WO2020120539A1 - New pyrrolidine-2-carboxylic acid derivatives for treating pain and pain related conditions - Google Patents

New pyrrolidine-2-carboxylic acid derivatives for treating pain and pain related conditions Download PDF

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Publication number
WO2020120539A1
WO2020120539A1 PCT/EP2019/084577 EP2019084577W WO2020120539A1 WO 2020120539 A1 WO2020120539 A1 WO 2020120539A1 EP 2019084577 W EP2019084577 W EP 2019084577W WO 2020120539 A1 WO2020120539 A1 WO 2020120539A1
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Prior art keywords
methyl
pyrrolidine
dimethylamino
carboxylic acid
phenylcyclohexyl
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PCT/EP2019/084577
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French (fr)
Inventor
Anita Wegert
Carmen ALMANSA-ROSALES
Antoni Torrens-Jover
Menno-Cornelis-Franciscus MONNEE
Wouter DE GRAAF
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Esteve Pharmaceuticals, S.A.
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Publication of WO2020120539A1 publication Critical patent/WO2020120539A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new compounds that show dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels, and the m-opiod receptor (MOR or mu-opioid).
  • VGCC voltage-gated calcium channels
  • MOR or mu-opioid m-opiod receptor
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid agonists opioid agonists
  • calcium channel blockers and antidepressants
  • antidepressants but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.
  • Voltage-gated calcium channels are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et al.; Pharmacol. Rev.; 2015; 67; 821-870).
  • the VGCC are assembled through interactions of different subunits, namely a1 (Caval), b (CavP) a2d (Cava23) and g (Ca v y).
  • the a1 subunits are the key porous forming units of the channel complex, being responsible for Ca 2+ conduction and generation of Ca 2+ influx.
  • VGCC can be subdivided into low voltage-activated T-type (Ca v 3.1 , Ca v 3.2, and Ca v 3.3), and high voltage-activated L- (Ca v 1.1 through Ca v 1.4), N- (Ca v 2.2), P/Q-(Ca v 2.1), and R-(Ca v 2.3) types, depending on the channel forming Cava subunits.
  • Current therapeutic agents include drugs targeting L-type Cav1.2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension.
  • T-type (Cav3) channels are the target of ethosuximide, widely used in absence epilepsy.
  • Ziconotide a peptide blocker of N-type (Cav2.2) calcium channels, has been approved as a treatment of intractable pain.
  • the Ca v 1 and Ca v 2 subfamilies contain an auxiliary a2d subunit which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain (Perret and Luo, 2009; Vink and Alewood; British J. Pharmacol.; 2012; 167; 970- 989).
  • a2d subunits each encoded by a unique gene and all possessing splice variants.
  • Each a2d protein is encoded by a single messenger RNA and is post-translationally cleaved and then linked by disulfide bonds.
  • Four genes encoding a2d subunits have now been cloned.
  • the a2d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution.
  • the a2d-2 and a2d-3 subunits were subsequently cloned from brain.
  • the most recently identified subunit, a2d-4 is largely non-neuronal.
  • the human a2d-4 protein sequence shares 30, 32 and 61 % identity with the human a2d-1 , a2d-2 and a2d-3 subunits, respectively.
  • the gene structure of all a2d subunits is similar. All a2d subunits show several splice variants (Davies et al.; Trends Pharmacol. Sci.; 2007; 28; 220-228; Dolphin, A. C.; Nat. Rev. Neurosci.; 2012; 13; 542-555; Dolphin, A.C.; Biochim. Biophys. Acta; 2013; 1828; 1541- 1549).
  • the Ca v a23-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009; Vink and Alewood, 2012).
  • Biochemical data have indicated a significant Ca v a23-1, but not Ca v a23-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development.
  • DRG dio root ganglia
  • blocking axonal transport of injury-induced DRG Ca v ⁇ x 2 5-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca v ⁇ x25-1 subunit contributes to neuropathic allodynia.
  • the Ca v ⁇ x25-1 subunit (and the Ca v ⁇ x25-2, but not Ca v ⁇ x25-3 and Ca v ⁇ x25-4, subunits) is the binding site for gabapentin which has anti-allodynic/hyperalgesic properties in patients and animal models.
  • injury-induced Ca v ⁇ x25-1 expression correlates with neuropathic pain, development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability
  • injury-induced Ca v ⁇ x25-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn.
  • Intrathecal antisense oligonucleotides against the Ca v ⁇ x25-1 subunit can block nerve injury-induced Ca v ⁇ x25-1 upregulation and prevent the onset of allodynia and reserve established allodynia.
  • the a2d subunits of VGCC form the binding site for gabapentin and pregabalin which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations.
  • the binding of gabapentin and pregabalin to the Ca v ⁇ x25-1 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management.
  • Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009; Vink and Alewood, 2012, Zamponi et al., 2015).
  • MOR m-opioid receptor
  • MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain.
  • the finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 113-6 (2005)].
  • prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. Consequently, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.
  • Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity.
  • the effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect.
  • Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents.
  • multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al.; Lancet Neurol.; 2013; 12(1 1); 1084-1095). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al; J. Pharmacol. Exp. Ther.; 2011 ; 337; 312-320; Zhang et al.; Cell Death Dis.; 2014; 5; e1138; Gilron et al., 2013).
  • An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008).
  • the compounds of the present invention having affinity for the a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels, additionally have affinity towards the m-receptor and are, thus, more effective to treat chronic pain.
  • the present invention relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels) which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).
  • m-receptor agonist and blocker of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).
  • the present invention discloses novel compounds with dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltagegated calcium channels, and the m-opiod receptor (MOR or mu-opioid), thus resulting in a dual activity for treating pain and pain related disorders.
