DIARYLALKYLA INE REV-E B ANTAGONISTS AMD THEIR USE AS

MEDICAMENTS"

TECHNICAL FIELD

The present invention relates to novel diarylalkylamine compounds and their use as antiproliferative and pro-apoptotlc agents for cancer therapy.

BACKGROUND ART

Progress in the circadian rhythm field suggests that many key physiological mechanisms are remarkably dependent on the biological clock. It has also become clear that a number of diseases with important unmet medical need display marked circadian variation in their symptoms and severity. Indeed, abnormal functioning of the clock results in severe dysfunctions and pathologies, including cancer. As an example, the circadian organization tends to be lost and possibly replaced with an ultradian periodicity in rapidly growing or advanced stage tumors (Mormont et al . , Int. J. Cancer, 1997; 70: 241-247).

Recent developments in our understanding of circadian biology also indicate that time and duration of dosing may have profound consequences for the efficacy and safety of new and existing therapeutic agents. Indeed, an increasing number of drugs show a circadi.an-dependency of their pharmacodynamics (Paschos et al . , Annu . Re . Pharmacol . Toxicol., 2010 ; 50: 187-214) .

Circadian dosing time appears to influence the extent of toxicity of numerous anticancer drugs , including cytostatics and cytokines, in mice or rats (Paschos et a.2. , Annu. Rev. Pharmacol. To icol . , 2010; 50: 187-214) . For all these drugs, the survival rates are reported to vary by ≥ 50% according to a circadian dosing time of a potentially lethal dose. Such a large difference is observed irrespective of injection route - (intravenous or intraperitoneal) or the number of injections (single or repeated) - (Mormont et al . ,. Cancer, 2003 ; 97: 155-169} .

A remarkable observation reveals that risk for breast cancer is significantly higher in industrialized societies . and the risk increases as developing countries become more westernized (Sahar et al . , Cell Cycle, 2007; 6: 1329-1331) . Incidence of breast cancer increases significantly in women working nightshifts, being higher among individuals who spent more years and hours per week working at night. From a clinical point of view, prognosis of cancer is poorer in patients with altered circadian rhythm compared to patients with normal rhythm (Sahar et al., Ceil Cycle, 2007; 6: 1329-1331) .

In 2007 , the International Agency for Research on Cancer (IARC) classified shift work with circadian disruption or chronodisruption as a probable human carcinogen ' Errer. et al . , Dtsch. Arztebl . Int., 2010; 107 : 657-662) . Interestingly, disruption of circadian endocrine rhythms, either by pinealectomy or through constant light exposure , increases the formation of spontaneous mammary tumors in rodents (Sahar et al . , Ceil Cycle, 2007; 6: 1329- 1331) .

Breast cancer is the second most common type of cancer after lung cancer worldwide and the fi th most common cause of cancer death. It is found more in women as compared to men. Worldwide more than one million new cases of breast cancer are diagnosed every year . New breast cancer cases are mostly found in North America. Breast cancer is usually found in women over the age of 40 years. Breast ca cer cases have risen about 30% in the pas 25 years in western countries like the US and Europe .

Although a continuous perturbation of the circadian rhythm has been proposed as a probable human carcinogen, a surprising observation showed that some alteration of the circadian clock may include beneficial effects. As an example, in mice bearing a deletion of the tumor suppressor p53 the genetic ablation of the two circadian regulators CRYI and CRY2 decreased the development of tumors and increased the survival of the animals (Ozturk et al . , Proc . Natl. Acad. Sci . U. S. A., 2009; 106 : 2841-2846) .

Taken collectively, these observations open up the possibility to identify novel pharmacological targets for cancer treatment among the molecular factors involved in the circadian regulation.

A decade ago, the R.EV-ERB/NR1D subgroup receptors, REV-ERBa (NR1D1) and REV-ΕΚΒβ (NR1D2 ) , was identified as an integral component of the circadian clock machinery (Teboul et al . , J. Appi . Physiol . , 2009; 107 : 1965-1971 ; Ripperger et al., Cell Res . , 2012 ; 22:1319-1321). Both REV-ER.Es receptors lack the classical nuclear receptor AF-2 trans- activating domain and represses gene activity by associating with a co- repressor complex (Ripperger et al . , Cell Res., 2012; 22:1319-1321; Phelan et al . , Nat. Struct. Mol. Biol . , 2010; 17 : 808-814) .

In the presence of the natural ligand (heme) , REV- ERB/co-repressor complex interaction is enhanced and he transcriptional repression of target genes is achieved (Ripperger et al., Cell Res., 2012 ; 22 : 1319-1321) . The selection of the targets is obtained by the binding of the DNA binding domain of REV- ERBs with specific cis-elemen s within the promoter of the genes.

Being historically first discovered, the biological function of REV-ERBa has been the most characterized. Indeed, REV-ERBa has been implicated in the regulation of several processes , including circadian rhythm, adipogenesis , inflammation (Phelan et al . , Nat . Struct. Mol. Biol., 2010; 17: 808-814) .

At the molecular level, several genes , which activity is regulated by REV-ERB , have been reported (Phelan et al. , Nat . Struct. Mol. Biol., 2010; 17 : 808-814) . Notably, in addition to genes involved in the above mentioned processes, REV-ERBa regulated targets also include important cell cycle regulatory genes , such as the Cyclindependent, kinase inhibitor p21 (Cinkla/p21) (Burke et al., Nucleic Acids Research , 1996; 24: 3481-3489; Borgs et al . , Cell Cycle, 2009; 8: 832-837) .

REV-ERBa has been also reported to repress the transcription of genes such as Elovl3 (a very long-chain fatty acid elongase) (Anzulovich et al . , J . Lipid Res., 2006; 47: 2690-2700) and PAT - 1 (Plasminogen Activator Inhibitor 1 , a regulator of the fibrinolytic system and modulator of inflammation, atherothrombosis and atherosclerosis) (Wang et al., J. Biol . Chem. , 2006; 281 : 33842-33848). Because several responses mediated by REV- ERBa feel the influence of the circadian rhythm, it has been postulated that REV-ERBa activity may have the potential to contribute to - or even to control - the crosstalk between circadian and many other physiological processes .

However, due to the modest clock phenotypes of REV- ERBa- deficient mice, REV-ERBa has been proposed to confer robustness to the oscillatory clock rather than being a pacemaker component essential for rhythm generation, such as other circadian regulators (i.e., Email) (Teboul et al . , J. Appl. Physiol., 2009; 107: 1965-1971). This view has been recently challenged by a recent publication that strongly supports a much more prominent role of REV-ERBs receptors in the core clock mechanism than anticipated (Cho et al. , Nature, 2012; 485: 123-127). In fact, the comparative analysis of genome sequences on which REV-ERBa and REV- ΕΚΒ β are recruited revealed an extensive overlap between the cistromes of the two receptors (Cho et al. , Nature, 2012 ; 485: 123 -- 127) . This result suggests that REV- ERBa and REV-ERBp isoforms can compensate each other for the repression of several target genes , including several members of the circadian regulators .

In line with this observation, the generation of liver-specific REV-ERBa/REV-ERBp double-knockout mice ( L - DKO) demonstrated that 90% of the approximately 900 genes rhythmically expressed in the liver of wild-type animals became arrhythmic in the liver of the L-DKO mice (Cho et al., Nature, 2012; 485 : 123-127) .

Nevertheless, some biological responses may depend on the activity of a specific REV-ERBs isoform. Indeed _, , genetic ablation of REV-ERBa or genetic knockdown of REV- ERBa expression have been reported to modulate the production and release of the proinflammatory cytokine IL-6 (Gibbs et al . , Proc . Natl. Acad. Sci . U. S . A., 2012 ; 109 : 582-587) .

A role of REV-ERBa as a survival factor for breast cancer cells with the ErbB2 signature has been also reported (Kourtidis et a.2. , Cancer Research, 2010; 70: 1783-1792 ) . The proto- oncogene ErbB2 (Her2) is overexpressed in about the 30% of breast carcinoma (ErbB2 positive breast tumors ) . REV-ERBa has been reported to be co-overexpressed with ErbB2 , suggesting that this gene may represent novel factor influencing ErbB2 -positive tumors. More importantly, the genetic inhibition o REV-ERBa was able to block the proliferation of ErbB2 positive breast cancer cells (Kourtidis et a.l„, Cancer Research, 2010; 70 : 1783-1792) .

Notably, it has been recently reported that the protein DBC1 (Deleted in Breast Cancer 1) modulates the stability and. function of REV-ERBa ( Chini et al . , The Biochemical Journal, 2013; 51 : 453-461) . DBC1 was originally identified during a genetic search for candidate breast tumor suppressor genes on a human chromosome 8p21 region frequently deleted in breast cancers (Trauernicht et al., Cell Cycle, 2010; 9: 1218-1219) . However, further analyses revealed that DBC1 expression is not substantially lost in cancers from any source. In fact, DBC1 has been found to be upregulated in breast carcinoma versus normal breast tissue and in breast ductal carcinoma versus other cancers (Trauernicht et al . , Cell Cycle, 2010; 9: 1218- 1219) . The fact that DBC1 enhances REV-ERBa protein stability ( Chini et al . , The Biochemical Journal, 2013; 451: 453- 61) reveals an interesting molecular connection between DBC1 and REV-ERBa overexpressinq breast tumors.

Although the molecular mechanism of REV-ERBa mediated growth inhibition of ErbE2 -positive breast cancer cells has not deeply been investigated yet, biological data (Kour idis ev al . , Cancer Research, 2010 70 : 1783-1792 ) support the idea that a pharmacological repression of REV- ERBa activity may be used for breast cancer therapy .

In addition, considering that REV-ERBa and REV-ERB(3 showed a co- recruitment on the promoters of several genes involved in cell cycle regulation, including p21 (Borgs et al., Cell Cycle, 2009; 8: 832-837; Cho et al . , Nature, 2012 ; 485 : 123-127; , the co- repression of both REV-ERBs iscforms may even have more pronounced effects on the proliferation and viability of cancer cells.

The first REV-ERBa ligand, the agonist tertiary amine GSK4112, has been recently identified (Grant et al . , ACS Chemical Biology, 2010; 5: 925-932) . GS 4112 was identified in a FRET assay as capable to dose- dependently increase the interaction of a peptide derived from NCoR (Nuclear receptor Co-Repressor) with REV-ERB« ( Grant et al . , ACS Chemical Biology, 2010 ; 5 : 925-332) . The treatment with GSK4112 decreases BrnaH expression in cell culture in a dose-dependent manner and induces adipogenesis in 3T3-L1 cells as demonstrated by lipid accumulation and increased expression of key adipogenic genes (Koj etin et al .. Current Pharm. Design, 2011; 17 : 320-324) . GSK4112 behaves therefore as a REV-ERBa agonist, regulating the expression of REV-ERBor responsive target genes in a manner similar to the physiological ligand, heme (Ripperger et al. , Cell Res., 2012; 22 : 1319-1321) .

The ligand binding domain (LBD) of REV-ERBa shares a high homology degree with the REV-ERB LBD. Indeed, GSK4112 has been reported to act on both isoforms (Solt et al., Nature, 2012; 485 : 62-68) . GSK 112 displays poor pharmacokinetic properties because of high clearance and rapid metabolism that decrease its bioavailability. (Solt et al., Nature, 2012; 485: 62-68) .

REV- ERE ligands, such as the REV-ERB agonists SR9009, SR9011 and an logs , are known from WO 2013/033310. They are closely related to GSK4112 by sharing a common tertiary amine scaffold and two out of the three substituents at the amine nitrogen, and they are disclosed as useful treatments of malconditions such as diabetes, obesity, atherosclerosis, dyslipidemia and coronary artery disease. Compounds SR9009 and SR9011 have been tested in mice for their possibility to induce metabolic responses iSolt et al . , Nature , 2012 ; 485: 62-68) . These compounds, in addition to influence the circadian clock, were also able to improve he metabolic parameters of diet -induced obese mice . The changes measured on biochemical parameters were also associated to a modified gene expression profile in metabolic tissues such as liver, skeletal muscle and adipose tissue. However, the use of SR9009 and SR9011 to interrogate REV-ERBcx biology is complicated by high metabolic clearance rates that necessitate high dosing to achieve meaningful levels of exposure in vivo (Solt et al . , Nature, 2012 ; 485: 62-68) . Furthermore , the unfavorable DMPR (Drug Metabolism and Pharmacokinetic) profile of GSK4112 , SR9009 and SR9011 renders these compounds unsuitable as truly effective remedies for the clinical treatment of diseases and pathologies associated to the unbalance of the circadian clock .

In addition, the tertiary amines mentioned above have known activity on the nuclear receptor LXRcx, a potential liability for interpretation of results f om cell-based and animal pharmacology (Trump et al . , J. Med. Chem. , 2013; 56 : 4729-4737) . Indeed, further studies demonstrated that GSK4112 also agonizes LXRcx. Notably, SR9009 and SR9011 resulted 100 times more active toward LXRa than REV-ERBs (Trump ez al . , J. Med. Chem. , 2013 ; 56: 4729-4737) . Novel triarylmethylamines related to GSK4112, SR9009 and SR9011 and showing high REV-ERBa agonist potency, selectivity, and bioavailability have been reported (Trump et al . , J. Med . Chem. , 2013 ; 55 : 4729-4737) . Notably, these GS 4112 analogues displayed a much lower effect than GSK4112 on the reduction of LPS-mediated IL-6 transcriptional activation.

WO 2013/045519 claims certain substituted triazolopyridazines as REV-ERB agonists useful for treating any disease wherein the activation of REV-ERB has therapeutic effects, for instance in inflammatory and circadian rhythm- elated disorders or cardi ometabolic diseases .

Finally, certain dibenzylamine derivatives are claimed in WO 2007/065261 as inhibitors of PAI-1 and, as such, claimed to be therapeutically useful , mainly, in several cardiovascular diseases and noninsulin dependent diabetes mellitus .

The only reported REV-ERBa antagonist described in the literature is the 1,2,3,4 tetrahydroisoquinoline derivative SR8278 which, differently from GSK4112, features an amidie nitrogen as the core element, thus shifting away from basic compounds (Koj etin et al., ACS Chem. Biol . , 2011; 6: 131- 134). SR8278 is described as a REV-ERBa antagonist based on its ability to inhibit REV-ERBa LBD/NcoR interaction in a FRET-based assay and to induce the expression of two REV-

ERBa target genes in cultured cells (Kojetin et al . , ACS Chem. Biol., 2011; 6: 131-134) . These results suggest that SR8278 acts with a molecular mechanism similar to GS 4112 , i.e. REV-ERB/NCOR association, but with an opposite outcome. Also SR8278, as mentioned by its disclosers, displayed poor pharmacokinetic properties limiting its pharmacological uses (Kojetin et al . , ACS Chem. Biol . , 2011; 6 : 131-134) .

There is thus the need in the art to find new REV-ERB antagonists .

DISCLOSURE OF INVENTION

The aim of the present invention is to provide novel compounds having anti -proliferative and pro-apoptotic activity for their use in cancer therapy, part icularly in a breast cancer with the ErbB2 -signature and in liver and colon cancers , independent ly from the expression of the tumor suppressor p53 (i.e. tumors expressing a wild-type or mutated p53 protein, and tumors in which p53 expression is ablated) .

The aforementioned objective has been met according to compounds of claim 1 , tc a pharmaceutical composition of claim 10 , to the uses of claims 11 , 12 and 13. Preferred embodiments are set out within the dependent claims.

The following paragraphs provide definitions of the various chemical moieties of the compounds according to the invention and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

The term "alkyl" , as used herein, refers to saturated or unsaturated aliphatic hydrocarbon groups . Such term includes straight (unbranched) chains or branched chains. It includes alkenyl groups or alkynyl groups.

Non- limiting examples of alkyl groups according to the invention are, for example, methyl , ethyl, propyl , isopropyl, n-butyl, iso-butyl , tert-butyl, n-pentyl , iso- pentyl, n-hexyi , ethenyl , 1 -propenyl , 2 -propenyl , 1 - or 2- butenyl , ethynyl , 1-propynyl, 2 -propyny1 , 1- or 2-butynyl, and the like .

Alkyl groups according to the present invention may be unsubstituted or substituted by one or more substituents .

The term "cycloalkyl", as used herein, refers to a saturated or partially unsaturated carbocyclic group having a single ring. It includes cycloalkenyl groups .

Non- limiting examples of cycloalkyl groups according to the invention are , for example, cyclopropane, cyclobutane , cycl.openta.ne , cyclohexane, cycloheptane , cyclopentene , cyclohexene, cyclohexadiene and the like .

Cycloalkyl groups according to the present invention may be unsubstituted or substituted by one or more substituents .

The term "heteroalkyl" , as used herein, refers to an alkyl group , as defined above , that is linked to the remainder of the compound via an heteroatom. Heteroalkyl groups can be unsubstituted or substituted by one or more substituents .

As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatom typically is meant to include oxygen (O) , nitrogen (N) , and sulphur (S) .

The term "alkoxy" , as used herein, refers to an alkyl group that is linked to the remainder of the compound by an oxygen atom.

The term "heterocycloalkyl" group, ("non-aromatic heterocycle " group) , refers to a cycloalkyl group (non aromatic group) that wherein at least one of the carbon atoms has been replaced by a heteroatom selected from nitrogen, oxygen and sulfur . Heterocycloalkyl groups can be unsubstituted or substituted.

Examples of heterocycloalkyls include, but are not limited to , lactams, lactones, cyclic imides , cyclic thioimides , cyclic carbamates, 1- ( 1 , 2 , 5 , 6 - tetrahydropyridyl) , tetrahydrothiopyran, K-pyra , tetrahydropyran, piperidine ( 2 -piperidinyl , 3- piperidinyl) , 1 , 3 -dioxin, 1,3-dioxane, 1 , 4 -dioxin , 1,4- dioxane, piperazine, 1,3- oxa hiane , 1,4- oxathiin, 1,4- oxathiane, tetrahydro-1, - thiazine, 2H-1, 2-oxazine, morpholine (4-morpholinyl, 3 -raorpholin 1 ) trioxane, hexahydro- 1 , 3 , 5- triazine , tetrahydrothiophene , tetrahydrofuran ( tetrahydrofuran- 2 -yl , tetrahydrofuran- 3- yl) , pyrroline, pyrrolidine, pyrrol idone , pyrrolidione , pyrazolone, pyrazolidine , imidazoline, imidazolidine , 1 , 3 dioxole, 1 , 3 -dioxolane , 1 , 3 -dithiole , 1 , 3 -dithiolane , isoxazoline, isoxazolidine , oxazoline, oxazolidine, oxazolidinone, thiazoline , thiazolidine , and 1,3- oxathiolane .

The term "halogen", as used herein, refers to fluorine, chlorine , bromine and iodine .

The term "aryl", as used herein, refers to a hydrocarbon consisting of a unsubstituted or substituted mono-, bi- or tricarbocyclic ing system, wherein the rings are fused together and at leas one of the carbocyclic ring is aromatic. The term "aryl" means for example a cyclic aromatic such as a 6 -membered. hydrocarbon ring , a two six- membered fused hydrocarbon rings . Non- limiting examples of aryl groups are, for example , phenyl , alpha- or beta- aphthyl , 9 , 10 -dihydroanthracenyl , indanyl , fluorenyl and the like . Aryl grou s according to the present invention may be unsubstituted or substituted by one or more substituents .

