, C(O)NR ^c3 R ^d3 , OR ^a3 or C(O)OR ^a3 ; each R ⁵ and R ⁶ is H;

R ^Z is H, C _1-4 alkyl, or C _6-10 aryl-C _1-4 alkyl, where each is C _1-4 alkyl and C ₆ . ₁₀ aryl-C _1-4 alkyl is optionally substituted with halo or OR ^a4 ;

each R ^a2 , R ^b2 , R ^c2 and Rd ² is independently selected from H, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C ₃ . ₁₀ cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, (5-10-membered heteroaryl) - C _1-4 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl, where the specified C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl-, C ₃ . ₁₀ cycloalkyl-C _1-4 alkyl, (5-10 membered heteroaryl)-C _1-4 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents , independently selected from C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 cyanoalkyl, halogen, CN, OR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , S(O)R ^b5 and S(O)2NR ^c5 R ^d5 ;

each R ^a4 is independently selected from H, C1-6 alkyl and C1-4 haloalkyl;

each R ^a3 , R ^b3 , R ^c3 and R ^d3 is independently selected from H, C1-6 alkyl and C1-4 haloalkyl;

each R ^a5 , R ^b5 , R ^c5 and R ^d5 is independently selected from H, C1-4 alkyl and C1-4 haloalkyl;

m is 0;

n is 0 or 1;

p is 0 or 1 and q is 0 or 1;

each heteroaryl independently contains 1, 2, 3 or 4 ring heteroatoms independently selected from nitrogen, sulfur and oxygen;

each heterocycloalkyl independently contains 1, 2, 3 or 4 ring heteroatoms independently selected from sulfur, oxygen and nitrogen; and each carbon atom or heteroatom in the ring of the heterocycloalkyl group may be oxidized to form a carbonyl, sulfinyl, or sulfonyl group, or the nitrogen atom may be quaternized.

In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is of the formula (IVa)

IVa.

In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, has the formula (IVb) (R ³ ) _P

IVb.

In some embodiments, a compound of the invention has the formula Va or Vb

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or a pharmaceutically acceptable salt thereof.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, q is 0.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, q is 1.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, n is 0.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, n is 1.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is F.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, ring C is azetidinyl or piperidinyl.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, ring C is azetidinyl.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, ring C is piperidinyl.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-4 alkyl optionally substituted with CN, C(O)NR ^c3 R ^d3 or C(O)OR ^a3 .

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ⁴ is -CH2-CN, -CH ₂ -C(=O)OH, -CH ₂ -C(=O)NH(CH ₃ ), -CH ₂ -C(=O)N(CH ₃ ) ₂ or -CH ₂ CH ₂ OH.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, each R ³ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 , where each is C1-6 alkyl, C6. ₁₀ aryl, 5-10 membered heteroaryl, C3 _-1 o cycloalkyl and 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, C _1-4 alkyl, C 1 _-4 haloalkyl, C 1 _-4 cyanoalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S (O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 , and S(O)2NR ^c2 R ^d2 .

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, each R ³ is independently selected from C1.6 alkyl, C6.10 aryl, 5-10 membered heteroaryl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 , wherein each of said Ci-6 alkyl, C^o aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, C _1-4 alkyl, C 1 _-4 haloalkyl, C _{1 -4} cyanoalkyl, CN, NO ₂ , ORa2, SRa2, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O) NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 .

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, each R ³ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 and S(O)2R ^b2 where each is C1 _-6 alkyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C _1-4

- 6 042621 alkyl, C _1-4 haloalkyl, C _1-4 cyanoalkyl, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 ,

OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 ,

NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 .

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ^Z is C _1-4 alkyl.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ^Z is C _1-4 alkyl substituted with methoxy.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ^Z is C _6-10 aryl-C _1-4 alkyl substituted with fluoro.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ^Z is H, methyl, methoxymethyl, or 4-fluorophenylmethyl.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, R ^Z is H.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, p is 0.

In some embodiments, in a compound of the invention, or a pharmaceutically acceptable salt thereof, p is 1.

In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is in the trans configuration on the disubstituted cyclopropyl group shown in claim 1.

The term z-membered (where z is an integer) usually describes the number of ring-forming atoms in a fragment, where the number of ring-forming atoms is z. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

The term carbon refers to one or more carbon atoms.

In the context of this application, the term Ci-j alkyl, used alone or in combination with other terms, refers to a saturated hydrocarbon group, which may be straight or branched chain, containing from i to j carbon atoms. In some embodiments, said alkyl group contains 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl.

In the context of this application, the term Ci-alkoxy, used alone or in combination with other terms, refers to a group of the formula -O-alkyl, where the specified alkyl group contains from i to j carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, and propoxy (eg, npropoxy and isopropoxy). In some embodiments, said alkyl group contains from 1 to 3 carbon atoms.

As used herein, Ci-j alkenyl, used alone or in combination with other terms, refers to an unsaturated hydrocarbon group containing one or more carbon-carbon double bonds and i to j carbon atoms. In some embodiments, said alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, Ci-j alkynyl, used alone or in combination with other terms, refers to an unsaturated hydrocarbon group containing one or more carbon-carbon double bonds and i to j carbon atoms. Examples of alkynyl groups include, without limitation, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, said alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

In the context of this application, the term Ci-j alkylamino, used alone or in combination with other terms, refers to a group of the formula -NH(alkyl), where the specified alkyl group contains from i to j carbon atoms. In some embodiments, said alkyl group contains 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino and the like.

In the context of this application, the term di-C _i .j-alkylamino, used alone or in combination with other terms, refers to a group of the formula -N(alkyl)2, where each of the two alkyl groups independently contains i to j carbon atoms . In some embodiments, each alkyl group independently contains 1 to 6 or 1 to 4 carbon atoms. In some embodiments, said dialkylamino group is -N(C1-4 alkyl)2, such as, for example, dimethylamino or diethylamino.

In the context of this application, the term Ci-j alkylthio, used alone or in combination with other terms, refers to a group of the formula -S-alkyl, where the specified alkyl group contains from i to j carbon atoms. In some embodiments, said alkyl group contains 1 to 6 or 1 to 4 carbon atoms. In some embodiments, said alkylthio group is C alkylthio, such as, for example, methylthio or ethylthio.

In the context of this application, the term amino, used alone or in combination with other terms, refers to a group of the formula -NH2.

In the context of this application, the term aryl, used alone or in combination with other terms, refers to a monocyclic or polycyclic (for example, containing 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, without limitation, phenyl, 1naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl and the like. In some embodiments, aryl is C _6-10 aryl. In some embodiments, said aryl group is a naphthalene ring or a phenyl ring. In some embodiments, said aryl group is phenyl.

In the context of this application, the term carbonyl, used alone or in combination with other terms, refers to the group -C(O)-.

In the context of this application, the term Ci-cyanoalkyl, used alone or in combination with other terms, refers to an alkyl group substituted with a CN group.

In the context of this application, the term Ci-j cycloalkyl, used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon fragment containing from i to j carbon atoms forming a ring, which may optionally contain one or more alkenylene groups as parts of the ring structure. Cycloalkyl groups may include mono- or polycyclic (eg containing 2, 3 or 4 fused rings) ring systems. Also included within the definition of cycloalkyl are moieties containing one or more aromatic rings fused (ie, sharing a common bond) with a cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. One or more ring-forming carbon atoms of the cycloalkyl group may be oxidized to form carbonyl bonds. In some embodiments, cycloalkyl is C _3-10 cycloalkyl, C _3-7 cycloalkyl, or C _5-6 cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl and the like. Additional examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the present application, Ci-j haloalkoxy, used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl containing from i to j carbon atoms. An example of a haloalkoxy group is OCF3. An additional example of a haloalkoxy group is OCHF2. In some embodiments, said haloalkoxy group is only fluorinated.

In some embodiments, said alkyl group contains 1 to 6 or 1 to 4 carbon atoms. In some embodiments, said haloalkoxy group is Cm haloalkoxy.

In the context of this application, the term halogen, used alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, halogen refers to a halogen atom selected from F, Cl, or Br. In some embodiments, said halo substituent is F.

In the context of this application, the term Ci-j haloalkyl, used alone or in combination with other terms, refers to an alkyl group containing from one to 2s+1 halogen atoms, which may be the same or different, where s is the number of carbon atoms in the alkyl group, and the alkyl group contains from i to j carbon atoms. In some embodiments, said haloalkyl group is only fluorinated. In some embodiments, said haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, said haloalkyl group is trifluoromethyl. In some embodiments, said alkyl group contains 1 to 6 or 1 to 4 carbon atoms.

In the context of this application, the term heteroaryl, used alone or in combination with other terms, refers to a monocyclic or polycyclic (for example, containing 2, 3 or 4 fused rings) aromatic heterocyclic fragment containing as ring members one or more heteroatoms selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms as ring members. In some embodiments, said heteroaryl group contains 1, 2, or 3 heteroatoms as ring members. In said heteroaryl group contains 1 or 2 heteroatoms as ring members. In some embodiments, said heteroaryl group contains 1 heteroatom as a ring member. In some embodiments, said heteroaryl group is 5-10 membered or 5-6 membered. In some embodiments, said heteroaryl group is 5-membered. In some embodiments, said heteroaryl group is 6-membered. When said heteroaryl group contains more than one heteroatom as a ring member, said heteroatoms may be the same or different. Nitrogen atoms in a ring

- 8 042621 (rings) of the heteroaryl group can be oxidized to form N-oxides. Examples of heteroaryl groups include, without limitation, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl and the like.

A 5-membered heteroaryl group is a heteroaryl group containing 5 ring-forming atoms in which one or more ring-forming atoms is independently selected from N, O, and S. In some embodiments, said 5-membered heteroaryl group contains 1, 2, or 3 heteroatoms as members of the ring. In some embodiments, said 5-membered heteroaryl group contains 1 or 2 heteroatoms as ring members. In some embodiments, said 5-membered heteroaryl group contains 1 heteroatom as a ring member. Examples of ring-forming members include CH, N, NH, O and S. Examples of five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1,3, 4-triazolyl, 1,3, 4-thiadiazolyl and 1,3,4-oxadiazolyl.

A 6-membered heteroaryl group is a heteroaryl group containing six ring-forming atoms in which one or more ring-forming atoms is N. In some embodiments, said 6-membered heteroaryl group contains 1, 2, or 3 heteroatoms as ring members. In some embodiments, said 6-membered heteroaryl group contains 1 or 2 heteroatoms as ring members. In some embodiments, said 6-membered heteroaryl group contains 1 heteroatom as a ring member. Examples of ring-forming members include CH and N. Examples of six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

In the context of this application, the term heterocycloalkyl, used alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system which may optionally contain one or more unsaturated bonds as part of a ring structure, and which contains as a ring member at least one heteroatom independently selected from nitrogen, sulfur and oxygen. In some embodiments, said heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms as ring members. In some embodiments, said heterocycloalkyl group contains 1, 2, or 3 heteroatoms as ring members. In some embodiments, said heterocycloalkyl group contains 1 or 2 heteroatoms as ring members. In some embodiments, said heterocycloalkyl group contains 1 heteroatom as a ring member. When the heterocycloalkyl group contains more than one heteroatom in the ring, these heteroatoms may be the same or different. Examples of ring-forming members include CH, CH ₂ , C(O), N, NH, O, S, S(O) and S(O) ₂ . Heterocycloalkyl groups may include mono- or polycyclic (eg, containing 2, 3, or 4 fused rings) ring systems, including spiro systems. Also included within the definition of heterocycloalkyl are moieties containing one or more aromatic rings fused (ie, sharing a common bond) with a non-aromatic ring, such as 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, and the like. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group may be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized bond), or the nitrogen atom may be quaternized. In some embodiments, said heterocycloalkyl is 5-10-membered, 4-10-membered, 4-7-membered, 5-membered, or 6-membered. Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl.

The compounds described in this application may be asymmetric (eg, contain one or more stereocenters). All stereoisomers are meant, such as enantiomers and diastereoisomers, unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, for example by separation of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds described in this application, and all such stable isomers are meant in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms.

When the compounds of the present invention contain a chiral center, said compounds may be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center may be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can be independently (R) or (S) for each of the centers, so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R) or (S) and

- 9 042621 (S). In compounds with three chiral centers, the stereochemistry of the chiral centers can be independently (R) or (S) for each of the three centers, thus the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R) or (S), (S) and (S).

Separation of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. An example of such a method includes fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization processes are, for example, optically active acids such as the D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β -camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization processes include stereoisomerically pure forms of α-methylbenzylamine (eg, S- and R-forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Separation of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (eg dinitrobenzoylphenylglycine). A suitable solvent composition for elution can be determined by a person skilled in the art.

The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the replacement of a single bond by an adjacent double bond, as well as parallel migration of a proton. Tautomeric forms include prototropic tautomers that are in isomeric protonation states having the same empirical formula and overall charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which the proton can occupy two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2Hi 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomeric forms may be in equilibrium or may be spatially contained in one form by suitable substitution.

The compounds of the present invention may also include all isotopes of atoms occurring in intermediate or final compounds. Isotopes include all atoms that have the same atomic number but different mass numbers.

The term compound in the context of this application is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures shown. Compounds in this application defined by name or structure as one particular tautomeric form are intended to include other tautomeric forms, unless otherwise indicated (e.g., in the case of purine rings, unless otherwise indicated, when the name or structure of a compound contains the 9H tautomer, understand tautomer 7H is also included).

All compounds and their pharmaceutically acceptable salts may be coexistent with other substances such as water and solvents (eg hydrates and solvates) or may be isolated.

In some embodiments, the compounds of the present invention, or salts thereof, are substantially isolated. By substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or found. Partial separation may include, for example, a composition enriched with a compound of the present invention. The separation can essentially include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% by weight of the compounds of the present invention, or a salt thereof. Methods for isolating compounds and their salts are generally accepted in the art.

The phrase pharmaceutically acceptable is used in this application to refer to those compounds, substances, compositions and/or dosage forms that are medically suitable for use in contact with human and animal tissues without causing undue toxicity, irritation, allergic reaction or other problem or complication. according to a reasonable ratio of risk and benefit.

The expressions air temperature and room temperature in the context of the present application are understood in this area and generally refer to a temperature, for example, a reaction temperature, which is approximately equal to the temperature in the room in which said reaction is carried out, for example, a temperature from about 20 to about 30 ° C.

The present invention also includes pharmaceutically acceptable salts of the compounds described in this application. In the context of the present application, pharmaceutically acceptable salts refer to derivatives of the compounds disclosed herein, wherein the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, without limitation, salts of inorganic or organic acids and basic residues such as amines; alkali and organic salts of acid residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts according to the present invention include known non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acid moiety by known chemical methods. In general, such salts may be prepared by reacting the free acid or base forms of such compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or mixtures thereof; in general, non-aqueous media such as ether, ethyl acetate, alcohols (eg methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, ^17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used in this application:

AcOH (acetic acid);

Ac ₂ O (acetic anhydride);

water. (water);

atm (atmosphere(s));

Boc (t-butoxycarbonyl);

BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate);

br (wide);

Cbz (carboxybenzyl);

Comput. (calculated);

d (doublet);

dd (doublet of doublets);

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene);

DCM (dichloromethane);

DIAD (N,N'-diisopropyl azidodicarboxylate);

DIEA (N,N-diisopropylethylamine);

DIPEA (N,N-diisopropylethylamine);

DMF (N,N-dimethylformamide);

EA (ethyl acetate);

Et (ethyl);

EtOAc (ethyl acetate);

g (gram);

h(hour(s));

HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate);

HCl (hydrochloric acid);

HPLC (high performance liquid chromatography);

Hz (hertz);

J (interaction constant);

LCMS (liquid chromatography - mass spectrometry);

m (multiplet);

M (mol);

mCPBA (3-chloroperoxybenzoic acid);

MS (Mass Spectrometry);

Me (methyl);

MeCN (acetonitrile);

MeOH (methanol);

mg (milligram);

min (minutes);

ml (milliliter (milliliters));

mmol (millimole);

n. (normal);

nM (nanomole);

NMP (N-methylpyrrolidinone);

NMR (nuclear magnetic resonance spectroscopy);

OTf (trifluoromethanesulfonate);

Ph (phenyl);

- 11 042621 pM (picomole);

RP-HPLC (reverse phase high performance liquid chromatography);

s (singlet);

t (triplet or tertiary);

TBS (tert-butyldimethylsilyl);

tert (tertiary);

tt (triplet of triplets);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran);

mcg (micrograms);

μl (microliter(s));

μM (micromoles);

wt.% (mass percent).

Synthesis

The compounds of the present invention, including their salts, may be prepared by known organic synthesis techniques, and may be synthesized according to any of a variety of possible synthetic routes.

Reactions to prepare compounds of the present invention can be carried out in suitable solvents, which can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents may not substantially react with the starting materials (reagents), intermediates, or products at the temperatures at which the reactions are carried out, for example, temperatures that range from the freezing point of the solvent to the boiling point of the solvent. A particular reaction can be carried out in a single solvent or in a mixture of more than one solvent. Suitable solvents for a particular reaction step can be selected by one skilled in the art depending on the particular reaction step.

The preparation of compounds of the present invention may include protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of suitable protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in PG M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, ^4th Ed., Wiley & Sons, Inc., New York (2006), which is incorporated into this application. in its entirety by reference. Protecting groups are usually designated PG in synthetic schemes.

The progress of the reactions can be monitored by any suitable method known in the art. For example, product formation can be observed by spectroscopic means, such as nuclear magnetic resonance spectroscopy (for example, 1H or ¹³ C), infrared spectroscopy, spectrophotometry (for example, optical), mass spectrometry, or chromatographic methods such as high performance liquid chromatography. (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC). Those skilled in the art can purify compounds using a variety of techniques, including Preparative LC-MC Purification: Improved Compound Specific Method Optimization Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi Chem 2004, 6(6), 874-883, which is hereby incorporated by reference in its entirety) and normal phase silica gel chromatography.

Compounds of formula 3 can be prepared by the methods indicated in Scheme 1. A cyclopropylamine derivative of formula 1 can be reacted with aldehydes of formula 2 under reductive amination conditions well known in the art of organic synthesis to give the corresponding products of formula 3. For example, a reductive amination reaction can be carried out in a suitable solvent such as DCM or THF using a reducing agent such as but not limited to sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid. If any functional groups in compound 1 or 2 are protected to avoid any side reactions, a subsequent deprotection step may be carried out to obtain the final product of formula 3. Deprotection conditions can be found in the literature or detailed description in the specific examples described below. Starting materials of formula 1 or 2 are either available from commercial sources, or can be obtained as described in this application, or obtained using methods described in the literature.

- 12 042621

Scheme 1

I) (3)

Alternatively, compounds of formula 3a can be synthesized using the methods shown in scheme 2. Reductive amination of cyclopropylamine derivatives of formula 1 with aldehydes of formula 4 under conditions similar to those described in scheme 1 can lead to the formation of compounds of formula 5. Then the free amino group in compound 5 may be protected with a suitable protecting group (PG) such as, but not limited to, CF ₃ CO and Cbz, followed by selective deprotection of Boe with an acid to give compound 6. Reductive amination of compound 6 with ketone 7 in a suitable a solvent such as DCM with a reducing agent such as sodium triacetoxyborohydride can give compound 8 which can be deprotected to give compounds of formula 3a.

Compounds of formula 3b can be prepared using the methods shown in Scheme 3, starting with compounds of formula 1 and compound 9 by reductive amination in a suitable solvent such as DCM or THF using a reducing agent such as but not limited to sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid. If any functional groups in compound 1 or 9 are protected to avoid any side reactions, a subsequent deprotection may be carried out to obtain the final product of formula 3b.

Scheme 3

(1) (3b)

The cyclopropylamine derivatives of Formula 1 can be prepared using the methods outlined in Scheme 4, starting with the α,β-unsaturated esters of Formula 10 (where R is alkyl, such as ethyl), which are either available from commercial sources or prepared using the described in the literature or the methods given here. Cyclopropanation of compound 10 under standard conditions, such as the Corey-Tchaikovsky reaction, can give cyclopropyl derivatives of formula 11. The ester can be saponified to form acids of formula 12, which can be subjected to standard Curtius rearrangement conditions followed by deprotection to give cyclopropylamine derivatives of formula 1.

- 13 042621

Scheme 4

Application methods

The compounds of the present invention are inhibitors of LSD1 and thus are suitable for use in the treatment of diseases and disorders associated with LSD1 activity. For the uses described below, any of the compounds of the present invention, including any of their embodiments, may be used.

In some embodiments, the compounds of the present invention are more selective for LSD1 than for LSD2, that is, the compounds bind to or inhibit LSD1 with greater affinity or greater activity than LSD2. In general, selectivity can be at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least at least 500 times or at least 1000 times.

As inhibitors of LSD1, the compounds of the present invention are suitable for use in the treatment of LSD1-mediated diseases and disorders. The term LSD1-mediated disease or LSD1-mediated disorder refers to any disease or disease state in which LSD1 plays a role, or to cases in which the disease or disease state is associated with the expression or activity of LSD1. Therefore, the compounds of the present invention are suitable for use in the treatment or alleviation of diseases and conditions in which LSD1 is known to play some role.

Diseases and conditions that may be treated with the compounds of the present invention generally include cancers, inflammation, autoimmune diseases, viral pathogenesis, beta-globinopathies, and other diseases associated with LSD1 activity.

Cancers that may be treated with the compounds of the present invention include, for example, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, urinary tract cancers, liver cancers, bone cancers, nervous system cancers. systems, gynecological cancers and skin cancers.

Examples of hematological cancers include, for example, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed and refractory non-Hodgkin's lymphoma (NHL) and recurrent follicular non-Hodgkin's lymphoma), Hodgkin's lymphoma, myeloproliferative disorders (eg, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), and multiple myeloma.