  • VGCC voltage-gated calcium channels
  • MOR or mu-opioid m-opiod receptor
  • the main aspect of the present invention is related to compounds of general formula (I):
  • Wi is -0-, -NR a or -CH 2 -;
  • R a is a hydrogen atom or a branched or unbranched C1-6 alkyl radical; n and m are independently from one another 0 or 1 ;
  • Ri, R ⁇ and R 4 are independently from one another a hydrogen atom; a branched or unbranched C1-6 alkyl radical; a halogen atom; a -C(0)H radical; a branched or unbranched C1-6 alkoxy radical; a -NR b R c radical; a -CN radical; a hydroxyl radical; or a Ci- 6 haloalkyl radical;
  • R b and R c are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical
  • R3 is selected from: W 2 is -C(O)-, -CH 2 - or bond;
  • A is C or N; the dotted line represents an optional double bond;
  • R3 a and R 3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or
  • R3 a and R3 b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;
  • R3 C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - CN radical; a Ci-e haloalkyl radical; or a -NR3 d R3 e radical;
  • R 3d and R3 e are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • Re is a hydrogen atom or a -C(0)Rs a radical
  • Re a is a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(ChbJrNRs b Rs c radical; a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 5g -(CH2)s-CH(R 5f )-NR5eR5d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
  • Re b , e c , Re d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -CORs h radical
  • Re h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Re is a -C(0)R 6a radical; an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
  • R 6a is a hydroxyl radical, a branched or unbranched Ci- 6 alkoxy radical; a -(ChhX- NRebRec radical; a -0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 6g -(CH2)v-CH(R 6f )- NR6eR6d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
  • R 6b , Re c , R 6d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -COR 6h radical
  • Re h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • Another aspect of the invention refers to the use of such compounds of general formula (I) for the treatment and/or prophylaxis of a2d mediated disorders and more preferably for the treatment and/or prophylaxis of disorders mediated by the a2d-1 subunit of voltage-gated calcium channels and the m-receptor.
  • the compounds of the present invention are particularly suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain and pain related or pain derived conditions.
  • a further aspect of the invention refers to pharmaceutical compositions comprising one or more compounds of general formula (I) with at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions in accordance with the invention can be adapted in order to be administered by any route of administration, be it orally or parenterally, such as pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with the invention may be adapted for topical or systemic application, particularly for dermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral application.
  • the invention first relates to compounds of general formula (I)
  • Wi is -0-, -NR a 01- -CH2-;
  • R a is a hydrogen atom or a branched or unbranched C1 -6 alkyl radical; n and m are independently from one another 0 or 1 ;
  • Ri, R ⁇ and R4 are independently from one another a hydrogen atom; a branched or unbranched C1 -6 alkyl radical; a halogen atom; a -C(0)H radical; a branched or unbranched Ci-e alkoxy radical; a -NR b R c radical; a -CN radical; a hydroxyl radical; or a Ci- 6 haloalkyl radical;
  • R b and R c are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • R 3 is selected from
  • W 2 is -C(O)-, -CH 2 - or bond
  • A is C or N; the dotted line represents an optional double bond;
  • R 3a and R 3b are independently from one another a hydrogen atom or a branched or unbranched C 1-6 alkyl radical; or
  • R 3a and R 3b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched C 1-6 alkyl radical or a branched or unbranched C 1-6 alkoxy radical;
  • R 3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched C 1-6 alkyl radical; a branched or unbranched C 1-6 alkoxy radical; a - CN radical; a C 1-6 haloalkyl radical; or a -NR d R e radical;
  • R 3d and R 3e are independently from one another a hydrogen atom or a branched or unbranched C 1-6 alkyl radical; f3 ⁇ 4 is a hydrogen atom or a -C(0)Rs a radical;
  • Re a is a hydrogen atom; a branched or unbranched Ci- 6 alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(Chh -NRs b Rs c radical; a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 5g -(CH2)s-CH(R 5f )-NR5eR5d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
  • Re b , Re c , Re d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -CORs h radical
  • Re h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Re is a -C(0)R 6a radical; an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
  • R 6a is a hydroxyl radical, a branched or unbranched Ci-e alkoxy radical; a -(ChhX- NRebRec radical; a -0CH(CH 3 )0C(0)CH(CH 3 ) 2 radical; or a -NR 6g -(CH2)v-CH(R 6f )- NR6eR6d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
  • R 6b , Re c , R 6d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -COR 6h radical
  • Re h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the compounds of the invention are also meant to include isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms.
  • compounds having the present structures except for the replacement of at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by 13 C- or 14 C-enriched carbon, or the replacement of at least one nitrogen by 15 N-enriched nitrogen are within the scope of this invention.
  • the compounds of general formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • Halogen or“halo” as referred in the present invention represents fluorine, chlorine, bromine or iodine.
  • halo When the term“halo” is combined with other substituents, such as for instance“Ci-e haloalkyl” or“Ci-e haloalkoxy” it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom.
  • a leaving group is a group that in a heterolytic bond cleavage keeps the electron pair of the bond.
  • Suitable leaving groups are well known in the art and include Cl, Br, I and -O- SO2R’, wherein R’ is F, Ci-4-alkyl, Ci-4-haloalkyl, or optionally substituted phenyl.
  • the preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate.
  • Protecting group is a group that is chemically introduced into a molecule to avoid that a certain functional group from that molecule undesirably reacts in a subsequent reaction. Protecting groups are used, among others, to obtain chemoselectivity in chemical reactions.
  • the preferred protecting group in the context of the invention are Boc (te/f-butoxycarbonyl) or Teoc (2-(trimethylsilyl)ethoxycarbonyl).
  • C1 -6 alkyl are saturated aliphatic radicals. They may be unbranched (linear) or branched and are optionally substituted. Ci- 6 -alkyl as expressed in the present invention means an alkyl radical of 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Preferred alkyl radicals according to the present invention include but are not restricted to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, n-pentyl, 1 , 1- dimethyl propyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl or 1-methylpentyl.
  • the most preferred alkyl radical are C1-4 alkyl, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl or 1 , 1 -dimethylethyl.