The term "heteroaryl " , as used herein, refers to an aryl as defined above wherein one to four carbon atoms are independently replaced by heteroatoms chosen from the group consisting of nitrogen, oxygen and sulphur . Non- limiting examples of heteroaryl groups are , for example, pyrrolyl, furyl, thiophenyl , imidazolyl , pyrazolyl, oxazolyl, isoxazoiyl , thiazolyl, isothiazolyl , indolyl , benzofuranyl , benzothiophenyl , benzimidazolyl , benzopyrazclyl , benzoxazolyl , benzoisoxazolyl , benzothiazolyl , benzoisothiazolyl , triazolyi, oxadiazolyl, tetrazolyl, pyridyl , pyrazinyl, pyrirnidinyl, pyridazinyl, quinolinyl, isoquinolinyl , quinazolinyl , quinoxalinyl . Heteroaryl groups according to the present invention may be unsubstituted or substituted by one or more substituents .

The term "aromatic ring", as used herein, refers to a moiety wherein the constituent carbon atoms make up an unsaturated ring system, all atoms in the ring system are sp ² hybridized and the total number of n-electrons is equal to 4n+2 , wherein n is an integer .

The term "heteroaromatic ring", as used herein, refers to an "aromatic ring'' as defined above wherein one or more carbon atoms are independently replaced by heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur .

Unless otherwise indicated, the term "substituted", as used herein, means that one or more hydrogen atoms of the above mentioned groups are replaced with another non- hydrogen atom or functional group, provided that normal valencies are maintained and that the substitution results in a stable compound . Hon- limiting example of substitution are , for example, alkyl , substituted alkyl , aryl , substituted aryl , arylalkyl , alkoxy, cycloalkyloxy, arylox , arylalkyloxy, hydroxy , heteroaryl , heteroaryloxy, heterocyclylox , trifluoromethyl , trifluoromethoxy , carboxy, acyl , aroyl , heteroaroyl, halogen, nitro, cyano , alkoxycarbonyl , aryloxycarbonyl , aralky1oxycarbony1 , eyeloalkyloxycarbony1 , heteroaryloxycarbonyl , acyloxy , alkylthio, arylthio, alkylsulfinyl , arylsulfinyl , alkylsulfonyl , arylsulfonyl , -0- aroyl , -O-heteroaroyl , oxo (=0), -C ( =0) -NR ^h R ^k , and -NR ^p R ^q , wherein each of R ^h , R ^k , R ^p , and R ⁹ independently represents hydrogen, unsubstituted or substituted alkyl , unsubstituted or substituted cycloalkyl , unsubstituted or substituted aryl , unsubstituted or substituted arylalkyl , unsubstituted or substituted heteroaryl , unsubstituted or substituted heterocyclyl , acyl , aroyl, heteroaroyl, and when R ^h and R ^k , or R ^p and R ^q are taken together with the nitrogen atom to which they are bound, the group -NR ^h R ^k or the group NR ^p R ^q represent a heterocyclyl residue and wherein the terms alkyl , cycloalkyl , aryl , heteroaryl , heterocyclyl are as above defined. The term "pharmaceutically acceptable salts" refers to salts of the below identified compounds of Formula (I) that retain the desired biological activity and are accepted by regula ory authorities.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base and internally formed salts. Typically, such salts have a physiologically acceptable anion or cation.

Furthermore , the compounds of Formula (I) may form an acid addition salt or a salt with a base, depending on the kind of the substituents , and these salts are included in the present invention, as long as they are pharmaceutically acceptable salts.

Examples of such salts include, but are not restricted to acid addi ion sal s formed with inorganic acids (e . q . hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid , nitric acid, and the like) , and salts formed with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, male ic acid, ascorbic acid, benzoic acid, alginic acid, polyglutamic acid and naphthalene sulfonic acid. The hydrochloric salt is preferred .

Physiologically or pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound.

Pharmaceutically acceptable salts may also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of Formula (I) using conventional methods .

The terms ""derivative" and "derivatives" refer to each of the compounds of Formula (I) and are meant to include their pharmaceutically acceptable hydrates , solvates, crystalline forms , isotopi cally- labelled derivatives, tautomers, geometrical or optical isomers , stereoisomers, pharmaceutically active derivatives and also any suitable forms as illustrated hereinafter.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known a s "solvates". For example, a complex with water i s known a s a "hydrate". Solvates of the compounds of the invention are within the scope of the invention . The compounds of Formula (I) may readily be isolated in association with solvent molecules by crystallization or evaporation of an appropriate solvent to give the corresponding solvates.

The compounds of Formula (I) may be in crystalline form. In, certain embodiments, the crystalline forms of the compounds of Formula (I) are polymorphs.

The subject invention also includes isotopicaliy- labelled compounds , which are identical to those recited in Formula (I) and following, but differ for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature . Examples of isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, "C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ 1 , ¹²⁵ I.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention . Isotopically- labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated, are useful in drug and/ or substrate tissue distribution assays . Tritiated, i.e. ³ H, and carbon- 14, i.e. ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability . ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (Positron Emission Tomography) , and ¹²⁼ I isotopes are particularly useful in SPECT (Single Photon Emission Computerized Tomography) , all useful in brain imaging. Furthermore , substitution with heavier isotopes such as deuterium, i.e. ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half - life or reduced dosage, requirements and , hence , may be preferred in some circumstances. Isotopically- labelled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by replacing a non- isotopically- labelled reagent with a readily available isotopically- labelled reagent.

Certain groups/ substituents included in the present invention may be present as isomers or in one or more tautomeric forms. Accordingly, in certain embodiments , the compounds of Formula (I) may exist in the form of other tautomers or geometrical isomers in some cases, depending o the kinds of the substituents. In the present specification, the compounds may be described in only one form of such isomers, but the present invention includes all such isomers, isolated forms of the isomers, or a mixture thereof. Furthermore, the compounds of Formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases and, correspondingly, it may exist in the form of optical isomers such as an (R) -form, an (S) -form, and the like. The present invention includes within the scope all such isomers, including racemates, enantiomers and mixtures thereof.

I particular, within the scope of the present invention are included all stereoisomeric forms , including enantiomers, diastereoisomers , and mixtures thereof , including racemates and the general reference to the compounds of Formula (I) includes all the stereoisomeric forms , unless otherwise indicated .

In general , the compounds Its of the invention should be interpreted as excluding those compounds (if any) which are so chemically unstable , either per se or in wa er , that they are clearly unsuitable for pharmaceutical use through all administration routes, whether oral, parenteral, or otherwise. Such compounds are known to the skilled chemist.

The term "pharmaceutically active derivative" refers to any compound derived from the compounds of Formula (I) that upon administration to the recipient, is capable f providing directly or indirectly, t e activity disclosed herein.

The present invention also encompasses active metabolites of compounds of Formula ( I) .

According to a first aspect of the invention, compounds of Formula (I)

or pharmaceutically acceptable salts or solvates thereof are provided.

In the compounds of Formula (I) :

Ar and Ar ' are independently selected f om the group consisting of a 5- to 10 -membered aromatic or heteroaromatic single or fused rings comprising up to 3 heteroatoms selected f om N, O, S ;

R is selected from the group consisting of hydrogen, a l near or branched unsubstituted or substituted Ci _. _ ₆ alkyl and an unsubstituted or substituted aryl C _1-6 alkyl;

i, R ₂ , R ₃ and R ₄ are independently selected from the group consisting of H, halogen, linear or branched, unsubstituted or substituted Ci_ ₆ alkyl , C^g alkoxy, hydroxy Cx-6 alkyl, OH, CN, fluoro C _1-6 alkyl , fluoro Ci-ε alkoxy; R _lf R _2/ 3 and R ₄ can be attached to any position of Ar and Ar' grou , respectively; Y is selected from the group consisting of N or CH;

X is selected from the group consisting of CH or N;

R ₅ and R ₆ are independently selected from the group consisting of H, halogen, unsubstituted or substituted linear or branched C _1-e alkyl, =0, unsubstituted or substituted aryl , unsubstituted or substituted aryl Ci- 6 alkyl, hydroxy Ci- ₆ alkyl, Ci_ _e alkylCO , unsubstituted or substituted arylCO, unsubstituted or substituted aryl Ci- ₆ alkylCO, C00R ₇ , CONR ₈ R ₉ , SO ₂ Ri ₀ wherein R ₇ R ₈ , R _s and R ₁₀ are independently selected from the group consisting of hydrogen, linear or branched. Ci_ ₆ alkyl ; R ₅ and R ₆ can be. attached to any carbon atom of the ring to which they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring; and

En is selected from the group consisting of H, linear or branched Ci_ ₆ alkyl, Ci- ₆ alkylCO , aryl, aryl C _x ^ ₆ alkyl; or R ₅ and R ₆ , or R ₅ and R- _Xl or R _s and R ₁ are linked together to form an unsubstituted or substituted 4- to 10 - membered ring, saturated or unsaturated, and containing up to two nitrogen atoms;

q and p are , independently, 0 or an integer from 1 to 2 with the proviso that when both Y and X are N, neither q and p are 0 ;

R ₁₂ and R ₁₃ are independently selected from the group consisting of H, F, Ci_ ₆ alkyl , C _1-s alkyl-OH, =0, OH, COOH, C0 ₂ Me, CONH ₂ , CONHMe , CONMe ₂ and can be attached to any position of the ring to which, they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring ;

W is selected from the group consisting of a bond and a heteroatom selected from the group consisting of 0, S and NR ₁₄ , wherein R ₁₄ is selected from the group consisting of H, linear or branched C _1-6 alkyl , C _1-6 alkylCO, unsubstituted or substituted aryl , unsubstituted or substituted aryl Ci _-6 alkyl , unsubstituted or substituted arylCO , S0 ₂ Ri ₅ , CONRi ₆ R ₁₇ , COORie, wherein R ₁₅ , R ₁₆ , R ₁₇ and R ₁₈ are independently selected from the group consisting of H, linear or branched C _1-6 alkyl;

m is an integer from 1 to 3 , n is 0 or an integer from 1 to 3 with the proviso that when W is bond, n is not 0 ; provided that the compound of Formula (I) is not

4 - [ [ [1- (4 -methoxypheny1) cyclopentyl] amino] methyl] - 2 - [ (4 -methyl- 1-piperazinyl) methyl] -phenol ;

4- [ [ [1- (2-fluorophenyl) cyclopentyl] amino] methyl] -2- [ (4 -methyl -1-piperazinyl) methyl] -phenol and

4 - [ [ [1 - ( 2 -methoxypheny1) cyclopentyl] amino] methyl] - 2- [ (4 -methyl- 1-piperazinyl) methyl] -phenol.

Preferably, Ar and Ar ' are, independently, selected from benzene, pyridine, naphthalene , thiophene rings;

R is selected from the group consisting of H, CH ₃ , unsubstituted or substituted phenylCK-. ;

Ri, , R ₃ and R ₄ are independently selected from the group consisting of H, F, CI, CH ₃ , OH, 0CH ₃ , CH ₂ 0H, CF ₃ , CHF ₂ , CH ₂ F, CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF _3f CN;

R ₅ and R ₆ are independently selected from the group consisting of H, F, CH ₃ , =0 , unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl , unsubstituted or substituted phenylC¾ , CH ₂ 0H, CH ₃ C0, unsubstituted or substituted phenylCO, unsubstituted or substituted phenylCH ₂ CO, COOR ₇ , CONR ₈ R ₉ , SO ₂ R ₁₀ wherein R ₇ , R ₈ , R _s and R _ie are independently selected from the group consisting f H and CH ₃ ;

Rii is selected from the group consisting of K, CH ₃ , Et, ί-Pr , henylCi-6 alkyl, CH ₃ C0, phenyl ;

or R ₅ and R ₆ , or R ₅ and R _u or R ₆ and Rj.i are linked together to form a ring an thus the moiety

has a meaning selected from the group consisting of

p and q are , independently, 0 or 1 ;

Ri2 and R _i3 are independently selected from the group consisting of H, F, CH ₃ , CH ₂ OH, OH, =0, and they are connected to the same carbon atom or to different carbon atoms of the ring;

W is selected from the group consisting of a bond and a heteroatom selected from the group consisting of 0 and NRi , wherein R ₁₄ is H, CH ₃ , C0CH ₃ , unsubstituted or substituted phenyl, unsubstituted or substituted phenyl CH ₂ , unsubstituted or substituted phenylCO, S0 ₂ Ri5 , CONRi ₆ i7, COORis, wherein R ₁₅ , Ri ₆ , R- ₇ and R ₁₈ are independently selected from the group consisting of H and CH ₃ ; more preferably W is selected from the group consisting of a bond, O, NH, NCH ₃ , NCOCH ₃ ; NCH ₂ phenyl ;

m is an integer from 1 to 3, and n is an integer from 1 to 2.

According to a first embodiment of the above aspect, the compounds of the invention can have the following Formula (I' ) :

d ' )

wherein Ar , Ar ' , R, R _lt R ₂ , R ₃ , ₄ RB» Rg» Rii, Ri2» 12,

Y , W, n , m, p and q are as defined above.

In particular, according to this embodiment:

Ar and Ar' are , independently, selected from benzene, pyridine, naphthalene, thiophene rings ;

R is selected from the group consisting of K and CH ₃ ; Ri and R ₃ are independently selected from the group consisting of H, F, CH ₃ , 0CH ₃ , OH, CF ₃ , CN; R ₂ and R are , independently, H, F;

p and q are equal to 1 , m is an integer from 1 to 2 , n is an integer from 1 to 2 ;

Ei2 and Ri ₃ are independently selected from the group consis ing of H, F, CH ₃ , CH ₂ 0H, =0, OH, and they are connected to the same carbon atom or to different carbon atoms of the ring;

W is a bond or O, NH, NCH ₃ , NC0CH ₃ , NC¾phenyl;

Y is selected from the group consisting of N and CH;

R _s and Rs are independently selected from the group consisting of H, F , CH ₃ , =0, phenyl , pyridyl, phenylCH; , CH ₂ 0H, CH ₃ C0 , COOH;

R11 is selected f om the group consisting of H, CH ₃ , Et , i - Pr, phenylCH ₂ , CH ₃ CO , phenyl , pheny (CH ₂ ) ₂ ;

or R ₅ and R ₆ , R≥ and Rn or R ₆ and R _; are linked together to form an unsubstituted or substituted 4- to 10- membered ring wherein the moiety :

has a meaning selected from the group consisting

In particular, the moiety:

has a meaning selected from the group consisting of:

According to a second embodiment of the above aspect, the compounds of the invention can have the following Formula (I' ' ) :

⁽ I " ⁾ wherein Ar , Ar ' , R, R _lf R ₂ , R ₃ , R ₄ , R ₅ - ₆ » In, ₁₂ , R ₁₃ ,

Y, W, n, m, p and q are as defined above .

In particular, according to this embodiment :

Ar and Ax ' are, independently, selected from benzene, pyridine, naphthalene, thiopherie rings, in particular Ar and Ar' are benzene ;

R is H and CH ₃ ;

Ri and ¾ are independently selected from the group consisting of H, F, CH ₃ , OCH ₃ , OH, CF ₃ ;

2 and R ₄ are both H ;

p and q are equal to 1 , m is an integer from 1 to 2 , n is an integer from I to 2 ;

Ri2 and R ₁₃ are independently selected from the group consisting of H, F, CH ₃ , CH ₂ 0H, =0, OH, or R ₁₂ and R ₁₃ are connected to the same carbon atom and have both the same meaning selected from F and CH ₃ ;

W is a bond or 0, H , NCH ₃ , NCOCH ₃ ; NCH ₂ phenyl ;

Y is N or CH;

R ₅ and R ₆ are independently selected from the group consisting of H, F, CH ₃ , =0, phenyl, pyridyl, phenyl.CH ₂ , CH ₂ 0H, CH ₃ C0, COOH;

Ria is selected from the group consisting of H, CH ₃ , Et, i-Pr, phenylCH ₂ , CH ₃ C0, phenyl ;

or R ₅ and R ₆ , R ₅ and R _X1 or R _s and En are linked together to form an unsubstituted or substituted 4- to 10- membered ring wherein the moiety :

has a meaning selected from the group consisting

In particular, the moiety :

has a meaning selected from the group consisting

According to a urther embodiment of the above aspect , the compounds of Formula (I) can be selected from the group consisting of:

4 - [ [ [1- ( 2 - fluorophenyl ) cyclopentyl] amino] methyl] -2 - (1- piperidylmethyl ) phenol dihydrochloride ;

- [ [ [1- (2- fluorophenyl) cyclohexyl] amino] methyl] -2- [ (4 - methyipiperazin - 1 -yl ) methyl] phenol trihydrochloride;

1- ( 2 - fluorophenyl ) - - [ [3- [ (4 -methylpiperazin-1- yl) methyl] phenyl] methyl] cyclopentanamine trihydrochloride ;

1- (2-fluorophenyl) -N- [ [4 -methoxy- 3- [ (4 - methyipiperazin- 1-yl ) methyl] henyl] methyl] cyclopentanamine trihydrochloride ;

4- [ [ [1- ( 2 - fluorophenyl ) cyclopentyl] -methyl- amino] methyl] - 2 - [ (4 -methyipiperazin- 1-yl) methyl] henol trihydrochloride ;

2 - [ (4 -methylpiperazin-l-yl) methyl] -4- [ [ (1- phenylcyclopentyl) amino] methyl] phenol trihydrochloi ^_ ide ;

1- [4- [ [5- [ [ [1- ( 2 - fluorophenyl ) cyclopentyl] amino] methyl] - 2 -hydroxyphenyl] methyl] piperazin- 1-yl] ethanone dihydrochloride ;

4 - [ [ [1- (2 -fluorophenyl) cyclopentyl] amino] methyl] - 2 - [ (4 -phenylpiperazin- 1-yl ) methyl] henol trihydrochloride ;

2- [ (4 -ethylpiperazin-l-yl ) methyl] -4 - [ [ [1- (2- fluorophenyl) cyclopentyl] amino] methyl] phenol

trihydrochloride ;

4- [ [ [1- ( 2 - f luoropheny1 ) cyclopentyl] amino] methyl] -2- (piperazin-l-ylmethyl) phenol ;

2- [ (4 -benzylpiperazin-l-yl) methyl] -4 - [ [ [1- (2 - fluorophenyl) cyclopentyl] amino] methyl] phenol

trihydrochloride ;

4 - [ t [1- (2 -fluorophenyl) cyclopentyl] amino] methyl] -2 ~ [ ( -isopropylpiperazin-l-yl) methyl] henol trihydrochloride;

4- [ [ [1- ( 2 - f luoropheny1 ) tetrahydropyran-4 - yl] amino] methyl] -2- [ (4 -methylpiperazin-l -yl) methyl] phenol trihydrochloride ;

4 - ( 2 - f luoropheny1 ) -4 - [ [4 -hydroxy- 3- [ (4 -methylpiperazin -1-yl) methyl] phenyl] methylamino] cyclohexanone

trihydrochloride ;

4 - [ [ [ , 4 -difluoro-1 - ( 2 -fluorophenyl ) cyclohexyl] aminoj methyl] -2- [ (4 -methyl-piperazin-l-yl) methyl] phenol

trihydrochlorid ;

1- ( 2 - f luoropheny1 ) -N- [ [3- [ (1 -methyl -4 -piperidyl) methyl] phenyl] methyl] eye 1open ana i e dihydrochloride ;

1- (2-f luoropheny1) -N-methyl-N- [ [3 - [ (1 -methyl -4 - piperidyl) methyl] phenyl] methyl ] cyclopentanamine dihydrochloride ;

4- [ [ [1 -benzyl- 4 - ( 2 -fluorophenyl) -4 -piperidyl] amino] methyl] - 2 - t (4 -methylpiperazin- 1-yl ) methyl] phenol

e ranydroc loride ;

4 - [ [ [1- ( 2 , 4 -difluorophenyl) cyclopentyl] amino] methyl] - 2- t (4-methylpiperazin-l-yl) methyl] phenol trihydrochloride

4- t [ [1- ( 3 - fluorophenyl ) cyclopentyl] amino] methyl] -2 - [ (4-methylpiperazin-l-yl) methyl] phenol trihydrochloride ;

4 - [ [ [1- (4 -fluorophenyl) cyclopentyl] amino] methyl] -2 -

[ (4 -methylpiperazin- 1-yl ) methyl] henol trihydrochloride ;

2 - [ (4 -methylpiperazin-l-yl) methyl] -4 - [ [ [1- (3 - thienyl ) cyclopentyl] amino] methyl] henol trihydrochloride .