Examples of sarcomas include, for example, chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, hamartoma, and teratoma.

Examples of lung cancers include, for example, non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Examples of cancers of the gastrointestinal tract include, for example, cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma ), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) and colorectal cancer.

Examples of cancers of the genitourinary tract include, for example, cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Examples of liver cancers include, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Examples of bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoxanthoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfromoma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

Examples of cancers of the nervous system include, for example, cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), brain membranes (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Examples of gynecological cancers include, for example, cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, precancerous cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucus-forming cystadenocarcinoma, unclassified carcinoma), granulosa cell tumors, sertolileydig tumors cells, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma) and fallopian tubes (carcinoma).

Examples of skin cancers include, for example, melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus syndrome, lipoma, angioma, dermatofibroma, and keloids.

Compounds of the present invention may additionally be used to treat types of cancer in which LSD1 may be overexpressed, including, for example, cancer of the breast, prostate, head and neck, larynx, mouth, and thyroid (e.g., papillary thyroid carcinoma) .

The compounds of the present invention may additionally be used in the treatment of genetic disorders such as Cowden's syndrome and Bannayan-Zonan's syndrome.

The compounds of the present invention may additionally be used to treat viral diseases such as herpes simplex virus (HSV), varicella zoster virus (VZV), human cytomegalovirus, hepatitis B virus (HBV) and adenovirus.

Compounds of the present invention may additionally be used to treat beta-globinopathies, including, for example, beta-thalassemia and sickle cell anemia.

In the context of the present application, the term bringing into contact refers to the association of the designated fragments in an in vitro system or in an in vivo system. For example, contacting an LSD1 protein with a compound of the present invention comprises administering a compound of the present invention to an individual or patient such as a human having an LSD1 protein, as well as, for example, administering a compound of the present invention to a sample containing a cell preparation or purified preparation, containing the LSD1 protein.

In the context of this application, the terms individual or patient, used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably a human. .

As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human being sought by a researcher, veterinarian, physician, or other clinician.

In the context of the present application, the term treat or treatment refers to the inhibition of a disease; for example, inhibition of a disease, condition, or disorder in an individual having or exhibiting a pathology or symptomatology of said disease, condition, or disorder (ie, cessation of further development of the pathology and/or symptomatology) or reduction of the intensity of the disease; for example, reducing the intensity of a disease, condition, or disorder in an individual having or exhibiting a pathology or symptomatology of said disease, condition, or disorder (ie, reversal of the pathology and/or symptoms), for example, reducing the severity of the disease.

In the context of this application, the term prevent or prevention refers to the prevention of disease; for example, preventing a disease, condition, or disorder in an individual who may have a predisposition to said disease, condition, or disorder, but

- 15 042621 does not yet have or does not show the pathology or symptoms of the specified disease.

Combination Therapy

The compounds of the present invention can be used in combination therapy in which the compound of the present invention is administered in conjunction with other drugs, for example, the administration of one or more additional therapeutic agents. These additional therapeutic agents are usually agents that are typically used to treat a particular condition. These additional therapeutic agents may include, for example, chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, as well as inhibitors of Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K for the treatment of LSD1-mediated diseases, disorders or conditions. These one or more additional pharmaceutical agents may be administered to the patient simultaneously or sequentially.

In some embodiments, the compounds of the present invention may be used in combination with a therapeutic agent that acts on an epigenetic regulator. Examples of epigenetic regulators include histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, for example, vorinostat.

For the treatment of cancer and other proliferative diseases, the compounds of the present invention may be used in combination with chemotherapeutic agents or other antiproliferative agents. The compounds of the present invention may also be used in combination with therapy such as surgery or radiation therapy, eg gamma radiation, neutron beam radiation therapy, proton therapy, brachytherapy and systemic radioactive isotope therapy. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, oral busulfan, busulfan for intravenous administration, busulfan for intravenous administration, busulfan for intravenous administration, busulfan for intravenous administration, busulfan injectables, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlormabucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabin, denileukin, denileukin diftitox, dexrazoxane, doxoropidostanol, doxoropidostanol, doxoropidostanolone, doxoropidostanol, doxetaxel , eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomabdarubamidamid, ifosimab tiuxetan, ifos mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxalene, mitomycin C, mitotane, mitoxantrone, nandrolone, fenpropionate, nomotane , oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pegaspargasa, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruscolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide , thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

For the treatment of cancer and other proliferative diseases, the compounds of the present invention may also be used in combination with ruxolitinib.

For the treatment of cancer and other proliferative diseases, the compounds of the present invention may be used in combination with targeted therapies, including JAK kinase inhibitors (Ruxolitinib, JAK1-selective), Pim kinase inhibitors, PI3 kinase inhibitors, including PI3K-delta-selective, and broad spectrum PI3K inhibitors. Spectrum inhibitors, MEK inhibitors, cyclin-dependent kinase inhibitors, b-RAF inhibitors, mTOR inhibitors, proteasome inhibitors (Bortezomib, Carfilzomib), HDAC inhibitors (Panobinostat, Vorinostat), DNA methyltransferase inhibitors, dexamethasone, inhibitors of bromo- and extraterminal family members, and indolamine inhibitors -2,3 dioxygenases.

For the treatment of autoimmune or inflammatory conditions, the compound of the present invention may be administered in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

For the treatment of autoimmune or inflammatory conditions, a compound of the present invention may be administered in combination with an immunosuppressant such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon) or cyclosporine (Restasis®).

For the treatment of autoimmune or inflammatory conditions, a compound of the present invention may be administered in combination with one or more additional agents selected from Dehydrex™ (Holies Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST- 603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P) (Argentis), sodium ecabeta (Senju-Ista), gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S) -HETE), forearm

- 16 042621 lemin, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Doramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R, 5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyloxolan-2-carbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis), RX-10045 (synthetic analogue of resolvin, Resolvyx), DYN15 (Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science ), REV131 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate , rituximab, tetrasodium diquafosol (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, sodium mycophenolate, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), or thalidomide.

In some embodiments, a compound of the present invention may be administered in combination with one or more agents selected from antibiotics, antifungals, antivirals, anesthetics, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatory agents, and antiallergic agents. Examples of suitable drugs include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin and enoxacin; naphthyridine; sulfonamides; polymyxin; chlormafenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (rifampins); cycloserine; beta lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; Suprofen; cromolyn; lodoxamide; levocabastine; naphazoline; antazolin; pheniramine; or azalide antibiotics.

Other examples of agents with one or more of which a compound of the present invention may be combined include therapeutics for Alzheimer's disease such as donepezil and rivastigmine; therapy for Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl and amantadine; an agent for the treatment of multiple sclerosis (PC) such as beta-interferon (eg, Avonex® (Avonex®) and Rebif® (Rebif®), glatiramer acetate and mitoxantrone; an asthma therapy such as albuterol and montelukast; an agent for the treatment of schizophrenia such as ziprexa, risperdal, seroquel and haloperidol; an anti-inflammatory agent such as a corticosteroid such as dexamethasone or prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; an immunomodulatory agent including immunosuppressive agents such as cyclosporine, tacrolimus , rapamycin, mycophenolate mofetil, interferon, corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor such as an acetylcholinesterase inhibitor, a MAO inhibitor, interferon, an anticonvulsant, an ion channel blocker, riluzole, or an anti-Parkinson agent; an agent for the treatment of cardiovascular disease such as a beta blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker or a statin, an agent for treating liver disease such as a corticosteroid, cholestyramine, interferon and an antiviral agent; a blood disease treatment agent such as a corticosteroid, an antileukemia agent, or a growth factor; or an agent for the treatment of immunodeficiency disorders such as gamma globulin.

Biological drugs such as antibiotics and cytokines useful as anti-cancer agents can be combined with the compounds of the present invention. In addition, drugs that modulate the microenvironment or immune responses can be combined with the compounds of the present invention. Examples of such drugs are anti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1, αntu-PD-1, anti-PDL1 and other immunotherapeutic drugs.

Composition, dosage forms and administration

When used as drugs, the compounds of the present invention may be administered in the form of pharmaceutical compositions. Such compositions may be prepared by methods well known in the pharmaceutical art and may be administered in a variety of ways depending on whether local or systemic treatment is required and on the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (eg, by inhalation or insufflation of powders and aerosols, including by inhaler; intratracheal or intranasal) , oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular administration or injection or infusion; or intracranial, eg intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus injection or, for example, using a continuous perfusion pump. Pharmaceutical compositions and topical formulations may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. It may be necessary or desirable to use standard pharmaceutical carriers, aqueous, powder or oil bases, thickeners, and the like.

The present invention also includes pharmaceutical compositions which contain, as an active ingredient, a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (auxiliaries). In some embodiments, said composition is suitable for topical use. In preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or enclosed in such a carrier in the form of, for example, a capsule, sachet, paper or other container. When an excipient acts as a diluent, it may be a solid, semi-solid or liquid substance which serves as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight, active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

Upon receipt of the composition of the active compound can be crushed to obtain a suitable particle size before combining it with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size can be adjusted by milling to obtain a substantially uniform distribution in the formulation, eg, about 40 mesh.

The compounds of the present invention may be milled using known milling techniques, eg wet milling, to obtain a particle size suitable for tableting or other types of formulation. Finely divided (composed of nanoparticles) compositions of compounds according to the present invention can be obtained by methods known in this field, for example, see international patent application No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavor additives. The compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient, using techniques known in the art.

The compositions may be formulated into unit dosage form, with each dosage containing from about 5 to about 1000 mg (1 g), more typically from about 100 mg to about 500 mg, of the active ingredient. The term unit dosage form refers to physically discrete units suitable for use as unit doses in human or other animal subjects, each unit form containing a predetermined amount of the active substance, calculated to provide the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

The active compound may be effective over a wide dosage range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound to be actually administered will generally be determined by the attending physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the age, body weight and response of the individual patient, the severity patient symptoms and the like.

To obtain solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid precomposition containing a homogeneous mixture of the compound of the present invention. When such solid pre-compositions are referred to as homogeneous, this means that the active ingredient is usually evenly dispersed throughout the composition, such that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that provides the benefit of prolonged release. For example, a tablet or pill may contain an internal and external dosage component, the latter being in the form of a coating over the former. These two

- 18 042621 components can be separated enteric layer, which serves to prevent splitting in the stomach and allows the internal component to pass intact into the duodenum or be released with delay. A variety of substances can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the compounds and compositions of the present invention may be formulated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via the oral or nasal airway for local or systemic action. The compositions may be formulated into sprayable form using inert gases. Solutions in nebulized form can be inhaled directly from a nebulizing device, or the nebulizing device can be attached to a face mask or intermittent positive pressure breathing device. Compositions in the form of solutions, suspensions or powders can be administered orally or nasally using devices that deliver the composition in a suitable manner.

Topical formulations may contain one or more conventional carriers. In some embodiments, the ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. Cream carrier compositions may be based on water in combination with glycerol and one or more other components, for example glycerol monostearate, PEGglycerol monostearate and cetyl stearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other ingredients such as, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt.%, compounds according to the present invention. Formulations for topical application may be suitably packaged in tubes of, for example, 100 g capacity, which are optionally supplied with instructions for the treatment of the selected indication for use, for example, psoriasis or other skin disease.

The amount of a compound or composition to be administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or therapy, the condition of the patient, the route of administration, and the like. In therapeutic use, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. Effective doses will depend on the disease being treated, as well as the judgment of the attending physician, depending on such factors as the severity of the disease, the age, body weight and general condition of the patient, etc.

Compositions for administration to a patient may be in the form of the pharmaceutical compositions described above. Such compositions can be sterilized using standard sterilization techniques or subjected to sterile filtration. Aqueous solutions may be packaged for use as is or lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle prior to administration. The pH of formulations of the compounds will typically be between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of the specific excipients, carriers or stabilizers listed above will result in the formation of pharmaceutical salts.

The therapeutic dose of a compound of the present invention may vary depending on, for example, the particular purpose for which the treatment is being used, the route of administration of the compound, the state of health of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present invention in a pharmaceutical composition may vary depending on a number of factors including dose, chemical characteristics (eg hydrophobicity) and route of administration. For example, the compounds of the present invention may be provided in an aqueous physiological buffer solution containing from about 0.1% to about 10% w/v. compounds for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dosage range is from about 0.01 to about 100 mg/kg of body weight per day. The dosage is likely to depend on variables such as the type and extent of progression of the disease or disorder, the general health of the individual patient, the relative biological potency of the compound chosen, the composition of the excipient, and the route of administration. Effective doses can be extrapolated from curves

- 19 042621 dose-response obtained in in vitro testing systems or experimental animal models.

Compositions according to the present invention may further contain one or more additional pharmaceutical agents, such as a chemotherapeutic, steroid, anti-inflammatory compound or immunosuppressant, examples of which are given in the present description above.

The compounds of the present invention may be provided or used in combination with an accompanying diagnostic device. As used herein, the term companion diagnostic device refers to a diagnostic device suitable for determining the safe and effective use of a therapeutic agent. For example, a companion diagnostic device can be used to individualize the dose of a therapeutic agent for a particular subject, determine suitable subpopulations for treatment, or determine populations that should not receive a particular treatment due to an increased risk of serious side effects.

In some embodiments, a companion diagnostic device is used to monitor a patient's response to treatment. In some embodiments, a companion diagnostic device is used to determine a subject who is likely to benefit from a particular compound or therapeutic agent. In some embodiments, a companion diagnostic device is used to determine a subject at high risk of unwanted side effects from administration of a therapeutic agent compared to a reference standard. In some embodiments, the companion diagnostic device is an in vitro diagnostic or imaging device selected from a list of FDA approved or FDA approved companion diagnostic devices. In some embodiments, the associated diagnostic device is selected from a list of tests that have been approved or approved by the Center for Devices and Radiological Health.

Labeled compounds and methods of analysis

Another aspect of the present invention relates to labeled compounds of the present invention (radioisotopically labeled, fluorescein labeled, etc.) which are suitable for use not only in imaging techniques but also in assays, both in vitro and in vivo, to localize and enumerate LSD1 in tissue samples, including human tissues, and to detect LSD1 ligands by suppressing labeled compound binding. Accordingly, the present invention encompasses LSD1 assays that include such labeled compounds.

The present invention further includes isotopically labeled compounds according to the present invention. An isotopically or radioisotopically labeled compound is a compound of the present invention in which one or more atoms have been replaced or replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., natural origin). Suitable radionuclides that may be incorporated into the compounds of the present invention include, without limitation, ^3H (also referred to as T-tritium), 11C, ^13C , ^14C , ^13N , ^15N , ^15O , ¹⁷⁰ , ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I. The radionuclide that is incorporated into the present radioisotopically labeled compounds will depend on the particular application of such radioisotopically labeled compound.

It should be understood that a radioisotopically labeled or labeled compound is one in which at least one radionuclide is incorporated. In some embodiments, such a radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br. In some embodiments, 1, 2, or 3 deuterium atoms are incorporated into the compound.

The present invention may further include synthetic methods for incorporating radioisotopes into the compounds of the present invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those of ordinary skill in the art will readily recognize methods applicable to the compounds of the present invention.

The labeled compound of the present invention can be used in a screening assay for the determination/evaluation of compounds. For example, a labeled compound that has been synthesized or identified (ie, a test compound) can be assessed for its ability to bind LSD1 by observing its concentration change upon contact with LSD1, via label tracking. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound known to bind to LSD1 (ie, a standard compound). Accordingly, the ability of a test compound to compete with a reference compound for binding to LSD1 is directly correlated with its binding capacity. Conversely, in some screening assays, the reference compound is labeled and the test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored to

- 20 042621 to evaluate the competition between the standard compound and the test compound, and thus establish the relative binding capacity of the test compound.

The present invention will be described in more detail using specific examples. The following examples are offered for illustrative purposes and are not intended to limit the scope of the present invention in any way. Those skilled in the art will recognize various non-critical parameters that can be changed or modified to produce substantially the same results. The compounds in the examples were found to be inhibitors of LSD1, as described below.

Examples

Experimental methods for obtaining compounds according to the present invention are given below. Pre-purification by LC-MS for some of the obtained compounds was carried out on Waters mass directed fractionation systems. The main hardware settings, protocols and control software for the operation of such systems are described in detail in the literature. See, for example, Two-Pump At Column Dilution Configuration for Preparative LC-MC, K. Blom, J. Combi. Chem. 4, 295 (2002); Optimizing Preparative LC-MC Configurations and Methods for Parallel Synthesis Purification, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and Preparative LC-MC Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds to be separated were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) to assess purity under the following conditions: Instrument; Agilent 1100 Series, LC/MSD, Column: Waters Sunfire™ C ₁₈ 5 µM, 2.1 x 5.0 mm, Buffers: Mobile phase A: 0.025% TFA in water and Mobile phase B: acetonitrile; gradient from 2 to 80% B over 3 min at a flow rate of 2.0 ml/min.

Some of the resulting compounds were also separated on a preparative column using reverse phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the examples. Typical conditions for performing preparative reverse phase high performance liquid chromatography (RP-HPLC) columns are shown below:

purification pH=2: Waters Sunfire™ C ₁₈ with 5 μM particle size, 19x100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 ml/min, the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature [see. Preparative LCMS Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 ml/min was used on a 30x100 mm column.

purge pH=0: Waters XBridge C ₁₈ 5 µM particle size, 19x100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 ml/min, the separation gradient was optimized for each compound using the Compound-Specific Method Optimization protocol [cf. Preparative LCMS Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 ml/min was used on a 30x100 mm column.

Example 1 (1-{4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}cyclobutyl)acetonitrile

Step 1: [1-(4-oxopiperidin-1-yl)cyclobutyl]acetonitrile

To a mixture of piperidin-4-one hydrochloride hydrate (154 mg, 1.00 mmol, Aldrich, cat#151769) in acetonitrile (2 mL, 40 mmol) was added DBU (225 μL, 1.50 mmol) followed by cyclobutylidene acetonitrile (187 mg , 2.00 mmol, obtained using methods described in the literature, for example, in the application WO 2009/114512). The resulting mixture was heated to 70° C. and stirred overnight. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture was then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate (yellow oil) was used in the next step without further purification. LC-MS calculated for C11H17N2O (M+H)+: m/z=193.1; Comput. 193.2.

Step 2: (1-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}cyclobutyl)acetonitrile

To a solution of 2-phenylcyclopropanamine hydrochloride (36 mg, 0.21 mmol) (trans, racemic, Acros: Cat#130470050, Lot: A0295784) and [1-(4-oxo-piperidin-1-yl)cyclobutyl]acetonitrile (41 mg, 0.21

- 21 042621 mmol) (crude product from stage 1) in DCM (2 ml) was added acetic acid (36 μl, 0.64 mmol). The resulting yellow solution was stirred at room temperature for 2 hours. Na(OAc) ₃ BH (140 mg, 0.64 mmol) was then added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, then washed with saturated Na ₂ CO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was purified with prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) gave the product as a white solid (trans, racemic). LC-MS calculated for C ₂₀ H ₂₈ N ₃ (M+H) ⁺ : m/z=310.2; Comput. 310.2.

Example 2 (1-Methyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

Stage 1: tert-butyl-3-(cyanomethyl)-3-(4-oxopiperidin-1-yl)azetidine-1-carboxylate

To a solution of piperidin-4-one hydrochloride hydrate (1.08 g, 7.00 mmol) and tert-butyl-3(cyanomethylep)azetidine-1-carboxylate (2.04 g, 10.5 mmol, obtained by the methods similar to those described in the literature, for example, in the application WO 2009/114512) in acetonitrile (7 ml) was added DBU (1.36 ml, 9.10 mmol). The resulting mixture was stirred at room temperature for 15 minutes until complete dissolution of the solid. The resulting solution was then heated to 70° C. and stirred for 48 hours. The mixture was cooled to room temperature, diluted with EtOAc, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was purified with a silica gel column eluting with 0 to 7% MeOH/DCM to give the product (844 mg, 41%) as a yellow oil. LC-MS calculated for C11H ₁₆ N ₃ O ₃ (M-tBu+2H) ⁺ : m/z=238.1; Comput. 238.2.

Stage 2: tert-butyl-3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1 yl}azetidine-1-carboxylate

N

Vos

To a solution of 2-phenylcyclopropanamine hydrochloride (540 mg, 3.2 mmol, Acros: Cat#130470050, Lot: A0295784) and tert-butyl-3-(cyanomethyl)-3-(4-oxo-piperidin-1-yl)azetidin-1 -carboxylate (937 mg, 3.19 mmol) in DCM (15 ml) was added acetic acid (540 μl, 9.6 mmol). The resulting yellow solution was stirred at room temperature overnight then Na(OAc) ₃ BH (1.4 g, 6.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with saturated Na ₂ CO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 10% MeOH/DCM to give the desired product (1.07 g, 82%) as a yellow oil. LC-MS calculated for C ₂₄ H ₃₅ N ₄ O ₂ (M+H) ⁺ : m/z=411.3; Comput. 411.3.

Step 3: tert-Butyl-3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]piperidin-1-yl}azetidine-1-carboxylate

F ₃ C^O

N

Vos

To a solution of tert-butyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1 yl}azetidine-1-carboxylate (1.07 g, 2.61 mmol) in DCM (15 ml) at 0° C. DIEA (1.4 ml, 7.8 mmol) was added and then trifluoroacetic anhydride (0.41 ml, 2.87 mmol) was added dropwise. The resulting yellow solution was stirred at 0° C. for 1 h, then the reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then filtered and concentrated. The precipitate was purified on a silica gel column eluting with 0 to 60% EtOAc/hexanes to give the desired product (922 mg, 70%) as a yellow oil which solidified on standing to give a light yellow solid. LC-MS calculated for C26H34F3N4O3 (M+H) ⁺ : m/z=507.3; Comput. 507.4.