  • Alkyl radicals are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci- 6 -alkoxy radical, a branched or unbranched Ci- 6 -alkyl radical, a Ci- 6 -haloalkoxy radical, a Ci- 6 -haloalkyl radical, CN, a trihaloalkyl radical, hydroxyl group and an amino radical such as -NR’R” wherein R’ and R” are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical .
  • Ci- 6 alkoxy as referered to in the present invention, is understood as meaning an alkyl group as defined above attached via oxygen linkage to the rest of the molecule.
  • alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy or tert-butoxy.
  • Heterocycloalkyl as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), generally 5, 6 or 7 membered cyclic hydrocarbons which can optionally be unsubstituted, mono- or polysubstituted and which have at least one heteroatom in their structure selected from N, O or S.
  • heterocycloalkyl radical preferably include but are not restricted to pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyrane, tetrahydrofurane, dioxane, dioxolane, oxazolidine, piperidine, piperazine, homopiperazine, morpholine, azepane or diazepane.
  • Heterocycloalkyl radicals are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci- 6 -alkyl radical, a branched or unbranched Ci- 6 -alkoxy radical, a Ci- 6 -haloalkoxy radical, a Ci- 6 -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. More preferably heterocycloalkyl in the context of the present invention are 6 or 7-membered ring systems optionally at least monosubstituted.
  • Heteroaryl as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and contain one or more heteroatoms from the group consisting of N, O or S and may optionally be mono- or polysubstituted by substituents independently selected from a halogen atom, a branched or unbranched Ci- 6 -alkyl radical, a branched or unbranched Ci- 6 -alkoxy radical, a Ci-e- haloalkoxy radical, a Ci- 6 -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group.
  • heteroaryls include but are not restricted to furan, benzofuran, thiophene, thiazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, imidazole, imidazo[4,5-b]pyridine, isoxazole, oxadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole or quinazoline. More preferably heteroaryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.
  • Heterocyclic system comprise any saturated, unsaturated or aromatic carbocyclic ring systems which are optionally at least mono substituted and which contain at least one heteroatom as ring member.
  • Preferred heteroatoms for these heterocyclyl groups are N, S or O.
  • Preferred substituents for heterocyclyl radicals, according to the present invention are F, Cl, Br, I, NH2, SH, OH, SO2, CF 3 , carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, -SO2NH2, C 1-6 alkyl and/or Ci- 6 -alkoxy.
  • ring system refers to a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.
  • The“ring system” thus defined comprises saturated, unsaturated or aromatic carbocyclic rings which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted and may be joined to other carbocyclic ring systems such as aryl radicals, heteroaryl radicals, cycloalkyl radicals etc.
  • room temperature in the context of this invention is to be understood as temperature between 20 and 25°C.
  • salt is to be understood as meaning any form of the active compound according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • a counter-ion a cation or anion
  • complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
  • the definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to “pharmacologically acceptable salts”.
  • pharmaceutically acceptable salts in the context of this invention means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly as a result of the counter-ion) when used in an appropriate manner for a treatment, particularly applied or used in humans and/or mammals.
  • physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention - normally an acid (deprotonated) - such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used on humans and/or mammals.
  • Salts with alkali and alkali earth metals are particularly preferred, as well as those formed with ammonium cations (NhV).
  • Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium.
  • These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals.
  • This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e.
  • salts of a specific active compound with physiologically tolerated organic or inorganic acids particularly when used on humans and/or mammals.
  • this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • solvate is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds of the invention: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (april 2002).
  • any compound that is a prodrug of a compound of formula (I) is within the scope of the invention.
  • Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Wi is -0-.
  • Wi is -NR a -.
  • R a is a branched or unbranched Ci-e alkyl radical; more preferably methyl.
  • Wi is -CH2-.
  • n 0.
  • n and m are 0.
  • Ri, R ⁇ and R 4 are independently from one another a hydrogen atom; a branched or unbranched C1 -6 alkyl radical, more preferably methyl; a halogen atom, more preferable fluorine or chlorine; a -C(0)H radical; a branched or unbranched C1 -6 alkoxy radical, more preferably methoxy; a -CN radical; or a Ci- 6 haloalkyl radical, more preferably a -CF 3 radical.
  • R3 is in meta position.
  • R3 is selected from: In another particular and preferred embodiment of the invention R3 a and R3 b are independently from one another a C1 -6 alkyl radical, more preferably methyl.
  • R3 a and R3 b together with the bridging nitrogen form an unsubstituted 4, 5 or 6-membered heterocycloalkyl radical, more preferably azetidine.
  • R3 C is a hydrogen atom; a hydroxyl radical; or a halogen atom, more preferably fluorine or chlorine.
  • Rs is a hydrogen atom.
  • Rs a is a branched C1-6- alkoxy radical; a -(Chh -NRs b Rs c radical, more preferably -CH2-NH2; or a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical.
  • both Rs b and Rs c are a hydrogen atom.
  • R 6a is a hydroxyl radical, an unbranched Ci- 6 alkoxy radical, more preferably methoxy or ethoxy; or a -NH-(CH2)4- CH(COOH)-NH 2 radical.