The following compounds may be also synthesized with the same method used for the compounds above:

2- [ [ [1- (2- fluorophenyl) cyclohexyl] amino] methyl] - 6- [ (4 - methylpiperazin- 1-yl ) methyl] phenol ;

1- ( 2 - fluorophenyl ) -N- [ [2- [ (4 -methylpiperazin-:. -yl) methyl] -4-pyridyl] methyl] cyclohexanamine ;

4- [ [ [1- (2 -fluorophenyl) cyclohexyl] mino] methyl] - 2 - [ (5- methyl-2 , 5 -diazabicyclo [2.2.2] octan-2 -yl) methyl] phenol ;

4- [ [ [1- (2 -fluorophenyl) cyclohexyl] amino] methyl] - 2 - [ (4- methyl-2 , 3 -dihydroquinoxalin-l-yl) methyl] phenol ;

2 - (1,3,4,6,7,8,9, 9a-octahydropyrido [1 , 2 -a] pyra in- 2 - ylmethyl) -4- [ [ [1- (2- fluorophenyl) cyclohexyl] amino] methyl] henol ;

4 - [ [ [1- (2 -fluorophenyl) cyclohexyl] mino] methyl] -2- [ (9- methyl-3 , 9 -diazabicyclo [3.3.1] nonan-3-yl) methyl] phenol ;

4- [ [ [1- ( 2 - fluorophenyl ) cyclohexyl] amino] methyl] - 2 - [ (8- methyl-3 , 8 -diazabicyclo [3.2.1] octan- 3 -yl ) methyl] phenol ;

4- [ [ [1- (3 , 5-difluorophenyl) cyclopentyl] amino] methyl] - 2 - [ (4 -methylpiperazin-l-yl) methyl] phenol ;

4- [ [ [1- (3~fluoro-2-naphthyl) cyclohexyl] amino] methyl] - 2- [ (4 -methylpiperazin- 1-yl) methyl] phenol ;

4 - [ [ [1- ί 2 - f luorophenyl ) cyclohexyl] amino] methyl] - 3 - [ (4- methylpiperaz in- 1-yl) methyl] phenol ;

2- [ [ [1- (2 -fluorophenyl) cyclohexyl] amino] methyl] -4 - [ (4 - methylpiperazin-l-yl) methyl] phenol ;

4- [ [ [1- ( 2 -hydroxyphenyl ) cyclohexyl] amino] methyl] -2 - [ (4-methylpiperazin~l-yl)methyl] phenol ;

4- [ [ [1- ( 2 - fluorophenyl ) -4 -methyl-cyclohexyl] amino] methyl] -2- [ (4 -methylpiperazin- 1-yl) methyl] phenol ;

4 - [ [ [1- (2 -fluorophenyl) -4- (hydroxymethyl) cyclohexyl] amino] methyl] -2- [ (4 -methylpiperazin-l-yl ) methyl] phenol ;

4- [ [ [1- ( 2 - fluorophenyl ) -4 -hydroxy-cyclohexyl] amino] methyl] -2- [ (4 -methylpiperazin- 1-yl) methyl] phenol ;

1- ( 2 - fluorophenyl) -N - [ [3- [ ( l-phenethyl-4 - piperidyl) methyl] henyl] methyl] eyelohexanamine ;

4 - [ [ [1- ( 2 - fluorophenyl ) -4 -hydroxy-4 -methyl -cyclohexyl] amino] methyl] -2- [ ( 4 -methylpiperazin-l-yl ) methyl] phenol ; 4- [ [ [1- (2-fluorophenyl) -4 , -dimethyl-cyclohexyl] amino] me hyl] -2- [ ( -methylpiperazin- 1-yl ) methyl] henol ;

4 - [ [5 - t f [1- (2 -fluorophenyl) cyclohexyl] amino] methyl] -2- hydroxy-phenyl ] methyl] -l-methyl-piperidine-2-carboxylic acid;

1- ( 2 - fluorophenyl ) -N- [ [3- [ ( l-methyl-4 -piperidyl) methyl] henyl] methyl] eyelohexanamine ;

1- ( 3 - fluorophenyl ) -N- [ [3- [ ( 1 -methyl- 4- piperidyl ) me hyl ] phenyl] methyl] cyclopentanamine ;

N- [ [3 - [ (l~benzyl-4-piperidyl)methyl] henyl] methyl] -1-

( 2 - f luorophenyl ) eyelohexanamine ;

1- (2-fluorophenyl) -N- [ [3- [ ( 1 -methyl -3 , 4 -dihydro-2H- guinolin-4 -yl) methyl] phenyl ] methyl] eyelohexanamine ;

N- [ f3 - ( eyelohexylmethyl) phenyl] methyl] -1- (2- fluorophenyl) eye lohexanamine ;

1- ί 2 - fluorophenyl } -N- [ [3- [ ( 4 -methylcyclohexyl ) methyl] phenyl] methyl] eyelohexanamine .

The compounds exemplified in this invention may be prepared, from readily availa le starting materials using the following general methods and procedures for example exemplified in Michael Smith, Jerry March - March's Advanced Organic Chemistry: reactions mechanisms and structure - 6th Edition, John Wiley & Sons Inc. , 2007.

It is well known to one of ordinary skill in the art that transformation of a chemical f nction into another may require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent de -protection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in Theodora W. Green and Peter G.M. Wuts - Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons Inc., 2006.

It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time , moles of reagents, solven s etc . ) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.

The synthesis of a compound of Formula (I) , according to the synthetic processes described below, can be conducted in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques such as, for example , column chromatography, before carrying out the subsequent reaction. Alternatively, two or more s e s of the synthetic sequence can be carried out in a so-called "one-pot" procedure, as known in the art , whereby only the compound resulting from the two or more steps is isolated and purified.

The compounds of Formula (I) , prepared with the methods described herein below, may be treated or purified by conventional techniques or means for example by filtration, d stillation, chromatography, recrystailization and combination thereof.

The salts of compounds of Formula (I) may be prepared by reaching a basic compound with the desired acid in solution .

General procedures

In one embodiment, a compound of Formula (I) can be obtained by application of the chemical transformations reported in the schemes herein described.

According to Scheme 1 , compounds of Formula (I) , wherein R is H and R _lf R ₂ , R _3i 4 , i2» R:s, R ₅ , R ₆ , Rn, Ar , Ar' , X, Y, W, n , m, p and q are as defined in Formula (I) above , named compounds of Formula la, can be prepared by reductive amination reaction of aldehydes of Formula II wherein R ₃ , R ₄ , R _s , R ₆ , Ri- , Ar' , X, Y, p and q are as defined in Formula (I ) above with amines of Formula ill wherein R _:L , R ₂ , R12, R13, Ar , Vf, n and m are as defined in Formula (I ) in the presence of reducing agent, such as sodium triacetoxyborohydride (NaBH (OAc) ₃ ) and using a moderately polar aprotic solvent, such as dichloromethane (DCM) . Scheme 1

la

According to Scheme 2, compounds of Formula (I) , wherein R is different from H, and ¾, R ₂ , R ₃ , R ₄ , R _ii: R _13/ R ₅ , R ₆ , Rii, Ar , Ax' , X, Y , W, n , m, p and q are as defined in Formula (I) above , named compounds of Formula lb, can be prepared by reductive amination reaction of compounds of Formula la with aldehydes of Formula IV where R' is H, C _x - ₅ alkyl or aryl Ci- ₅ alkyl .

Scheme 2

NaBH(OAc} ₃ , DCM

reductive amination

ib

Alternatively, according to Scheme 3, compounds of Formula Ib can be prepared by "one-pot" procedure, consisting of reductive amination reaction of aldehydes of Formula II (or IV, where R' is H, C _1-E alkyl or aryl C _1-5 alkyl) with amines of Formula III i the presence of a reducing agent, such as NaBH(0Ac) ₃ and using modera ely polar aprotic solvent, such as DCM until to complete transformation of the starting materials, followed by the add tion of the appropriate aldehydes of Formula IV (or II) , where R' is H, C ₁ -5 alkyl or aryl Ci _-5 alkyl .

Scheme 3

lb

Synthesis of compounds of Formula (II)

According to Scheme 4, compounds of Formula II , wherein Y is N and at least one of R ₃ and R _{4 /} is OH or OMe and R ₅ , R _6f Rii , Ar ' , X , p and q are as defined in Formula ( I ) above, named compounds of Formula I la , can be prepared by Mannich reaction of aldehydes of Formula Va with amines of Formula VI in presence of formaldehyde (HCHO) . The reaction is preferably conducted in polar solvent, such as e hane1 (EtOH) or moderately polar aprotic solvent as DCM, at temperatures ranging from 45 °C to 80 °C for 12 h. Scheme 4

l!a

According to Scheme 5, compounds of Formula II , wherein Y is N and both R ₃ and R ₄ are different from OH or OMe and R ₅ , R ₆ , Rn, Ar' , X, p and q, are as defined in Formula (I) above, named compounds of Formula lib , can be prepared in. a three steps procedure which consists of : 1) reductive amination reaction of a1ky1carboxylate- arylaldehydes (preferably methylcarboxylate- aryla Idehydes or ethy1carboxy1ate - ary1 1dehydes ) of Formula Vb with amines of Formula VI in the presence of a reducing agen , such as, NaBH (OAc) ₃ in moderately polar aprotic solvent, such as DCM; 2 ) reduction reaction of alkylcarboxylates (preferably methylearboxy1ates o ethylcarboxylates ) of Formula lib ' in the presence of a reducing agent, such as lithium aluminum hydride (LiAlH ₄ ) ; and 3 ) oxidation of the primary alcohols of Formula lib' ' to aldehydes of Formula lib using oxidizing agents, such as manganese dioxide (Mn0 ₂ ) in apolar aprotic solvent, such as diethyl ether (Et ₂ 0) .

S

lib" lib

According to Scheme 6 , compounds of Formula II , wherein Y is CH and R ₃ , R ₄ , R ₅ , R ₆ , Ru, Ar' , X, q and p are as defined in Formula (I) above , named compounds of Formula lie , can be prepared in a five steps procedure which consists of : 1) preparation of triphenyIphospheni m salts of Formula lie' by treatment of compound of Formula VII where Z is Br, or I , with triphenylphosphine in aprotic solvent as toluene; 2 ) olefination reaction of compounds of Formula lie' with ketones of Formula VIII in the presence of bases such as LHMDS at room temperature in apolar aprotic solvent such as tetrahydrofurane (THF) ; 3) hydrogenation reaction of compounds of Formula lie' ' in the presence of palladium/ carbon (Pd/C) and triethylsilane (Et ₃ SiH) in polar solvent such as methanol (MeOH) ; 4 ) reduction reaction of alkylcarboxyiat.es (preferably methylcarboxylates or ethylcarboxylates } of Formula lie''' in the presence of a reducing agent, such as LiAlH ₄ ; and 5) oxidation of primary alcohols of Formula lie' ' ' ' in aldehydes o Formula lie using oxidizing agents, such as manganese dioxide (Mn0 ₂ ) in apolar aprotic solvent , such as Et ₂ 0.

Scheme 6

Synthesis of compounds of Formula (III)

According to Scheme 7 (Method A) , compounds of Formula

III , wherein W is a bond , R ₁₂ and ₁₃ is H and R _lf R ₂ , Ar, n and m, are as defined in Formula (I) above, named compounds of Formula Ilia , can be prepared following a standard synthetic procedure reported in Balderman et al . , Synthesis, 1978; 24 - 26 , , which consists of: 1) nucieophilic addition of the corresponding organolithium or Grignard derivatives of arylhalides of Formula IX, where Z is Br or I, to ketones of Formula Xa; 2 ) treatment of arylcycloalkanols of Formula Ilia' with sodium azide (NaN ₃ ) in the presence of trifluoroacetic acid (TFA) in DCM at low temperature from -20°C to 5°C, preferably at 0 °C; and 3) reduction of azides of Formula Ilia' ' by using LiAlH ₄ in aprotic polar solvent such as THF.

Scheme 7

Method A

Ilia' lila

ethod C

IX O lllc'

lllc" lllc

According to Scheme 7 (Method B) , compounds of Formula III , wherein W is a bond or O and R ₁₂ and R _i? is different from H and ¾, R ₂ , Ar , n and m are as defined in Formula (I ) above , named compounds of Formula Illb, can be prepared following standard synthetic procedure reported in McMahon et al., Org. Lett., 2004 ; 6: 1645-1647 ; Ellmann et al . , Acc . Chem . Res., 2002; 35: 984-995, which consists in: 1) nucleophilic addition of the corresponding organolithium or Grignard derivatives of arylhalides of Formula IX, where Z is I, or Br, to terc -butyl su ^' i f inyl ketimines of Formula Xb and 2 ) treatment of sulfanamide of Formula Illb' under acidic conditions, such as HC1 solution in MeOH .

According to Scheme 7 (Method C) , compounds of Formula III , wherein W is a bond or N and R ₁₂ , R13 , Ri, R ₂ , Ar , n and m are as defined in Formula (I ) above, named compounds of Formula IIIc , can be prepared following a standard synthetic procedure reported in de Koning et al . , Org. Process . Dev., 2011 ; 15: 1256-1265; Content at al . , Org . Process. Dev., 2013 ; 17 : 193-201, which consists of: 1) nucleophilic addition of the corresponding organolithium or Grignard derivates of arylhalides of Formula IX, where Z is I , or Br , to ketones of Formula Xc ; 2) treatment of eyeloa1kanoIs of Formula IIIc ' with chloroacetonitrile in the presence of strong acid such as sulfuric acid. (H ₂ S0 ) or TFA and 3 ) chloroace amide cleavage of compounds of Formula IIIc' ' by using thiourea under acidic conditions , as for example acetic acid (CH ₃ C0 ₂ H) in a polar solvent such as MeOH .

According to Scheme 8 , compounds of Formula Xb wherein W, Ri ₂ , Ri ₂ , n and m are as defined in Formula (I ) above, can be prepared by condensation of tert-butanesulfinamide with cyclic ketones of Formula Xa , employing titanium (IV) isopropoxide [Ti (OiPr) ₄ ] in THF at room temperature (McMahon et al . , Org. Lett., 2004 ; 6: 1645-1647 ; Ellmann et a . , Acc . Chem. Res., 2002 ; 35: 984-995) .

Scheme

Xa Xb

Compounds of Formula IV , Va , Vb , VI, VII , VIII , IX , Xa and Xc are known compounds or can be easily prepared from known compounds by known methods .

A second aspect of the present invention is related to a pharmaceutical composition comprising a compound of Formula (I) as disclosed above, included 4- [ [ f 1- (4 - methoxyphenyl) cvclopentyl] amino] methyl] -2- [ (4 -methyl - 1 - piperazinyl) methyl] -phenol , 4 - [ [ [1- (2 - fluoropheny1 ) cyclopentyl] amino] methyl] -2- [ (4 -methyl -1- iperazinyl) methyl] -phenol and 4 - [ [ [1- (2 -methoxyphenyl) cyclopentyl] amino] methyl] -2- [ ( 4 -methyl - 1 -piperazinyl ) methyl] -phenol and a pharmaceutically acceptable carrier, stabilizer, diluent or excipient thereof.

A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.

The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be laced into he form of pharmace tical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same , all for oral use, or in the form of sterile injectable solutions for parenteral administration ( including subcutaneous and intravenous use) . Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions , with or without additional active compounds or principles , and such uni dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be em loyed.

Pharmaceutical compositions containing a compound of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like .

The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral , rectal, transdermal, subcutaneous, intravenous, intramuscular, intranasal and pulmonary routes. The compositions for oral administration can take the form of bulk liquid solu ions or suspensions, or bulk powders. More commonly, however, the. compositions are presented in unit dosage forms to facilitate accurate dosing . The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals , each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre- filled, pre-measured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants , flavours and the like. Solid forms may include , for example, any of the following ingredients , or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring .

Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other inj ectable carriers known in the art .

The pharmaceutical compositions may be in the form of tablets, pills, capsules, solutions , suspensions, emulsion, powders, suppository and as sustained release formulations .

If desired, tablets may be coated by standard aqueous or non-aqueous techniques. In certain embodiments, such compositions and preparations can contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course , be varied and may conveniently be between about 1 percent to about SO percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that therapeutically active dosage will be obtained. The active compounds can also be administered intranasally as , for example, liquid drops or spray .

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of t e above type , a liquid carrier such as a fatty oil . Various other materials may be present as coatings or to modify the physical form of the dosage unit . For instance , tablets may be coated with shellac, sugar or both . A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent , methyl and propylparabens as preservatives, a dye and a flavoring agent such as cherry or orange flavor . To prevent breakdown during transit through the upper portion of the gastrointestinal tract, the composition be an enteric coated formulation.

Compositions for topical administration include, but are not limited to, ointments, creams, lotions , solutions , pastes, gels , sticks, liposomes, nanoparticles , patches, bandages and wound dressings. In certain embodiments , the topical formulation comprises a penetration enhancer .

Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound of Formula (I) or a salt thereof , and the powder of a suitable carrier ana/or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powde inhaler device known to a person skilled in the art.

Administration of the compositions is performed under a protocol and at a dosage sufficient to reduce the inflammation and pain in the subject. In some embodiments, in the pharmaceutical compositions of the present invention the active principle or active principles are generally formulated in dosage units. The dosage unit may contain from 0.1 to 1000 mg of a compound of Formula (I) per dosage unit for daily administration.

In some embodiments . the amounts effective for topical formulation will depend on the severity of the disease, disorder or condition, previous therapy, the individual's health status and response to the drug . In some embodiments, the dose is in the range from 0.001% by weight to about 60% by weight of the formulation.