- 22 042621

Step 4: N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]piperidin-1-yl}azetidine-1-carboxylate (922 mg, 1.82 mmol) in DCM (7.2 ml) was added TFA (2.80 ml, 36.4 mmol). The resulting yellow solution was stirred at room temperature for 1 hour then concentrated. The precipitate was dissolved in EtOAc, then washed with saturated NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 20% MeOH/DCM to give the desired product (700 mg, 95%) as a yellow oil which solidified on standing to give a light yellow solid. LC-MS calculated for C ₂₁ H ₂₆ F ₃ N ₄ O (M+H)+: m/z=407.2; Comput. 407.2.

Step 5: N-{1-[3-(cyanomethyl)-1-methylazetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide

F ₃ C^O

Ϊ

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (24 mg, 0.059 mmol) in DCM (2 ml) was added formaldehyde (37 wt.%, in water, 22 μl, 0.30 mmol) and then acetic acid (10. μl, 0.18 mmol). The resulting mixture was stirred at room temperature overnight, then Na(OAc) ₃ BH (38 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then neutralized with saturated Na ₂ CO ₃ solution and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₂ H ₂₈ F ₃ N ₄ O (M+H) ⁺ : m/z=421.2; Comput. 421.2.

Stage 6: (1-methyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

The crude product from step 5 was dissolved in THF (1 ml) and MeOH (1 ml), then 2.0 M sodium hydrochloride in water (0.15 ml, 0.30 mmol) was added. The resulting mixture was stirred at 30° C. for 1 h, cooled to room temperature, diluted with acetonitrile, then filtered and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) gave the product as the TFA salt as a white solid. LC-MS calculated for C ₂₀ H ₂₉ N ₄ (M+H) ⁺ : m/z=325.2; Comput. 325.2.

Example 3 (3-{4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

To a solution of tert-butyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1yl}azetidine-1-carboxylate (20 mg, 0.049 mmol, prepared as described in Example 2 , stage 2) in DCM (1 ml) was added TFA (0.5 ml). The resulting yellow solution was stirred at room temperature for 1 hour then concentrated. The precipitate was dissolved in acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₁₉ H ₂₇ N ₄ (M+H) ⁺ : m/z=311.2; Comput. 311.2.

Example 4 (1-Benzyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (24 mg, 0.059 mmol, obtained , as described in example 2, step 4) in DCM (2 ml) was added benzaldehyde (30 μl, 0.29 mmol) and then acetic acid (10 μl, 0.18 mmol). The resulting mixture was stirred at room temperature overnight, then Na(OAc)3BH (38 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for

- 23 042621 for 2 hours, while LC-MS showed that the reaction is complete, then the mixture was neutralized with a saturated solution of Na ₂ CO ₃ and was extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was dissolved in THF (1 ml) and MeOH (1 ml), then 2.0 M sodium hydrochloride in water (0.15 ml, 0.30 mmol) was added. The resulting mixture was stirred at 30°C for 1.5 h, then cooled to room temperature and diluted with acetonitrile, then the mixture was filtered and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₆ H ₃₃ N ₄ (M+H)+: m/z=401.3; Comput. 401.2.

Example 5 3-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin1-yl)propanoic acid coon

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (33 mg, 0.081 mmol , obtained as described in example 2, stage 4) in acetonitrile (1 ml) was added methyl acrylate (36 μl, 0.40 mmol) and then DBU (12 μl, 0.081 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was dissolved in THF (1 ml) and MeOH (1 ml), then 2.0 M sodium hydrochloride in water (0.30 ml, 0.60 mmol) was added. The resulting mixture was stirred at 30° C. for 1 h, then diluted with MeOH/acetonitrile, then the mixture was filtered and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₂ H ₃₁ N ₄ O ₂ (M+H)+: m/z=383.2; Comput. 383.3.

Example 6 (1-Acetyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

A ⁿ

N

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (22 mg, 0.054 mmol, obtained as described in example 2, step 4) in THF (1.0 ml) was added DIEA (47 μl, 0.27 mmol) and then acetyl chloride (7.7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 h, then MeOH (1.0 ml) was added followed by 2.0 M sodium hydrochloride in water (0.14 ml, 0.27 mmol). The resulting mixture was stirred at room temperature for 2 hours, while LC-MS showed that the reaction was complete to obtain the desired product. The reaction mixture was diluted with acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₁ H ₂₉ N ₄ O (M+H)+: m/z=353.2; Comput. 353.3.

Example 7 (1-Benzoyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

^N0 and

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (22 mg, 0.054 mmol , obtained as described in example 2, stage 4) in THF (1.0 ml) was added DIEA (47 μl, 0.27 mmol) and then benzoyl chloride (12 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 h, then MeOH (1.0 ml) was added followed by 2.0 M sodium hydrochloride in water (0.14 ml, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then diluted with acetonitrile and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₆ H ₃₁ N ₄ O (M+H)+: m/z=415.2; Comput. 415.3.

- 24 042621

Example 8 Methyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidine-1-carboxylate

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (20 mg, 0.049 mmol, obtained , as described in example 2, step 4) in THF (1.0 ml) was added DIEA (43 μl, 0.25 mmol) and then methyl chloroformate (7.6 μl, 0.098 mmol). The resulting mixture was stirred at room temperature for 1.5 h, then MeOH (1.0 ml) was added followed by 2.0 M sodium hydrochloride in water (0.12 ml, 0.25 mmol). The mixture was stirred at room temperature for 2 h, then diluted with acetonitrile and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₁ H ₂₉ N ₄ O ₂ (M+H) ⁺ : m/z=369.2; Comput. 369.3.

Example 9 (1-(Methylsulfonyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile

To a solution of N-{1 -[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl} -2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (20 mg, 0.049 mmol, obtained as described in example 2, stage 4) in THF (1.0 ml) was added DIEA (43 μl, 0.25 mmol) and then methanesulfonyl chloride (7.6 μl, 0.098 mmol). The resulting mixture was stirred at room temperature for 1.5 h, then MeOH (1.0 ml) was added followed by 2.0 M sodium hydrochloride in water (0.12 ml, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with acetonitrile and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₂₀ H ₂₉ N ₄ O ₂ S (M+H) ⁺ : m/z=389.2; Comput. 389.2.

Example 10 2-(3-(Cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin1-yl)nicotinonitrile

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (23 mg, 0.056 mmol , obtained as described in example 2, stage 4) and 2fluoronicotinonitrile (14 mg, 0.11 mmol) in NMP (1.0 ml, 10. mmol) was added DIEA (39 μl, 0.23 mmol). The resulting mixture was heated to 120°C and stirred for 1 h, while LC-MS showed that the reaction was complete to obtain the desired intermediate. The reaction mixture was cooled to room temperature, then MeOH (1.0 ml) was added followed by 2.0 M sodium hydrochloride in water (0.14 ml, 0.28 mmol). The resulting mixture was stirred at room temperature for 2.5 h, then diluted with acetonitrile and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a yellow solid. LC-MS calculated for C ₂₅ H ₂₉ N ₆ (M+H) ⁺ : m/z=413.2; Comput. 413.3.

Example 11 3-Cyano-4-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1yl}azetidin-1-yl)benzoic acid

This compound was prepared using methods analogous to those described in Example 10, replacing 2-fluoronicotinonitrile with 3-cyano-4-fluorobenzoic acid. The product was purified using prep.

HPLC (pH=2, acetonitrile/water+TFA) to give the compound as the TFA salt as a white solid. LC-MS calculated for C ₂₇ H ₃₀ N ₅ O ₂ (M+H)+: m/z=456.2; Comput. 456.3.

Example 12 2-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin1-yl)benzonitrile

This compound was obtained using methods similar to those described in example 10, replacing 2-fluorobenzonitrile with 2-fluoronicotinonitrile. The product was purified using prep. HPLC (pH=2, acetonitrile/water+TFA) to give the compound as the TFA salt as a white solid. LC-MS calculated for C ₂₆ H ₃₀ N ₅ (M+H)+: m/z=412.2; Comput. 412.3.

Example 13 4-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin1-yl)benzonitrile

This compound was prepared using methods analogous to those described in Example 10, substituting 4-fluorobenzonitrile for 2-fluoronicotinonitrile. The product was purified using prep. HPLC (pH=2, acetonitrile/water+TFA) to give the compound as the TFA salt as a white solid. LC-MS calculated for C ₂₆ H ₃₀ N ₅ (M+H)+: m/z=412.2; Comput. 412.3.

Example 14 [1-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)cyclobutyl]acetonitrile

Stage 1: tert-butyl-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl 3-formylazetidine-1-carboxylate (556 mg, 3.00 mmol, Alfa Aesar: Cat#H52794) and 2-phenylcyclopropanamine hydrochloride (600. mg, 3.54 mmol, trans, racemic, J&W Pharmlab : Cat#20-0073S, Lot: JW152-128A) in DCM (10 ml) was added acetic acid (510 μl, 9.0 mmol). The resulting yellow solution was stirred at room temperature overnight then Na(OAc) ₃ BH (1.9 g, 9.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM, washed with saturated Na2CO3, water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 100% EtOAc/hexanes to give the desired product (513 mg, 57%) as a light yellow oil. LC-MS calculated for C ₁₄ H ₁₉ N ₂ O ₂ (M-tBu+2H)+: m/z=247.1; Comput. 247.2.

Stage 2: tert-butyl-3-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl 3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate (513 mg, 1.70 mmol, obtained in step 7) in DCM (5 ml, 80 mmol) was added DIEA (890 μl, 5.1 mmol) and then allyl chloroformate (234 μl, 2.20 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 40 minutes, then quenched with water and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 60% EtOAc/hexanes to give the desired product (632 mg, 96%) as

- 26 042621 light yellow oil. LC-MS calculated for C ₂₂ H ₃₁ N ₂ O ₄ (M+H)+: m/z=387.2; Comput. 387.2. Stage 3: allyl-(azetidin-3-ylmethyl)(trans-2-phenylcyclopropyl)carbamate

TFA ( 3 ml). The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in EtOAc, then washed with saturated NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₁₇ H ₂₃ N ₂ O ₂ (M+H) ⁺ : m/z=287.2; Comput. 287.2.

Step 4: allyl-({1-[1-(cyanomethyl)cyclobutyl]azetidin-3-yl}methyl)(trans-2-phenylcyclopropyl)carbamate

To a solution of allyl-(azetidin-3-ylmethyl)(trans-2-phenylcyclopropyl)carbamate (48mg, 0.17mmol) and cyclobutylideneacetonitrile (31mg, 0.34mmol, prepared by methods described in the literature, e.g., in WO 2009/114512) in acetonitrile (0.5 ml) was added DBU (10 μl, 0.08 mmol). The resulting mixture was stirred at room temperature overnight then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 10% MeOH/DCM to give the desired product (26 mg, 41%) as a yellow oil. LC-MS calculated for C ₂₃ H ₃₀ N ₃ O ₂ (M+H) ⁺ : m/z=380.2; Comput. 380.2.

Step 5: [1-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)cyclobutyl]acetonitrile

A mixture of allyl-({1-[1-(cyanomethyl)cyclobutyl]azetidin-3-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (26 mg, 0.068 mmol) and tetrakis(triphenylphosphine)palladium(0) (4 mg , 0.003 mmol) in THF (3 mL) was degassed, then refilled with nitrogen and N-ethylethanamine (71 μL, 0.68 mmol) was added. The resulting mixture was heated to 85°C and stirred for 2 h, while LC-MS showed that the reaction was complete. The mixture was cooled to room temperature, then diluted with acetonitrile, filtered and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of a TFA salt as a white solid. LC-MS calculated for C ₁₉ H ₂₆ N ₃ (M+H) ⁺ : m/z=296.2; Comput. 296.2.

Example 15 (1'-(Ethylsulfonyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-3'yl)acetonitrile

This compound was obtained using methods similar to those described in example 14, replacing [1-(ethylsulfonyl)azetidine-3-ylidene]acetonitrile (obtained under conditions similar to those described in the literature, for example, in application WO 2009/114512) cyclobutylideneacetonitrile at the stage 4. The product was purified using prep. HPLC (pH=2, acetonitrile/water+TFA) to give the compound as the TFA salt as a white solid. LC-MS calculated for C ₂₀ H ₂₉ N ₄ O ₂ S (M+H) ⁺ : m/z=389.2; Comput. 389.2.

Example 16 [4-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile

- 27 042621

Stage 1: tert-Butyl-4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1yl)piperidine-1-carboxylate

This compound was obtained using methods similar to those described in example 14, replacing tert-butyl-4-(cyanomethylene)piperidine-1-carboxylate (prepared under conditions similar to those described in the literature, for example, in application WO 2008/064157) cyclobutylideneacetonitrile with stage 4, and the reaction in stage 4 was carried out at 60°C for 48 hours LC-MS calculated for C ₂₅ H ₃₇ N ₄ O ₂ (M+H)+: m/z=425.3; Comput. 425.3.

Step 2: [4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile

The crude product from step 1 was dissolved in DCM (1 ml), then TFA (1 ml) was added. The mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in MeOH, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as a TFA salt. LC-MS calculated for C ₂₀ H ₂₉ N ₄ (M+H)+: m/z=325.2; Comput. 325.2.

Example 17 [1-Methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4yl]acetonitrile

Stage 1: tert-butyl-3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidine-1 carboxylate

To a solution of tert-butyl 3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate (187 mg, 0.618 mmol, prepared as described in Example 14, step 1) in DCM (5 ml) triethylamine (0.431 ml, 3.09 mmol) was added at 0° C. and then trifluoroacetic anhydride (114 μl, 0.804 mmol) was added dropwise. The resulting yellow solution was stirred at 0° C. for 1 h, then quenched with saturated NaHCO ₃ solution and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was purified on a silica gel column eluting with 0 to 60 EtOAc/hexanes to give the desired product (228 mg, 93%) as a yellow oil. LC-MS calculated for C16H18F3N2O3 (M- ^t Bu+2H)+: m/z=343.1; Comput. 343.2.

Step 2: N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl 3-{[(trans-2-phenylcyclopropyl)-(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate (228 mg, 0.572 mmol) in DCM (3 ml) was added TFA (3 ml). The resulting light yellow solution was stirred at room temperature for 1 hour then concentrated. The precipitate (TFA salt) was used in the next step without further purification. LC-MS calculated for C ₁₅ H ₁₈ F ₃ N ₂ O (M+H)+: m/z=299.1; Comput. 299.2.

Step 3: tert-Butyl-4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxylate

To a solution of N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (TFA salt: 0.93 g, 2.2 mmol), tert-butyl-4 -(cyanomethylene)piperidine-1-carboxylate (0.50 g, 2.2 mmol, obtained under conditions similar to those described in the literature, for example, in application WO 2008/064157) in ace

- 28 042621 tonitrile (5 ml) DBU (0.7 ml, 4 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-50%) to give the desired product (95 mg, 8%). LC-MS calculated for C ₂₇ H ₃₆ F ₃ N ₄ O ₃ (M+H)+: m/z=521.3; Comput. 521.2.

Step 4: N-({1-[4-(cyanomethyl)piperidin-4-yl]azetidin-3-yl}methyl)-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide

To a solution of tert-butyl 4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxylate (95 mg, 0. 18 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₂ H ₂₈ F ₃ N ₄ O (M+H) ⁺ : m/z=421.2; Comput. 421.2.

Step 5: [1-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4yl]acetonitrile

To a solution of N-({1-[4-(cyanomethyl)piperidin-4-yl]azetidin-3-yl}methyl)-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (TFA salt, 10 mg, 0.02 mmol) in THF (0.5 ml) was added a solution of 10.0 M formaldehyde in water (10 μl, 0.1 mmol) and then acetic acid (5.8 μl, 0.10 mmol). The reaction mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (22 mg, 0.10 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then MeOH (1 ml) and 2N hydrochloric acid were added. NaOH in water (0.2 ml). The reaction mixture was stirred at 40° C. for 1 h, then cooled to room temperature, filtered and purified with prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₁ H ₃₁ N ₄ (M+H) ⁺ : m/z=339.3; Comput. 339.3.

Example 18 [1-Acetyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin4-yl]acetonitrile

To a solution of N-({1-[4-(cyanomethyl)piperidin-4-yl]azetidin-3-yl}methyl)-2,2,2-trifluoro-N-(trans-2phenylcyclopropyl)acetamide (a salt of TFA obtained as described in example 17, step 4: 9 mg, 0.02 mmol) and DIEA (8.8 μl, 0.05 mmol) in THF (1 ml) was added acetic anhydride (3.2 μl, 0.034 mmol). The reaction mixture was stirred at room temperature for 1 h, then 1N hydrochloric acid was added. NaOH in water (0.5 ml) and MeOH (1 ml). The resulting mixture was stirred at room temperature for 1 hour, then purified with prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₂ H ₃₁ N ₄ O (M+H)+: m/z=367.2; Comput. 367.3.

Example 19 [1-(4-Fluorobenzoyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1yl)piperidin-4-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 18, substituting 4-fluorobenzoyl chloride for acetic anhydride. LC-MS calculated for C ₂₇ H ₃₂ FN ₄ O (M+H) ⁺ : m/z=447.3; Comput. 447.3.

Example 20 [1-(Methylsulfonyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1yl)piperidin-4-yl]acetonitrile

- 29 042621

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing acetic anhydride with methanesulfonyl chloride. LC-MS calculated for C ₂₁ H ₃₁ N ₄ O ₂ S (M+H)+: m/z=403.2; Comput. 403.2.

Example 21 [4-(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)-1-(phenylsulfonyl)piperidin-4-yl]acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing acetic anhydride with benzenesulfonyl chloride. LC-MS calculated for C ₂₆ H ₃₃ N ₄ O ₂ S (M+H)+: m/z=465.2; Comput. 465.2.

Example 22 Ethyl 4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1yl)piperidine-1-carboxylate

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing acetic anhydride with ethyl chloroformate. LC-MS calculated for C ₂₃ H ₃₃ N ₄ O ₂ (M+H)+: m/z=397.3; Comput. 397.2.

Example 23 4-(Cyanomethyl)-N,N-dimethyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing N,N-dimethylcarbαmoyl chloride acetic anhydride. LC-MS calculated for C ₂₃ H ₃₄ N5O (M+H)+: m/z=396.3; Comput. 396.3.

Example 24 4-(Cyanomethyl)-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing acetic anhydride with 2-isocyanatopropane. LC-MS calculated for C ₂₄ H ₃₆ N ₅ O (M+H)+: m/z=410.3; Comput. 410.3.

- 30 042621

Example 25 4-(Cyanomethyl)-N-(4-fluorophenyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide

This compound was obtained using methods similar to those described for the synthesis of example 18, replacing 1-fluoro-4-isocyanatobenzene acetic anhydride. LC-MS calculated for C ₂₇ H ₃₃ FN ₅ O (M+H)+: m/z=462.3; Comput. 462.2.

Example 26 (3-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-3'-yl)acetonitrile

Stage 1: tert-butyl-3'-(cyanomethyl)-3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}-1,3'-biazetidine-1'-carboxylate

Vos

N ^F 3 ^c x^° Sy^CN

I / Nc

To a solution of N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (30 mg, 0.07 mmol, prepared as described in Example 17, step 2) , tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (27 mg, 0.14 mmol, obtained by methods similar to those described in the literature, for example, in application WO 2009/114512) in acetonitrile (1.0 ml) was added DBU (20 µl, 0.1 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then filtered and concentrated. The precipitate was used in the next step without further purification. LCMS calculated for C ₂₅ H ₃₂ F ₃ N ₄ O ₃ (M+H) ⁺ : m/z=493.2; Comput. 493.2.

Step 2: (3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-3'-yl)acetonitrile

To a solution of the crude product from step 1 in THF (1 ml) and MeOH (1 ml) was added a solution of 2N. NaOH in water (0.5 ml). The resulting mixture was stirred at 30°C for 1 h, then cooled to room temperature and concentrated. The precipitate was dissolved in DCM, then filtered and concentrated. The precipitate was then dissolved in DCM (1 ml) and TFA (1 ml) was added. The mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₁₈ H ₂₅ N ₄ (M+H) ⁺ : m/z=297.2; Comput. 297.2.

Example 27 4-(3'-(cyanomethyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-1'yl)-2,5-difluoro-N-[ (1S)-2,2,2-trifluoro-1-methylethyl]benzamide

To a TFA solution of the N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide salt (25 mg, 0.061 mmol, prepared as described in Example 17, step 2) and 4-[3(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (24 mg, 0.070 mmol, obtained from using methods similar to those described in the literature, for example, in the application WO 2012/177606) in acetonitrile (1.0 ml) was added DBU (12 mg, 0.08 mmol). The resulting mixture was stirred at room temperature overnight, then 2N hydrochloric acid was added. NaOH (1 ml) and MeOH (1 ml). The reaction mixture was stirred at room temperature overnight, then filtered and purified with prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₈ H ₃₁ F ₅ N ₅ O (M+H) ⁺ : m/z=548.2; Comput. 548.2.

- 31 042621

Example 28 N-{[1-(1-Methylpiperidin-4-yl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine

To a solution of N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-M-(trans-2-phenylcyclopropyl)acetamide salt TFA (30 mg, 0.07 mmol, prepared as described in Example 17, step 2) and 1-methyl-4-piperidinone (11 mg, 0.10 mmol) in THF (1.0 ml) was added acetic acid (17 μl, 0.30 mmol). The reaction mixture was stirred at room temperature overnight, then Na(OAc) ₃ BH (64 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then 2N hydrochloric acid was added. NaOH in water (0.5 ml) and MeOH (1 ml). The resulting mixture was stirred at 40°C for 1 h, then cooled to room temperature, filtered and purified using RP-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to obtain the desired product. LC-MS calculated for C ₁₉ H ₃₀ N ₃ (M+H)+: m/z=300.2; Comput. 300.2.