  • a particularly preferred embodiment of the invention is represented by compounds of general formula (I’a):
  • n 0 or 1 ;
  • Ri are independently from one another a hydrogen atom; a branched or unbranched Ci- 6 alkyl radical, more preferably methyl; a halogen atom, more preferable fluorine or chlorine; a -C(0)H radical; a branched or unbranched Ci- 6 alkoxy radical, more preferably methoxy; a -CN radical; or a Ci- 6 haloalkyl radical, more preferably a -CF 3 radical;
  • R 3 is selected from:
  • R 3a and f3 ⁇ 4 3b are independently from one another a Ci-e alkyl radical, more preferably methyl or R3 a and R 3b together with the bridging nitrogen form an unsubstituted 4, 5 or 6-membered heterocycloalkyl radical, more preferably azetidine;
  • R3 C is a hydrogen atom; a hydroxyl radical; or a halogen atom, more preferably fluorine or chlorine;
  • Re is a hydrogen atom
  • Re a is a branched Ci- 6 -alkoxy radical; a -(CH 2 ) r -NR5 b R5 c radical, more preferably -CH 2 - NH 2 ; or a -0CH(CH 3 )0C(0)CH(CH 3 )2 radical;
  • Re b and Rs c are a hydrogen atom
  • R 6a is a hydroxyl radical, an unbranched Ci- 6 alkoxy radical, more preferably methoxy or ethoxy; or a -NH-(CH 2 )4-CH(COOH)-NH 2 radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the compounds of the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of double bonds (e.g. Z, E).
  • the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • the compounds of general formula (I) are represented by the S,S-isomers according to the following subformula la:
  • VGCC voltage-gated calcium channels
  • MOR or mu-opioid m-opiod receptor
  • the invention refers to the processes for the preparation of the compounds of general formula (I).
  • Method A represents first processes for synthesizing compounds according to general formula (I).
  • Method A allows the preparation of: • compounds of general formula (A1) that is compounds of general formula (I) where Wi is -CH2-, m is 0 and n is 0, namely Method A1 ;
  • Ri, R 2 , R 3 , R 4 , Rs and R6 have the meanings as defined above, can be prepared by means of a Wittig reaction by treating a pyrrolidyl-ketone of general formula (lla):
  • Ri , R2, R3 and R4 have the meanings as defined above and Z represents triphenylphosphonium salt; in the presence of a suitable base, such as sodium hydride, and with stirring at suitable temperature, for example 70 °C, followed by hydrogenation of the formed alkene with hydrogen and a suitable catalyst, such as platinum(IV)oxide in a suitable solvent, like EtOAc (ethyl acetate), and with heating at a suitable temperature, like 60 °C.
  • a suitable base such as sodium hydride
  • Ri , R 2 , R 3 , R 4 , Rs, and R6 have the meanings as defined above, can be prepared by treating a pyrrolidinol derivative of general formula (Mb):
  • Ri , R2, R3 and R4 have the meanings as defined above; under Mitsunobu conditions, with a suitable coupling agent, such as cyanomethylenetributylphosphorane (CM BP), or diisopropyl azodicarboxylate (DIAD) in the presence of a phosphine, such as triphenylphosphine (PhbP), in a suitable solvent, such as toluene or tetrahydrofuran (THF), at a suitable temperature, between room temperature and 100 °C, preferably room temperature.
  • CM BP cyanomethylenetributylphosphorane
  • DIAD diisopropyl azodicarboxylate
  • a phosphine such as triphenylphosphine (PhbP)
  • a suitable solvent such as toluene or tetrahydrofuran (THF)
  • Ri, R 2 , R 3 , R 4 , Rs, and R6 have the meanings as defined above, can be prepared by means of alkylation of a suitable pyrrolidine derivative of general formula (Mb):
  • Ri , R2, R3 and R 4 have the meanings as defined above and X stands for halogen; in the presence of a base such as sodium hydride, in a suitable solvent, for example N,N- dimethylformamide (DMF) or THF, at a suitable temperature, such as between 0 °C and room temperature.
  • a base such as sodium hydride
  • a suitable solvent for example N,N- dimethylformamide (DMF) or THF
  • Ri , R 2 , R 3 , R 4 , Rs, R 6 and R a have the meanings as defined above, can be prepared by means of a Buchwald-Hartwig coupling reaction of a suitable pyrrolidine- amine of general formula (lie):
  • Ri , R2, R3 and R4 have the meanings as defined above and X stands for halogen; using suitable reagents, like 2-dicyclohexylphosphino-2',6'-diisopropoxy biphenyl (Ru- Phos), cesium carbonate and a suitable palladium catalyst, for example Pd2(dba)3, with heating under microwave at a suitable temperature, like 60 °C,
  • suitable reagents like 2-dicyclohexylphosphino-2',6'-diisopropoxy biphenyl (Ru- Phos), cesium carbonate and a suitable palladium catalyst, for example Pd2(dba)3, with heating under microwave at a suitable temperature, like 60 °C,
  • a compound of general formula (A5) as defined above: wherein Ri , R 2 , R 3 , R 4 , Rs, R 6 and R a have the meanings as defined above, can be prepared by reaction of a suitable amine of general formula (lid):
  • Ri , R2, R3 and R 4 have the meanings as defined above and X stands for halogen; using suitable reagents, such as Pd2(dba)3 and 2-(dicyclohexylphosphino)-3,6- dimethoxy-2'-4'-6'-tri-i-propyl-1 ,1 '-biphenyl (Brett-Phos) or 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-Phos) in suitable solvents, such as a,a,a-trifluorotoluene or 1 ,4-dioxane, at a suitable temperature between 100 °C to 1 10 °C, and optionally under microwave heating.
  • suitable solvents such as a,a,a-trifluorotoluene or 1 ,4-dioxane
  • Ri, R 2 , R 3 , R 4 , Rs, R 6 and R a have the meanings as defined above, can be obtained by means of reductive amination reactions of a suitable amine of general formula (lie):
  • Ri, R 2 , R 3 and R 4 have the meanings as defined above; using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture, at a suitable temperature, such as room temperature.