When used in combination with one or more other active ingredients , the compound of the present invention and the other active ingredient may be used in lower doses than when each is used singly.

With respect to formulations with respect to any variety of routes of■ administration, methods and formulations for the administration of drugs are disclosed in Remington ' s Pharmaceutical Sciences, 17 ^th Edi ion, Gennaro et al. Eds., Mack Publishing Co., 1985, and Remington' s Pharmaceutical Sciences, Gennaro AR ed. 20 ^th Edition, 2000 , Williams & Wilkins PA, USA, and Remington: The Science and Practice of Pharmacy, 21 ^st Edition, Lippincott Williams & Wilkins Eds. , 2005; and in Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8 ^th Edition, Lippincott Williams & Wilkins Eds., 2005.

The above described components for orally administered or injectable compositions are merely representative.

The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.

Moreover, the pharmaceutical compositions according to the invention may comprise a second therapeutic agent, for exam le known anticancer agents for which cancer cells develop resistance to the treatment.

A third aspect of the present invention is related to the use of compounds of Formula (I) as disclosed above, included 4 - [ [ [1- ( 4 -methoxypheny1 ) cyclopentyl] amino] methyl] - 2- [ ( -methyl -1-piperazinyl) methyl] -phenol, 4 ~ [ [ [1- (2- f luorophenyl) cyclopentyl] amino] methyl] - 2 - [ (4 -methyl- 1- piperazinyl) methyl] -phenol and 4- [ [ [1- ( 2 -methoxyphen 1 ) cyclopentyl] amino] methyl] -2- [ ( 4 -methyl -1-piperazinyl ) methyl] -phenol or the pharmaceutical composition thereof , or their pharmaceutically acceptable salts or solvates as a medicament .

In parti ular the medicament is suitable for modulating REV-EREs activity in a subject. According to this aspect, compounds of Formula (I) are suitable for the use in the treatment of pathologies associated with dysfunction of circadian rhythm and with benefi from an inhibition of REV-ERBs activity in tissues/cells with a chronodisruption .

Moreover, the compounds of Formula (I) and their pharmaceutical compositions are suitable for use in the treatment of cancers in which a modified circadian pattern of gene/protein expression occurs, in particular of Erb-E2 positive cancers , more particularly selected from the group consisting of breast cancer, ovary cancer, colon cancer, liver cancer, central nervous system cancer, kidney cancer pancreas cancer and prostate cancer. Preferred Erb-B2 cancer is Erb-B2 positive breast cancer.

Moreover, the compounds of Formula (I) and their pharmaceutical compositions are suitable for use in the treatment of cancers with deletion o mutation of the tumor suppressor p53 gene.

In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention .

The following abbreviations are hereinafter used in the accompanying examples :

Acetic acid (AcOH) , acetonitrile (MeC ) , ammonia (NH ₃ ) , ammonium chloride (NH ₄ C1 ) , n-butyl lithium (n-BuLi) , chloroform (CHC1 ₃ ) , cyclohexane (Cy) , diatomaceous earth (Celite) , deuterated chl oform (CDC1 ₃ ) , deuterated dimethylsulfoxide (DMSO- d ₆ ) , deuterium oxide (D ₂ 0) , dichloromethane (DCM) , diethyl ether (Et ₂ 0) , electrospray (ES) , dimethylsulfoxide (DMSO) , ethanol (EtOH) , ethyl aceta e (EtOAc) , formaldehyde (HCHO) , hydrochloric acid (HC1) , lithium aluminium hydride (LiAlH ₄ ) , lithium hexame hyldisilazane (LHMDS) , manganese dioxide (Mn0 ₂ ) , mass spectrometry (MS) , methanol (MeOH) , monopotassium phosphate (KH ₂ P0 ) , nuclear magnetic resonance (NMR) , palladium on carbon (Pd/C), potassium carbonate ( ₂ C0 ₃ ) , retention time (Rt) , room temperature (rt) , tetrahydrofuran (THF) , sodium bicarbonate (NaHC0 ₃ ) , sodium hydroxide (NaOH) , sodium sulphate (Na ₂ S0 ₄ ) , sodium triacetoxyborohydride (NaBH (OAc) ₃ ) , sulfuric acid (H ₂ S0 ₄ ) , titanium tetraisopropoxide (Ti ( iOPr) ) , thin layer chromatography

(TLC) , triethylamine ( Et ₃ N) , trifluoroacetic acid (TFA) . Chemicals , materials and methods Solvents and reagents were obtained from commercial suppliers and were used without further purification. Automated column chromatography purifications were run using a Teledyne ISCO apparatus (CombiFlash° Rf ) with pre- packed silica gel columns of different sizes (from 4 g up to 24 g) . Flash column chromatography was performed manually on pre-packed silica cartridges (from 2 g up to 10 g) from Biotage . I both cases, mixtures of increasing polarity of Cy and EtOAc or DCM and MeOH were used as eluents . Preparative TLCs were performed using Macherey- agel pre-coated 0.05 mm TLC plates (SIL G-50 UV254) . NMR experiments were run on a Bruker Avance III 400 system (400.13 MHz for ¾, and 100.62 MHz for ¹³ C) , equipped with a BBI probe and Z -gradients . Spectra were acquired at 300 K, using deuterated dimethylsulfoxide (DMS0~d ₆ ) , deuterated chloroform (CDCl ₃ ) as solvents. Chemical shifts (δ) for ¹ H and ¹³ C spectra are reported in parts per million (ppm) using the residual non-deuterated solvent resonance as the internal standard (for CDC1 ₃ : 7.26 ppm, ¹ H and 77.16 ppm, ¹³ C; for D ₂ 0: 4.79 ppm, ¾; for DMSO-d ₆ : 2.50 ppm , ¾; 39.52 ppm, ¹³ C) . Data are reported as follows: chemical shift (sorted in descending order) , multiplicity (indicated as: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet,- p, pentet; m, multiplet and combinations thereof), coupling cons ants (J) in Hertz ( Hz ) and integration. UPLC- MS analyses were run on a Waters ACQUITY UPLC - MS system consisting of a SQD (Single Quadropole Detector) Mass Spectrometer equipped with an Electrospray Ionization interface and a Photodiode Array Detector. PDA range was 210-400 nm. Electrospray ionization in positive and negative mode was applied. UPLC mobile phases were : (A) 10 mM N¾0Ac in H ₂ 0, pH 5 ; (B) 10 mM H.OAc in MeCN/¾0 (95:5) pH 5. Analyses were performed with method A below reported. Method A- UPLC (generic) : Gradient: 5 to 95% B over 3 min. Flow rate 0.5 mL/min. Temperature 40 °C. Pre. column: Vanguard BEH C18 (1.7 μτ 2.1x5 mm) . Column: BEH CIS (1.7μπι 2.1x50mm) . Purifications by preparative HPLC/MS were run on a Waters Autopuri f i cat i on system consisting of a 3100 Single Quadropole Mass Spectrometer equipped with an Electrospray Ionization interface and a 2998 Photodiode Array Detector. HPLC system included a 2747 Sample Manager, 2545 Binary Gradient Module , System Fluidic Organizer and 515 HPLC Pump . PDA range was 210-400 nm. Purifications were performed on a XBridgeTM Prep d ₈ OBD column (100xl9mmID, particle size 5/im) with a XBridgeTM Prep C18 (10xl9mmID, particle size 5μχα) Guard Cartridge. Mobile phases were lOmM NH ₄ OAc in H ₂ 0 at. pH 5 adjusted with AcOH (A) and lOmM NH ₄ OAc in MeCN/H ₂ 0 (95:5) at pH 5.0 ( B ) . Electrospray ionization in positive and negative mode was used.

With the aim of better illustrating the present invention, the syntheses of example compounds reported in Tables 1 and 17 are provided.

The compounds reported in Tables 1 and 17 were synthesized as described below.

General Procedure for the synthesis of the amines of

Formula Ilia (Scheme 7, Method A)

Step 2

To a solution of IX (1.0 equiv. ) in anhydrous THF (0.2

M) at -78 °C under argon atmosphere, a solution of n-BuLi (1.0 equiv., 2.5 M in hexanes) was added dropwise. The reaction mixture was stirred for 1 h at the same temperature, and then 1.0 equi . of Xa was added dropwise. Stirring was continued until the disappearance of the starting material was noted by TLC analysis. The reaction mixture was then quenched with saturated aqueous NH C1 solution and extracted with DCM. The organic layer was washed with brine and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the residue of Ilia' was used in the next step without further purification.

Step 2

To a solution of Ilia' (1.0 equiv . ) in anhydrous DCM (0.4 M) sodium azide (2.2 equiv . ) at rt under nitrogen atmosphere was added . The suspension was cooled at - 5 °C and then a 1:2 mixture of TFA: DCM (8.4 equiv . of TFA) was added dropwise under vigorous stirring over a period of 15 min . The resulting suspension was stirred at 0 °C for additional 1 h . To the cold solution distilled water was then added dropwise , followed by the addition of a mixture of distilled water and aqueous 28% NH ₄ 0H solution (1:1) dropwise (5.0 mL) . After 30 min, the reaction mixture was extracted with DCM, and the organic layer was washed with water, 1.0 N KH ₂ P0 ₄ solution, brine and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the crude of Ilia' ' was purified by column chromatography eluting with Cy (100%) .

Step 3

To a solution of Ilia' ' (1.0 equi . ) in anhydrous THF (0.3 M) LiAlH ₄ (1.05 equiv., 2.0 M solution in THF) at 0 °C under nitrogen atmosphere was added. The reaction mixture was stirred at rt for 3 h, and then quenched with 1.0 N NaOH . The reaction mixture was then portioned between Et ₂ 0 and 1.0 N HC1 solution. The aqueous layer was collected and basified with 28% NH OH solution up to pH 8.0, and then extracted with DCM . After evaporation of the solvent , the residue of Ilia was used in the next step without further purification.

General Procedure for the synthesis of amines of Formula IIlb (Scheme 7, Method B)

Step 1

To a solution of IX (1.1 equiv . ) in anhydrous THF (0.2 M) at -78 °C under argon atmosphere, a solution of n-3uLi (1.0 equiv . , 2.5 M in exanes) was added drop ise. The reaction mixture was stirred for 1 h at the same temperature, and then a solution of Xb (1.0 equiv. ) in anhydrous THF (1.0 M) was added. The reaction mixture was stirred at -78 °C for 1 h and then allowed to warm to room temperature. Stirring was cont inued until the disappearance of the s arting material was noted by TLC analysis. The reaction mixture was then quenched with saturated aqueous NH ₄ C1 solution and extracted with DCM . The organic layer was washed with brine and dried over Na ₂ S0 ₄ . After evaporation of the solvent , the crude of Illb' was purified by column chromatography eluting with gradient mixture of DCM/ eOH or EtOAc,/MeOH .

Step 2

To a stirred solution of Illb' (1.0 equiv . ) in anhydrous MeOH (1.0 M) 4.0 M HC1 in dioxane (4.0 equiv . ) was added. The reaction mixture was stirred a rt for 45 min, and then diluted with EtOAc (5.0 mL) . The organic layer was washed with 1.0 N NaOH (5.0 mL) , brine and dried over Ka ₂ S0 ₄ . After evaporation of the solvent, the residue of Illb was used in the next step without further purification .

General Procedure for the synthesis of amines of

Formula IIIc (Scheme 7, Method C)

Step 2 To a solution of IX (1.1 equiv. ) in anhydrous THF (0.2 M) at -78 °C under argon atmosphere, a solution of n-BuLi (1.0 equiv., 2.5 M in hexanes) was added dropwise. The reaction mixture was stirred for 1 h at the same temperature, and then 1.0 equiv. of Xc was added dropwise. The reac ion mixture was stirred at -78 °C for 1 h and then allowed to warm to rt . Stirring was continued until the disappearance of the starting material was noted by TLC analysis . The reaction mixture was then quenched with saturated aqueous NH ₄ C1 solution and extracted with DCM. The organic layer was washed with brine and dried over Na ₂ S0 ₄ . After evaporation of the solvent , the residue of II Ic ' was used in the next s ep without further purification.

St ep 2

To a mixture of II Ic ' (1.0 equiv. ) and chloroacetonitrile (3.5 equiv . ) AcOH (1.0 mL) was added, followed by the addition of ¾S0 ₄ (1.0 mL) . The reaction mixture was stirred at rt overnight and then diluted with EtOAc (4.0 mL) , washed with saturated aqueous NH ₄ C1 solution and water and dried over Na ₂ S0 ₄ . After evaporation of th solvent, the crude of II I c ' ' was purified by column chromatography elut ng with gradient mixture of solvent DCM/MeOH.

Step 3 To a solution of IIIc' ' (1.0 equiv. ) in EtOK (0.13 M) thiourea (1.1 equiv.) and AcOH (6.0 equiv.) were added . The reaction mixture was heated at 80 °C overnight and then cooled at rt, diluted with EtOAc (4.0 ml), washed with 1.0 M NaOH solution (2.0 mL) and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the residue of IIIc was used in the next step without further purification.

General Procedure for t e synthesis of aldehydes of Formula Ila (Scheme 4)

A mixture of Va (1.0 equiv.), VI (1.0 equiv.) and HCKO

(1.0 equi . , 36% solution in water) in EtOH (0.8 M) was heated at reflux for 2 h, then an additional amount of HCHO (1.0 equiv.) was added . The reaction mixture was stirred at reflux overnight. After evaporation of the solvent, the crude of Ila was purified by column chromatography eluting with gradient mixture of DCM/MeOH or EtOAc/MeOH.

General Procedure for the synthesis of aldehydes of Formula lib (Scheme 5)

Step 2

To a solution of Vb (1.0 equiv.) and VI (1.0 equi . ) in anhydrous DCM (0.4 M) , NaBH ( OAc ) ₃ (2.0 equi . ) was added at rt and the resulting suspension was stirred at room temperature overnight . The reaction mixture was extracted with DCM (10.0 mL) , washed with aqueous 10% K ₂ C0 ₃ solution and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the residue of lib' was used in the next step without further purification.

Step 2

To a solution of lib' (1.0 equiv. ) in anhydrous THF (0.2 M) LiAlH ₄ was carefully added (1.05 equiv. , 2.0 M solution in THF) at rt under nitrogen atmosphere. Stirring was continued for 1.5 h at room temperature un il the disappearance of the starting material was noted by TLC analysis. The reaction mixture was then quenched with water with the formation of precipitate. The reaction mixture was carefully quenched by the addition of 2.0 M HC1 (5.0 mL) and then extracted with DC (3 x 10.0 mL) . After evaporation of the solvent, the residue of lib' ' was used in the next step without furt er purification.

Step 3

To a solution of lib' ' (1.0 equiv. ) in Et ₂ 0 (0.22 M) , activated Mn0 ₂ (6.4 equiv.) was added. The reaction mixture was stirred at rt overnight and then filtered through a pad of Celite and washed with DCM (3 x 15.0 mL) . After evaporation of the solvent, the residue of lib was used in the next step without further purification.

General Procedure for the synthesis of aldehydes of Formula lie (Scheme 6)

Step 1

To a stirred solution of compound VII (1.0 equiv.) in dry toluene (0.2 M) triphenylphosphine (1.0 equiv . ) was added. The resulting mixture reaction was s irred at 120 °C overnight, after which time a white precipitate had formed. The reaction was cooled at rt and then was collected the solid by filtration. The solid was washed with minimum amount of cold toluene to afford the compound lie' as white solid, which was used in the next step without furt er purification,

Step 2

To a solution of lie' (1.0 equiv.) in anhydrous THF

(0.16 M) at -78 °C under argon atmosphere, a solution of LHMDS {5.0 equiv. , 1.0 M in THF) was added dropwise. The reaction mixture was stirred for 15 min at the same temperature, and then 1.0 equiv . of VIII was added dropwise. The mixture reaction was stirred at rt for 3h. Then the solvent was evaporated under reduce pressure and the residue was dissolved in DCM (6.0 mL) and was washed twice with water. The resulted organic phase was dried over Na _: ,S0.: . After evaporation of the solvent, the crude of lie' ' was purified by column chromatography e luting with gradient mixture of solvent Cy/EtOAc .

Step 3

To a stirred suspension of ie'' (1.0 equiv.) and 10% Pd-C (0.1 equiv.) in MeOH (0.05 M) neat triethylsilane (10.0 equi . ) was added dropwise by he use of a pressure- equalizing dropping funnel under nitrogen atmosphere. After 15 min, the reaction mixture was filtered through a pad of Celite and the solvent was removed under reduce pressure affording the intermediate lie' ' ' which was used in the next step without futher purification.

Step 4

To a solution of lie''' (1.0 equiv.) in anhydrous THF (0.2 M) LiAlH ₄ was carefully added (1.05 equiv. , 2.0 M solution in THF) at rt under nitrogen atmosphere. Stirring was continued for 1.5 h at rt until the disappearance of the starting material was noted by TLC analysis. The reaction mixture was then quenched with water with the formation of precipitate. The reaction mixture was carefully quenched by the addition of 2.0 M HC1 (5.0 mL) and then extracted with DC (3 x 10.0 mL) . After evaporation of the solvent, the residue of lie' ' ' ' was used in the next step without further purification.

Step 5

To a solution of lie' ' ' ' (1.0 equiv. ) in Et ₂ 0 (0.22 M) , activated Mn0 ₂ (6.4 equiv. ) was added . The reaction mixture was stirred at rt overnight and then filtered through a pad of Celite and washed with DCM (3 x 15.0 mL) . After evaporation of the solvent, the residue of lib was used in the next step without further purification.

General Procedure for the synthesis of N- tert- butylsulfinyl ketimines of Formula Xb (Scheme 8)

To a solution of Xa (1.2 equiv . ) in THF (0.5 M) Ti (OiPr) 4 (2.0 equiv.) is added under nitrogen atmosphere followed by the addition of tert-butanesulfinamide (1.0 equiv . ) . The reaction mixture was stirred for 2 h , poured into a saturated aqueous NaHC0 ₃ solution (4.0 mL) under vigorous stirring and then immediately filtered through a pad of Celite and washed with EtOAc. The two phases are separated and the aqueous layer is extracted with EtOAc (3 x 8.0 mL) . The combined organic layer is cried over Na ₂ S0 ₄ . After evaporation of the solvent , the crude of Xb was purified by column chromatography eluting with gradient mixture of DCM/MeOH and stored into a container at -20 °C until further use .