Example 29 trans-2-Phenyl-N-{[1-(1-phenylpiperidin-4-yl)azetidin-3-yl]methyl}cyclopropanamine

This compound was obtained using methods similar to those described for the synthesis of example 28, replacing 1-phenylpiperidin-4-one with 1-methyl-4-piperidinone. LC-MS calculated for C ₂₄ H ₃₂ N ₃ (M+H)+: m/z=362.3; Comput. 362.2.

Example 30 1-Phenyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)cyclohexanecarbonitrile

This compound was obtained using methods similar to those described for the synthesis of example 28, replacing 4-oxo-1-phenylcyclohexanecarbonitrile (Lancaster, cat#5281) 1-methyl-4piperidinone. The product was purified using prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) yielding two isomers corresponding to trans- and cis-cyclohexyl. LC-MS calculated for C ₂₆ H ₃₂ N ₃ (M+H)+: m/z=386.3;

Isomer (I): LC-MS (pH=2, acetonitrile/water+TFA): calc. m/z=386.2; retention time=1.45 min.

Isomer (II): LC-MS (pH=2, acetonitrile/water+TFA): calc. m/z=386.2; retention time=1.55 min.

Example 31 [1-(Ethylsulfonyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-3-yl]acetonitrile

Step 1: {1-(ethylsulfonyl)-3-[4-(hydroxymethyl)piperidin-1-yl]azetidin-3-yl}acetonitrile

To a solution of 4-piperidinemethanol (60 mg, 0.5 mmol) and [1-(ethylsulfonyl)azetidine-3ylidene]acetonitrile (110 mg, 0.60 mmol) obtained using conditions similar to those described in the literature, for example, in the application WO 2009/114512) in acetonitrile (1.0 ml) DBU (20 μl, 0.1 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours, then diluted with DCM, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated. The precipitate was purified by flash chromatography on a silica gel column,

- 32 042621 eluting with MeOH in DCM (0-8%) to give the desired product. LC-MS calculated for C13H24N3O3S (M+H)+: m/z=302.2; Comput. 302.1.

Step 2: [1-(ethylsulfonyl)-3-(4-formylpiperidin-1-yl)azetidin-3-yl]acetonitrile

Dess Martin reagent (420 mg, 1.0 mmol). The reaction mixture was at room temperature for 3 h, then a saturated aqueous solution of Na ₂ S ₂ O ₃ was added and stirred for 10 min. The mixture was diluted with DCM, washed with 1 N. NaOH, water and saline. The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0-8%). LC-MS calculated for C ₁₃ H ₂₂ N ₃ O ₃ S (M+H)+: m/z=300.1; Comput. 300.1.

Step 3: [1-(ethylsulfonyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1 yl)azetidin-3-yl]acetonitrile

To a solution of [1-(ethylsulfonyl)-3-(4-formylpiperidin-1-yl)azetidin-3-yl]acetonitrile (15.0 mg, 0.050 mmol) and 2-phenylcyclopropanamine (10.0 mg, 0.075 mmol, trans , racemic, Acros: Cat#130470050) in DCM (0.5 ml) was added acetic acid (4.3 μL, 0.075 mmol). The mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was dissolved in acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the product as the TFA salt. LCMS calculated for C ₂₂ H ₃₃ N ₄ O ₂ S (M+H)+: m/z=417.2; Comput. 417.1.

Example 32 [1-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetonitrile

Step 1: {1-[4-(hydroxymethyl)piperidin-1-yl]cyclobutyl}acetonitrile

To a solution of 4-piperidinemethanol (230 mg, 2.0 mmol) and cyclobutylidene acetonitrile (280 mg, 3.0 mmol, obtained using methods described in the literature, for example, in application WO 2009/114512) in acetonitrile (2.0 ml ) was added DBU (90 μl, 0.6 mmol). The reaction mixture was stirred at 65° C. overnight. The mixture was cooled to room temperature, then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered and then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0-8%). LC-MS calculated for C ₁₂ H ₂₁ N ₂ O (M+H)+: m/z=209.2; Comput. 209.2.

Step 2: [1-(4-Formylpiperidin-1-yl)cyclobutyl]acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 31, stage 2, starting with {1-[4-(hydroxymethyl)piperidin-1-yl]cyclobutyl}acetonitrile. LC-MS calculated for C ₁₂ H ₁₉ N ₂ O (M+H)+: m/z=207.1; Comput. 207.1.

Step 3: [1-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetonitrile

This compound was obtained using a method similar to that described for the synthesis of example 31, stage 3, starting with [1-(4-formylpiperidin-1-yl)cyclobutyl]acetonitrile. The product was purified using prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₁ H ₃₀ N ₃ (M+H)+: m/z=324.2; Comput. 324.3.

- 33 042621

Example 33 [3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile

Stage 1: tert-butyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (430 mg, 2.0 mmol) and trans-2-phenylcyclopropanamine (0.35 g, 2.6 mmol, Acros: Cat#130470050) in DCM (9 mL) was added acetic acid (0.17 ml, 3.0 mmol). The resulting mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (1.3 g, 6.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. NaOH, water and saline.

The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated. The precipitate was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0-10%). LCMS calculated for C ₁₆ H ₂₃ N ₂ O ₂ (M-tBu+2H)+: m/z=275.2; Comput. 275.2.

Stage 2: tert-Butyl-4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate

Allyl chloroformate (0.23 ml, 2.2 mmol) was added to a solution of tert-butyl 4-{[(trans-2phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate (0.59 g, 1.8 mmol) and N ,N-diisopropylethylamine (0.63 ml, 3.6 mmol) in DCM (9.0 ml) at 0°C, and then the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with saturated NaHCO ₃ , water and saline solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%). LC-MS calculated for C ₂₄ H ₃₄ N ₂ NaO ₄ (M+Na) ⁺ : m/z=437.2; Comput. 437.3.

Step 3: Allyl-(trans-2-phenylcyclopropyl)(piperidin-4-ylmethyl)carbamate

U ⁰ g% ⁿ

To a solution of tert-butyl 4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate (225.0 mg, 0.5428 mmol) in DCM (2 ml) was added 4.0 M hydrogen chloride in dioxane (2 ml). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated. The precipitate was dissolved in DCM, washed with 1 N. NaOH and saline. The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with methanol in DCM (0-10%) to give the desired product. LC-MS calculated for C ₁₉ H ₂₇ N ₂ O ₂ (M+H) ⁺ : m/z=315.2; Comput. 315.2.

Step 4: tert-Butyl 3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate

To a solution of allyl-(trans-2-phenylcyclopropyl)(piperidin-4-ylmethyl)carbamate (80.0 mg, 0.254

- 34 042621 mmol) and tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (59 mg, 0.30 mmol) in acetonitrile (0.5 ml) was added DBU (10 μl, 0.08 mmol). The resulting mixture was stirred at room temperature for 3 hours, then diluted with DCM, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by flash chromatography on a silica gel column eluting with EtOAc in DCM (0-20%) to give the desired product. LC-MS calculated for C ₂₉ H ₄₁ N ₄ O ₄ (M+H)+: m/z=509.3; Comput. 509.3.

Stage 5: allyl-({1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate

To a solution of tert-butyl 3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (100, 0 mg, 0.1966 mmol) in DCM (0.5 ml) was added 4.0 M hydrogen chloride in dioxane (0.5 ml, 2 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H) ⁺ : m/z=409.3; Comput. 409.3.

Step 6: [3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile

Mixture of allyl-({1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (30.1 mg, 0.0736 mmol), tetrakis(triphenylphosphine )palladium(0) (8.5 mg, 0.0074 mmol) and N,N-diethylamine (0.0761 ml, 0.736 mmol) in THF (1.0 ml) were stirred at 85° C. for 2 h under atmosphere nitrogen, then cooled to room temperature and filtered. The filtrate was purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C ₂₀ H ₂₉ N ₄ (M+H) ⁺ : m/z=325.2; Comput. 325.3.

Example 34 2-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-1-yl]nicotinonitrile

Oh ^N'J

Λ Η G I

O'

Stage 1: allyl-({1-[3-(cyanomethyl)-1-(3-cyanopyridin-2-yl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate / / $ ^N N

O'

To a solution of allyl-({1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (25.0 mg, 0.0612 mmol, obtained as described in example 33, step 5) and 2-fluoronicotinonitrile (15 mg, 0.12 mmol) in NMP (0.6 ml) was added DIEA (43 μl, 0.24 mmol). The reaction mixture was stirred at 120°C for 2 h, then cooled to room temperature and diluted with methylene chloride, then the mixture was washed with saturated NaHCO ₃ , water and saline. The organic layer was dried over Na2SO4, filtered and concentrated.

The precipitate was used in the next step without further purification. LC-MS calculated for C30H35N6O2 (M+H) ⁺ : m/z=511.3; Comput. 511.3.

Step 2: 2-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-1-yl]nicotinonitrile

The crude product from step 1 was dissolved in THF (0.5 ml), after which was added diethylamine (60 μl) and then Pd(PPh ₃ ) ₄ (10 mg). The container with the resulting mixture was emptied, then filled with nitrogen and stirred at 80° C. for 2 hours. The mixture was cooled to room temperature, filtered, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₆ H ₃₁ N ₆ (M+H) ⁺ : m/z=427.3; Comput. 427.3.

Example 35 4-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1 yl)azetidin-1-yl]-2,5-difluoro-N- isopropylbenzamide

- 35 042621

This compound was prepared using methods similar to those described for the synthesis of Example 34, replacing 2,4,5-trifluoro-N-isopropylbenzamide with 2-fluoronicotinonitrile in step 1. LC-MS calculated for C ₃₀ H ₃₈ F ₂ N ₅ O (M +H) ⁺ : m/z=522.3; Comput. 522.4.

Example 36 {3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[3-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 34, replacing 2-fluoro-3-(trifluoromethyl)pyridine with 2-fluoronicotinonitrile in step 1. LC-MS calculated for C ₂₆ H ₃₁ F ₃ N ₅ (M+H ) ⁺ : m/z=470.3; Comput. 470.2.

Example 37 {3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 34, replacing 2-fluoro-5-(trifluoromethyl)pyridine with 2-fluoronicotinonitrile in step 1. LC-MS calculated for C ₂₆ H ₃₁ F ₃ N ₅ (M+H )+: m/z=470.3; Comput. 470.2.

Example 38 2-Chloro-6-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin1-yl)azetidin-1-yl]benzonitrile

This compound was obtained using methods similar to those described for the synthesis of example 34, replacing 2-chloro-6-fluorobenzonitrile 2-fluoronicotinonitrile in step 1. LC-MS calculated for C ₂₇ H ₃₁ ClN ₅ (M+H) ⁺ : m/ z=460.2; Comput. 460.1.

Example 39 2-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-1-yl]benzonitrile

This compound was prepared using methods similar to those described for the synthesis of example 34, replacing 2-fluorobenzonitrile with 2-fluoronicotinonitrile in step 1. LC-MS calculated for C ₂₇ H ₃₂ N ₅ (M+H) ⁺ : m/z=426, 3; Comput. 426.3.

Example 40 4-[3-(Cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-1-yl]benzonitrile

- 36 042621

This compound was prepared using methods similar to those described for the synthesis of Example 34, substituting 2-fluorobenzonitrile for 4-fluoronicotinonitrile in Step 1. LC-MS calculated for

C ₂₇ H ₃₂ N ₅ (M+H) ⁺ : m/z=426.3; Comput. 426.3.

Example 41 Methyl 3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidine-1-carboxylate

Methyl chloroformate (7.6 µl, 0.098 mmol) was added to a solution of allyl-({1-[3-(cyanomethyl)azetidin3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (20.0 mg , 0.0490 mmol, obtained as described in example 33, stage 5) and triethylamine (27 μl, 0.20 mmol) in DCM (0.5 ml) at 0°C. The resulting mixture was stirred for 30 min at 0°C, then diluted with DCM and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was dissolved in THF (0.5 ml), after which was added diethylamine (60 μl) and then Pd(PPh ₃ ) ₄ (10 mg). The container with the resulting mixture was emptied, then filled with nitrogen, and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, filtered, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₂ H ₃₁ N ₄ O ₂ (M+H) ⁺ : m/z=383.2; Comput. 383.3.

Example 42 3-(Cyanomethyl)-N-(2,4-difluorophenyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide

This compound was obtained using methods similar to those described for the synthesis of example 41, replacing 2,4-difluoro-1-isocyanatobenzene with methyl chloroformate. LC-MS calculated for C27H32F2N5O (M+H) ⁺ : m/z=480.3; Comput. 480.3.

Example 43 N-(3-Chloro-2-fluorophenyl)-3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide

this compound was obtained using methods similar to those described for the synthesis of example 41, replacing 1-chloro-2-fluoro-3-isocyanatobenzene with methyl chloroformate. LC-MS calculated for C ₂₇ H ₃₂ ClFN ₅ O (M+H)+: m/z=496.2; Comput. 496.2.

Example 44 [1-(3,5-Difluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-3-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 41, replacing methyl chloroformate with 3,5-difluorobenzoyl chloride. LC-MS calculated for C ₂₇ H ₃₁ F ₂ N ₄ O (M+H)+: m/z=465.2; Comput. 465.2.

Example 45 [1-Benzoyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin3-yl]acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 41, replacing methyl chloroformate with benzoyl chloride. LC-MS calculated for C ₂₇ H ₃₃ N ₄ O (M+H) ⁺ : m/z=429.3; Comput. 429.2.

Example 46 [1-(2-Fluoro-benzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetide in-3-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 41, replacing methyl chloroformate with 2-fluorobenzoyl chloride. LC-MS calculated for C ₂₇ H ₃₂ FN ₄ O (M+H) ⁺ : m/z=447.3; Comput. 447.3.

Example 47 [1-(3-Fluoro-benzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetidin-3-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 41, replacing 3-fluorobenzoyl chloride with methyl chloroformate. LC-MS calculated for C ₂₇ H ₃₂ FN ₄ O (M+H) ⁺ : m/z=447.3; Comput. 447.3.

Example 48 [1-(4-Fluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)azetide in-3-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 41, replacing 4-fluorobenzoyl chloride with methyl chloroformate. LC-MS calculated for C ₂₇ H ₃₂ FN ₄ O (M+H) ⁺ : m/z=447.3; Comput. 447.3.

Example 49 [ 1 -Methyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3yl]acetonitrile

To a solution of allyl-({1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (20.0 mg, 0.0490 mmol, obtained as described in example 33, step 5) in DCM (0.5 ml) was added 7.0 M formaldehyde in water (2.7 μl, 0.019 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (16 mg, 0.076 mmol) was added. The reaction mixture was stirred for another 1 h at room temperature, then diluted with DCM and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then filtered and concentrated. The precipitate was dissolved in THF (0.5 ml), after which was added diethylamine (60 μl) and then Pd(PPh ₃ ) ₄ (10 mg). The container with the mixture was emptied, then filled with nitrogen, after which the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, filtered, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C21H31N4 (M+H) ⁺ : m/z=339.3; Comput. 339.3.

Example 50 [3-(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetic acid

Stage 1: tert-butyl-3-(2-tert-butoxy-2-oxoethylidene)azetidine-1-carboxylate

To a solution of tert-butyl-(diethoxyphosphoryl)acetate (Aldrich, cat#348333: 1.1 g, 4.6 mmol) in THF (15 ml) at 0°C was added 1.0 M potassium tert-butoxide in THF (4 .6 ml, 4.6 mmol). The resulting mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, then a solution of tert-butyl-3-oxoazetidine-1-carboxylate (Aldrich, cat#696315: 0.6 g, 4 mmol) in THF (5 ml) was added. The mixture was warmed to room temperature, stirred overnight, then diluted with ethyl acetate and washed with saturated NaHCO3, water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product. LC-MS calculated for C ₆ H ₈ NO ₄ (M-2tBu+3H) ⁺ : m/z=158.0; Comput. 158.1.

Step 2: tert-Butyl-3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-3-(2-tert-butoxy-2-oxoethyl )azetidine-1-carboxylate

To a solution of allyl-(trans-2-phenylcyclopropyl)(piperidin-4-ylmethyl)carbamate (80.0 mg, 0.254 mmol, prepared as described in Example 33, step 3) and tert-butyl-3-(2-tert -butoxy-2oxoethylidene)azetidine-1-carboxylate (82 mg, 0.30 mmol) in acetonitrile (0.5 ml) DBU (10 μl, 0.08 mmol) was added. The resulting mixture was stirred at 65° C. overnight, then cooled to room temperature, diluted with DCM, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-30%) to give the desired product. LC-MS calculated for C ₃₃ H ₅₀ N ₃ O ₆ (M+H) ⁺ : m/z=584.4; Comput. 584.3.

Step 3: [3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetic acid

Tetrakis(triphenylphosphine)palladium(0) (8.5 mg) was added to the mixture of tert-butyl-3-(4{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl) -3-(2-tert-butoxy2-oxoethyl)azetidine-1-carboxylate (43.0 mg, 0.0736 mmol) and diethylamine (0.0761 ml, 0.736 mmol) in THF (1.0 ml). The container with the resulting mixture was emptied, then filled with nitrogen, and the mixture was stirred at 85°C for 2 hours, the Mixture was cooled to room temperature, then concentrated. The precipitate was dissolved in CH2Cl2 (0.5 ml), then TFA (0.5 ml) was added. The resulting mixture was stirred at room temperature for 3 h, then concentrated. The precipitate was dissolved in acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₃₀ N ₃ O ₂ (M+H) ⁺ : m/z=344.2; Comput. 344.2.

Example 51 N-Methyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3yl)acetamide

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Step 1: [3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)-1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid

To a solution of tert-butyl-3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-3-(2-tert-butoxy-2-oxoethyl) Azetidine-1-carboxylate (0.10 g, 0.17 mmol, prepared as described in Example 50, Step 2) in DCM (1.0 ml) was added with TFA (1.0 ml). The resulting mixture was stirred at room temperature for 5 hours, then concentrated. The precipitate was dissolved in THF (4 ml)/water (1 ml), then di-tert-butyl dicarbonate (56 mg, 0.26 mmol) and sodium carbonate (73 mg, 0.68 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with diethyl ether. The aqueous phase was then acidified by adding cold 1N. HCl and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4 then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₉ H ₄₂ N ₃ O ₆ (M+H) ⁺ : m/z=528.3; Comput. 528.3.

Step 2: tert-Butyl-3-(4-(((allyloxycarbonyl)(trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)-3-(2-(methylamino)-2-oxoethyl)azetidine- 1-carboxylate

To a solution of [3-(4-{[[(allyloxy)carbonyl](trans-2-phenylcyclopropyl)amino]methyl}piperidin-1yl)-1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid (20, 0 mg, 0.0379 mmol) and BOP (27 mg, 0.060 mmol) in DMF (0.9 ml) were added 2.0 M methylamine in THF (0.4 ml, 0.7 mmol) and then triethylamine (36, 6 µl, 0.263 mmol). The resulting mixture was stirred at room temperature for 1 h, then diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₃₀ H ₄₅ N ₄ O5 (M+H)+: m/z=541.3; Comput. 541.3.

Step 3: N-Methyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3yl)acetamide

The crude product from step 2 was dissolved in THF (1.0 ml) after which Pd(PPh ₃ ) ₄ (10.0 mg) was added followed by diethylamine (0.1 ml). The container with the mixture was emptied, then refilled with nitrogen and the mixture was stirred at 80°C for 2 hours, the Reaction mixture was cooled to room temperature, then concentrated. The precipitate was dissolved in CH ₂ Cl ₂ (0.5 ml) then TFA (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in acetonitrile, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₁ H ₃₃ N ₄ O (M+H) ⁺ : m/z=357.3; Comput. 357.3.

Example 52 N,N-Dimethyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3-yl)acetamide

This compound was obtained using methods similar to those described for the synthesis of example 51, replacing N,N-dimethylamine methylamine in step 2. LC-MS calculated for C ₂₂ H ₃₅ N ₄ O (M+H) ⁺ : m/z=371 ,3; Comput. 371.3.

Example 53 {1-[4-(4-Fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1yl]cyclobutyl}acetic acid

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Stage 1: 1-tert-butyl-4-methyl 4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate

To a solution of Ν,N-diisopropylamine (4.9 ml, 35 mmol) in tetrahydrofuran (80 ml) at -78°C was added n-butyllithium (2.5 M in hexanes, 14 ml, 35 mmol). The resulting mixture was heated to -20°C and stirred for 10 min, then cooled to -78°C and a solution of 1-tert-butyl-4methyl-piperidine-1,4-dicarboxylate (AstaTech, cat#B56857: 6, 08 g, 25.0 mmol) in THF (10 ml). The reaction mixture was slowly warmed to -40° C. and stirred for 1 h, then the mixture was cooled to -78° C. and α-bromo-4-fluorotoluene (4.9 ml, 40. mmol) was added. The reaction mixture was stirred at -78°C for 1 h, then quenched with saturated NH4Cl solution, warmed to room temperature and diluted with ethyl ether, then the mixture was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product (6.5 g, 74%). LCMS calculated for C ₁₅ H ₁₉ FNO ₄ (M-tBu+2H)+: m/z=296.1; Comput. 296.1.

Stage 2: tert-butyl-4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate

LiAlH ₄ ( 1M in THF, 24 ml, 24 mmol). The resulting mixture was stirred at 0°C for 30 min, then water (0.9 ml) was added and then NaOH (15 wt.%, in water, 0.9 ml) and water (0.9 ml). The mixture was stirred for 20 min, then filtered and washed with THF. The filtrate was concentrated and the residue (5.8 g, 97%) was used in the next step without further purification. LC-MS calculated for C ₁₄ H ₁₉ FNO ₃ (M-tBu+2H)+: m/z=268.1; Comput. 268.1.