  • a reducing reagent such as sodium triacetoxyborohydride
  • a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture
  • Method B represents an alternative process for synthesizing compounds according to general formula (I) from a compound of general formula (V):
  • Ri, R 2 , R 4 , Rs, R6, Wi, m and n have the meanings as defined above and Y represents a group that can be converted into R 3 , being R 3 : W 2 is -C(O)-, -CH 2 - or bond;
  • A is C or N; the dotted line represents an optional double bond;
  • Method B allows the preparation of:
  • Suitable reagents such as tris(dibenzylideneacetone)-dipalladium (0) (Pd 2 (dba) 3 ) , 2-dicyclohexyl phosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and sodium te/f-butoxide, in suitable solvents, such as 1 ,4-dioxane, and with conventional heating at a suitable temperature, for example 110 °C and optionally under microwave heating, or
  • phosphine ligand such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and cesium carbonate
  • suitable solvent mixtures such as THF and water, and with conventional heating at a suitable temperature, for example 80 °C or
  • Y is an aldehyde by reaction with a compound of general formula (VI) using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture, at a suitable temperature, such as room temperature.
  • a suitable solvent such as tetrahydrofuran
  • a compound of general formula (B2) wherein W2 is a -CH2- can be obtained from a compound of general formula (V) wherein Y is a halogen atom, preferably a bromine atom, by reaction with a suitably olefin derivative of general formula (X) or (XI):
  • a suitable catalyst such as palladium(ll) acetate and phosphine ligand, such as tri-o-tolylphosphine
  • an organic base such as N,N- diisopropylethylamine (DIPEA)
  • DIPEA N,N- diisopropylethylamine
  • a compound of general formula (B3) wherein W2 is a -C(O)- can be obtained from a compound of general formula (V) wherein Y is a carboxylic acid by reaction with a compound of general formula (VI) using for example A/-[(dimethylamino)-1 /-/-1 ,2,3- triazolo-[4,5-Jb]pyridin-1-ylmethylene]-/ ⁇ /-methylmethanaminium hexafluorophosphate N- oxide (HATU) as coupling reagent in a suitable solvent, like DMF, at a suitable temperature, such as room temperature.
  • a suitable solvent like DMF
  • the intermediate of general formula (V) can be prepared by reaction of a compound of general formula (lla), (Mb), (lie) or (lid):
  • a compound where R6 is carboxylic acid can be esterified by reaction with thionyl chloride, in a suitable alcohol solvent, for example n-butanol, at a suitable temperature, such as between 0 °C and room temperature.
  • a compound where F3 ⁇ 46 is carboxylic acid can be converted to an amide by reaction with a suitable amine, and using suitable coupling reagents, such as N- (3-dimethylaminopropyl)-/V'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
  • suitable coupling reagents such as N- (3-dimethylaminopropyl)-/V'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
  • a compound where f3 ⁇ 4 6 is tetrazole can be prepared from a compound where R 6 is nitrile by the reaction with sodium azide and ammonium chloride in DMF at elevated temperature, for example 80 °C.
  • a compound where f3 ⁇ 4 is hydrogen can be converted to a compound where Rs is an amide group with a suitable carboxylic acid, using suitable coupling reagents, such as A/-(3-dimethylaminopropyl)-/ ⁇ /'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
  • suitable coupling reagents such as A/-(3-dimethylaminopropyl)-/ ⁇ /'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
  • a compound where Rs is hydrogen can be converted to a compound where Rs is a carbamate, by means of a reaction with a suitable reagent, for example 1- [[(4-nitrophenoxy)carbonyl]oxy]ethyl 2-methylpropanoate, in the presence of a suitable organic base, such as triethylamine, in a solvent such as dichloromethane with stirring at room temperature.
  • a suitable reagent for example 1- [[(4-nitrophenoxy)carbonyl]oxy]ethyl 2-methylpropanoate
  • a suitable organic base such as triethylamine
  • the compounds of general formula (X) and (XI) can be obtained from the compounds of general formula (VIII) and (IX), respectively, by means of a Wittig type reaction, using a suitable phosphonium salt, for instance methyltriphenylphosphonium bromide, in the presence of a suitable base, for example potassium tert- butoxide, in an appropriate solvent like THF, with stirring at room temperature or elevated temperature, for example 50 °C.
  • a suitable phosphonium salt for instance methyltriphenylphosphonium bromide
  • a suitable base for example potassium tert- butoxide
  • THF an appropriate solvent like THF
  • protecting groups such as for example Boc ( tert - butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, methyl or tert- butyl ester for the carboxylic acid group and common silyl protecting groups for the protection of the hydroxyl group.
  • Boc tert - butoxycarbonyl
  • Teoc 2-(trimethylsilyl)ethoxycarbonyl)
  • benzyl for the protection of amino groups
  • methyl or tert- butyl ester for the carboxylic acid group
  • common silyl protecting groups for the protection of the hydroxyl group.
  • the simultaneous removal of a methyl ester and Boc-group may be carried out in aqueous HCI, optionally in the presence of a suitable co-solvent like acetonitrile, and at a suitable reaction temperature, e.g. heating at 60 °C.
  • a compound of general formula (I) can be obtained in enantiopure form by resolution of a racemic compound of general formula (I) either by chiral preparative HPLC, or by crystallization of a diastereomeric salt or co-crystal.
  • the resolution step can be carried out at a previous stage, using any suitable protected intermediate.
  • R 5 and/or contains a Protecting Group (PG), such as Boc or 2-(trimethylsilyl)ethylcarbamate), or R 5 and/or R 6 represents a moiety which can be easily converted, can be used as intermediates useful for the preparation of other compounds of general formula (I) as defined above.
  • PG Protecting Group
  • these intermediate compounds of general formula (I) are selected from:
  • the invention also relates to the therapeutic use of the compounds of general formula (I).
  • compounds of general formula (I) show a strong affinity both to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels as well as to the m-receptor and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments.
  • compounds of general formula (I) are suitable for the treatment and/or prophylaxis of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression anxiety and attention-deficit-/hyperactivity disorder (ADHD).
  • ADHD attention-deficit-/hyperactivity disorder
  • the compounds of general formula (I) are especially suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripferal neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.
  • PAIN is defined by the International Association for the Study of Pain (IASP) as“an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.
  • compounds of the invention are used for the treatment and/or prophylaxis of allodynia and more specifically mechanical or thermal allodynia.