General Procedure for the synthesis of amines of

Formula la (Scheme 1)

A mixture of II (1.0 equiv.) and III (1.0 equi . ) in anhydrous DCM (0.06 M) was s irred for 10 min at rt and then NaBH (OAc) ₃ (2.0 equiv.) was added. Stirring was continued at rt overnight. The reaction mixture was diluted with DCM (4.0 mL) _; washed with aqueous 10% K ₂ C0 ₃ solution and dried over Na ₂ S0 ₄ . After evaporation of the solvent, the crude of la was purified by column chromatography eluting with gradient mixture of DCM/MeOH, DCM/MeOH/E1 ₃ N , DCM/MeOH/NH ₃ or Cy/EtOAc . General Procedure for the synthesis of amines of

Formula lb (Scheme 3)

A mixture of II (1.0 equiv . ) and III (1.0 equiv. ) in anhydrous DCM (0.06 M} was stirred for 10 min at rt and then NaBH (OAc) ₃ (2.0 equiv. ) was added. Stirring was continued overnight at rt, then IV (1.1 equiv. ) was added followed by an additional amount. of NaBH (OAc) ₃ (2.0 equiv.) . Stirring was continued unti1 the disappearance of the starting material was noted by TLC analysis. The reaction mixture was then quenched with aqueous 10%- K ₂ C0 ₃ solution and the two phases were separated. The organic layer was dried over Na ₂ S0 ₄ . After evaporation of the solvent , the crude of lb was purified by column chromatography e luting with DCM/MeOH.

Tables of intermediates of Formula Ilia (Scheme 7,

Method A)

Alcohol intermediates of Formula Ilia' (Scheme 7, Method A, step 1) and their physico-chemical properties are described in Tables 2 and 18.

Aziae intermediates of Formula. Ilia' ' (Scheme 7,

Method A, step 2 ) and their physico-chemical properties are described in Tables 3 and 19.

Amine intermediates of Formula Ilia (Scheme 7 , Method A, step 3) ana their physico-chemical properties are described in Tables 4 and 20 (INTERMEDIATE 1, 2, 3, 19, 20, 21, 22, 23, 24)

Tables of intermediates of Formula Illb (Scheme 7,

Method B)

tert-Butylsulfinamide intermediates of Formula Illb' (Scheme 7, Method B , s ep 1 ) and their physico-chemical properties are described in Table 5.

Amine intermediates of Formula Illb (Scheme 7 , Method B , s ep 2 ) and thei physico-chemical properties are described in Table 6 ( INTERMEDIATE 4, 5, 6) .

Tables of intermediates of Formula ITib (Scheme 7,

Method C)

Chloroacetamid.es intermediates of Formula IIIc' (Scheme 7, Method C, step 1) arid their physico-chemical properties are described in Table 7.

Amine intermediates of formula IIIc (Scheme 6, Me hod

C, step 2 ) and their physico-chemical properties are described in Table 8 { INTERMEDIATE 7 ) .

Preparation of 4 - Hydroxy - 3 - ^" ( 4 -methylpiperazir.- 1 - yl) methyl] benzaldehyde (Intermediate 8, scheme 4 )

Intermediate 8 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxybenzaldehyde (1.0 g, 8. IS mmol) , IV-meth l piperazine (664.0 L, 8.19 mmol) and HCHO (1.8 mL, 16.34 mmol) in EtOH (10.0 mL) . The crude was purified by column chromatography (DCM/ 20% MeOH in DCM, from 100:0 up to 50:50) to afford the title compound as a white solid (1.1 g, 57%) . UPLC- S (method generic) Rt 1.14. min; MS (ES) Ci ₃ H ₁₈ N ₂ 0 ₂ requires m/z 234, found 235 [M+H] ⁺ . ¾ NMR (400 MHz , DMSO-d _fi ) δ 9.79 (s, 1H) , 7.73 - 7.61 (m, 2H) , 6.95 - 6.85 (m, 1H) , 3.71 (s , 2H) , 2.45 - 2.26 (bs, 8H) , 2.18 (s, 3H) .

Preparation of 4 -Hydroxy- 3- (l-piperidylmethyl )_

benzaldehyde (Intermediate )

Intermediate 9 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxybenzaldehyde (500.0 mg, 4.09 mmol) , piperidine (404.0 /iL, 4.09 mmol) and HCHO (678.0 μΐ., 8.19 mmol) in EtOH (6.0 mL) . The crude was purified by column chromatography (Cy/EtOAc, 95: 15 to 30: 70 ) to afford the title compound as colorless oil (600.0 mg, 67%) . UPLC-MS (method generic) Rt 1.75 min, MS (ES) C ₁₃ H ₁₇ N0 ₂ requires m/z 219, found 220 [M+H] ⁺ . ¹ H-NMR (400 MHz, CDC1 ₃ ) δ 9.82 (s, 1H) , 7.70 (dd, J = 8.4, 2.1 Hz , 1H) , 7.56 (dt, J = 1.9, 0.9 Hz, 1H) , 6.91 (d, J = 8.3 Hz, 1H) , 3.77 (s, 2H) , 2.57 (bs, 5H) , 1.82 - 1.27 (m, 5H) .

Preparation of 3 - [ (4 -Acetylpiperazin-l-yl) methyl] -4 -

Intermediate 10 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxvbenzaldehyde (250.0 mg, 2.05 mmol) , .W-acetyl piperazine (315.0 mg, 2.46 mmol) and HCHO (340.0 μΐ,, 4.10 mmol) in 5.0 mL of EtOH. The crude mixture was purified by column chromatography (DCM/MeOH (20% in DCM) , from 100:0 up to 50:50) to afford the title compound as a colorless oil (140.0 mg, 26%) . UPLC-MS (method generic) Rt 1.27 min, MS (ES) Ci ₄ Hi _{8 2} 0 ₃ requires m/z 262, found 263 [M+H] ⁺ . ¹ H MR (400 MHz , DMSO~d ₆ ) δ 9.80 (s, 1H) , 7.75 (d, J = 2.1 Hz, 1H) , 7..70 (dd, J = 8.3, 2.1 Hz, 1H) , 6.96 (d, J = 8.3 Hz, 1H) , 3.67 (s, 2H) , 3.63 - 2.90 (m, 8H) , 1.99 (s, 3H) .

Preparation of 4 -Hydroxy-3 - [ (4 -phenylpiperazin-1- yl) methyl] benzaldehyde (Intermediate 11, scheme 4.)

Intermediate 11 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxybenzaldehyde (2.05 mmol, 250.0 mg) , iV-phenyl piperazine (2.46 mmol , 375.0 μΐ,} and HCHO (4.10 mmol, 340.0 μΐι) in 5.0 mL of DCM. The crude mixture was purified by column chromatography (EtOAc/MeOH gradient 100:0 up to 95:5) to afford the title compound as colorless oil (500.0 mg, 82%) . UPLC-MS (method generic) Rt 2.42 min, MS (ES) Ci ₈ H ₂₀ N ₂ O ₂ requires m/z 296, found 297 [M+H] ⁺ . ¾ N R (400 MHz, DMSO-d ₆ ) δ 9.B1 (s, 1H) , 7.76 (d, J - 2.1 Hz, 1H) , 7.71 (dd, J = 8.3, 2.1 Hz, 1H) , 7.22 (t, J = 7.8 Hz, 2H) , 6.95 (dd, J = 8.3, 5.5 Hz, 3H) , 6.79 (t, J = 7.2 Hz, 1H) , 3.75 (ε , 2H) , 3.18 (t, J 4.9 Hz, 4H) , 2.64 (t, J = 4.9 Hz, 4H) .

Preparation of 3- [ ( -Ethylpiperazin-l-yl) methyl] -4- hydroxy-benzaldehyde (Intermediate 12, scheme 4)

Intermediate 12 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxybenzaldehyde (2.05 mmol, 250.0 mg) , JV- ethyl piperazine (2.46 mmol, 316.0 /xL) and HCHO (4.10 mmol, 340.0 L) in 5.0 mL of EtOH. The crude mixture was purified by column chromatography (EtOAc/MeOH gradient 100:0 up to 85:15) to afford the title compound as a white solid (265.0 mg, 52%) . UPLC-MS (method generic) Rt 1.14 min, MS (ES) C ₁₄ H ₂₀ N ₂ O ₂ requires m/z 248 , found 297 [M+H] . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H) , 7.70 (d, J = 2.2 Hz , 1H) , 7.68 (m, 2H) , 6.95 - 6.82 (m, 1H) , 3.71 (s, 2H) , 3.65 - 3.02 (bs, 8H) , 2.45 - 2.15 (q, J = 7.2 Hz, 2H) , 0.99 (t , J = 7.2 Hz, 3H) .

Preparation of tert-Butyl 4- [ (5- formyl- 2 -hydroxy- phenyl) methyl] piperazine-l-carboxylate (Intermediate 1.3 , scheme 4 )

Intermediate 13 was prepared according to the general procedure for the synthesis of aldehydes of Formula I la using 4-hydroxybenzaldehyde (2.05 mmol, 250.0 mg) , W-Boc piperazine (2.46 mmol, 457.0 mg) and HCHO (4.10 mmol, 340.0 pL) in 5.0 mL of EtOH . The crude mixture was purified by column chromatography (Cy/EtOAc gradient 95:5 up to 50:50) to afford the title compound as a white solid (453.0 mg, 70%) . UPLC-MS (method generic) Rt 2.37 min, MS (ES) Ci ₇ H ₂₄ N ₂ 0 ₄ requires m/z 320, found m/z 320 [M] ⁺ . ^X H MR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H) , 7.79 - 7.75 (m, 1H) , 7.75 - 7.66 (m, 1H) , 7.02 - 6.80 (m, 2H) , 3.65 (s, 2H) , 3.50 - 3.15 (bm, 4 H) , 3.35 (t, J = 5.1 Hz, 2H) , 2.41 (t, J = 5.1 Hz, 2H) , 1.40 (d, J = 1.8 Hz, 9H) .

Preparation of 3- [ (4-Benzylpiperazin-l-yl) methyl ] - 4- hyd oxy-benzaldehyde ( intermediate 14 , scheme )

Intermediate 14 was prepared according to the general procedure for the synthesis of aldehydes of Formula I la using 4-hydroxybenzaldehyde (1.18 mmol , 144.0 mg) , N-benzyl piperazine (1.41 mmol, 250.0 mg) and HCHO (2.36 mmol, 196.0 μΐΐ) in 5.0 niL of EtOH . The crude mixture was purified by column chromatography (Cy/EtOAc gradient 95:5 up to 0:100) to afford the title compound as a white solid (240.0 mg, 66%). UPLC-MS (method generic) Rt 1.97 min, MS (ES) C ₁ 9H ₂₂ N ₂ O ₂ requires m/z 310, found m/z 311 [M+H] ⁺ . ^Χ Η NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 7.73 - 7.62 (in, 2H) , 7.36 - 7.28 (m, 4H), 7.28 - 7.22 (m, 1H) , 6.94 - 6.83 (m, 1H) , 3.88 - 3.40 (m, 8H) , 3.71 (s, 2H) , 3.49 (s, 2H) .

Preparation of 4-Hydroxy-3- [ ( 4-isopropylpiperazin-l- yl ) methyl ] benzaldehyde ( Intermediate 15, scheme 4)

Intermediate 15 was prepared according to the general procedure for the synthesis of aldehydes of Formula Ila using 4 -hydroxybenzaldehyde (2.05 mmol , 250.0 mg) , N- isopropyl piperazine (2.46 mmol , 351.0 pL) and HCHO (4.10 mmol, 340.0 pL) in 5.0 mL of EtOH. The crude mixture was purified by column chromatography ( EtOAc/MeOH gradient

100:0 up to 85:15) to afford the title compound as yellow

011 (310.0 mg, 58%) . UPLC-MS (method generic) Rt 1.19 min, MS (ES) C ₁₅ H _{22 2} O ₂ requires m/z 262, found m/z 263 [M-H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H) , 7.69 (d, J = 8.2 Hz, 2H) , 6.90 (d, J = 8.1 Hz, 1H) , 3.71 (s, 2H) , 2.64 (dt, J = 13.1, 6.5 Hz, 1H) , 2.54 - 2.42 (bm, 8H) , 0.97 (d, J = 6.5 Hz, 6H) .

Tables of intermediates of Formula lib (Scheme 5) Methyl carboxylate arylamine intermediate of Formula lib' ( Scheme 5 , step 1 ) and their physico-chemical properties are described in Tables 9 and 21.

Alcohol intermediate of Formula lib' ' (Scheme 5 , step

2) and their physico-chemical properties are described in Tables 10 and 22.

Aldehyde intermediates of Formula lib (Scheme 5 , step

3) and their physico-chemical properties are described in Tables 11 and 23 (INTERMEDIATE 16, 17 , 25, 26, 27) .

Triphenylphosphonium salt of Formula lie' ( Scheme 6, step 1) and its physico-chemical properties are described in Table 12.

Compounds of Formula lie'' (Scheme 6, step 2) and their physico-chemical properties are described in Tables

13 and 24.

Compounds of Formula lie''' ( Scheme 6 , step 3 ) and their physico-chemical properties are described in Tables

14 and 25.

Alcohol intermediates of Formula lie'''' (Scheme 6, step 4) and their physico-chemical properties are described in Tables 15 and 26.

Aldehyde intermediates of Formula lie (Scheme 6, step 5) and their physico-chemical properties are described in Tables 16 and 27 (INTERMEDIATES 18, 28, 29 .

BEST MODE FOR CARRYING OUT THE INVENTION

Preparetion of 4- [ [ [ 1 - ( 2 - Fluorophenyl ) cyclopentyl ] amino ] methyl ] -2- [ ( 4-methy.lpiperazin-l-yl ) methyl] phenol trihydrochloride (Example 1_ [CAS number: 1287451-26-6 ] )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (100.0 mg, 0.42 mmol), INTERMEDIATE 8 (75.0 mg, 0.42 mmol) and NaBH (OAc) ₃ (178.0 mg, 0.84 mmol) in DCM (4.5 rriL ) . The crude was purified by column chromatography [DCM and MeOH/NH ₃ (19% MeOH and 1% NH ₃ in DCM), from 95:5 to 100:0] to afford the free base of the title compound as a colorless oil (137.0 mg, 82 %) . UPLC-MS (method generic) : Rt 1.58 min, MS (ES) C ₂₄ H ₃₂ FN ₃ O requires m/z 397, found m/z 398 [M-H] ⁺ . The free base (60.0 mg, 0.15 mmol ) was then dissolved in DCM (1.5 mL) and 2.0 M HC1 solution in Et ₂ 0 (1.5 mL, 3.0 mmol, 20.0 equiv. ) was added observing the formation of precipitate. The excess of solvent was removed under reduce pressure and the resulting solid was triturated with Et ₂ 0. The resulting solid was dissolved in a solution of CH ₃ CN/H ₂ O (1:1) and lyophilized, affording the title compound as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.07 (bs, 1H) , 10.71 (bs, 1H) , 9.53 (s, 2H), 7.65 (t, J = 8.0 Hz, 1H) , 7.56 - 7.47 (m, 1H) , 7.41 (s, 1H) , 7.37 - 7.28 (m, 2H) , 7.23 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H) , 3.73 (t, J = 5.6 Hz, 2H) , 3.71 - 3.22 (m, 10H) , 2.79 (s, 3H) , 2.51 (m, 2H) , 2.37 (dt, J = 12.4, 5.7 Hz, 2H), 2.02 - 1.83 (m, 2H) , 1.67 - 1.48 (m, 2H) .

Preparation of 4- [ [ [ 1- ( 2 -Fluorophenyl ) cyclopentyl] amino] methyl ] -2 - ( 1-piperidylmethyl ) phenol dihydroch1oride (Example 2)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (68.0 mg, 0.36 mmol), INTERMEDIATE 9 (80.0 mg, 0.36 mmol) and NaBH (OAc) ₃ (152.0 mg, 0.72 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [Cy/EtOAc, from 90:10 to 0:100] to afford the free base of the title compound as a colorless oil (45.0 mg, 33%) . UPLC-MS (method generic) : Rt 1.85 min, MS (ES) C ₂₄ H ₃₁ F ₂ O reguires m/z 382, found m/z 383 [M-H] ⁺ . The free base (40.0 mg, 0.10 mmol) was then dissolved in 1.0 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.0 mL, 2.0 mmol, 20.0 eguiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^X H NMR (400 MHz, DMSO- ₆ ) δ 10.61 (s, 1H) , 10.16 (s, 1H) , 9.54 (s, 2H) , 7.72 - 7.61 (m, 1H) , 7.58 - 7.45 (m, 2H) , 7.38 - 7.25 (m, 2H) , 7.21 (dd, J = 8.4, 2.2 Hz, 1H) , 6.96 (d, J = 8.4 Hz, 1H) , 4.13 (d, J = 4.4 Hz, 2H) , 3.84 - 3.63 (m, 2H) , 3.47 - 3.18 (m, 4H), 3.03 - 2.75 (m, 2H), 2.51 (dt, = 3.7, 1.9 Hz, 2H) , 2.37 (dd, J = 13.2, 6.4 Hz, 2H) , 1.92 (d, J = 8.2 Hz, 2H) , 1.79 (d, J = 12.9 Hz, 3H) , 1.70 - 1.49 (m, 3H) .

Preparation of 4 - [ [ [ 1- ( 2 "Fluorophenyl ) cyclohe y1 ]_ amino] methyl ] -2- [ ( 4-methylpiperazin- 1-yl ) methyl ] phenol tr ihydrochioride (Example 3)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMED IATE 3 (58.0 mg, 0.42 mmol), INTERMEDIATE 8 (70.0 mg, 0.42 mmol) and NaBH (OAc) ₃ (177.0 mg, 0.84 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM and MeOH/NH ₃ (19% MeOH and 1% NH ₃ in DCM), from 95:5 to 100:0] to afford the free base of the title compound as a colorless oil, (110.0 mg, 63%) . UPLC-MS (method generic) : Rt 1.67 rain, MS (ES) C ₂₅ H ₃₄ FN ₃ 0 requires m/z 382, found m/z 412 [M-H] ⁺ . The free base (76.0 mg, 0.18 mmol) was then dissolved in 1.5 ml and 2.0 M HC1 solution in Et ₂ 0 (1.5 mL, 3.6 mmol, 20.0 equi . ) was added. Evaporation of solvents afforded the title compound as a white powder. ^L H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (bs, 1H) , 10.71 (bs, 1H), 9.51 (s, 2H) , 7.78 (t, J = 8.1 Hz, 1H) , 7.56 (td, J = 7.4, 4.1 Hz, 1H) , 7.36 (ddd, J = 22.0, 14.6, 8.1 Hz, 3H) , 7.25 (dd, J = 8.6, 2.3 Hz, 1H) , 6.97 (d, J = 8.3 Hz, 1H), 4.52 - 3.90 (bm, 4H) , 3.80 - 3.50 (m, 6H) , 3.49 - 3.30 (bm, 2H) , 2.84 (dd, J = 36.7, 8.2 Hz, 2H) , 2.80 (bs, 3H) 2.12 (t, J = 12.2 Hz, 2H) , 1.77 (d, J = 13.1 Hz, 2H), 1.67 - 1.48 (m, 1H) , 1.34 - 1.05 (m, 3H) .