Stage 3: tert-butyl-4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate

O=\ /—\ -x /NBoc

A solution of dimethyl sulfoxide (4.3 ml, 60. mmol) in methylene chloride (6 ml) was added to a solution of oxalyl chloride (2.6 ml, 30 mmol) in methylene chloride at -78°C for 10 min and then the resulting mixture was heated to -60 °C for 25 min. A solution of tert-butyl 4-(4-fluorobenzyl)-4(hydroxymethyl)piperidine-1-carboxylate (5.2 g, 16 mmol) in methylene chloride (6 ml) was added slowly and then heated to -45°C for 30 min. Then N,N-diisopropylethylamine (21 ml, 120 mmol) was added and the mixture was heated to 0°C for 15 min. The mixture was poured into a cold aqueous solution of 1N. HCl and then extracted with ethyl ether. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product (4.3 g, 83%). LC-MS calculated for C ₁₄ H ₁₇ FNO ₃ (MtBu+2H)+: m/z=266.1; Comput. 266.1.

Stage 4: tert-Butyl-4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclonronyl]amino}methyl)niperidin1-carboxylate

To a solution of tert-butyl 4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate (4.2 13 mmol) and (1R,2S)-2-phenylcyclopropanamine (1.96 g, 14.7 mmol) ( obtained using the methods described in Bioorg. Med. Chem. Lett., 2011, 27, 4429) in 1,2-dichloroethane (50 ml) was added acetic acid (1.1 ml, 20. mmol). The resulting mixture was stirred at room temperature for 2 h, then sodium triacetoxyborohydride (5.7 g, 27 mmol) was added. The reaction mixture was stirred at room temperature for 5 h, then diluted with methylene chloride, washed with an aqueous solution of 1 N. NaOH, water and saline. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with MeOH in DCM (0-6%) to give the desired product (5.0 g, 87%). LC-MS calculated for C ₂₇ H ₃₆ FN ₂ O ₂ (M+H)+: m/z=439.3; Comput. 439.2.

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Step 5: tert-Butyl-4-(4-fluorobenzyl)-4-{[(1R,2S)-2-phenylpcyclopropyl-(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (2.08 mL, 14.7 mmol) was added to a solution of tert-butyl 4-(4fluorobenzyl)-4-([(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate ( 4.3 g, 9.8 mmol) and N,N-diisopropylethylamine (4.3 ml, 24 mmol) in methylene chloride (40 ml) at 0°C. The resulting mixture was stirred at 0° C. for 1 h, then diluted with ether and washed with 1N HCl. HCl, water and saline. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexanes (0-30%) to give the desired product (4.6 g, 88%). LC-MS calculated for C ₂₅ H ₂₇ F ₄ N ₂ O ₃ (M-tBu+2H)+: m/z=479.2; Comput. 479.2.

Step 6: 2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

Hydrogen chloride (4M in 1,4-dioxane, 20 mL, 80 mmol) was added to a solution of tert-butyl-4-(4fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino ]methyl} piperidine-1-carboxylate (4.6 g, 8.6 mmol) in methylene chloride (6 ml). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₄ H ₂₇ F ₄ N ₂ O (M+H)+: m/z=435.2; Comput. 435.2.

Stage 7: tert-butylcyclobutylidene acetate

To a suspension of sodium hydride (1.2 g, 30 mmol) in tetrahydrofuran (20 ml) at 0°C was added tert-butyl-(diethoxyphosphoryl)acetate (6.8 g, 27 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then cyclobutanone (1.0 g, 14 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-10%) to give the desired product (2.0 g, 84%).

Ή NMR (400 MHz, CDCl ₃ ) δ 5.50-5.46 (m, 1H), 3.14-3.05 (m, 2H), 2.84-2.76 (m, 2H), 2 .11-2.02 (m, 2H), 1.46 (s, 9H).

Step 8: tert-Butyl-[1-(4-(4-fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetate

1,8-Diazabicyclo[5.4.0]undec-7-ene (57 μl, 0.38 mmol) was added to a mixture of 2,2,2-trifluoro-N-{[4-(4fluorobenzyl)piperidin-4-yl] methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (step 6: 110 mg, 0.25 mmol) and tert-butylcyclobutylidene acetate (64 mg, 0.38 mmol) in acetonitrile (0.6 ml, 10 mmol). The resulting mixture was stirred at 65°C for 3 days, then cooled to room temperature and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc in hexane (0-20%) to give the desired product (90 mg, 59%). LC-MS calculated for C ₃₄ H ₄₃ F ₄ N ₂ O ₃ (M+H)+: m/z=603.3; Comput. 603.3.

Step 9: {1-[4-(4-Fluorobenzyl)-4-( {[(1 R,2S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 yl] cyclobutyl} acetic acid

Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl-[1-(4-(4-fluorobenzyl)-4{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine- 1-yl)cyclobutyl]acetate (22.0 mg, 0.0364 mmol) in methylene chloride (0.5 ml). The mixture was stirred at room temperature for 4 h, then concentrated. The precipitate was dissolved in THF/methanol (0.3/0.3 ml) and then NaOH (1N in water, 1.0 ml) was added. The mixture was stirred at 40° C. for 2 hours, then cooled to room temperature and purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₈ H ₃₆ FN ₂ O ₂ (M+H) ⁺ : m/z=451.3; Comput. 451.3.

Example 54 {1-[4-(Methoxymethyl)-4-( {[(1 R,2S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 yl] cyclobutyl} acetic acid

Stage 1: 1-tert-butyl-4-methyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate

Lithium diisopropylamide (2M in THF, 5.8 ml, 12 mmol). The resulting mixture was stirred at -40° C. for 30 min, then chloromethyl methyl ester (1.2 ml, 16 mmol) was added. The reaction mixture was stirred at -40°C for 1 h, then extinguished with a saturated aqueous solution of NH ₄ Cl and warmed to room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel flash column chromatography (0 to 20% EtOAc in hexanes) to give the desired product (2.6 g, 90%). LC-MS calculated for C9H18NO3 (M-Boc+2H) ⁺ : m/z=188.1; Comput. 188.1.

Stage 2: tert-butyl-4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate

LiAlH ₄ (1M in THF, 10 ml, 10 mmol). The resulting mixture was stirred at 0°C for 30 min, then quenched by adding water (0.1 ml), NaOH (15 wt.%, in water, 0.1 ml) and water (0.1 ml). The mixture was stirred for 10 min, then filtered and washed with THF. The filtrate was concentrated and the residue was used in the next step without further purification. LC-MS calculated for C ₉ H ₁₈ NO ₄ (M-tBu+2H) ⁺ : m/z=204.1; Comput. 204.1.

Stage 3: tert-butyl-4-formyl-4-(methoxymethyl)piperidine-1-carboxylate /\/=O

BocN °\

Dimethyl sulfoxide (1.7 ml, 24 mmol) in methylene chloride (2 ml) was added to a solution of oxalyl chloride (1.0 ml, 12 mmol) in methylene chloride (3 ml) at -78°C over 10 min. The resulting mixture was heated to -60°C for 25 min, then a solution of tert-butyl 4-(hydroxymethyl)-4(methoxymethyl)piperidine-1-carboxylate (1.6 g, 6.0 mmol) in methylene chloride ( 5 ml). The mixture was heated to -45°C for 30 min, then added triethylamine (6.7 ml, 48 mmol). The mixture was heated to 0°C for 15 min. The reaction mixture was then poured into a cold 1N aqueous solution. HCl and extracted with diethyl ether. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.3 g, 84%). LC-MS calculated for C8H16NO2 (M-Boc+2H) ⁺ : m/z=158.1; Comput. 158.1.

Stage 4: tert-butyl-4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

Mixture of tert-butyl 4-formyl-4-(methoxymethyl)piperidine-1-carboxylate (1.3 g, 5.0 mmol), acetic acid (0.43 ml, 7.5 mmol) and (1R,2S) -2-Phenylcyclopropanamine (699 mg, 5.25 mmol) in 1,2dichloroethane (20 ml) was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (2.1 g, 10 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then diluted with methylene chloride, washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 8% methanol in DCM to give the desired product (1.7 g, 91%). LC-MS designed for

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C22H35N2O3 (M+H)+: m/z=375.3; Comput. 375.2.

Stage 5: tert-Butyl-4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

H^NBoc

[G^]OMe

Trifluoroacetic anhydride (0.96 ml, 6.8 mmol) was added to a solution of tert-butyl-4(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate ( 1.7 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.1 mmol) in methylene chloride (25 ml) at 0°C. The resulting mixture was stirred at room temperature for 1 h, then diluted with methylene chloride, washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.8 g, 84%). LC-MS calculated for C ₁₉ H ₂₆ F ₃ N ₂ O ₂ (M-Boc+2H) ⁺ : m/z=371.2; Comput. 371.1.

Step 6: 2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl }-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M hydrogen chloride in dioxane (7 mL, 28 mmol) was added to a solution of tert-butyl-4(methoxymethyl)-4-{[[(1 R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl} piperidine-1-carboxylate (1.8 g, 3.8 mmol) in methylene chloride (4 ml). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₁₉ H ₂₆ F ₃ N ₂ O ₂ (M+H)+: m/z=371.2; Comput. 371.2.

Stage 7: methyl-[1-(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetate

1,8-Diazabicyclo[5.4.0]undec-7-ene (40. µl, 0.26 mmol) was added to a mixture of 2,2,2-trifluoro-N-{[4(methoxymethyl)piperidin-4-yl] methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (65 mg, 0.17 mmol) and methylcyclobutylidene acetate (SynChem, cat#SC-25429: 33 mg, 0.26 mmol) in acetonitrile (0. 4 ml). The resulting mixture was stirred at 65°C for 3 days, then cooled to room temperature, diluted with methylene chloride, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by flash chromatography on a silica gel column eluting with 0 to 50% EtOAc in hexanes to give the desired product. LC-MS calculated for C ₂₆ H ₃₆ F ₃ N ₂ O ₄ (M+H)+: m/z=497.3; Comput. 497.2.

Step 8: {1-[4-(methoxymethyl)-4-( {[(1 R,2S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 yl] cyclobutyl} acetic acid

To a solution of methyl-[1-(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetate (60.0 mg , 0.12 mmol) in MeOH/THF (0.5/0.5 ml) was added 1N. NaOH (1 ml). The resulting mixture was stirred at 40°C for 6 h, then cooled to room temperature and purified using prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₅ N ₂ O ₃ (M+H)+: m/z=387.3; Comput. 387.3.

Example 55 {1-[4-methyl-4-( {[(1 R,2 S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 -yl] cyclobutyl} acetic acid

Stage 1: tert-butyl-4-methyl-4-({[(1 R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1 carboxylate -

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A mixture of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (Synnovator, cat#PBN2011767: 2.50 g, 11.0 mmol), acetic acid (0.94 ml, 16 mmol) and (1R,2S )-2-phenylcyclopropanamine (1.54 g, 11.5 mmol) in 1,2-dichloroethane (40 ml) was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (4.7 g, 22 mmol) was added. The mixture was stirred at room temperature for 2 h, then diluted with methylene chloride, washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 8% MeOH in DCM to give the desired product (3.4 g, 90%). LC-MS calculated for C ₂₁ H ₃₃ N ₂ O ₂ (M+H)+: m/z=345.3; Comput. 345.2.

Step 2: tert-Butyl-4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 ml, 6.8 mmol) was added to a solution of tert-butyl-4-methyl-4({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate (1, 6 g, 4.5 mmol) and N,Ndiisopropylethylamine (1.6 ml, 9.1 mmol) in methylene chloride (25 ml) at 0°C. The resulting mixture was stirred at room temperature for 1 h, then diluted with methylene chloride, washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (1.8 g, 90%). LC-MS calculated for C ₁₉ H ₂₄ F ₃ N ₂ O ₃ (M-tBu+2H) ⁺ : m/z=385.2; Comput. 385.2.

Stage 3: 2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

F ₃ C^O G I

ABOUT'

To a solution of tert-butyl 4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate (1.5 g, 3.4 mmol) in methylene chloride (3 ml) was added hydrogen chloride (4M in 1,4-dioxane, 6 ml, 24 mmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₁₈ H ₂₄ F ₃ N ₂ O (M+H) ⁺ : m/z=341.2; Comput. 341.2.

Step 4: tert-butyl-[1-(4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetate

GzC^^O

ABOUT

1,8-Diazabicyclo[5.4.0]undec-7-ene (40. μl, 0.26 mmol) was added to a mixture of 2,2,2-trifluoro-N-[(4methylpiperidin-4-yl)methyl]-N -[(1R,2S)-2-phenylcyclopropyl]acetamide (60.0 mg, 0.176 mmol) and tert-butylcyclobutylidene acetate (Example 53, step 7: 44 mg, 0.26 mmol) in acetonitrile (0.4 ml). The resulting mixture was stirred at 65°C for 3 days, then cooled to room temperature and diluted with methylene chloride, washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 30% EtOAc in hexanes to give the desired product (60 mg, 67%). LC-MS calculated for C ₂₈ H ₄₀ F ₃ N ₂ O ₃ (M+H) ⁺ : m/z=509.3; Comput. 509.3.

Step 5: {1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1yl]cyclobutyl}acetic acid

To a solution of tert-butyl-[1-(4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-1-yl)cyclobutyl]acetate (60 mg) in methylene chloride (0.5 ml) was added trifluoroacetic acid (0.5 ml). The resulting mixture was stirred at room temperature for 4 h, then concentrated. The precipitate was dissolved in methanol/THF (0.5/0.5 ml), then NaOH (15 wt%, in water, 0.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₂ H ₃₃ N ₂ O ₂ (M+H) ⁺ : m/z=357.3; Comput. 357.2.

1H NMR (500 MHz, DMSO) δ 7.33-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.19-7.16 (m, 2H), 3, 16-2.97 (m, 6H), 2.96-2.89 (m, 1H), 2.83 (s, 2H), 2.48-2.42 (m, 3H), 2.30- 2.20 (m, 2H), 1.90-1.75 (m, 4H), 1.75-1.65 (m, 2H), 1.56-1.44 (m, 1H), 1, 32-1.21 (m, 1H), 1.10 (s, 3H).

- 45 042621

Example 56.

N,N-Dimethyl-2-{ 1-[4-methyl-4-( {[(1 R,2S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 -yl] cyclobutyl} acetamide

To a solution of {1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]cyclobutyl}acetic acid (Example 55: 9.0 mg, 0.025 mmol ) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (21 mg, 0.04 mmol) in N,N-dimethylformamide (0.6 mL) dimethylamine (2M in THF, 0.2 mL, 0.5 mmol) was added and then triethylamine (24 μl, 0.17 mmol). The resulting mixture was stirred at room temperature for 1 hour, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C ₂₄ H ₃₈ N ₃ O (M+H) ⁺ : m/z=384.3; Comput. 384.3.

Example 57 N-Methyl-2-{1-[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1yl]cyclobutyl}acetamide

This compound was obtained using methods similar to those described for the synthesis of example 56, replacing dimethylamine with methylamine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₆ N ₃ O (M+H) ⁺ : m/z=370.3; Comput. 370.3.

Example 58 [1-(Methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

Stage 1: tert-butyl-3-(cyanomethyl)-3-(4-oxopiperidin-1-yl)azetidine-1-carboxylate

To a mixture of piperidin-4-one hydrochloride hydrate (Aldrich, cat#151769: 1.54 g, 10.0 mmol) and tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (prepared by methods similar to those described in the literature , for example, in WO 2012/177606: 2.33 g, 12.0 mmol) in acetonitrile (10 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.94 ml, 13.0 mmol). The resulting mixture was heated to 75°C and stirred for two days, then cooled to room temperature and diluted with EtOAc, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 60% EtOAc in hexanes to give the desired product (2.26 g, 77%). LC-MS calculated for C11H16N3O3 (M- ^t Bu+2H) ⁺ : m/z=238.1; Comput. 238.2.

Step 2: tert-Butyl-3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidine-1-carboxylate

To a solution of (1R,2S)-2-phenylcyclopropanamine (2.16 g, 16.2 mmol) (prepared using the methods described in Bioorg. Med. Chem. Lett., 2011, 27, 4429) and tert-butyl- 3-(cyanomethyl)-3-(4oxo-piperidin-1-yl)azetidine-1-carboxylate (4.77 g, 16.2 mmol) in methylene chloride (80 ml) acetic acid (1.85 ml, 32.5 mmol) was added ). The resulting mixture was stirred at room temperature for 7 hours, then sodium triacetoxyborohydride (10.3 g, 48.8 mmol) was added portionwise. The reaction mixture was stirred at room temperature overnight, then cooled to 0° C. and quenched with saturated aqueous NaHCO ₃ . The mixture was extracted with DCM. The combined extracts were dried over Na ₂ SO 4 and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 10% MeOH in DCM to give the desired product (5.62 g, 84%). LCMS calculated for C ₂₄ H ₃₅ N ₄ O ₂ (M+H)+: m/z=411.3; Comput. 411.3.

Stage 3: tert-butyl-3-(cyanomethyl)-3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidine-1-carboxylate

To a solution of tert-butyl 3-(cyanomethyl)-3-(4-{[(1 R,2 S)-2-phenylcyclopropyl] amino} piperidin-1 yl)-azetidine-1-carboxylate (5.62 g, 13 .7 mmol) in methylene chloride (80 ml) at 0° C. was added N,Ndiisopropylethylamine (5.96 ml, 34.2 mmol) followed by trifluoroacetic anhydride (2.90 ml, 20.5 mmol). The resulting mixture was stirred at 0°C for 1 h, then extinguished with saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 60% EtOAc in hexanes to give the desired product (5.66 g, 82%). LC-MS calculated for C ₂₆ H ₃₄ F ₃ N ₄ O ₃ (M+H) ⁺ : m/z=507.3; Comput. 507.2.

Step 4: N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide

To a solution of the product (5.66 g) from step 3 in methylene chloride (60 ml) at 0° C. was added trifluoroacetic acid (10.5 ml). The resulting yellow solution was stirred at room temperature overnight then concentrated. The precipitate was dissolved in 50 ml DCM, then cooled to 0°C and neutralized with saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% MeOH in DCM to give the desired product (4.32 g). LC-MS calculated for C21H26F3N4O (M+H) ⁺ : m/z=407.2; Comput. 407.2.

Step 5: N-{1-[3-(cyanomethyl)-1-(methylsulfonyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoroN-[(1R,2S)-2- phenylcyclopropyl]acetamide

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (2.00 g, 4.92 mmol) in methylene chloride (30 ml) at 0° C. was added N,N-diisopropylethylamine (2.57 ml, 14.8 mmol) followed by methanesulfonyl chloride (0.57 ml, 7.38 mmol). The resulting yellow solution was stirred at 0°C for 1 h, then diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 50% EtOAc in hexanes to give the desired product (2.13 g, 89%) as a white solid. LCMS calculated for C ₂₂ H ₂₈ F ₃ N ₄ O ₃ S (M+H) ⁺ : m/z=485.2; Comput. 485.1.

Step 6: [1-(methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylpcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

To a solution of the product (2.13 g) from step 5 in tetrahydrofuran (20 ml) and methanol (10 ml) was added sodium hydrochloride (2M in water, 12 ml, 24 mmol). The resulting mixture was stirred at room temperature overnight, then quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The precipitate was purified by flash chromatography on a silica gel column eluting with 0 to 10% MeOH in DCM to give the desired product (1.48 g) as a white solid which was further purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as a TFA salt. LC-MS calculated for C20H29N4O2S (M+H) ⁺ : m/z=389.2; Comput. 389.2.

- 47 042621

1H NMR (500 MHz, DMSO) δ 9.07 (br, 2H), 7.33-7.27 (m, 2H), 7.24-7.20 (m, 1H), 7.19-7, 15 (m, 2H),

3.91-3.81 (m, 2H), 3.75-3.68 (m, 2H), 3.29-3.17 (m, 1H), 3.02 (s, 3H), 3, 00-2.92 (m, 3H), 2.86-2.75 (m, 2H),

2.45-2.36(m, 1H), 2.27-2.12(m, 2H), 2.09-1.96(m, 2H), 1.63-1.49(m, 2H ), 1.48-1.38 (m, 1H), 1.37-1.28 (m,

1H).

Example 59 [1-Methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetonitrile

O'

N I

To a solution of N-{1-[3-(cyanomethyl)αzetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (Example 58, stage 4: 50.0 mg, 0.123 mmol) in methylene chloride (4 ml) was added formaldehyde (37 wt.%, in water, 46 μl, 0.62 mmol) and then acetic acid (21 μl, 0.37 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added. The reaction mixture was stirred at room temperature overnight, then neutralized with saturated aqueous Na ₂ CO ₃ and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was dissolved in tetrahydrofuran (2 ml) and methanol (2 ml), then 2.0 M sodium hydrochloride in water (0.31 ml, 0.62 mmol) was added. The resulting mixture was stirred at 30° C. for 5 hours, then cooled to room temperature and diluted with DCM. The mixture was washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The precipitate was dissolved in acetonitrile, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₂₉ N ₄ (M+H) ⁺ : m/z=325.2; Comput. 325.2.

1H NMR (500 MHz, DMSO) δ 7.33-7.28 (m, 2H), 7.25-7.20 (m, 1H), 7.19-7.15 (m, 2H), 4, 31-4.11 (m, 2H), 3.98-3.78 (m, 2H), 3.32-3.18 (m, 1H), 3.08-2.94 (m, 3H), 2.94-2.76(m, 5H), 2.47-2.38(m, 1H), 2.31-2.20(m, 2H), 2.13-1.99(m, 2H ), 1.66-1.51 (m, 2H), 1.50-1.41 (m, 1H), 1.39-1.29 (m, 1H).