  • compounds of the invention are used for the treatment and/or prophylaxis of hyperalgesia.
  • compounds of the invention are used for the treatment and/or prophylaxis of neuropathic pain, central neuropathic pain and/or peripferal neuropathic pain, and more specifically for the treatment and/or prophylaxis of hyperpathia.
  • a related aspect of the invention refers to the use of compounds of general formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and the m-receptor, as explained before.
  • Another related aspect of the invention refers to a method for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d- 1 subunit of voltage-gated calcium channels and the m-receptor, as explained before comprising the administration of a therapeutically effective amount of a compound of general formula (I) to a subject in need thereof.
  • compositions which comprises at least a compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, isomer or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.
  • the pharmaceutical composition of the invention can be formulated as a medicament in different pharmaceutical forms comprising at least a compound binding to the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and the m-receptor and optionally at least one further active substance and/or optionally at least one auxiliary substance.
  • auxiliary substances or additives can be selected among carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, flavour conditioners such as sugars, antioxidants and/or agglutinants. In the case of suppositories, this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or carriers for parenteral application.
  • auxiliary materials and/or additives and the amounts to be used will depend on the form of application of the pharmaceutical composition.
  • composition in accordance with the invention can be adapted to any form of administration, be it orally or parenterally, for example pulmonarily, nasally, rectally and/or intravenously.
  • the composition is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.
  • composition of the invention can be formulated for oral administration in any form preferably selected from the group consisting of tablets, dragees, capsules, pills, chewing gums, powders, drops, gels, juices, syrups, solutions and suspensions.
  • the composition of the present invention for oral administration may also be in the form of multiparticulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.
  • Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays.
  • the compounds of the invention can be formulated as deposits in dissolved form or in patches, for percutaneous application.
  • the pharmaceutical compositions are in oral form, either solid or liquid.
  • Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in the normal pharmaceutical practice, in particular with an enteric coating.
  • compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form.
  • Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
  • the mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • CMBP Cyanomethylenetributylphosphorane
  • DIAD Diisopropyl azodicarboxylate
  • DIPEA /V,/V-Diisopropylethylamine
  • Method H Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelectTM CSH C18, 50 x 2.
  • Method J Apparatus: Agilent 1260 Bin.
  • Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Phenomenex GeminiNX C18, 50 x 2.0 mm, 3m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to 5% A, t3 .
  • MS parameters Source: ESI, Capillary voltage: 3000 V, Drying gas flow: 12 Umin, Nebulizer Pressure 60 psig, Drying Gas Temp: 350 °C, Fragmentor 70, MS scan: MS range 100-1000 (positive and negative mode), scan speed: 0.84 sec/cycle; Flow into MS 0.8 mUmin.
  • Intermediate 13 was prepared according to the method described for intermediate 12 using 4-bromobenzoic acid (150 mg, 0.746 mmol) and A/,/ ⁇ /-dimethyl-4-phenylpiperidin- 4-amine dihydrochloride (207 mg, 0.746 mmol). After stirring overnight at rt the mixture was concentrated. DCM (20 ml_) was added and the mixture was washed with water (2 x, each 20 ml_). The layers were separated (phase separator) and the organic layer was concentrated.
  • Intermediate 16 was obtained from intermediate 15 (400 mg, 1.024 mmol) and 10 eq. of formaldehyde (37 wt% solution in water) (0.491 mL, 6.53 mmol) using 2.5 eq. of AcOH (0.1 13 mL, 1.959 mmol) and sodium triacetoxyborohydride (543 mg, 2.56 mmol) according to the method for the preparation of intermediate 15.
  • DCM 50 mL
  • sat aqueous NaHCCh solution 50 mL
  • Crude yield 409 mg (99%).
  • Intermediate 18 was prepared according to the synthetic procedure as described for intermediates 3 and 9 starting from intermediates 13 (185 mg, 0.477 mmol) and 17 (150 mg, 0.477 mmol) using 0.08 eq. of X-Phos, 0.02 eq. of Pd2(dba)3, 1.2 eq. of sodium tert- butoxide with conventional heating at 110 °C for 1 h. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 12 g, gradient DCM / (5- 100% DCM/MeOH (9: 1)) in 25 Min) afforded 87 mg (19%) of the title compound as a glass-like solid. Purity according to LCMS: 67.5%. LCMS (Method B): Rt, 2.46 Min; ESI m/ . 621.4 [M+H] + .
  • Intermediate 20 was prepared according to the synthetic procedure described for intermediate 18 starting from intermediates 17 (439 mg, 1.397 mmol) and 19 (541 mg, 1.397 mmol) with conventional heating at 110 °C overnight. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 76 mg (8.7%) of the title compound as a glass-like solid. LCMS (Method B): Rt, 2.51 Min; ESI m/z. 621.5 [M+H] + .
  • Intermediate 21 was prepared according to the synthetic procedure for intermediate 4 starting from di-te/f-butyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (200 mg, 0.696 mmol) and methyl 3-chloro-5-hydroxybenzoate (130 mg, 0.696 mmol), using 1 eq. of DIAD and 1.2 eq. of triphenylphosphine with stirring at rt overnight. Purification (pre packed silica cartridge GraceResolvTM 24 g, gradient 5% EtOAc/heptane to 100% EtOAc in 35 Min) afforded 82 mg (25%) of the title compound as an oil.
  • Intermediate 23 was prepared according to the synthetic procedure for intermediate 12 starting from carboxylic acid 22 (73 mg, 0.165 mmol) and A/,/ ⁇ /-dimethyl-4- phenylpiperidin-4-amine dihydrochloride (45 mg, 0.165 mmol) in DMF (1 ml_), using 1 eq. of HATU and 3.5 eq. of TEA.
  • DCM 5 ml_
  • sat aqueous NaHCCh solution (10 ml_) were used for work-up/extraction.
  • the aqueous phase was separated (phase separator) and extracted with DCM (2 x, each 10 ml_).