Preparation. of 1- (2-Fluorophenyl ) -N- [ [ 3- [ (4- methylpiperazin-l-yl ) methyl] phenyl] methyl] -cyclopentanamine tr1hydrochloride (Example 4)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (72.0 mg, 0.40 mmol), INTERMEDIATE 16 (89.0 mg, 0.40 mmol) and NaBH (OAc) ₃ (144.0 mg, 0.68 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from. 95:5 to 50:50] to afford the free base of the title compound as a colorless oil, (76.0 mg, 50%) . UPLC-MS (method generic) : Rt 1.77 min, MS (ES) C ₂₄ H _{32 3} requires m/z 381, found m/z 382 [M-H] ⁺ . The free base (50.0 mg, 0.13 rrtmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.2 mL, 2.6 mmol, 20.0 equiv. ) was added. Evaporation of solvents afforded the title compound as a white powder ¹ R NMR (400 MHz, DMSO-d ₆ ) δ 12.18 (bs, 2H) , 9.74 (bs, 2H) , 7.65 (m, 2H) , 7.51 (t, J = 6.6 Hz, 2H) , 7.42 (d, J = 8.0 Hz, 2H) , 7.36 - 7.20 (m, 2H) , 3.97 - 3.72 (m, 2H) , 3.70 - 3.11 (m, 10H) , 2.80 (s, 3H) , 2.58 (dd, J = 14.1, 6.9 Hz, 2H) , 2.38 (dt, J = 12.1, 5.3 Hz, 2H) , 1.93 (q, J = 7.4, 6.8 Hz, 2H) , 1.60 (dt, J = 11.1, 5.4 Hz, 2H) .

Preparation of 1- ( 2 -Fluorophenyl ) -N- [ [4-methoxy~3~ [ (4- methylpiperazin-l-yl ) methyl ] -phenyl ] methyl ] cyclopentanamine trihydrochloride (Example 5)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (28.0 mg, 0.15 mmol), INTERMEDIATE 17 (38.0 mg, 0.15 mmol) and NaBH (OAc) ₃ (64.0 mg, 0.30 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM and MeOH/Et ₃ N (19% MeOH and 1% Et ₃ N in DCM), from 95:5 to 40:60] to afford the title compound as a colorless oil (40 mg, 65%) . UPLC-MS (method generic) : Rt 1.70 min, MS (ES) C25H3 ₄ FN 3O requires m/z 411, found m/z 412 [M+H] ⁺ . The free base (50.0 mg, 0.12 mmol) was then dissolved in 1.0 mL of DCM and 2.0 M HCi solution in Et ₂ 0 (1.2 mL, 2.4 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^λ Η NMR (400 MHz , D SO-d ₆ ) δ 12.07 (bs, 2H) , 9.65 (bs, 2H) , 7.66 (t, J = 7.8 Hz, 1H) , 7.50 (dq, J = 10.8, 6.8, 6.3 Hz, 2H) , 7.46 - 7.38 (m, 1H) , 7.37 - 7.26 (m, 2H) , 7.07 (d, J = 8.4 Hz, 1H) , 4.21 (bm, 2H) , 3.84 (s, 3H), 3.77 (m, 2H) , 3.72 (m, 8H) , 2.79 (bs, 3H) , 2.60 - 2.45 (m, 2H) , 2.37 (ra, 2H) , 2.09 - 1.77 (m, 2H) , 1.69 - 1.41 (m, 2H) .

Preparation of 4-[[[l- ( 2 -Fluorophenyl ) cyclopentyl ] - methyl-amino] methyl] -2- [ ( 4-methylp.iperazin-l-yl ) methyl ] phenol trihydrochlorrde (Example 6 )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula lb, starting from INTERMEDIATE 1 (32.0 mg, 0.18 mraol), INTERMEDIATE 8 (42.0 mg, 0.18 mmol), HCHO (240.0 iiL, 0.36 mmol) and NaBH(0Ac) ₃ (76.0 mg, 0.36 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM and MeOH/Et ₃ N (19% MeOH and 1% Et ₃ N in DCM), from 95:5 to 40:60] to afford the free base of the title compound as a colorless oil (65.0 mg, 62%) . UPLC-MS (method generic) : Rt 2.18 min, MS (ES) C ₂₅ H ₃₄ FN ₃ O requires m/z 411, found m/z 412 [M+H] ⁺ . The free base (30.0 mg, 0.08 mmol) was then drssolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.3 mL, 1.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^l H NMR (400 MHz, D SO-d ₆ ) δ 12.36 - 11.48 (m, 2H) , 10.78 (bs, 2H) , 7.87 (t, J = 7.5 Hz, 1H) , 7.70 - 7.53 (m, 2H) , 7.52 - 7.29 (m, 3H) , 7.01 (d, J = 8.0 Hz, 1H) , 4.63 (d, J = 12.3 Hz, 1H) , 4.38 - 4.00 (m, 2H) , 3.84 - 3.23 (m, 8H) , 3.18 - 2.98 (m, 1H), 2.97 - 2.71 (m, 3H) , 2.71 - 2.57 (m, 3H) , 2.52 - 2.42 (m, 3H) , 1.87 (ra, 2H) , 1.36 (m, 2H) .

Preparation of 2- [ ( 4-Methylpiperazin- 1-yl ) methyl ] -4 - [ [ ( 1-phenylcyclopentyl) amino ] methy]_._ -pheno1

trihydrochloride (Example 7)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 2 (40.0 mg, 0.24 mmol) , INTERMEDIATE 8 (58.0 mg, 0.24 mmol) and NaBH (OAc) ₃ ( 102.0 mg, 0.48 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% MeOH in DCM) , from 95:5 to 40:60] to afford the free base of the title compound as a colorless oil (57.0 mg, 63%) . UPLC-MS (method generic) : Rt 1.51 min, MS (ES) C ₂₄ H ₃₃ FN ₃ O requires m/z 379, found m/z 380 [M+H] ⁺ . The free base (57.0 mg, 0.15 mmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ <3 (1.5 mL, 3.0 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^l Yi NMR (400 MHz, DMSO-d ₆ ) δ 12.32 - 11.61 (bs, 1H) , 10.72 (bs, 1H) , 9.81 (bs, 2H) , 7.77 (m, 3H) , 7.51 (t, J = 7.2 Hz, 2H) , 7.47 - 7.33 (m, 2H) , 7.24 (d, J = 8.1 Hz, 1H) , 6.97 ( d , J = 8.0 Hz, 1H) , 3.80 - 3.13 (m, 12H) , 2.79 (s, 3H) , 2.45 - 2.30 (m, 4H) , 1.85 (m, 2H) , 1.65 - 1.37 (m, 2H) .

Preparation of 1- [ 4- [ [5- [ [_[ 1- (2 "Fluorophenyl) cyclopentyl] amino] methyl ] -2-hydroxyphenyl] -methyl] piperazin -1-yl ] ethanone dihydrochloride ( Example 8 )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (41.0 mg, 0.23 mmol ) , INTERMEDIATE 10 (60.0 mg, 0.23 mmol) and NaBH (OAc) ₃ (81.0 mg, 0.36 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography (EtCAc/Cy/Et^N, 4:1:0.1) to afford the free base of the title compound as a colorless oil (50.0 mg, 50%) . UPLC-MS (method generic) : Rt 1.88 mm, MS (ES) C ₂₄ H ₃₃ FN ₃ O requires m/z 425, found m/z 426 [M+H] ⁺ . The free base (36.0 mg, 0.08 mmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.0 mL, 1.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound 3.S 3. white powder. ^~ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (d, J = 11.3 Hz, 1H) , 10.63 (s, 1H) , 9.73 - 9.22 (m, 2H) , 7.64 (t, J = 1.9 Hz, 1H) , 7.59 - 7.40 (m, 2H) , 7.41 - 7.25 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H) , 6.94 (d, J = 8.2 Hz, 1H), 4.40 (d, J = 13.7 Hz, 1H) , 4.21 (bs, 2H), 3.97 (d, J - 13.1 Hz, 1H) , 3.73 (t, J = 5.3 Hz, 2H) , 3.55 (m, 1H) , 3.45 - 3.20 (m, 2H) , 3.21 - 2.97 (m, 2H), 2.88 (m, 1H), 2.54-2.46 (m, 2H) , 2.42 - 2.30 (m, 2H) , 2.03 (s, 3H) , 1.96 - 1.85 (m, 2H) , 1.63 - 1.50 (m, 2H) .

Preparation of 4- [ [ [ 1- ( 2 -Fluorophenyl ) cyclopentyl ] amino ] methyl ]^2 - [ ( 4-phenylpiperazin-l-yl) methyl] phenol trihydrochlor ide (Example 9)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (45.0 mg, 0.25 mmol), INTERMEDIATE 11 (74.1 mg, 0.25 mmol) and NaBH (OAc) ₃ (106.0 mg, 0.50 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography (Cy/EtOAc, from 100:0 to 60:40) to afford the free base of the title compound as a colorless oil (65.0 mg, 57%) . UPLC-MS (method generic) : Rt 3.24 min, MS (ES) C ₂₉ H ₃₄ FN ₃ O requires m/z 459, found m/z 460 [M+H] ⁺ . The free base (60.0 mg, 0.13 mmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.3 mL, 2.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ H NMR (400 MHz, DMSO-de) δ 10.71 (m, 2H) , 9.53 (bs, 2H) , 7.65 (t, J = 7.9 Hz, 1H) , 7.52 (m, 2H), 7.38 - 7.19 (m, 5H) , 6.98 (m, 3H) , 6.86 (t, J = 7.2 Hz, 1H) , 4.27 (bs, 2H) , 3.89 - 3.65 (m, 4H) , 3.44 (d, J = 9.4 Hz, 2H) , 3.17 (m, 4H), 2.55 - 2.50 (m, 2H) , 2.41 - 2.34 (m, 2H), 2.00 - 1.85 (m, 2H) , 1.67 - 1.53 (m, 2H) .

Preparatron of 2- [ (4-Ethylpiperazin-l-yl) methyl ] -4- [ [ [1- ( 2 -fluorophenyl ) cyclopentyl ] amino ] -methyl ] phenol trihydrochloride (Example 10)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMED IATE 1 (45.0 mg, 0.25 mmol) and INTERMED IATE 12 (62.0 mg, 0.25 mmol) and NaBH (OAc) ₃ (106.0 mg, 0.50 mmol) in DCM (3.0 ml) . The crude was purified by column chromatography [DCM and MeOH/Et ₃ N (19% MeOH and 1% Et ₃ N in DCM), from 95:5 to 40:60] to afford the free base of the title compound as a colorless oil (57.0 mg, 56%) . UPLC-MS (method generic) : Rt 1.63 min, MS (ES) C ₂₅ H ₃₄ FN ₃ O requires m/z 411, found m/z 412 [M+H] ⁺ . The free base (57.0 mg, 0.14 mmol) was then dissolved in 0.5 niL of DCM and 2.0 M HC1 solution in Et ₂ 0 (1.4 mL, 2.8 mmol, 20.0 eguiv. ) was added. Evaporation of solvents afforded the title compound as a white powder. ^:1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.99 (bs, 1H), 10.74 (bs, 1H) , 9.50 (bs, 2H) , 7.65 (t, J - 8.0 Hz, 1H) , 7.51 (m, 1H) , 7.44 (m, 1H) , 7.38 - 7.27 (m, 2H) , 7.24 (d, J = 8.2 Hz, 1H) , 6.96 (d, J = 8.3 Hz, 1H), 4.38 - 4.10 (m, 2H), 3.73 (bs, 2H) , 3.65 (s, 8H) , 3.28 - 2.96 (m, 2H) , 2.55 - 2.50 (m, 2H), 2.43 - 2.31 (m, 2H) , 1.96 - 1.85 (m, 2H) , 1.66 - 1.50 (m, 2H) , 1.26 (t, J = 7.0 Hz, 3H) .

Preparation of 4- [[[ 1- ( 2-Fluorophenyl ) cyclopentyl ] amino ] methyl ] ~2- (piperazin-l-ylmethyl) -phenol ( Examp1e 11 ) The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting f om INTERMEDIATE 1 (66.0 mg, 0.36 mmol) , INTERMEDIATE 13 (118.0 mg, 0.36 mmol) and NaBH (OAc) ₃ (152.0 mg, 0.72 mmol) in DCM (4.0 raL ) . The residue was dissolved in dioxane (1.0 mL) and HC1 4.0 M solution in dioxane (0.5 mL) was added and the reaction mixture stirred at rt for Ih. After evaporation of the solvents, the crude was purified by preparative HPLC/MS run on a Water autopurification system on a XBridge™ Prep Ci ₈ OBD column (100xl9mmID, particle size 5pm) with a XBridge™ Prep C18 (10xl9mmID, particle size 5pm) Guard Cartridge using a method with NH ₄ OAc lOmM in CH ₃ CN/water 95:5 at pH

5 as mobile phase to afford the title compound as white solid. UPLC-MS (method generic) : Rt 1.52 min, MS (ES) C ₂₃ H ₃₀ F ₃ O requires m/z 383, found m/z 384 [M+H] ⁺ . ^] Ή NMR (400 MHz, DMSO-de) δ 7.41 (td, J = 8.2, 1.9 Hz, IH) , 7.30 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H) , 7.21 - 7.08 (m, 2H) , 6.92 - 6.78 (m, 2H) , 6.59 (d, = 8.1 Hz, IH) , 3.53 (s, 2H) , 3.17 (bs, 2H) , 2.69 (m, 4H) , 2.35 (m, 4H), 2.20 - 2.07 (m, 2H) , 1.88 - 1.74 (m, 2H) , 1.70 - 1.55 (m, 4H) , 1.36 - 1.16 (m, 2H) .

Preparation of 2- [ ( 4-Benzylpiperazin-l-yl) methyl] -4- [ [ [1- (2- fluorophenyl) cyclopentyl ] amino] -methyl ] phenol trihydrochloride (Example 12 )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (78.0 mg, 0.44 mmol) , INTERMEDIATE 14 (136.0 mg, 0.44 mmol) and NaBH (OAc) ₃ (186.0 mg, 0.88 mmol) in DCM (6.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% MeOH in DCM), from 95:5 to 60:40] to afford the free base of the title compound as a white solid (64.0 mg, 31%) . UPLC-MS (method generic) : Rt 2.84 min, MS (ES) C ₃₀ H ₃₆ FN ₃ O reguires m/z 473, found m/z 474 [M+H] ⁺ . The free base (60.0 mg, 0.12 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.6 mL, 2.4 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ² H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (bs, 1H), 10.68 (bs, 1H), 9.47 (bs, 2H) , 7.73 - 7.57 (m, 3H), 7.57 - 7.48 (m, 1H) , 7.48 - 7.36 (m, 4H) , 7.37 - 7.27 (m, 2H), 7.23 (dd, J = 8.5, 2.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H) , 4.52 - 4.03 (m, 2H), 3.78 - 3.67 (m, 2H) , 3.67 - 3.13 (m, 10H) , 2.55 - 2.50 (m, 2H) , 2.42 - 2.31 (m, 2H) , 2.02 - 1.80 (m, 2H) , 1.65 - 1.50 (m, 2H) .

Preparation of 4- [ [ [1- (2-Fluorophenyl) cyclopentyi] amino ] methyl ] -2 - [ ( - i sopropylpipera zin- l-yl ) methy1 ] phenol trihydrochloride (Example 13)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (42.0 mg, 0.26 mmol), INTERMEDIATE 15 (70.0 mg, 0.26 mmol ) and NaBH (OAc) ₃ (110.0 mg, 0.52 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% MeOH in DCM), from 95:5 to 60:40] to afford the free base of the title compound as a colorless oil (81.0 mg, 74%) . UPLC-MS (method generic) : Rt 1.80 min, MS (ES) C ₂₆ H ₃₆ F ₃ O requires m/z 425, found m/z 426 [M+H] ⁺ . The free base (81.0 mg, 0.20 mmol) was then dissolved in 0.5 mi, of DCM and 2.0 M HC1 solution in Et ₂ 0 (2.0 mL, 4.0 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ ti NMR (400 MHz, D ₂ 0) δ 7.46 - 7.34 (bs, 2H) , 7.21 (t, J = 7.6 Hz, 1H) , 7.17 - 7.05 (m, 2H) , 7.03 (d, J - 2.2 Hz, 1H) , 6.83 (d, J = 8.4 Hz, 1H) , 4.26 (s, 2H) , 3.89 (s, 2H) , 3.73 - 3.25 (m, 10H) , 2.43 (dt, J = 12.0, 5.6 Hz, 2H) , 2.17 (dt, J = 14.4, 7.3 Hz, 2H) , 1.89 - 1.72 (m, 2H) , 1.63 (dt, J = 13.8, 5.2 Hz, 2H) , 1.27 (d, J = 6.6 Hz, 6H) .

Preparation of 4-[[[l-(2 - Fluorophenyl ) tet rahydropyran- 4 -yl ] amino ] methyl] -2- [ (4 -meth l-pipera zin- 1-yl ) methyl ] phenol tr ihydrochloride (Example 15)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 4 (45.0 mg, 0.23 mmol) , INTERMEDIATE 8 (54.0 mg, 0.23 mmol) and NaBH (OAc) ₃ (97.0 mg, 0.46 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography (DCM/MeOH 95:5) to afford the free base of title compound as a colorless oil (38.0 mg, 50%) . UPLC-MS (method generic) : Rt 1.56 min, MS (ES) C24H 32 FN 3O2 requires m/z 413, found m/z 414 [M+H] ⁺ . The free base (35.0 mg, 0.08 mmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (0.8 mL, 1.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^'L H NMR (400 MHz , D ₂ 0) δ 7.50 (dt, J = 19.0, 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.23 - 7.07 (m, 2H) , 7.04 (d, J = 2.2 Hz, 1H) , 6.83 (d, J = 8.4 Hz, 1H) , 4.27 (s, 2H) , 4.04 - 3.90 (m, 2H) , 3.85 ( s , 2H) , 3.67 - 3.25 (m, 10H) , 2.90 (s, 3H) , 2.78 (d, J = 13.6 Hz, 2H) , 2.12 (td, J = 12.9, 4.4 Hz, 2H) .

Preparation of 4- (2-fluorophenyl) -4 - [ [ -hydroxy- 3- [ (JL- methylpiperazin-l-yl ) methyl ] phenyl ] -methylamino]

cyclohexanone tr ihydrochloride (Example _y_6 )_

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 5 ( 5.0 mg, 0.22 mmol) , INTERMEDIATE 8 (51.0 mg, 0.22 mmol) and aBH (OAc) ₃ (97.0 mg, 0.46 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography f DCM/MeOH (20% MeOH in DCM), from 95:5 to 60: 40] to afford the free base of title compound a colorless oil, (44.0 mg, 46%) . UPLC-MS (method generic) : Rt 1.84 min, MS (ES) C25H32 FN3O2 requires m/z 425, found m/z 426 [M+H] ^1' . The free base (35.0 mg, 0.08 mmol) was then dissolved in 0.5 mL of DCM and 2.0 M HC1 solution in Et ₂ 0 (0.8 mL, 1.6 mmol, 20.0 equiv. ) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ H NMR (400 MHz , D ₂ 0) δ 7.64 (td, J = 8.4, 1.6 Hz, 1H) , 7.60 - 7.47 (m, 1H) , 7.34 (ddd, J = 9.2, 6.3, 1.4 Hz, 1H) , 7.25 - 7.05 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H) , 4.33 (s, 2H) , 4.00 (bs, 2H) , 3.77 - 3.37 (m, 8H) , 3.12 (bs, 1H) , 2.97 (s, 3H) , 2.82 (d, J = 13.5 Hz, 1H) , 2.60 - 2.35 (m, 4H) , 2.25 - 2.06 (m, 1H), 1.92 (d, J = 14.2 Hz, 1H) , 1.63 (t, J = 13.4 Hz, 1H) .