Example 60 [3-(4-{[(1 R,2S)-2-Phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

To a solution of tert-butyl 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidine-1-carboxylate (Example 58, step 2: 20 mg) TFA (0.5 ml) was added to DCM (0.5 ml). The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in acetonitrile, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₁₉ H ₂₇ N ₄ (M+H) ⁺ : m/z=311.2; Comput. 311.2.

Example 61 [3-(4-{[(1S,2R)-2-Phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained using methods similar to those described for the synthesis of example 60, replacing (1S,2R)-2-phenylcyclopropanamine (prepared using the methods described in Bioorg. Med. Chem. Lett., 2011, 27, 4429) (1R ,2S)-2-phenylcyclopropanamine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₁₉ H ₂₇ N ₄ (M+H) ⁺ : m/z=311.2; Comput. 311.2.

Example 62 [1-(Ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was prepared using methods similar to those described for the synthesis of Example 58. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₁ H ₃₁ N ₄ O ₂ S (M+H)+: m/z=403.2;

- 48 042621 calc. 403.2.

1H NMR (500 MHz, DMSO) δ 8.99 (br, 2H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.19-7, 16(m, 2H),

3.90-3.80 (m, 2H), 3.72-3.60 (m, 2H), 3.31-3.17 (m, 1H), 3.13 (q, J=7.3 Hz, 2H), 3.02-2.91 (m, 3H), 2.82-2.70 (m, 2H), 2.43-2.33 (m, 1H), 2.25-2, 13 (m, 2H), 2.06-1.97 (m, 2H), 1.62-1.47 (m, 2H), 1.46-1.38 (m, 1H), 1.371.30 ( m, 1H), 1.23 (t, J=7.3 Hz, 3H).

Example 63 3-(Cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclonpropyl]amino}piperidin-1yl)azetidine-1-sulfonamide

O ^'^CN

This compound was prepared using methods similar to those described for the synthesis of Example 58, substituting dimethylsulfamoyl chloride for methanesulfonyl chloride in Step 5. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₁ H ₃₂ N ₅ O ₂ S (M+H) ⁺ : m/z=418.2; Comput. 418.2.

Example 64 3-(Cyanomethyl)-N-methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}pineridin-1yl)azetidine-1-sulfonamide

This compound was prepared using methods similar to those described for the synthesis of Example 58, replacing methylsulfamoyl chloride with methanesulfonyl chloride in step 5. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₃₀ N ₅ O ₂ S (M+H) ⁺ : m/z=404.2; Comput. 404.2.

1H NMR (500 MHz, CD3CN) δ 7.37-7.29 (m, 2H), 7.28-7.22 (m, 1H), 7.19-7.12 (m, 2H), 3, 81 (d, J=8.1 Hz, 2H), 3.63 (d, J=8.5 Hz, 2H), 3.38-3.22 (m, 1H), 2.89-2.76 (m, 5H), 2.67 (s, 3H), 2.60-2.48 (m, 1H), 2.382.24 (m, 2H), 2.19-2.05 (m, 2H), 1.78-1.62(m, 2H), 1.63-1.51(m, 1H), 1.42-1.29(m, 1H).

Example 65 3-(Cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine1-sulfonamide

To a solution of chlorosulfonyl isocyanate (86 μl, 0.98 mmol) in methylene chloride (1.0 ml) at 0°C was added a solution of tert-butyl alcohol (94 μl, 0.98 mmol) in methylene chloride (1.0 ml). The resulting mixture was stirred at 0°C for 10 min, then warmed to room temperature and stirred for 1 h, then the mixture was added to a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4yl} -2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclonronyl]acetamide (Example 58, step 4: 100 mg, 0.246 mmol) and N,N-diisopropylethylamine (210 µl, 1.2 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NaHCO ₃ solution, then extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ and concentrated. The precipitate was dissolved in methylene chloride (1.5 ml), then trifluoroacetic acid (1.5 ml) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The precipitate was dissolved in tetrahydrofuran (2.0 ml) after which 2.0 M sodium hydrochloride in water (1.8 ml, 3.7 mmol) was added followed by methanol (2.0 ml). The resulting mixture was stirred at room temperature overnight then purified by prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product as a white powder. LC-MS calculated for C ₁₉ H ₂₈ N ₅ O ₂ S (M+H) ⁺ : m/z=390.2; Comput. 390.2.

1H NMR (500 MHz, DMSO) δ 7.23-7.18 (m, 2H), 7.12-7.06 (m, 1H), 7.02-6.98 (m, 2H), 6, 94 (s, 2H), 3.68-3.62 (m, 2H), 3.50-3.45 (m, 2H), 2.94 (s, 2H), 2.64-2.55 ( m, 2H), 2.55-2.50 (m, 1H), 2.37-2.28 (m, 1H), 2.21-2.11 (m, 3H), 1.81-1, 70 (m, 3H), 1.30-1.18 (m, 2H), 0.96-0.90 (m, 2H).

Example 66 [1-Methyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetic acid

- 49 042621

Stage 1: tert-butyl-3-(2-tert-butoxy-2-oxoethylidene)azetidine-1-carboxylate

1.0 M potassium tert-Butoxide in THF (20.0 ml, 20.0 mmol) was added to a solution of tert-butyl(diethoxyphosphoryl)acetate (5.00 g, 19.8 mmol) in tetrahydrofuran (22.0 ml) at 0°C. The mixture was stirred at room temperature for 30 min, then cooled to 0° C., and a solution of tert-butyl 3-oxoazetidine-1-carboxylate (2.83 g, 16.5 mmol) in 10 ml THF was added. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 20% EtOAc in hexanes to give the desired product (4.46 g, quant).

Step 2: tert-butyl-3-(2-tert-butoxy-2-oxoethyl)-3-(4-oxo-piperidin-1-yl)-azetidine-1-carboxylate

To a mixture of piperidin-4-one hydrochloride hydrate (922 mg, 6.00 mmol) in acetonitrile (5.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.08 ml, 7.0 ml). 20 mmol) and then tert-butyl-3-(2-tert-butoxy-2oxoethylidene)azetidine-1-carboxylate (1080 mg, 4.00 mmol). The resulting mixture was heated to 75°C and stirred for 2 days. The mixture was cooled to room temperature, then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 60% EtOAc in hexanes to give the desired product (424 mg, 29%). LC-MS calculated for C ₁₉ H ₃₃ N ₂ O ₅ (M+H)+: m/z=369.2; Comput. 369.2.

Stage 3: tert-butyl-3-(2-tert-butoxy-2-oxoethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1 -yl)azetidine-1 - carboxylate

To a solution of (1R,2S)-2-phenylcyclopropanamine (173 mg, 1.30 mmol) and tert-butyl-3-(2-tert-butoxy2-oxoethyl)-3-(4-oxopiperidin-1-yl)azetidine- 1-carboxylate (479 mg, 1.30 mmol) in methylene chloride (6 ml) was added acetic acid (150 μl, 2.6 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (550 mg, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM, washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 10% MeOH in DCM to give the desired product (512 mg, 81%). LCMS calculated for C ₂₈ H ₄₄ N ₃ O ₄ (M+H)+: m/z=486.3; Comput. 486.4.

Step 4: tert-Butyl-3-(2-tert-butoxy-2-oxoethyl)-3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidine -1 -carboxylate

To a solution of tert-butyl-3-(2-tert-butoxy-2-oxoethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate (497 mg, 1.02 mmol) in methylene chloride (8 ml) at 0°C was added N,N-diisopropylethylamine (530 μl) and then trifluoroacetic anhydride (190 μl, 1.3 mmol). The resulting yellow solution was stirred at 0° C. for 1 h, then quenched with saturated NaHCO ₃ solution. The resulting mixture was extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was purified by flash chromatography on a silica gel column,

- 50 042621 eluting with 0 to 60% EtOAc in hexanes to give the desired product (583 mg, 98%). LC-MS calculated for C ₃₀ H ₄₃ F ₃ N ₃ O ₅ (M+H)+: m/z=582.3; Comput. 582.3.

Step 5: (3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin1-yl}azetidin-3-yl)acetic acid dihydrochloride

To a solution of the product from step 4 in methylene chloride (6 ml) was added 4.0 M hydrogen chloride in 1,4-dioxane (2.0 ml, 8.0 mmol). The resulting mixture was stirred at room temperature overnight then concentrated to give a light yellow solid (548 mg) which was used in the next step without further purification. LC-MS calculated for C ₂₁ H ₂₇ F ₃ N ₃ O ₃ (M+H) ⁺ : m/z=426.2; Comput. 426.1.

Step 6: [1-methyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetic acid

To a solution of (3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidin-3-yl)acetic acid dihydrochloride (30 mg, 0.060 mmol) in methylene chloride (2 ml, 30 mmol) formaldehyde (37 wt%, in water, 22 μl, 0.30 mmol) was added followed by acetic acid (10 μl, 0.18 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then concentrated. The precipitate was dissolved in tetrahydrofuran (1.0 ml) after which 2.0 M sodium hydrochloride in water (1.0 ml, 2.0 mmol) was added followed by methanol (1.0 ml). The resulting mixture was stirred at room temperature overnight, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₃₀ N ₃ O ₂ (M+H) ⁺ : m/z=344.2; Comput. 344.3.

¹ H NMR (500 MHz, DMSO) δ 7.33-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.19-7.14 (m, 2H), 4 .40-4.28 (m, 1H), 4.15-4.03 (m, 1H), 3.99-3.87 (m, 1H), 3.84-3.70 (m, 1H) , 3.31-3.17(m, 1H), 3.03-2.75(m, 6H), 2.74-2.59(m, 2H), 2.47-2.36(m, 1H), 2.18-2.08 (m, 2H), 2.07-1.96 (m, 2H), 1.65-1.49 (m, 2H), 1.50-1.40 ( m, 1H), 1.381.25 (m, 1H).

Example 67 [1-Ethyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid

This compound was obtained using methods similar to those described for the synthesis of example 66, replacing formaldehyde with acetaldehyde (5 M in THF). The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C ₂₁ H ₃₂ N ₃ O ₂ (M+H) ⁺ : m/z=358.2; Comput. 358.2.

Example 68 N,N-Dimethyl-2-[1-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetamide

Stage 1: tert-butyl-[ 1 - (4-oxo-piperidin-1 -yl) cyclobutyl] acetate

To a mixture of piperidin-4-one hydrochloride hydrate (614 mg, 4.00 mmol) in acetonitrile (3.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.69 ml, 4.0 ml). 6 mmol) and then tert-butylcyclobutylidene acetate (336 mg, 2.00 mmol). The resulting mixture was heated to 75°C and stirred for 2 days. The mixture was cooled to room temperature, then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 50% EtOAc in hexanes to give the desired product (57 mg, 11%). LC-MS calculated for C ₁₅ H ₂₆ NO ₃ (M+H) ⁺ : m/z=268.2; Comput. 268.1.

- 51 042621

Stage 2: butyl]acetate tert-butyl-[ 1 -(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1 -yl)cyclo-

To a solution of (1R,2S)-2-phenylcyclopropanamine (28 mg, 0.21 mmol) and tert-butyl-[1-(4oxo-piperidin-1-yl)cyclobutyl]acetate (57 mg, 0.21 mmol) in methylene chloride ( 3 ml) was added acetic acid (24 μl, 0.43 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (90 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 10% MeOH in DCM to give the desired product (79 mg, 96%). LC-MS calculated for C ₂₄ H ₃₇ N ₂ O ₂ (M+H)+: m/z=385.3; Comput. 385.3.

Step 3: [1-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetic acid dihydrochloride

The product from step 2 was dissolved in methylene chloride (3 ml), then 4.0 M hydrogen chloride in 1,4-dioxane (0.533 ml, 2.13 mmol) was added. The resulting mixture was stirred at room temperature overnight then concentrated. The precipitate (73 mg, white solid) was used in the next step without further purification. LC-MS calculated for C ₂₀ H ₂₉ N ₂ O ₂ (M+H)+: m/z=329.2; Comput. 329.2.

Step 4: N,N-dimethyl-2-[ 1 -(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetamide

N ,Ndiisopropylethylamine (100 µl, 0.574 mmol) and 2.0 M dimethylamine in THF (0.15 ml, 0.30 mmol). The mixture was stirred at room temperature for 5 minutes, then benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29 mg, 0.066 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then diluted with acetonitrile and purified by prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product as a white solid. LC-MS calculated for C ₂₂ H ₃₄ N ₃ O (M+H)+: m/z=356.3; Comput. 356.3.

Example 69 N-Methyl-2-[1-(4-{[(1 R,2 8)-2-phenylcyclopropyl]amino}piperidin-1-yl)cyclobutyl]acetamide

II ⁿ

[I Ί \Ζ o

This compound was prepared using methods similar to those described for the synthesis of example 68, substituting methylamine (2M in THF) for dimethylamine. The resulting mixture was purified by prepHPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product as a white solid. LC-MS calculated for C ₂₁ H ₃₂ N ₃ O (M+H)+: m/z=342.3; Comput. 342.3.

Example 70 2-[1-(Ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]-N,N-dimethylacetamide

Stage 1: tert-Butyl-3-(2-methoxy-2-oxoethyl)-3-(4-oxo-piperidin-1-yl)azetidine-1-carboxylate

Vos

To a mixture of piperidin-4-one hydrochloride hydrate (0.77 g, 5.0 mmol) and tert-butyl 3-(2-methoxy-2oxoethylidene)azetidine-1-carboxylate (MolBridge, cat#MB00001187: 1.2 g , 5.5 mmol) in acetonitrile (5

- 52 042621 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 ml, 6.0 mmol). The resulting mixture was heated to 75°C and stirred for two days. The mixture was diluted with EtOAc, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 70% EtOAc in hexanes to give the desired product (1.08 g, 66%). LC-MS calculated for C ₁₂ H ₁₉ N ₂ O ₅ (M-tBu+2H)+: m/z=271.1; Comput. 271.2.

Step 2: tert-butyl-3-(2-methoxy-2-oxoethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate

V°

Vos

To a solution of (1R,2S)-2-phenylcyclopropanamine (133 mg, 1.00 mmol) and tert-butyl-3-(2-methoxy-2oxoethyl)-3-(4-oxo-piperidin-1-yl)azetidin-1- carboxylate (326 mg, 1.00 mmol) in methylene chloride (8 ml) was added acetic acid (110 μl, 2.0 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (420 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then diluted with DCM and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 10% MeOH in DCM to give the desired product (483 mg, quant). LC-MS calculated for C ₂₅ H ₃₈ N ₃ O ₄ (M+H)+: m/z=444.3; Comput. 444.3.

Step 3: tert-Butyl-3-(2-methoxy-2-oxoethyl)-3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidine-1 -carboxylate

To a solution of tert-butyl 3-(2-methoxy-2-oxoethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate (444 mg, 1.00 mmol) in methylene chloride (8 ml) was added N,N-diisopropylethylamine (520 μl, 3.0 mmol) followed by trifluoroacetic anhydride (180 μl, 1.3 mmol). The resulting yellow solution was stirred at room temperature for 1 h, then quenched with saturated aqueous NaHCO ₃ and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 60% EtOAc in hexanes to give the desired product (446 mg, 83%). LC-MS calculated for C ₂₇ H ₃₇ F ₃ N ₃ O ₅ (M+H)+: m/z=540.3; Comput. 540.2.

Step 4: Methyl-(3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidin-3-yl)acetate dihydrochloride

To a solution of the product from step 3 in methylene chloride (6 ml) was added 4.0 M hydrogen chloride in 1,4-dioxane (2.50 ml, 10.0 mmol). The resulting mixture was stirred at room temperature overnight then concentrated to give 400 mg of a light yellow solid which was used in the next step without further purification. LC-MS calculated for C ₂₂ H ₂₉ F ₃ N ₃ O ₃ (M+H)+: m/z=440.2; Comput. 440.2.

Step 5: methyl-(1-(ethylsulfonyl)-3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1-yl}azetidin-3-yl)acetate

A suspension of methyl-(3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1yl}azetidin-3-yl)acetate dihydrochloride (150 mg, 0.29 mmol) in tetrahydrofuran ( 5 ml) was added N,Ndiisopropylethylamine (255 μl, 1.46 mmol), then ethanesulfonyl chloride (55.5 μl, 0.585 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 1 h, then

- 53 042621 was quenched with water and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 60% EtOAc in hexanes to give the desired product. LC-MS calculated for C ₂₄ H ₃₃ F ₃ N ₃ O ₅ S (M+H) ⁺ : m/z=532.2; Comput. 532.2.

Step 6: [1-(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid

The product from step 5 was dissolved in tetrahydrofuran (2.5 ml) and methanol (2.5 ml), then 2.0 M sodium hydrochloride in water (1.0 ml, 2.0 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then purified with prep. HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₁ H ₃₂ N ₃ O ₄ S (M+H) ⁺ : m/z=422.2; Comput. 422.1.

Step 7: 2-[1-(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]-N,N-dimethylacetamide

To a solution of bis(trifluoroacetate) [1-(ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid (36 mg, 0.055 mmol) in tetrahydrofuran (2.0 ml) was added N,N-diisopropylethylamine (58 μl, 0.33 mmol) and then 2.0 M dimethylamine in THF (150 μl, 0.30 mmol), then benzotriazole hexafluorophosphate was added 1-yloxytris-(dimethylamino)phosphonium (27 mg, 0.061 mmol). The resulting mixture was stirred at room temperature for 1 h, then diluted with acetonitrile and purified with prep. HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product as a white solid. LC-MS calculated for C ₂₃ H ₃₇ N ₄ O ₃ S (M+H) ⁺ : m/z=449.3; Comput. 449.3.

1H NMR (500 MHz, CD3CN) δ 7.27-7.20 (m, 2H), 7.16-7.10 (m, 1H), 7.07-7.01 (m, 2H), 3, 99-3.90 (m, 2H), 3.78-3.69 (m, 2H), 3.07-2.95 (m, 5H), 2.85 (s, 3H), 2.75- 2.66 (m, 2H), 2.62 (s, 2H), 2.61-2.53 (m, 1H), 2.32-2.24 (m, 1H), 2.18-2, 06 (m, 2H), 1.88-1.80 (m, 2H), 1.80-1.73 (m, 1H), 1.37-1.22 (m, 5H), 1.03- 0.91 (m, 2H).

Example 71 2-[1-(Ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]-N-methylacetamide

This compound was prepared using methods similar to those described for the synthesis of Example 70, substituting methylamine (2M in THF) for dimethylamine in step 7. Prep HPLC reaction (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product as solid white matter. LC-MS calculated for C ₂₂ H ₃₅ N ₄ O ₃ S (M+H) ⁺ : m/z=435.2; Comput. 435.3.

Example 72 [1-(trans-4-hydroxycyclohexyl)-3-(4-{[(1B^)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

Step 1: N-{1-[1-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-3-(cyanomethyl)azetidin-3yl]piperidin-4-yl}-2,2,2 -trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2

4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (Aldrich, cat#638153: 62 µl, 0.25 mmol) and then acetic acid (8.4 µl, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h, then neutralized with saturated NaHCO ₃ solution and extracted with DCM. The combined extracts were dried over Na ₂ SO ₄ then concentrated. The precipitate was used in the next step without further purification. LC-MS calculated for C ₃₃ H ₅₀ F ₃ N ₄ O ₂ Si (M+H)+: m/z=619.4; Comput. 619.3.

Step 2: N-{1-[3-(cyanomethyl)-1-(4-hydroxycyclohexyl)αzetidin-3-yl]piperidin-4-yl}-2,2,2trifluoro-N-[(1R,2S) -2-phenylcyclopropyl]acetamide

The crude product from step 1 was dissolved in THF (1 ml), then 4.0 M hydrogen chloride in 1,4-dioxane (0.5 ml, 2 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The precipitate was used in the next step without further purification. LC-MS calculated for C ₂₇ H ₃₆ F ₃ N ₄ O ₂ (M+H) ⁺ : m/z=505.3; Comput. 505.3.

Step 3: [1-(trans-4-hydroxycyclohexyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

The crude product from step 2 was dissolved in THF (1 ml) and MeOH (1 ml), then 2.0 M sodium hydrochloride in water (0.5 ml, 1 mmol) was added. The resulting mixture was stirred at room temperature for 2 h to give a mixture of cis and trans products, which were separated and purified by prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH). LC-MS calculated for C ₂₅ H ₃₇ N ₄ O (M+H) ⁺ : m/z=409.3; Comput. 409.2.

For the trans isomer: 1H NMR (500 MHz, CD3CN) δ 7.26-7.21 (m, 2H), 7.15-7.10 (m, 1H), 7.06-7.01 (m, 2H), 3.50-3.40 (m, 1H), 3.22 (d, J=7.8 Hz, 2H), 2.83 (d, J=7.4 Hz, 2H), 2, 75 (s, 2H), 2.66-2.53 (m, 3H), 2.292.18 (m, 3H), 2.03-1.95 (m, 1H), 1.86-1.68 ( m, 7H), 1.30-1.11 (m, 4H), 1.02-0.90 (m, 4H). the transconfiguration of the cyclohexane ring was confirmed by 2D NMR. Retention time on analytical LC-MS (pH=10, acetonitrile/aq+NH ₄ OH) t=1.91 min.

Example 73 [1-(cis-4-Hidroxycyclohexyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

The cis isomer was also obtained from the reaction of example 72, step 3. It was isolated by prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₅ H ₃₇ N ₄ O (M+H) ⁺ : m/z=409.3; Comput. 409.2.

1H NMR (500 MHz, CD3CN) δ 7.29-7.24 (m, 2H), 7.18-7.13 (m, 1H), 7.09-7.05 (m, 2H), 3, 68-3.61 (m, 1H), 3.30-3.24 (m, 2H), 2.85-2.80 (m, 4H), 2.71-2.56 (m, 3H), 2.33-2.22(m, 4H), 1.89-1.78(m, 3H), 1.66-1.59(m, 2H), 1.54-1.44(m, 4H ), 1.44-1.36 (m, 2H), 1.32-1.22 (m, 2H), 1.02-0.96 (m, 2H). Retention time on analytical LC-M (pH=10, acetonitrile/water+NH ₄ OH) t=2.06 min.