  • the combined organic phases were concentrated and diluted with EtOAc (20 ml_).
  • A/,/ ⁇ /-dimethyl-4-phenylpiperidin-4-amine (196 mg, 0.959 mmol) was suspended in dry THF (2 ml_). Potassium (bromomethyl)trifluoroborate (193 mg, 0.959 mmol) and f-BuOH (500 pl_) were added and the suspension was stirred in a sealed reaction vial at 80 °C for 2 h. After cooling down to rt the mixture was concentrated. DCM ( ⁇ 5 ml_) was added and the white suspension was filtered over a nylon microfilter and the filtrate was concentrated to dryness.
  • Intermediate 32 was prepared from intermediates 25 (112 mg, 0.345 mmol) and 31 (1 11 mg, 0.266 mmol) according to the method described for intermediate 26 with heating overnight at 80 °C. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 12 g, gradient DCM / (5-100% DCM / (7 M NH 3 in MeOH) (9:1) in 25 Min, 100% DCM / (7 M NH 3 in MeOH) (9: 1) for 15 Min) afforded 91 mg (61 %) of the title compound as a glass-like solid. Purity according to LCMS: 92.1 %.
  • Intermediate 34 was obtained from intermediate 33 (128 mg, 0.376 mmol) and intermediate 24 (1 16 mg, 0.289 mmol) according to the method described for the preparation of intermediate 26.
  • Purification conditions flash column chromatography (pre-packed silica cartridge GraceResolvTM 12 g, gradient DCM / (5-100% DCM / (7 M NHs in MeOH) (9: 1)) in 25 Min, 100% DCM / (7 M NH 3 in MeOH (9: 1) for 15 Min). Yield: 57 mg (35%) of the title compound as a glass-like solid.
  • Purity according to LCMS 92.2%.
  • Intermediate 36 was prepared according to the synthetic procedure for intermediate 3 from intermediate 35 (97 mg, 0.251 mmol) and A/,/ ⁇ /-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (77 mg, 0.276 mmol), using 0.2 eq. of X-Phos, 0.05 eq. of Pd (dba) and 3 eq. of sodium tert- butoxide with conventional heating at 1 10 °C for 3 h. After cooling down to rt the mixture was concentrated to give the crude title compound which was used as such in the next step.
  • magnesium turnings (112 mg, 4.60 mmol; first grinded with a mortar and pestle to obtain gleaming metallic magnesium turnings) was suspended in dry THF (10 ml_). The resulting mixture was heated to 60 °C and iodine (crushed grain; 5 mg, 0.020 mmol) was added (not stirred for 5 min after the addition of the iodine). The reaction mixture was stirred for 1 h at 60 °C.
  • the aqueous phase was separated (including the solid residues) and extracted with Et2 ⁇ D (2 x).
  • the combined organic phases were washed with brine, dried with Na2SC>4, filtered and concentrated to dryness.
  • the crude material (1.1 1 g,‘120%’) was used as such for the next step.
  • Aryl ether intermediates 41-64 were prepared from 1-(te/f-butyl) 2-methyl (2S,4R)-4- hydroxypyrrolidine-1 ,2-dicarboxylate or 1-(te/f-butyl) 2-methyl (2S,4S)- 4- hydroxypyrrolidine-1 ,2-dicarboxylate and suitable phenol starting materials similar to the synthesis and purification method as described for intermediate 4 (Mitsunobu conditions, using DIAD and triphenylphosphine, Method M) and described for the preparation of intermediate 24, using CMBP (Method C). For LCMS analysis method B was used.
  • a capped reaction vial containing A/,/ ⁇ /-dimethyl-4-methylene-1-phenylcyclohexan-1- amine (1 g, 4.64 mmol) was flushed with nitrogen.
  • a solution of 9-BBN in THF 0.5 M, 13.0 mL, 6.5 mmol was added and the mixture was stirred at 75 °C for 3 h. Complete conversion of the starting material was observed on TLC (EtOAc/heptane, 1 :1). The solution was used as such for the next step.
  • Intermediate 123 was prepared from triflate 122 (450 mg, 0.89 mmol) and 1.2 eq. of intermediate 65 according to the method described for intermediate 66 (MW-heating for 4 h at 80 °C). Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 12 g, gradient 15% DCM to 100% DCM/MeOH (9: 1)) in 40 Min) gave 130 mg (25%) of the title compound.
  • intermediate 24 (929 mg, 2.322 mmol) and A/,/ ⁇ /-dimethyl-4-methylene-1-phenylcyclohexan-1 -amine (500 mg, 2.322 mmol) were dissolved in anh ACN (10 ml_) and the solution was flushed with nitrogen for 10 Min.
  • Tri- o-tolylphosphine (70.7 mg, 0.232 mmol), palladium(ll) acetate (26.1 mg, 0.116 mmol) and DIPEA (0.809 ml, 4.64 mmol) were added and the mixture was flushed with nitrogen again for 10 min, followed by MW-heating at 150 °C for 1 h.
  • intermediate 67 250 mg, 0.466 mmol was dissolved in anh ACN (3 ml_). The solution was cooled to 0 °C and 1.2 eq. of /V-iodosuccinimide (126 mg, 0.559 mmol) was added. The reaction mixture was then allowed to reach rt and stirring was continued for 20 h. The reaction mixture was diluted with EtOAc (40 ml_) and quenched by the addition of aqueous 5% sodium metabisulfite solution (50 ml_).
  • methyltriphenylphosphonium bromide (1.594 g, 4.46 mmol) was suspended in dry THF (10 ml_). The mixture was cooled to 0 °C, then 1.6 M n-butyllithium in hexanes (2.79 ml_, 4.46 mmol) was slowly added dropwise. The resulting orange suspension was stirred at rt for 60 min, forming a slightly turbid solution. Then at rt, a solution of 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexan-1-one (0.7 g, 2.97 mmol) in dry THF (5 ml_) was added, once more forming a thick suspension.