Preparation of 4- [ [ [ 4 , 4-difluoro-1- (2-fluorophenyl) cyclohexyl ] amino ] methyl ] -2- [ ( 4 -methyl-piperazin- 1- yl ) methyl ] phenol trihydrochloride (Example 17 )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 7 (53.0 mg, 0.23 mmol) , INTERMEDIATE 8 (54.0 mg, 0.23 mmol) and NaBH (OAc) ₃ (97.0 mg, 0.46 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [ DC /MeOH (20% MeOH in DCM), from 100:0 to 60:40] to afford the free base of title compound a colorless oil, (53.0 mg, 50%) . UPLC-MS (method generic) : Rt 2.49 min, MS (ES) C25H 32 3N 3O requires m/z 447, found m/z 448 [M+H] ⁺ . The free base (50.0 mg, 0.11 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in Et ₂ 0 (1.0 mL, 2.2 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^l R NMR (400 MHz, DMS0-d ₆ ) δ 11.98 (bs, 1H) , 10.81 (bs, 1H) , 9.86 (s, 2H) , 7.85 (t, J = 8.1 Hz, 1H) , 7.62 (ddt, J = 8.3, 5.4, 3.2 Hz, 1H) , 7.49 - 7.33 (m, 3H) , 7.27 (dd, J = 8.5, 2.3 Hz, 1H) , 6.97 (d, J = 8.4 Hz, 1H) , 4.30 - 4.05 (m, 2H) , 3.72 (bs, 2H) , 3.70 - 3.24 (m, 8H) , 2.98 (d, J = 12.5 Hz, 2H) , 2.68 (bs, 3H) , 2.45 (d, J = 12.1 Hz, 2H) , 2.35 - 2.13 (m, 2H) , 1.80 ~ 1.51 (m, 2H) .

Preparation of 1- ( 2-fluorophenyl ) -N- [ [3- [1 -methyl- 4- piperidyl ) methyl ] phenyl ] methyl ] cyclopentanamine

dihydrochloride (Example 18)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (50.0 mg , 0.23 mmol ) , INTERMEDIATE 18 (60.0 mg, 0.23 mmol) and NaBH (OAc) ₃ (97.0 mg, 0.46 mmol) in DCM (3.0 rtiL) . The crude was purified by column chromatography [DCM/MeOH (20% MeOH in DCM), from 90:10 to 0:100] to afford the free base of title compound a colorless oil, (60.0 mg, 57%) . UPLC-MS (method generic) : Rt 2.04 min, MS (ES) C ₂₅ H ₃₃ FN ₂ requires m/z 380, found m/z 381 [M+H]+. The free base (30.0 mg, 0.08 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in Et ₂ 0 (0.4 mL, 1.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ ti NMR (400 MHz, DMSO-d<j) δ 10.49 (bs, 1H), 9.52 (bs, 2H), 7.62 (td, J = 8.5, 8.1, 1.9 Hz, 1H) , 7.56 - 7.48 (m, 1H) , 7.42 - 7.23 (m, 3H) , 7.21 - 7.14 (m, 2H) , 7.11 (s, 1H) , 3.83 (t, J = 5.1 Hz, 2H) , 3.42 - 3.42 (m, 2H) , 2.94 - 2.73 (m, 2H) , 2.68 (d, J = 4.8 Hz, 2H) , 2.56 - 2.45 (m, 5H) , 2.37 (dt, J - 12.4, 5.6 Hz, 2H) , 1.92 (td, J = 11.9, 9.5, 5.5 Hz, 2H) , 1.80 ^■ 1.64 (m, 3H) , 1.64 - 1.41 (m, 4H) .

Preparation of 1- ( 2 -fluorophenyl ) -N-methyl-N- [ [3- [ timethyl- 4 -piperidyl ) methyl ] phenyl ] methyl ] cyclopentanamine dihydrochloride (Example 19)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula lb, starting from INTERMEDIATE 1 (15.0 mg, 0.08 mmol) , INTERMEDIATE 18 (18.0 mg , 0.08 mmol) , HCHO (20.0 p.L, 0.8 mmol) and NaBH (OAc) ₃ (33.0 mg, 0.16 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography using Biotage column SI 2g using as eluent DCM/MeOH 90:10 to afford the free base of the title compound as a colorless oil (20.0 mg, 65%) . UPLC-MS (method generic) : Rt 2.90 min, MS (ES) C ₂₆ H ₃₅ FN ₂ requires m/z 394, found m/z 395 [ +H]+. The free base (20.0 mg, 0.05 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in Et ₂ 0 (0.250 mL, 1.0 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ H NMR (400 MHz, DMSO-de) δ 10.84 (bs, 1H) , 10.54 (bs, 1H) , 7.94 - 7.79 (m, 1H) , 7.65 (q, J = 7.2, 6.8 Hz, 1H) , 7.46 - 7.37 (m, 4H) , 7.32 (t, J - 7.5 Hz, 1H) , 7.24 (d, J = 7.5 Hz, 1H) , 4.76 - 4.60 (m, 1H) , 3.60 - 3.45 (m, 2H) , 3.37 - 3.25 (m, 2H) , 3.17 - 3.04 (m, 2H), 2.88 - 2.68 (m, 3H) , 2.75 - 2.61 (m, 5H) , 2.51 (s, 3H), 2.03 - 1.61 (m, 5H) , 1.60 - 1.14 (m, 4H) .

Preparat ion of 4 - [ [ [ 1 -Benzyl-4- (2-fluorophenyl) -4- piperidylj_aniino ]_methyl ] -2- [ (4-methylpiperazin-l- yl ) methyl ] phenol tetrahydrochloride (Example 20)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 6 (25.0 mg, 0.09 mitiol) , INTERMEDIATE 8 (21.0 mg, 0.09 mmol) and NaBH (OAc) ₃ (38.0 mg, 0.18 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% MeOH in DCM), from 90:10 to 0:100] to afford the free base of title compound as colorless oil, (28.0 mg, 64%) . UPLC-MS (method generic) : Rt 1.84 mm, MS (ES) C ₃ 1H ₃₉ FN ₄ O requires m/z 502, found m/z 503 [M+H] + . The free base (28.0 mg, 0.05 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in Et ₂ 0 (0.370 mL, 1.5 mmol, 30.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^X H NMR (400 MHz, DMS0-d _& ) δ 11.96 (bs, lHj, 11.38 (bs, 1H) , 10.74 (bs, 1H), 10.08 (bs, 2H) , 7.87 (t, J = 8.3 Hz, 1H) , 7.81 - 7.70 (m, 1H), 7.70 - 7.53 (m, 3H),7.52 - 7.32 (m, 6H), 7.31 - 7.13 (m, 2H) , 6.97 (d, J = 8.4 Hz, 1H) , 4.60 - 4.50 (m, 1H) , 4.32 - 3.97 (m, 3H) , 3.85 - 3.35 (m, 13H) , 3.24 - 3.04 (m, 2H) , 2.99 - 2.56 (m, 6H) .

Preparation of l-(2-Fluorophenyl ) -N- [ [ 3- ( 1-piperidylmethyl ) phenyl ] methyl] cyclopentanamine dihydrochloride (Example 21) The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (50.0 mg, 0.24 mmol) , INTERMEDIATE 25 (44.0 mg, 0.24 mmol) and NaBH (OAc) ₃ (102.0 mg, 0.48 mmol) in DC (3.0 mL) . The crude was purified by column chromatography [DC /MeOH, from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil (50.0 mg, 57%) . UPLC-MS (method generic A) : Rt 2.12 min, MS (ES) C ₂ H ₃₁ F ₂ requires m/z 366, found m/z 367 [M+H] ⁺ . The free base (50.0 mg, 0.14 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.7 mL, 2.8 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^;L H NMR (400 MHz, DMSO-dg) δ 10.72 (bs, 1H) , 9.71 (d, J = 8.7 Hz, 2H) , 7.65 (s, 2H) , 7.58 (s, 1H) , 7.57 - 7.47 (m, 1H), 7.46 - 7.37 (m, 2H) , 7.35 - 7.23 (m, 2H) , 4.20 (d, J = 5.1 Hz, 2H) , 3.86 (t, J = 5.5 Hz, 2H) , 3.33 - 3.15 (m, 2H) , 2.96 - 2.74 (m, 2H) , 2.62 - 2.47 (m, 2H) , 2.46 - 2.28 (m, 2H) , 2.06 - 1.50 (m, 9H) , 1.47 - 1.15 (m, IH) .

Preparation of 4- [ [ [1- ( 3-Fluorophenyl) cyclopentyl] amino] methyl ] -2- [ ( 4-methylpiperazin-l-yl) methyl] phenol

trihydrochlo iole (Example 22)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 19 (46.0 mg, 0.19 mmol) , INTERMEDIATE 8 (35.0 mg, 0.19 mmol) and NaBH (OAc) ₃ (80.0 mg, 0.38 mmol) in DCM (2.5 ml) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 95:5 to 50:50] to afford the free base of the title compound as a colorless oil, (50.0 mg, 67%) . UPLC- S (method generic A) : Rt 1.70 min, MS (ES) C ₂ H ₃₂ FN ₃ O requires m/z 397, found m/z 398 [M+H] ⁺ . The free base (50.0 mg, 0.12 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.6 mL, 2.4 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder IH NMR (400 MHz, DMSO-d δ 11.82 (bs, IH), 10.72 (bs, IH), 9.92 (bs, 2H), 7.74 - 7.50 (m, 4H) , 7.43

(s, IH) , 7.34 7.20 (m, IH), 6.97 (d, J - 8.4 Hz, IH),

4.38 - 3.98 (m, 2H) , 3.78 - 3.50 (m, 8H) , 3.51 - 3.22 (m, 2H) , 2.81 (s, 3H) , 2.47 - 2.30 (m, 4H) , 2.01 - 1.78 (m, 2H) , 1.64 - 1.40 (m, 2H) .

Preparation of 4- [ [ [ 1- ( -Fluorophenyl ) cyclopentyl ] amino] methyl] -2- [ { 4-methylpiperazin-l-yl ) methyl] phenol trihydrochloride (Example 23)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 20 (46.0 mg, 0.19 mmol) , INTERMEDIATE 8 (35.0 mg, 0.19 mmol) and NaBH (OAc) ₃ (80.0 mg, 0.38 mmol ) in DCM (2.5 mL) . The crude was purified by column chromatography [ DCM/MeOH (20% in DCM), from 95:5 to 50:50] to afford the free base of the title compound as a colorless oil, (53.0 mg, 69%) . UPLC-MS (method generic A): Rt 1.66 min, MS (ES) C ₂₄ H ₃₂ F ₃ O requires m/z 397, found m/z 398 [M+H] ⁺ . The free base (53.0 mg, 0.13 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.65 mL, 2.6 mmol , 20.0 GC^UIV » ) ei. S added . Evaporation of solvents afforded the title compound as a white powder. ¹ H NMR (400 MHz, DMSO-dg) δ 11.85 (bs, 1H) , 10.71 (bs, 1H) , 9.85 (s, 2H) , 7.83 (dd, J = 8.7, 5.2 Hz, 2H) , 7.41 (s, 1H) , 7.33 (t, J - 8.7 Hz, 2H) , 7.29 - 7.20 (m, 1H) , 6.98 (d, J = 8.4 Hz, 1H), 4.50 - 3.97 (m, 2H) , 3.79 - 3.50 (m, 10H) , 2.81 (s, 3H) , 2.48 - 2.29 (m, 4H) , 1.94 - 1.78 (m, 2H) , 1.57 - 1.41 (m, 2H) .

Preparation of 1- (2-Fluorophenyl ) -N- [ [ 3- [ ( 4- ethylcyclohexyl ) methyl ] phenyl ] methyl ] cyclopentanamine hydrochloride (1:1 cis: trans ratio) (Example 24)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (25.0 mg, 0.11 mmol) , INTERMEDIATE 28 (20.0 mg, 0.11 mmol) and NaBH (OAc) ₃ (50.0 mg, 0.22 mmol) in DCM (2.5 inL) . The crude was purified by column chromatography (Cy/EtOAc from 100:0 to 30:70) to afford the free base as mixture of 1:1 cis: trans stereoisomers, as colorless oil (31.0 mg, 75%) . UPLC-MS (method generic B) : Rt 3.05 min, MS (ES) C ₂₆ H ₃₄ F requires m/z 379, found m/z 380 [M+H] ⁺ . The free base (31.0 mg, 0.08 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.05 mL, 0.16 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^X H NMR (400 MHz, DMSO-d _ff ) δ 9.44 (bs, 4H) , 7.64 - 7.56 (m, 2H) , 7.56 - 7.47 (m, 2H), 7.35 - 7.28 (m, 4H) , 7.28 - 7.20 (m, 2H) , 7.16 - 7.10 (m, 4H) , 7.07 (d, J = 7.3 Hz, 2H) , 3.82 (dd, J = 7.2, 4.7 Hz, 4H) , 2.52 - 2.29 (m, 12H) , 2.01 - 1.82 (m, 4H) , 1.73 - 1.51 (m, 10H), 1.49 - 1.20 (m, 10H) , 1.04 - 0.64 (m, 10H) .

Preparation of 2- [ ( 4 -Methylpipera zin-l-yl) methyl ] -4- [ [ [ 1- (2-thienyl) cyclopentyl ] amino] methyl ] phenol trihydrochloride (Example 25)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 21 (35.0 mg, 0.15 mmol), INTERMEDIATE 8 (25.0 mg, 0.15 mmol) and NaBH (OAc) ₃ (64.0 mg, 0.30 mmol) in DCM (2.5 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a. colorless oil, (36.0 mg, 60%) . UPLC-MS (method generic A): Rt 1.44 min, MS (ES) C ₂₂ H _{31 3} OS requires m/z 385, found m/z 386 [M+H] ⁺ . The free base (36.0 mg, 0.10 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.50 mL, 2.0 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ½ NMR (400 MHz, DMS0-d _< j) 10.68 (bs, 1H) , 9.91 (bs, 2H) , 7.71 (dd, J = 5.1, 1.1 Hz, 1H) , 7.55 (dd, J = 3.7, 1.2 Hz, 1H) , 7.52 - 7.38 (m, 1H) , 7.38 - 7.26 (m, 1H), 7.19 (dd, J = 5.1, 3.6 Hz, 1H) , 7.08 - 6.85 (m, 1H) , 4.46 - 3.97 (m, 2H), 3.86 - 3.67 (m, 2H) , 3.67 - 3.53 (m, 2H) , 3.52 - 3.12 (m, 6H) , 2.81 (s, 3H) , 2.49 - 2.26 (m,

4H) , 2.02 - 1.74 (m, 2H) , 1.70 - 1.41 (m, 2H) .

Preparation of 4- [ [ [ 1- ( 2 , -Difluorophenyl ) cyclopentyl ] amino] methyl] -2- [ { 4-methylpiperazin-l-yl ) methyl ] phenol trihydrochloride (Example 26)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 22 (46.0 mg, 0.19 mmol) , INTERMEDIATE 8 (36.0 mg, 0.19 mmol) and NaBH (OAc) ₃ (80.0 mg, 0.38 mmol) in DCM (2.5 mL) . The crude was purified by column chromatography [ DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (50.0 mg, 67%) . UPLC-MS (method generic A) : Rt 2.30 min, MS (ES) reguires m/z 415, found m/z 416 [M+H] ⁺ . The free base (50.0 mg, 0.12 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.60 mL, 2.4 mmol, 20.0 equiv . ) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ U NMR (400 MHz, DMSO-d ₆ ) δ 12.86 - 11.30 (m, 1H) , 10.73 (bs, 1H) , 9.32 (bs, 2H) , 7.55 (ddd, J = 14.6, 8.4, 6.1 Hz, 1H) , 7.48 (s, 1H) , 7.33 ^~ 7.07 (m, 3H) , 6.93 (d, J = 8.4 Hz, 1H), 4.57 - 3.97 (m, 2H) , 3.95 - 3.79 (m, 2H) , 3.78 - 3.58 (m, 2H) , 3.41 (s, 6H) , 2.81 (s, 3H) , 2.75 - 2.57 (m, 2H) , 2.42 - 2.18 (m, 2H) , 2.10 - 1.85 (m, 2H) , 1.81 - 1.52 (m, 2H) .

Pre aration of 4 - [ [ [ 1- ( 3-Methoxyphenyl) cyclopentyl] amino ] methyl] -2- [ (4 -methylpipera in-l-yl ) methyl ] phenol trihydrochloride (Example 27)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 23 (42.0 mg, 0.18 nimol), INTERMEDIATE 8 (35.0 mg, 0.18 mmol) and NaBH (OAc) ₃ (76.0 mg, 0.36 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [ DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (50.0 mg, 68%) . UPLC-MS (method generic A): Rt 1.63 min, MS (ES) C25H35N3O2 requires m/z 409, found m/z 410 [M+H] ⁺ . The free base (50.0 mg, 0.12 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.60 mL, 2.4 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^X H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H) , 10.76 (s, 1H) , 9.76 (m, 2H) , 7.47 - 7.34 (m, 3H) , 7.26 (m, 2H) , 7.05 - 6.93 (m, 2H), 4.46 - 3.99 (m, 2H) , 3.82 (s, 3H) , 3.61 (m, 8H) , 3.50 - 3.25 (m, 2H) , 2.82 (s, 3H) , 2.44 - 2.25 (m, 4H) , 1.85 (i, 2H) , 1.52 (m, 2H) .

Preparation of 1- (2- Fluorophenyl ) -N- [ [ 4- [ ( 4 -methyl piperazin-l-yl ) methyl ] phenyl ] methyl ] cyclopentanamine

trihydrochloride (Example 28)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (35.0 mg, 0.19 mmol) , INTERMEDIATE 26 (43.0 mg, 0.19 mmol) and NaBH (OAc) ₃ (80.0 mg, 0.38 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (52.0 mg, 72%) . UPLC- S (method generic A) : Rt 2.06 min, MS (ES) C ₂₄ H ₃ 2F ₃ requires m/z 381, found m/z 382 [M+H] ⁺ . The free base (50.0 mg, 0.12 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.60 mL, 2.4 mmol , 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ½ MR (400 MHz, DMSO-d ₆ ) δ 12.07 (bs, 1H) , 9.69 (bs, 2H) , 7.67 - 7.53 (m, 3H), 7.48 (tdd, J = 7.3, 5.0, 1.6 Hz, 1H) , 7.40 (d, J = 7.8 Hz, 2H) , 7.34 - 7.19 (m, 2H) , 4.28 (s, 2H), 3.88 (t, J = 5.7 Hz, 2H), 3.65 - 3.55 (m, 2H) , 3.54 - 3.20 (m, 6H) , 2.77 (s, 3H) , 2.60 - 2.55 (m, 2H) , 2.40 -2.32 (m, 2H) , 2.04 - 1.79 (m, 2H) , 1.71 - 1.47 (in, 2H) .