Example 74 [1-(2-Hydroxyethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 72, replacing {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (Aldrich, cat#449458) 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone in step 1. the mixture was purified by prep-HPLC (pH=10,

- 55 042621 acetonitrile/water+NH ₄ OH) to obtain the desired product. LC-MS calculated for C21H31N4O (M+H) ⁺ : m/z=355.2; Comput. 355.2.

Example 75 [3-(4-{[(1R,2S)-2-Phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran4-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 72, replacing tetrahydro-4Hpyran-4-one (Aldrich, cat#198242) 4-{[tert-butyl(dimethyl)silyl]oxy}-cyclohexanone in step 1. The reaction mixture was purified at prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₄ H ₃₅ N ₄ O (M+H) ⁺ : m/z=395.3; Comput. 395.2.

Example 76 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino }piperidin-1-yl)-1-(tetrahydrofuran-3yl)azetidin-3-yl]acetonitrile (mixture of diastereomers)

This compound was prepared according to the methods described in Example 72, substituting dihydrofuran 3(2H)-one (J&W Pharmlab, cat#10-0169) for 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone in step 1. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH ₄ OH) to give the desired product. LC-MS calculated for C ₂₃ H ₃₃ N ₄ O (M+H) ⁺ : m/z=381.3; Comput. 381.2.

Example 77 2-(3-(Cyanomethyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidin-1-yl)-N,N-dimethylacetamide l n

ABOUT

N

Stage 1: [3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1yl]acetic acid

About A^cn

Nk^O

HE

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (example 58, step 4: 150 mg, 0.37 mmol) and 5.0 M ethyl glyoxylate in toluene (88 μl, 0.44 mmol) in methylene chloride (2 ml) were added acetic acid (62.9 μl, 1.11 mmol). The resulting mixture was stirred at room temperature overnight, then sodium triacetoxyborohydride (160 mg, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM, washed with saturated NaHCO ₃ , water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was dissolved in THF (2 ml) and MeOH (2 ml), then a solution of lithium hydroxide monohydrate (46 mg, 1.1 mmol) in water (1 ml) was added. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was adjusted to pH=4 with HCl (aq.) and concentrated under reduced pressure to give a crude product which was used in the next step without further purification. LC-MS calculated for C ₂₁ H ₂₉ N ₄ O ₂ (M+H) ⁺ : m/z=369.2; Comput. 369.2.

Step 2: 2-(3-(cyanomethyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidin1-yl)-N,N-dimethylacetamide

2.0 M Dimethylamine in THF (41 μl, 0.081 mmol) was added to a mixture of [3-(cyanomethyl)-3-(4-{[(1R,2S)2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine- 1-yl]acetic acid (20 mg, 0.05 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29 mg, 0.065 mmol) in DMF (1 ml), then triethylamine (20 μl) was added , 0.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, then adjusted to pH=2 with TFA and purified by pre-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₄ N ₅ O (M+H)+: m/z=396.3; Comput. 396.2.

Example 7 8. 2-[3-(Cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]-N-methylacetamide

This compound was obtained according to the methods described in example 77, replacing dimethylamine with methylamine in step 2. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₂ H ₃₂ N ₅ O (M+H)+: m/z=382.3; Comput. 382.2.

Example 7 9 2-[3-(Cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]acetamide

This compound was obtained according to the methods described in example 77, replacing dimethylamine ammonium carbonate in step 2. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as a TFA salt. LC-MS calculated for C ₂₁ H ₃₀ N ₅ O (M+H)+: m/z=368.2; Comput. 368.2.

Example 80 [1-[(1-Methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl) azetidin-3-yl]acetonitrile

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (35 mg, 0.079 mmol) was added to a mixture of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2- trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (Example 58, step 4: 25 mg, 0.061 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (Aldrich, cat#682063: 9.9 mg, 0.079 mmol) in acetonitrile (1.0 ml) and then triethylamine (25 μl, 0.18 mmol) was added. The reaction mixture was stirred at room temperature overnight, then quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was dissolved in THF (1 ml) and MeOH (1 ml), then 2N hydrochloric acid was added. NaOH (1 ml). The resulting mixture was stirred at room temperature for 3 hours, then acidified with TFA and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₁ N ₆ O (M+H)+: m/z=419.3; Comput. 419.3. The TFA salt of the product was neutralized to give the free base form of the product, which was used to obtain NMR data.

1H NMR (500 MHz, DMSO) δ 8.15 (s, 1H), 7.74 (s, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.09 (t, J =7.3 Hz, 1H), 7.00 (d, J=7.5 Hz, 2H), 4.26-4.13 (m, 2H), 3.88-3.76 (m, 5H) , 2.94 (s, 2H), 2.72-2.62 (m, 2H), 2.56-2.50 (m, 1H), 2.22-2.10 (m, 3H), 1 .84-1.70 (m, 3H), 1.34-1.20 (m, 2H), 0.99-0.89 (m, 2H).

Example 81 [1-[(1-Methyl-1H-pyrazol-5-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl) azetidin-3-yl]acetonitrile

- 57 042621

This compound was prepared according to the methods described in Example 80, replacing 1-methyl-1H-pyrazole-5-carboxylic acid with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₁ N ₆ O (M+H) ⁺ : m/z=419.3; Comput. 419.3.

Example 82 [1-[(trans-4-Hydroxycyclohexyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 80, replacing trans-4hydroxycyclohexanecarboxylic acid 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₆ H ₃₇ N ₄ O ₂ (M+H) ⁺ : m/z=437.3; Comput. 437.3.

Example 83 [1-[(cis-4-hydroxycyclohexyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 80, replacing cis-4hydroxycyclohexanecarboxylic acid with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₆ H ₃₇ N ₄ O ₂ (M+H) ⁺ : m/z=437.3; Comput. 437.3.

Example 84 [1-[(1-Hydroxycyclopropyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 80, replacing 1-hydroxycyclopropanecarboxylic acid with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₁ N ₄ O ₂ (M+H) ⁺ : m/z=395.2; Comput. 395.2.

Example 85 [1-[(1-Hydroxycyclopentyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 80, replacing 1-hydroxycyclopentanecarboxylic acid with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₅ H ₃₅ N ₄ O ₂ (M+H) ⁺ : m/z=423.3; Comput. 423.3.

Example 86 [1-(Morpholin-4-ylcarbonyl)-3-(4-{[(1 R,28)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl]acetonitrile

Phosgene (15 wt.%, in toluene, 80 μl, 0.1 mmol) was added to a mixture of N-{1-[3-(cyanomethyl)azetidine-58 042621

3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 58, step 4: 30 mg, 0.08 mmol) and triethylamine (30 µl, 0.2 mmol) in acetonitrile (1 ml) at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. A solution of morpholine (10 µl, 0.11 mmol) and triethylamine (20 µl, 0.2 mmol) in acetonitrile (1 ml) was added to the precipitate. The reaction mixture was stirred at room temperature for 30 min, then 2N hydrochloric acid was added. MaOH (1 ml). The reaction mixture was stirred at room temperature for 3 h, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₄ N ₅ O ₂ (M+H) ⁺ : m/z=424.3; Comput. 424.3.

Example 87 [1-[(4-Hidroxypiperidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino }piperidin-1-yl)azetidine-3 - yl]acetonitrile

This compound was obtained according to methods similar to those described in example 86, replacing morpholine with 4hydroxypiperidine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C25H36N5O2 (M+H) ⁺ : m/z=438.3; Comput. 438.3.

Example 88 [1-[(4-Methoxypiperidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl ]acetonitrile

This compound was obtained according to the methods described in example 86, replacing morpholine with 4-methoxypiperidine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₆ H ₃₈ N ₅ O ₂ (M+H) ⁺ : m/z=452.3; Comput. 452.3.

Example 89 [1-[(3-Hidroxyazetidin-1-yl)carbonyl]-3-(4- {[(1 R,2S)-2-phenylcyclopropyl]amino } piperidin-1 -yl)azetidine-3 - yl]acetonitrile

This compound was prepared according to the methods described in Example 86, substituting azetidin-3-ol hydrochloride for morpholine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₂ N ₅ O ₂ (M+H) ⁺ : m/z=410.3; Comput. 410.3.

Example 90 N,N-dimethyl-2-(1-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidin-3-yl)acetamide

This compound was obtained according to the methods described in example 70, replacing methanesulfonyl chloride with ethanesulfonyl chloride in step 5. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₂ H ₃₅ N ₄ O ₃ S (M+H) ⁺ : m/z=435.2; Comput. 435.3.

Example 91 N-Methyl-2-[1-(methylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetamide

- 59 042621

This compound was obtained according to the methods described in example 70, replacing methanesulfonyl chloride with ethanesulfonyl chloride in step 5; and methylamine dimethylamine in step 7. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C21H33N4O3S (M+H)+: m/z=421.2; Comput. 421.3.

Example 92 2-[1-(Ethylsulfonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]αmino}piperidin-1yl)azetidin-3-yl]ethanol

To a solution of bis(trifluoroacetate) [ 1 -(ethylsulfonyl)-3 -(4-{[(1 R,2S)-2-phenylcyclopropyl] amino } piperidin-1-yl)azetidin-3-yl]acetic acid (Example 70 , stage 6: 33 mg, 0.051 mmol) in tetrahydrofuran (1.5 ml) at 0°C was added dropwise 1.0 M lithium tetrahydroaluminate in THF (300 μl, 0.30 mmol). The resulting mixture was stirred at 0° C. for 1.5 h, then quenched with 0.1 ml water, 0.1 ml NaOH (15% in water), then 0.3 ml water. The resulting mixture was stirred at 0°C for 10 min, then diluted with THF and filtered. The filtrate was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C21H34N3O3S (M+H)+: m/z=408.2; Comput. 408.2.

Example 93 2-[ 1 -(Methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]ethanol

Q ^/Ν^χ^ΟΗ N o

This compound was obtained according to the methods described in example 70 (stage 5, 6) and example 92; replacing methanesulfonyl chloride with ethanesulfonyl chloride in Example 70, Step 5. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₃₂ N ₃ O ₃ S (M+H)+: m/z=394.2; Comput. 394.2.

Example 94 Methyl 3-[2-(dimethylamino)-2-oxoethyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino }piperidin-1-yl)azetidine-1-carboxylate

This compound was obtained according to the methods described in example 70, replacing ethanesulfonyl chloride with methyl chloroformate. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₅ N ₄ O ₃ (M+H)+: m/z=415.3; Comput. 415.3.

Example 95 Methyl 3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate

This compound was obtained according to the methods described in example 70, replacing dimethylamine with methylamine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₂ H ₃₃ N ₄ O ₃ (M+H)+: m/z=401.3; Comput. 401.2.

- 60 042621

Example 96 3-[2-(Dimethylamino)-2-oxoethyl]-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine- 1-carboxamide

This compound was prepared according to the methods described in Example 70, replacing N,N-dimethylcarbamoyl chloride with ethanesulfonyl chloride in Step 5. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₈ N ₅ O ₂ (M+H)+: m/z=428.3; Comput. 428.3.

Example 97 N,N-Dimethyl-3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine- 1-carboxamide

This compound was prepared according to the methods described in Example 70, replacing N,N-dimethylcarbamoyl chloride with ethanesulfonyl chloride in step 5 and methylamine dimethylamine in step 7. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of TFA salt. LC-MS calculated for C ₂₃ H ₃₆ N ₅ O ₂ (M+H)+: m/z=414.3; Comput. 414.2.

Example 98 [1-(1-Methyl-1H-pyrazol-4-yl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin1-yl)azetidin-3-yl ]acetonitrile

A mixture of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 58 , stage 4: 40 mg, 0.1 mmol), 4-bromo-1-methyl-1H-pyrazole (24 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004 mmol), dicyclohexyl(2',4',6'triisopropylbiphenyl-2-yl)phosphine (8.2mg, 0.017mmol) and cesium carbonate (70mg, 0.22mmol) in toluene (2mL) purged with nitrogen, then stirred at 110°C overnight. The reaction mixture was cooled to room temperature, then quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitate was dissolved in THF (2 ml), then 2N hydrochloric acid was added. NaOH (2 ml). The reaction mixture was stirred at room temperature for 2 hours, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₁ N ₆ (M+H)+: m/z=391.3; Comput. 391.2.

Example 99 Tetrahydrofuran-3-yl 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxylate (mixture of diastereomers)

To a mixture of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (Example 58, step 4: 20 mg, 0.05 mmol) and triethylamine (20 μl, 0.14 mmol) in acetonitrile (0.8 ml), 4-nitrophenyltetrahydrofuran-3-yl carbonate (prepared as described in WO 2010/108059: 16 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitate was dissolved in THF (1 ml), then 2N hydrochloric acid was added. NaOH (1 ml). The reaction mixture was stirred at room temperature for 2

- 61 042621 h, then purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to obtain the desired product as a TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O3 (M+H)+: m/z=425.3; Comput. 425.3.

Example 100 [1-[(1-Methyl-1H-pyrazol-4-yl)sulfonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino }piperidin-1-yl) azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 58, replacing 1-methyl-Spyrazole-4-sulfonyl chloride with methanesulfonyl chloride in step 5. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of TFA salt. LC-MS calculated for C ₂₃ H ₃₁ N ₆ O ₂ S (M+H)+: m/z=455.2; Comput. 455.2.

Example 101 [3-(4-{[(1 R,2 S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(methylsulfonyl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 58, replacing (1R,2S)-2-(4fluorophenyl)cyclopropanamine (Enamine, cat#EN300-189082) (1R,2S)-2-phenylcyclopropanamine in step 2. The reaction mixture was purified at prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₀ H ₂₈ FN ₄ O ₂ S (M+H)+: m/z=407.2; Comput. 407.1.

Example 102 3-(Cyanomethyl)-3-(4-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1 yl)azetidine-1-sulfonamide

This compound was obtained according to the methods described in example 65, replacing (1R,2S)-2-(4fluorophenyl)cyclopropanamine (Enamine, cat#EN300-189082) (1R,2S)-2-phenylcyclopropanamine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₁₉ H ₂₇ FN ₅ O ₂ S (M+H)+: m/z=408.2; Comput. 408.1.

Example 103 [3-(4-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(4-hydroxycyclohexyl)azetidin-3-yl]acetonitrile (isomer 1)

This compound was obtained according to the methods described in example 72, replacing (1R,2S)-2-(4fluorophenyl)cyclopropanamine (Enamine, cat#EN300-189082) (1R,2S)-2-phenylcyclopropanamine. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to separate the two isomers as their respective TFA salts. Isomer one was isolated as example 103. LC-MS calculated for C ₂₅ H ₃₆ FN ₄ O (M+H)+: m/z=427.3; Comput. 427.2.

Example 104 [3-(4-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(4-hydroxycyclohexyl)azetidin-3-yl]acetonitrile ( isomer 2)

- 62 042621

This compound was obtained according to the methods described in example 72, replacing (1R,2S)-2-(4fluorophenyl)cyclopropanamine (Enamine, cat#EN300-189082) (1R,2S)-2-phenylcyclopropanamine. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to separate the two isomers as their respective TFA salts. Isomer two was isolated as example 104. LCMS calculated for C ₂₅ H ₃₆ FN ₄ O (M+H) ⁺ : m/z=427.3; Comput. 427.2.

Example 105 {1-[4-({[(1 R,2 S)-2-phenylcyclopropyl] amino} methyl) piperidin-1 -yl] cyclobutyl} acetic acid

This compound was obtained according to the methods described in example 55, replacing 1-boc-4piperidinecarboxaldehyde (Arkpharm, cat#AK-21827) tert-butyl-4-formyl-4-methylpiperidine-1carboxylate in step 1. The reaction mixture was purified using prep -HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as a TFA salt. LC-MS calculated for C ₂₁ H ₃₁ N ₂ O ₂ (M+H) ⁺ : m/z=343.2; Comput. 343.2.

Example 106 [1-(3-Hydroxycyclobutyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl]acetonitrile

To a solution of N-{1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}-2,2,2-trifluoro-N-[(1R,2S)-2phenylcyclopropyl]acetamide (example 58, step 4: 20 mg, 0.05 mmol) in methylene chloride (2 ml) was added 3-oxocyclobutyl benzoate (19 mg, 0.098 mmol) followed by acetic acid (8.4 μl, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h, then quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitate was dissolved in acetonitrile (1 ml), then 4N sodium hydroxide was added. NaOH (1 ml). The reaction mixture was stirred at room temperature for 2 hours, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₃ N ₄ O (M+H) ⁺ : m/z=381.3; Comput. 381.2.

Example 107 2-(3-(4-((( 1 R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(tetrahydrofuran-2carbonyl)azetidin-3-yl)acetonitrile

This compound was obtained according to the methods described in example 80, replacing 1-methyl-1H-pyrazole-4-carboxylic acid with tetrahydrofuran-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H) ⁺ : m/z=409.3; Comput. 409.2.

Example 108 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydrofuran-3ylcarbonyl)azetidin-3-yl]acetonitrile

- 63 042621

This compound was obtained according to the methods described in example 80, replacing tetrahydrofuran-3-carboxylic acid with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H)+: m/z=409.3; Comput. 409.3.

Example 109 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]acetonitrile

This compound was prepared according to the methods described in Example 80, replacing thiazole-5-carboxylic acid (AstaTech, cat#69866) with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₈ N ₅ OS (M+H)+: m/z=422.2; Comput. 422.2.

Example 110 [1-(Isothiazol-5-ylcarbonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin1-yl)azetidin-3-yl]acetonitrile

This compound was prepared according to the methods described in Example 80, substituting isothiazole-5-carboxylic acid (AstaTech, cat#62856) for 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₈ N ₅ OS (M+H)+: m/z=422.2; Comput. 422.2.

Example 111 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperudin-1-yl)-1-(pyrazin-2-ylcarbonyl)azetidin-3-yl]acetonitrile

This compound was obtained according to the methods described in example 80, replacing 2-pyrazinecarboxylic acid (Aldrich, cat#P56100) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₂₉ N ₆ O (M+H)+: m/z=417.2; Comput. 417.2.

Example 112 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1H-pyrazol-4ylcarbonyl)azetidin-3-yl]acetonitrile

This compound was prepared according to the methods described in Example 80, replacing 1H-pyrazole-4-carboxylic acid (Ark Pharm, cat#AK-25877) with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₉ N ₆ O (M+H)+: m/z=405.2; Comput. 405.3.

Example 113 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidun-1-yl)-1-(1H-pyrazol-5ylcarbonyl)azetidin-3-yl]acetonitrile

- 64 042621

This compound was prepared according to the methods described in Example 80, replacing 1H-pyrazole-5-carboxylic acid (Oakwood, cat#014533) with 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₉ N ₆ O (M+H)+: m/z=405.2; Comput. 405.2.

Example 114 {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3R)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl }acetonitrile

This compound was obtained according to the methods described in example 80, replacing (R)tetrahydrofuran-3-carboxylic acid (Aldrich, cat#712280) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H)+: m/z=409.3; Comput. 409.4.

Example 115 {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3S)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl}acetonitrile

This compound was obtained according to the methods described in example 80, replacing (S)tetrahydrofuran-3-carboxylic acid (Astech, cat#66517) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H)+: m/z=409.3; Comput. 409.3.

Example 116 {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile

This compound was obtained according to the methods described in example 80, replacing (S)-2tetrahydrofurancarboxylic acid (Aldrich, cat#527890) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H)+: m/z=409.3; Comput. 409.3.

Example 117 {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile

This compound was obtained according to the methods described in example 80, replacing (R)-2tetrahydrofurancarboxylic acid (Aldrich, cat#479292) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₃ N ₄ O ₂ (M+H)+: m/z=409.3; Comput.

- 65 042621

409.2.

Example 118 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyridin-2ylacetyl)azetidin-3-yl]acetonitrile

This compound was prepared according to the methods described in Example 80, replacing 1-methyl-1H-pyrazole-4-carboxylic acid with 2-pyridylacetic acid hydrochloride (Aldrich, cat#P65606). The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₆ H ₃₂ N ₅ O (M+H) ⁺ : m/z=430.3; Comput. 430.3.

Example 119 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4ylcarbonyl)azetidin-3-yl]acetonitrile

This compound was prepared according to the methods described in Example 80, substituting thiazole-4-carboxylic acid (Aldrich, cat#633658) for 1-methyl-III-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₈ N ₅ O _S (M+H) ⁺ : m/z=422.2; Comput. 422.2.

Example 120 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl] acetonitrile

This compound was obtained according to the methods described in example 80, replacing thiazole-2carboxylic acid (Ark Pharm, cat#AK-21895) 1-methyl-1H-pyrazole-4-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₂₈ N ₅ OS (M+H) ⁺ : m/z=422.2; Comput. 422.2.

Example 121 N,N-Dimethyl-2-[3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1(tetrahydro-2H-pyran-4-yl) azetidin-3-yl]acetamide

Step 1: [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4yl)azetidin-3-yl]acetic acid

To a solution of methyl-(3-{4-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]piperidin-1yl}azetidin-3-yl)acetate (Example 70, step 4: 150 mg, 0. 29 mmol) in methylene chloride (10 ml) was added tetrahydro-4H-pyran-4-one (Aldrich, cat#198242: 100 μl, 1 mmol) followed by acetic acid (100 μl, 2 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (190 mg, 0.88 mmol) was added. The reaction mixture was stirred at room

- 66 042621 temperature for 2 h, then diluted with DCM and washed with saturated NaHCO ₃ , water and saline. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was dissolved in tetrahydrofuran (2 ml), after which 2.0 M sodium hydrochloride in water (2 ml, 4 mmol) and then methanol (5 ml) were added. The resulting mixture was stirred at room temperature overnight, then diluted with MeOH, filtered and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₆ N ₃ O ₃ (M+H)+: m/z=414.3; Comput. 414.3.