Preparation of 1- ( 2 -Fluorophenyl ) -N- [ [ 2 - [ ( 4 -methyl piperazin-l-yl) methyl] phenyl ] methyl ] cyclopentanamine

trihydrochloride (Example 29)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 1 (46.0 mg, 0.26 mmol) , INTERMEDIATE 27 (56.0 mg, 0.26 mmol) and NaBH (OAc) ₃ (110.0 mg, 0.52 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/ eOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (52.0 mg, 55%) . UPLC-MS (method generic. A) : Rt 2.05 min, MS (ES) C ₂₄ H ₃₂ FN ₃ requires m/z 381, found m/z 382 [M+H.] ⁺ . The free base (52.0 mg, 0.13 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.65 mL, 2.6 mmol , 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^] Ή MR (400 MHz, DMS0-d ₆ ) δ 11.86 - 11.06 (bs, 1H), 10.17 - 9.24 (bs, 2H) , 7.70 (t, J = 8.1 Hz, 1H) , 7.60 - 7.43 (m, 2H) , 7.37 (q, J = 7.0 Hz, 2H) , 7.33 - 7.20 (m, 2H) , 7.07 (d, J = 7.6 Hz, 1H) , 4.07 (s, 2H) , 3.87 - 3.25 (m, 8H) , 3.36 - 3.00 (m, 2H) , 2.77 (s, 3H) , 2.62 - 2.36 (m, 4H) , 2.11 - 1.80 (m, 2H) , 1.75 - 1.42 (m, 2H) .

Preparation of _ 4- (2-Fluorophenyl) -N- [ [3- [ (1 -methyl- 4- piperidyl ) methyl J pheny1 ] methyl] tetrahydropyran-4-amine dihydrochloride (Example 30)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 4 (61.0 mg, 0.31 mmol), INTERMEDIATE 18 (68.0 mg, 0.31 mmol) and NaBH ( OAc ) ₃ (131.0 mg, 0.52 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (52.0 mg, 43%) . UPLC-MS (method generic .A) : Rt 2.16 min, MS (ES) C ₂₅ H ₃₃ O requires m/z 396, found m/z 397 [M4H] ⁺ . The free base (52.0 mg, 0.13 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.65 mL, 2.6 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ^X H NMR (400 MHz , DMSO-d ₆ ) δ 10.55 (bs, 1H) , 9.83 (bs, 2H), 7.87 - 7.73 (m, 1H), 7.66 - 7.44 (m, 1H) , 7.44 - 7.31 (m, 2H), 7.31 - 7.22 (m, 1H) , 7.22 - 7.09 (m, 3H) , 4.01 - 3.88 (m, 2H) , 3.76 (t, J = 6.1 Hz, 2H), 3.38 - 3.27 (m, 2H) , 3.25 - 3.08 (m, 2H) , 2.93 - 2.70 (m, 4H) , 2.66 (d, J - 4.7 Hz, 3H) , 2.52 - 2.32 (m, 4H) , 1.83 - 1.62 (m, 3H) , 1.49 (d, J = 2.0 Hz, 2H) .

Preparation of 4 - [ [ 3- [ [ [ 1 - ( 2 -Fluorophenyl) cyclopentyl] amino] methyl ] phenyl ] methyl ] cyclohexanol hydrochloride

(Exampl_e 31 )

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from. INTERMEDIATE 1 (24.0 mg, 0.13 mmol), INTERMEDIATE 29 (30.0 mg, 0.13 mmol) and NaBH (OAc) ₃ (55.0 mg, 0.26 mmol) in DCM (2.5 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (26.0 mg, 53%) . UPLC-MS (method generic A): Rt 2.92 min, MS (ES) C ₂₅ H ₃₂ F O requires m/z 381, found m/z 382 [M+H] ⁺ . The free base (26.0 mg, 0.07 mmol) was then dissolved in 0.5 mL of d nd 4.0 M HC1 solution in dioxane (0.34 mL, 1.4 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ¹ ¥l NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (bs, 2H) , 7.64 - 7.47 (m, 2H) , 7.35 -7.10 (m, 3H) , 7.15 -7.10 (m, 3H) , 3.81 (t, J = 5,8 Hz, 2H) , 2.46 - 2.32 (m, 7H) , 1.95 - 1.85 (m, 2H) , 1.82 - 1.73 (m, 2H) . 1.65 - 1.52 (in, 4H) , 1.46 - 1.28 (m, 2H) , 1.15 - 0.79 (m, 4H) .

Preparation of 1- ( 4 -Fluorophenyl ) -N- [ [3- [ ( 1-methyl- 4-_ piperidyl ) methyl ] phenyl ] methyl ] cyclopentanamine

dihydrochloride (Example 32)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 20 (41.0 mg, 0.23 mmol) , INTERMEDIATE 18 (50.0 mg, 0.23 mmol) and NaBH (OAc) ₃ (97.0 mg, 0.46 mmol) in DCM (3.0 rriL) . The crude was purified by column chromatography LDCM/MeOH (20% in DCM) , from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (45.0 mg, 52%) . UPLC-MS (method generic A) : Rt 2.31 min, MS (ES) C ₂₅ H ₃₃ FN ₂ requires m/z 380, found m/z 381 [M+H] ⁺ . The free base (40.0 mg, 0.11 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.55 mL, 2.2 mmol, 20.0 equiv.) was added. Evaporation of solvents afforded the title compound as a white powder. ½ NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (bs, 1H) , 9.88 (bs, 2H) , 7.81 (ddd, J = 8.7, 5.2, 2.5 Hz, 2H) , 7.41 - 7.26 (m, 3H) , 7.24 - 7.13 (m, 3H) , 3.73 - 3.62 (m, 2H) , 3.42 - 3.25 (m, 2H) , 2.93 - 2.72 (m, 2H) , 2.68 (d, J — 4.6 Hz, 3H) , 2.50 - 2.46 (m, 1H) , 2.44 - 2.28 (m, 4H) , 1.96 - 1.79 (m, 2H), 1.83 - 1.63 (m, 3H) , 1.65 - 1.35 (m, 4H) , 1.32 - 1.17 (m, 1H) .

Preparation of 4- [ [ [1- (2-Fluorophenyl ) cyclobutyl] amino] methyl ] -2- [ ( 4-methylpiperazin-l-yl ) methyl ] phenol

t rihydrochloride (Example 33)

The title compound was prepared according to the general procedure for the synthesis of compounds of Formula la, starting from INTERMEDIATE 24 (45.0 mg, 0.26 mmol) , INTERMED IATE 8 ( 61.0 mg, 0.26 mmol) and NaBH (OAc) ₃ (110.0 mg, 0.52 mmol) in DCM (3.0 mL) . The crude was purified by column chromatography [DCM/MeOH (20% in DCM), from 100:0 to 0:100] to afford the free base of the title compound as a colorless oil, (60.0 mg, 60%) . UPLC-MS (method generic A): Rt 1.70 min, MS (ES) C ₂₃ H ₃₀ F ₃ O requires m/z 383, found m/z 384 [M+H] ⁺ . The free base (50.0 mg, 0.13 mmol) was then dissolved in 0.5 mL of dioxane and 4.0 M HC1 solution in dioxane (0.65 mL, 2.6 mmol, 20.0 equiv. ) was added. Evaporation of solvents afforded the title compound as a white powder. ^] H NMR (400 MHz , DMSO-d ₆ ) δ 11.95 (bs, 1H) , 10.80 (bs, 1H), 9.95 (bs, 2H) , 7.71 - 7.61 (m, 1H) , 7.57 - 7.44 (m, 2H) , 7.38 - 7.23 (m, 3H) , 6.97 (d, J = 8.4 Hz, 1H) , 4.37 - 4.07 (m, 2H) , 3.80 - 3.65 (m, 2H) , 3.65 - 3.53 (m, 2H), 3.53 - 3.19 (m, 6H) , 2.99 - 2.84 (m, 2H) , 2.80 (s, 3H) , 2.76 - 2.61 (m, 2H) , 2.41 - 2.21 (m, 1H) , 1.90 - 1.67 (m, 1H) .

Biological methods to assess the activity of the compounds according to the invention

Luciferase-base assay to _assess the actiyity of the compounds on REV-ERB mediated transcriptional regulation In order to assess the effect of the compounds of the invention on REV-ERB activity the inventors exploited the ability of REV-ERB to repress gene transcription of a specific DNA cis-element. In fact, the DNA binding domain (DBD) of REV-ERB recognizes specific DNA sequences (called RevREs = Rev-erb Responsive Elements) which contains an AGGICA motif linked in 5' to an A/T rich sequence harboring the following consensus: A/T A A/T N T (Harding et al., Mol Cell Biol., 1993; 13:3113) .

Therefore, two repetitions of the RevRE consensus AGAATGTAGGTCA upstream a SV40 promoter driving the expression of a reporter gene were cloned. As reported, the luciferase enzyme from the ostracod Cypridina noctiluca was adopted. This luciferase does not require ATP and catalyzes the oxidation of its luciferin substrate in a photochemical reaction that can be measured by a luminometer . Cypridina luciferase (CLuc) is secreted from cells by virtue of its natural signal peptide and its luminescence can be measured from the supernatant of transfected cells. Therefore, cell lysis is not necessary. Secreted CLuc is a very stable protein. Because of this property, the activity measured from the supernatant reflects the amount of protein accumulated up to the time of sampling. Multiple samples can therefore be obtained from the same transfected cells, allowing an easy set-up of time-course experiments. In addition, the direct use of the supernatant makes the system easily prone to automation for High Throughput Screening .

In order to normalize the experiment for the transfection efficiency, it was used a plasmid containing a SV40 promoter driving the expression of a secreted form of human alkaline phosphatase (SEAP), which enzymatic activity in the supernatant can be measured with chemiluminescence substrates .

To be able to rule out false-positive, for example due to the interference of the compounds to be tested with the fluorescence and/or chemiluminescence reactions, it was used as control a mutated version of the RevRE (GAGCCCGTAGGTCA) that is no longer able to bind REV-ERB DBD (Harding et al . , Mol Cell Biol., 1993; 13:3113) . Agonists or antagonists of REV-ERB modify the expression of the CLuc reporter driven by the wild-type RevRE/SV40 promoter, but produce negligible effects on the CLuc reporter driven by the mutated RevRE/SV40 promoter.

The person skilled in the art will appreciate that an agonist will improve the ability of REV-ERB to repress the transcription, reducing the luminescence signal, while an antagonist will produce the opposite effect.

For the assay, HEK-293 cells were transfected with the reporter vectors and a plasmid expressing the REV-ERBa and/or β protein. After 6 h from transfection, the medium was replaced with fresh medium containing different doses of the compounds or vehicle (DMSO) . After 24 h post- transfection, the supernatant was analyzed for the secreted luciferase and AP activity according to the manufacture instruction. Data normalized as fold activation versus vehicle (DMSO) were fitted using a four-parameter dose- response curve to calculate the EC ₅₀ of the different compounds .

Growth inhibition assay

Given that REV-ERB target genes include several metabolic regulators, such as Pgc-ΐα and Nampt, it was decided to test the cell proliferation with a method that is independent from the metabolic state of the cell.

The CyQUANT© Cell Proliferation Assay Kit (Invitrogen) was used, an assay that has a linear detection range extending from 50 or fewer to at least 250,000 cells. The CyQUANT® method is rapid, does not rely on cellular metabolic activity, and uses a proprietary green fluorescent dye, CyQUANT© GR dye, which exhibits strong fluorescence enhancement when bound to cellular nucleic acids .

Frozen cells are simply thawed and lysed by addition of a buffer containing the CyQUANT®.

For the assay, tumorigenic breast cancer cells BT-474 cells were seeded at 2500 cells per well in a 96-well plate and incubated over-night at 3 °C. Then, fresh medium containing different concentration of the compounds or vehicle (DMSO) was added and cells were growth 48 h at 37°C. Finally, cells were frozen at 80°C and then processed according to the manufacture instructions. A minimum of triplicate data for each dose was used for the analysis.

Data were collected and analyzed with Prism 5 software to calculate the growth inhibition curve.

In particular, values obtained from the DMSO treated cells was set at 100% of growth. Data from treatment of cells with serial dilutions of the compounds were normalized versus the DMSO group and fitted using a four- parameter dose-response curve.

GI ₅ o was calculated as the concentration of compound that gives a response half way between bottom and top plateaus of the fitted curve.

The bottom plateaus of the fitted C11 VΘ ciS USed to calculate the Growth Inhibition max (GI _max ) , defined as the percentage of the reduction of cells after 48 h upon a saturating dose of compound. The results obtained are reported in Table 28 below.

Biological activities of the compounds of the examples

The different compounds were tested for their ability to inhibit the growth of the tumorigenic breast cancer cells BT-474 and for their antagonistic activity toward REV-ERB transcriptional repression, as described in the biological method section. The results are illustrated in Table 28.

Table 28

Cell Growth REV-ERB

Inibition antagonism

GI50

Example

(μΜ) Imax ( % ) EC50 (μΜ)

1 18 72% 25

2 30 55% 45

3 14 95% 20

4 30 73% 47

c, 26 75% 43

7 18 70% 24 9 30 50% 50

10 15 70% 25

11 24 70% 40

12 23 77% 40

14 19 82% 23

17 18 90% 21

18 2 95% 8

19 5 90% 11

20 11 92% 12

21 50 76% 35

22 14 80% 15

23 10 90% 10

25 18 70% 29

27 12 70% 16

30 3 95% 6

32 1 97% 2

33 30 70% 38

For the cell growth inhibition (GI) the growth inhibition 50 (GI ₅₀ ) and the growth inhibition max (GI _max ) are reported. GI ₅₀ corresponds to the concentration of compound that gives a response half between the Top (no inhibiti on=percentage of cells equal to DMSO group) and Bottom (percentage of cells after 48 h treatment) plateaus of the fitted curves. The bottom plateaus of the curve was used to calculate the Growth Inhibition max (GI _mnx ), defined as the percentage of the reduction of cells after 48 h upon a saturating dose of the administered compound. Compounds with a GI ₅ o <100μΜ were also tested for their antagonistic activity toward REV-ERB . For these compounds, the EC ₅₀ value is provided, calculated as the concentration of compound that gives a response half between the bottom (expression of the reporter in absence of compound) and the top (expression of the reporter at saturating doses of compound) plateaus of the fitted curves (see biological method section for a description of the reported assay) . n.d. = not determined; n.t. = not tested.

Gene expression analysis of endogenous REV-ERB target enes after treatment with the compound of example 1

In order to test the effect of the compound of example 1 on the endogenous REV-ERB mediated transcription, BT-474 cells were treated 24 h with different doses of the compound of the example 1 and then processed for RNA extraction .

Total RNA was extracted with Trizol reagent (Invitrogen) according to the manufacture instruction. One microgram of RNA was retro-transcribed with VILO retrotranscription mix (Invitrogen) and subsequently analyzed by qPCR as described in Grimaldi et al . , Cell Metab., 2010; 12:509-520.

The REV-ERB targets Perl, Bmall, Nampt, and p21 were analyzed. Gapdh gene was used to normalize the data, while Hprtl gene was used as independent REV-ERB gene (negative control ) .

Primers used for analysis are listed in Table 29.

Table 29

Indeed, example 1 induced in a dose-dependent manner the expression of REV-ERBs endogenous targets involved in circadian regulation (Perl and Bmall), metabolism (Nampt) and cell cycle (p21), while it showed negligible effects on the REV-ERB independent gene Hprtl. The results obtained are illustrated in Figure 1 Values are presented as Relative expression, calculated versus the normalizing gene Gapdh, and shown, as mean ± SEM from at least 3 independent experiments. The expression of the REV-ERBs independent gene, Hprtl, was used as negative control.

Growth Inhibition of different tumor _ce11_ lines after treatment with the compound of example 1

To test if the growth inhibition activity of the compound of example 1 was limited to breast cancer BT-474 cells, or if it could be generalized in other tumor cells from different tissues, the GI50 of compound of example 1 was tested in several cell lines. In addition, because biological data suggested a p53-independent activity of the compound of example 1, cells with a different status of the tumor suppressor p53 protein were exploited.

The results are illustrated in Table 30.

Table 30

Cell line Origin p53 status GI50 (μΜ)

HCT116 Colorectal Wi Id-Type 19

carcinoma

HCT116-E6 Colorectal No protein 20

carcinoma expression

CaC02 Colorectal No protein 18

adenocarcinoma expression

WiDr Colon Mutant- 12

adenocarci oma. protein Colo-205 Colon Mutant 30

metastatic protein

HepG2 Liver Wild-Type 10

hepatocellular

carcinoma

SK-Hepl Liver Wild-Type 50

adenocarcinoma

Hep3B Liver No protein 10

hepatocellular expression

carcinoma

HuH7 Liver Mutant 8

hepatocellular protein

carcinoma

Indeed, the compound of example 1 displayed growth inhibition activity in different tumor cell lines, independently from the expression (status) of the tumor suppressor p53 (i.e. cells expressing a wild-type or mutated p53 protein, and cells in which p53 expression is ablated) .

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table lb

Table 16

Table 17

Table 18

Table 19

Table 20

to to CM

H + !— 1

cd f¾ 4-1 0) 3 CM ^ ,Q

— - i¾ o 0 rH

H ίπ ϋ o . 3 υ

m to

Ϊ3

K

u

Table 21

able 22

7able 23

UPLC/MS

Aldehyde Molecular Molecular

MW Name E-NMR [m/z, rt Intermediate Structure Formula

(min) ]

^X H N R (400 MHz, CDC1 ₃ ) δ

10.05 (s , 1H) , 7.87

7.85 (ra, 1H) , 7.79 (dt, J

3 - ( 1 - 204

= 7.5, 1.5 Hz, 1H) , 7.64

ridyl

C ₁₃ H ₁₇ NO 203.13 pipe

(d, J = 7.6 Hz, 1H) , 7.50 [M+H] \ methyl )

(t, J = 7.6 Hz, 1H) , 3.56

benzaldehyde 1.12

(s, 2H) , 2.41 (bs, 4H) ,

1.67 - 1.65 (m, 4H) , 1.50

- 1.44 (m, 2H) . ^'

4- t (4- 219 raethylpipera

26 ^h

C ₁₃ H _le N ₂ 0 218.14 zin- 1- [M+H] \

yl) methyl] 1.10 benzaldehyde

H NMR (400 MHz , CDC1 ₃ ) δ

10.40 (s, 1H) , 7.90 (dd,

2 - [ ( -methyl J = 7.6, 1.5 Hz, 1H) , 219

27 piperazin-1- 7.61 - 7.52 (i, 1H) , 7.48

C ₁₃ H ₁₈ N ₂ 0 218.14 [M+H] ⁺ , yl ) methyl] (t, J = 7.5 Hz, 1H) , 7.41

benzaldehyde - 7.35 (m, 1H) , 3.71 (s, 1.26

2H) , 2.45 2.26 (bs ,

3H) , 2.18 (s, 3H)

Table 24

This intermediate was synthesized following the general procedure for the synthesis of aldehydes Formula lie , with a slight modification in step 2 in which were used as starting material methyl ( dimethoxyphosphoryImethyl) benzoate and 1, 4-dioxaspiro [4.5] decan-8-one in the presence of NaH .0 equi . ) as base .

Table 25

Table 26

Table 27