Step 2: N,N-dimethyl-2-[3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4- yl)azetidin-3-yl]acetamide

[3-(4-{[(1 R,2S)-2-Phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]acetic acid ( TFA salt, 20 mg) was dissolved in tetrahydrofuran (1 ml), then (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (19 mg, 0.037 mmol), N,N-diisopropylethylamine (150 μl, 0.86 mmol) and 2.0 M dimethylamine in THF (80 μl, 0.2 mmol). The mixture was stirred at room temperature for 2 hours, then diluted with MeOH and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LCMS calculated for C ₂₆ H ₄₁ N ₄ O ₂ (M+H)+: m/z=441.3; Comput. 441.3.

Example 122 N-Methyl-2-[3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl) azetidin-3-yl]acetamide

This compound was obtained according to the methods described in example 121, replacing dimethylamine with methylamine in step 2. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₅ H ₃₉ N ₄ O ₂ (M+H)+: m/z=427.3; Comput. 427.3.

Example 123 2-[1-(Cyclopropylmethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]-N,N-dimethylacetamide

This compound was obtained according to the methods described in example 121, replacing tetrahydro-4H-pyran-4-one with cyclopropanecarboxaldehyde in step 1. The reaction mixture was purified using prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product in the form of TFA salt. LCMS calculated for C ₂₅ H ₃₉ N ₄ O (M+H)+: m/z=411.3; Comput. 411.4.

Example 124 2-[1-(Cyclopropylmethyl)-3-(4-{[(1 R,2 S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]-N-methylacetamide

This compound was obtained according to the methods described in example 123, replacing dimethylamine with methylamine. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₇ N ₄ O (M+H)+: m/z=397.3; Comput. 397.3.

Example 125 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrimidin-2ylmethyl)azetidin-3-yl]acetic acid

This compound was obtained according to the methods described in example 121, stage 1, replacing pyrimidine-2-carbaldehyde (Synnovator, cat#PB00379) tetrahydro-4H-pyran-4-one. reaction mixture

- 67 042621 was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₂ N5O ₂ (M+H) ⁺ : m/z=422.3; Comput. 422.2.

Example 126 [3-(4-{[(1 R,2S)-2-phenylcyclonpropyl]amino}piperidin-1-yl)-1-(pyrimidin-5ylmethyl)azetidin-3-yl]acetic acid

This compound was prepared according to the methods described in example 121, step 1, replacing pyrimidine-5-carbaldehyde (Matrix Scientific, cat#007321) tetrahydro-4H-pyran-4-one. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₄ H ₃₂ N ₅ O ₂ (M+H) ⁺ : m/z=422.3; Comput. 422.2.

Example 127 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4ylmethyl)azetidin-3-yl]acetic acid

This compound was obtained according to the methods described in example 121, stage 1, replacing thiazole-4-carboxaldehyde (Aldrich, cat#681105) tetrahydro-4H-pyran-4-one. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C23H31N4O2S (M+H) ⁺ : m/z=427.2; Comput. 427.2.

Example 128 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5ylmethyl)azetidin-3-yl]acetic acid

This compound was obtained according to the methods described in example 121, stage 1, replacing thiazole-5-carboxaldehyde (Aldrich, cat#658103) tetrahydro-4H-pyran-4-one. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C23H31N4O2S (M+H) ⁺ : m/z=427.2; Comput. 427.2.

Example 129 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}πpiperidin-1-yl)-1-(1,3-thiazol-2ylmethyl)azetidin-3-yl]acetic acid

This compound was prepared according to the methods described in example 121, step 1, replacing thiazole-2-carboxaldehyde (Aldrich, cat#422460) tetrahydro-4H-pyran-4-one. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C ₂₃ H ₃₁ N ₄ O ₂ S (M+H) ⁺ : m/z=427.2; Comput. 427.2.

Example 130 [3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}pineridin-1-ul)-1-(3,3,3-trifluoropropyl)azetidin-3-yl]acetic acid

- 68 042621

This compound was prepared according to the methods described in Example 121, Step 1, replacing 3,3,3-trifluoropropanal (Alfa Aesar, cat#H50472) tetrahydro-4H-pyran-4-one. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the salt

TFU. LC-MS calculated for C ₂₂ H ₃ iF ₃ N ₃ O ₂ (M+H)+: m/z=426.2; Comput. 426.2.

Example A. Biochemical analysis of histone demethylase LSD1

LANCE LSD1/KDM1A demethylase assay - 10 µl 1 nM LSD-1 enzyme (ENZO BML-SE5440050) in assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20, 25 mM NaCl, 5 mM DTT) pre-incubated for 1 hour at 25° C. with 0.8 μl compound/DMSO dotted in black 384-well polystyrene plates. Reactions were started by adding 10 μl of assay buffer containing 0.4 μM Biotin-labeled Histone H3 peptide substrate: ART-K(Mel)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355) and incubated for 1 hour at 25°C. Reactions were stopped by adding 10 µl of 1x LANCE detection buffer (PerkinElmer CR97-100) enriched with 1.5 nM Eu-antiunmodified H3K4 antibody (PerkinElmer TRF0404) and 225 nM Ultra-Streptavidin LANCE (PerkinElmer TRF102), as well as 0.9 mM Tranylcypromine -HCl (Millipore 616431). After stopping the reactions, the plates were incubated for 30 min and read using a PHERAstar FS plate reader (BMG Labtech). Compounds with IC ₅₀ values of 1 μM or less were considered active. IC ₅₀ values for exemplary compounds are shown in the table (+ refers to IC ₅₀ <100 nM; ++ refers to IC ₅₀ >100 nM and <500 nM).

- 69 042621

- 70 042621

Various modifications of the present invention, in addition to those described in this application, will be obvious to experts in this field from the above description. It is also intended that such modifications fall within the scope of the appended claims. Every reference, including all patents, patent applications, and publications, cited in this application is incorporated herein by reference in its entirety.

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Claims (56)

CLAIM 1. Compound of formula (IVa) or formula (IVb) IVa or (R ³ )p IVb or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl; ring C is a monocyclic 4-7 membered heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 heteroatoms selected from N, O and S; each R ¹ is halogen; each R ³ is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, (5-10 membered heteroaryl)-C1-4 alkyl, (4-10 membered heterocycloalkyl)-C,.4 alkyl, CN , NO2, OR ^a2 , SRa ² , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 , where each C _M is alkyl, C2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, (5-10 membered heteroaryl)-C _1-4 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl optionally substituted with 1, 2, 3 or 4 substituents, independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 cyanoalkyl, CN, NO ₂ , ORa ² , SRa ² , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C (O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 ; R ⁴ is C _1-4 alkyl optionally substituted with CN, C(O)NR ^c3 R ^d3 , OR ^a3 or C(O)OR ^a3 ; each R ⁵ and R ⁶ is H; R ^Z is H, C _1-4 alkyl, or C _6-10 aryl-C _1-4 alkyl-, wherein each of said C _1-4 alkyl and C _6-10 aryl-C _1-4 alkyl- is optionally substituted with halo, or OR ^a4 ; each R ^a2 , R ^b2 , R ^c2 and R ^d2 is independently selected from H, C _1-6 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _{3- 10} cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, (5-10-membered heteroaryl) - C _1-4 alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl, where the specified C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-10 cycloalkyl , 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-10 cycloalkyl-C _1-4 alkyl, (5-10 membered heteroaryl)-C _{1 -4} alkyl and (4-10 membered heterocycloalkyl)-C _1-4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 cyanoalkyl, halogen, CN, OR ^a5 , C(O)R ^b5 , C(O)NR ^c5 R ^d5 , C(O)OR ^a5 , NR ^c5 R ^d5 , NR ^c5 C(O)R ^b5 , S(O) R ^b5 and S(O)2NR ^c5 R ^d5 ; each Ra ⁴ is independently selected from H, C _1-6 alkyl and C1. ₄ haloalkyl; each R ^a3 , R ^b3 , R ^c3 and R ^d3 is independently selected from H, C _1-6 alkyl and C _1-4 haloalkyl; each R ^a5 , R ^b5 , R ^c5 and R ^d5 is independently selected from H, C _1-4 alkyl and C _1-4 haloalkyl; m is 0; n is 0 or 1; p is 0 or 1 and q is 0 or 1; each heteroaryl independently contains 1, 2, 3 or 4 ring heteroatoms independently selected from nitrogen, sulfur and oxygen; each heterocycloalkyl independently contains 1, 2, 3 or 4 ring heteroatoms independently selected from sulfur, oxygen and nitrogen; and each carbon atom or heteroatom in the ring of a heterocycloalkyl group can be oxidized - 72 042621 to form a carbonyl, sulfinyl or sulfonyl group, or the nitrogen atom may be quaternized. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula (IVa) IVa. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula (IVb) (R ³ ) _P 4. A compound according to claim 1 having the formula Va or Vb ^C jAr ⁴ or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that q is 0. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that q is equal to 1. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that n is 0. 8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that n is 1. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is F. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that ring C is azetidinyl or piperidinyl. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that ring C is azetidinyl. 12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that ring C is piperidinyl. 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, characterized in that R ⁴ is C _1-4 alkyl optionally substituted with CN, C(O)NR ^c3 R ^d3 or C(O)OR ^a3 . 14. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, characterized in that R ⁴ is -CH2-CN, -CH2-C(=O)OH, -CH2-C(=O)NH (CH3), -CH2-C(=O)N(CH3)2 or -CH2CH2OH. 15. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10-membered heterocycloalkyl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 , where each specified C1 -6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-10 cycloalkyl and 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C _1-4 alkyl , C _1-4 haloalkyl, C _1-4 cyanoalkyl, CN, NO ₂ , ORa ² , SRa ² , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O )R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S (O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S (O)2NR ^c2 R ^d2 . 16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized - 73 042621 in that each R ³ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 , wherein each of said C1-6 alkyl, _C6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C _1-4 alkyl, C 1-4 haloalkyl, C _1-4 cyanoalkyl, CN, _{NO 2 ,} OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O) OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S( O)2R ^b2 and S(O)2NR ^c2 R ^d2 . 17. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 and S(O)2R ^b2 where each of said C _1-6 alkyl, C _6-10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, _C1-4 alkyl, C1-4 haloalkyl, CC cyanoalkyl, CN, NO2, OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C (O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O)2R ^b2 , NR ^c2 S(O)2NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O)2R ^b2 and S(O)2NR ^c2 R ^d2 . 18. A compound according to any one of claims 1-3 and 5-17, or a pharmaceutically acceptable salt thereof, characterized in that R ^Z is C _1-4 alkyl. 19. A compound according to any one of claims 1-3 and 5-17, or a pharmaceutically acceptable salt thereof, characterized in that R ^Z is C _1-4 alkyl substituted with methoxy. 20. A compound according to any one of claims 1-3 and 5-17, or a pharmaceutically acceptable salt thereof, characterized in that R ^Z is C _6-10 aryl-C _1-4 alkyl substituted with fluorine. 21. A compound according to any one of claims 1-3 and 5-17, or a pharmaceutically acceptable salt thereof, characterized in that R ^Z is H, methyl, methoxymethyl or 4-fluorophenylmethyl. 22. A compound according to any one of claims 1-3 and 5-17, or a pharmaceutically acceptable salt thereof, characterized in that R ^Z is H. 23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, characterized in that p is 0. 24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, characterized in that p is 1. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, having a trans configuration in the portion of the disubstituted cyclopropyl group shown in claim 1. 26. The compound according to claim 1, selected from the following compounds: (1-methyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; (3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; (1-benzyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; 3-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)propanoic acid; (1-acetyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; (1-benzoyl-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; methyl 3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidine-1-carboxylate; (1-(methylsulfonyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-3-yl)acetonitrile; 2-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)nicotinonitrile; 3-cyano-4-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1yl)benzoic acid; 2-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)benzonitrile; 4-(3-(cyanomethyl)-3-{4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}azetidin-1-yl)benzonitrile; (1'-(ethylsulfonyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-3'-yl)acetonitrile; [4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile; [1-methyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile; [1-acetyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4-yl]acetonitrile; [ 1 -(4-Fluorobenzoyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4yl]acetonitrile; [ 1 -(methylsulfonyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidin-4yl]acetonitrile; [4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)-1-(phenylsulfonyl)piperidin-4yl]acetonitrile; - 74 042621 ethyl 4-(cyanomethyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxylate; 4-(cyanomethyl)-N,N-dimethyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide; 4-(cyanomethyl)-N-isopropyl-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)piperidine-1-carboxamide; 4-(cyanomethyl)-N-(4-fluorophenyl)-4-(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1yl)piperidine-1-carboxamide; (3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-3'-yl)acetonitrile; 4-(3'-(cyanomethyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}-1,3'-biazetidin-1'-yl)-2,5-difluoro-N-[(1S )-2,2,2-trifluoro-1-methylethyl]benzamide; [ 1 -(ethylsulfonyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3yl]acetonitrile; [3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile; 2-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1yl]nicotinonitrile; 4-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1yl]-2,5-difluoro-N-isopropylbenzamide; {3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[3-(trifluoromethyl)pyridin-2yl]azetidin-3-yl}acetonitrile; {3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)-1-[5-(trifluoromethyl)pyridin-2yl]azetidin-3-yl}acetonitrile; 2-chloro-6-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1-yl]benzonitrile; 2-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1yl]benzonitrile; 4-[3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-1yl]benzonitrile; methyl 3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine 1-carboxylate; 3-(cyanomethyl)-N-(2,4-difluorophenyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin1-yl)azetidine-1-carboxamide; N-(3-chloro-2-fluorophenyl)-3-(cyanomethyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide; [1-(3,5-difluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin3-yl]acetonitrile; [ 1 -benzoyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile; [ 1 -(2-fluorobenzoyl)-3 -(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -(3-fluorobenzoyl)-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -(4-fluorobenzoyl)-3 -(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -methyl-3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetonitrile; [3-(4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidin-3-yl]acetic acid; N-methyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3-yl)acetamide and K,K-dimethyl-2-(3-(4-((trans-2-phenylcyclopropylamino)methyl)piperidin-1-yl)azetidin-3-yl)acetamide, or a pharmaceutically acceptable salt of any of the above compounds. 27. The compound according to claim 1, selected from the following compounds: [ 1 -(methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -methyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [3-(4-{[(1S,2R)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [ 1 -(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; 3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide; - 75 042621 3-(cyanomethyl)-N-methyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1sulfonamide; 3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide; [ 1 -methyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid; [ 1 -Ethyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetic acid; 2-[1-(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]N,N-dimethylacetamide; 2-[1-(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]N-methylacetamide; or a pharmaceutically acceptable salt of any of the above compounds. 28. The compound according to claim 1, selected from the following compounds: [1-(1-methyl-1H-pyrazol-4-yl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl] acetonitrile; [ 1 -(2-hydroxyethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -(3-hydroxycyclobutyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]acetonitrile; [ 1 -(cis-4-hydroxycyclohexyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [1-(isothiazol-5-ylcarbonyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin3-yl]acetonitrile; [ 1 -(morpholin-4-ylcarbonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin3-yl]acetonitrile; [ 1 -(trans-4-hydroxycyclohexyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [1-[(1-hydroxycyclopentyl)carbonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl]acetonitrile; [1-[(1-hydroxycyclopropyl)carbonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl]acetonitrile; [1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl ]acetonitrile; [1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl ]acetonitrile; [1-[(1-methyl-1H-pyrazol-5-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl ]acetonitrile; [1-[(3-hydroxyazetidin-1-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1yl)azetidin-3-yl]acetonitrile; [ 1 -[(4-hydroxypiperidin-1-yl)carbonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin1-yl)azetidin-3-yl]acetonitrile; [ 1 -[(4-Methoxypiperidin-1-yl)carbonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidin-3-yl]acetonitrile; [ 1 -[(cis-4-hydroxycyclohexyl)carbonyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin1-yl)azetidin-3-yl]acetonitrile; [1-[(trans-4-hydroxycyclohexyl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(4-hydroxycyclohexyl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)-1-(methylsulfonyl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5-ylcarbonyl)azetidine3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1H-pyrazol-4-ylcarbonyl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrazin-2-ylcarbonyl)azetidin-3yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydrofuran-3-yl)azetidin-3yl]acetonitrile; - 76 042621 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]acetonitrile; 2-(3-(4-((( 1 R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)-1-(tetrahydrofuran-2-carbonyl)azetidin-3-yl)acetonitrile; 2-(3-(cyanomethyl)-3-(4-((( 1 R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)azetidine-1-πλ)-Ν,Νdimethylacetamide; 2-[1-(ethylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]ethanol; 2-[1-(methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]ethanol; 2-[3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]acetamide; 2-[3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1-yl]-N-methylacetamide; 3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}piperidin-1-yl)azetidine-1sulfonamide; 3-[2-(dimethylamino)-2-oxoethyl]-N,N-dimethyl-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1- carboxamide; methyl-3-[2-(dimethylamino)-2-oxoethyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidine-1-carboxylate; methyl-3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidine-1-carboxylate; N,N-dimethyl-2-(1-(methylsulfonyl)-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1yl)azetidin-3-yl)acetamide; N,N-dimethyl-3-[2-(methylamino)-2-oxoethyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-carboxamide ; N-methyl-2-[1-(methylsulfonyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetamide; tetrahydrofuran-3-yl-3-(cyanomethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1 yl)azetidine-1-carboxylate; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1H-pyrazol-5-ylcarbonyl)azetidin-3-yl]acetonitrile; {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3R)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl}acetonitrile; {3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(3S)-tetrahydrofuran-3-ylcarbonyl]azetidin-3-yl}acetonitrile; {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile; {3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyridin-2-ylacetyl)azetidin-3yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4-ylcarbonyl)azetidine3-yl]acetonitrile; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-2-ylcarbonyl)azetidine3-yl]acetonitrile; N,N-dimethyl-2-[3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)azetidine -3-yl]acetamide; N-methyl-2-[3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(tetrahydro-2H-pyran-4yl)azetidin-3-yl ]acetamide; 2-[1-(cyclopropylmethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]-N,N-dimethylacetamide; 2-[1-(cyclopropylmethyl)-3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3yl]-N-methylacetamide; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrimidin-2-ylmethyl)azetidin-3yl]acetic acid; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(pyrimidin-5-ylmethyl)azetidin-3yl]acetic acid; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-4-ylmethyl)azetidin-3yl]acetic acid; [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-5-ylmethyl)azetidin-3yl]acetic acid; - 77 042621 [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(1,3-thiazol-2-ylmethyl)azetidin-3yl]acetic acid and [3-(4-{[(1 R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)-1-(3,3,3-trifluoropropyl)azetidin-3yl]acetic acid, or a pharmaceutically acceptable salt of any of the above compounds. 29. The compound according to claim 1, which is 3-(cyanomethyl)-3-(4-{[(1R,2S)-2phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, or its pharmaceutically acceptable salt. 30. The compound according to claim 1, which is 3-(cyanomethyl)-3-(4-{[(1R,2S)-2phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide. 31. The compound according to claim 1, which is [1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4{[(1R,2S)-2-phenylcyclopropyl]amino}piperidine -1-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof. 32. The compound according to claim 1, which is [1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4{[(1 R,2S)-2-phenylcyclopropyl]amino} piperidin-1-yl)azetidin-3-yl]acetonitrile. 33. The compound according to claim 1, which is 3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2phenylcyclopropyl]amino}piperidin-1-yl)azetidin-1- sulfonamide, or a pharmaceutically acceptable salt thereof. 34. The compound according to claim 1, which is 3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1 - sulfonamide. 35. The compound according to claim 1, which is 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-(4fluorophenyl)cyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide , or a pharmaceutically acceptable salt thereof. 36. The compound according to claim 1, which is 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-(4fluorophenyl)cyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfanilamide . 37. A pharmaceutical composition capable of inhibiting the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 29 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 38. A pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 30 and at least one pharmaceutically acceptable carrier. 39. A pharmaceutical composition capable of inhibiting the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 31 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 40. A pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 32 and at least one pharmaceutically acceptable carrier. 41. A pharmaceutical composition capable of inhibiting the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 33 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 42. A pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 34 and at least one pharmaceutically acceptable carrier. 43. A pharmaceutical composition capable of inhibiting the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to claim 35 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 44. Pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), containing the compound according to claim 36 and at least one pharmaceutically acceptable carrier. 45. A pharmaceutical composition having the ability to inhibit the activity of lysine-specific demethylase-1 (LSD1), containing a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 46. A method for inhibiting LSD1, comprising contacting a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, in vitro with said LSD1. 47. A method of treating a disease, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein said disease is a cancer. 48. The method of claim 47, wherein said cancer is a hematological cancer. 49. The method of claim 48, wherein said hematologic cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) , - 78 042621 diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), myelodysplastic syndrome (MDS) or multiple myeloma. 50. The method of claim 48 wherein the hematologic cancer is recurrent or refractory non-Hodgkin's lymphoma or recurrent follicular non-Hodgkin's lymphoma. 51. The method of claim 48 wherein the hematologic cancer is acute myeloid leukemia. 52. The method of claim 47, wherein said cancer is sarcoma, lung cancer, gastrointestinal cancer, urinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin cancer. 53. The method of claim 47 wherein the cancer is lung cancer. 54. The method of claim 47, wherein the cancer is non-small cell lung cancer, bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, chondromatous hamartoma, or mesothelioma. 55. A method of treating a disease, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein said disease is a viral disease or beta-globinopathy. 56. The method of claim 55 wherein the beta globinopathy is sickle cell anemia. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2