  • the resulting reaction mixture was heated to reflux temperature overnight, giving an almost clear solution.
  • the crude reaction mixture was quenched with water (20 ml_), and after the addition of EtOAc (10 ml_) the organic phase was separated.
  • the aqueous phase (pH ⁇ 9) was extracted once more with EtOAc (20 ml_).
  • the combined organic phases were extracted with aqueous 1 M KHSO4 solution (2 x, each 20 ml_).
  • the combined aqueous phases (pH ⁇ 1) were basified with aqueous 2 M NaOH solution and sat aqueous NaHCOs solution to pH ⁇ 10, forming a thick white precipitate.
  • the aqueous phase was extracted with EtOAc (2 x, each 50 ml_).
  • the organic layer of the first extraction was concentrated (to remove most of the THF) before combining with the organic layer from the second extraction.
  • the combined organic layers were washed with aqueous 1 M KHSCU solution (2 x, each 30 ml_).
  • the combined aqueous layers (pH ⁇ 1) were basified with 2 M aqueous NaOH solution (30 ml_) until pH ⁇ 10, forming a thick white precipitate.
  • the aqueous phase was extracted with EtOAc (2 x, each 50 ml_).
  • the combined organic layers were dried over Na 2 S0 4 and concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 373 mg (75%) of the title compound as an oil.
  • LCMS Methodhod A: Rt, 2.36 Min; ESI m/z ⁇ 250.1 [M+H] + , Cl-isotope pattern.
  • Intermediate 135 was prepared from intermediate 131 (500 mg, 2.143 mmol) and a solution of 9-BBN in THF (0.5 M, 6.5 ml_, 3.25 mmol) according to the method described for intermediate 65, and the solution was used directly for the next step.
  • Intermediate 136 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(4-fluorophenyl)- A/,A/-dimethylcyclohexan-1 -amine.
  • Intermediate 136 was prepared from intermediate 132 (372 mg, 1.594 mmol) and a solution of 9-BBN in THF (0.5 M, 5.1 ml_, 2.55 mmol) according to the method described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step.
  • Intermediate 137 was prepared from a solution of intermediate 133 (129 mg, 0.516 mmol) in 1 ,4-dioxane (0.5 ml_) and a solution of 9-BBN in THF (0.5 M, 1.446 ml_, 0.723 mmol) according to the procedure described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step.
  • Intermediate 138 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(4-chlorophenyl)- A/,A/-dimethylcyclohexan-1 -amine.
  • Intermediate 138 was prepared from intermediate 134 (373 mg, 1.493 mmol) and a solution of 9-BBN in THF (0.5 M, 4.18 ml_, 2.091 mmol) according to the procedure as described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step.
  • Intermediate 139 l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- (3-fluorophenyl)cyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
  • Intermediate 139 was obtained from bromide 24 (780 mg, 1.948 mmol) and 1.1 eq. of intermediate 135 according to the synthesis method as described for the preparation of intermediate 66, using a solution of sodium carbonate (516 mg, 4.87 mmol) in water (2 ml_), XantPhos (67.6 mg, 0.117 mmol), Pd2(dba)3 (53.5 mg, 0.058 mmol) and with MW- heating for 5.5 h at 80 °C. The crude reaction mixture was diluted with 1 ,4-dioxane and filtered over a pad of kieselguhr, which was rinsed with additional 1 ,4-dioxane.
  • Intermediate 164 was obtained from intermediate 163 (1.93 g, 4.23 mmol) by means of hydrogenation with platinum(IV)oxide (59.4 mg, 0.261) and hydrogen (balloon) at 60 °C overnight. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 120 g, gradient heptane to 15% EtOAc/heptane in 44 Min), followed by purification by preparative SFC afforded 1.21 g (62%) of the title compound as a paste. LCMS (Method C): Rt, 2.61 Min; ESI m/z ⁇ 346.0 & 348.0 [M-(2 x C 4 H 8 )+H] + , Br-isotope pattern.
  • Intermediate 165 was obtained from intermediate 164 (600 mg, 1.309 mmol) and a freshly prepared solution of 1.0 eq. of intermediate 65 (442 mg, 1.309 mmol) in THF (5 mL) according to the method described for the preparation of intermediate 66. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 40 g, gradient DCM to 100% DCM/MeOH (9:1) in 40 Min) afforded 188 mg (24%) of the title compound. LCMS (Method C): Rt, 3.17 Min; ESI m/z ⁇ 595.4 [M+H] + . Purity according to LCMS: 92.0%.
  • reaction mixture was flushed with argon using an ultrasonic bath (5 min). Subsequently, CS2CO3 (0.189 g, 0.581 mmol), Ru-Phos (9.03 mg, 0.019 mmol) and Pd2(dba)3 (8.86 mg, 9.68 pmol) were added with stirring under an atmosphere of argon for 5 Min.
  • the reaction mixture was heated under MW-conditions at 60 °C for 6 h in total. After cooling down the reaction mixture was filtered over a small pad of kieselguhr, which was rinsed with DCM and the filtrate was concentrated under reduced pressure.

Abstract

The present invention relates to new compounds that show pharmacological dual activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels, and the µ-opiod receptor (MOR or mu-opioid). The invention is also related to the process for the preparation of said compounds as well as to compositions comprising them, and to their use as medicaments (formula (I)).

Description

NEW PYRROLIDINE-2-CARBOXYLIC ACID DERIVATIVES FOR TREATING PAIN
AND PAIN RELATED CONDITIONS
FIELD OF THE INVENTION
The present invention relates to new compounds that show dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels, and the m-opiod receptor (MOR or mu-opioid). The invention is also related to the process for the preparation of said compounds as well as to compositions comprising them, and to their use as medicaments.
BACKGROUND OF THE INVENTION
The adequate management of pain represents an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk, D.C., Wilson, H.D., Cahana, A.; 2011 ; Lancet ; 377; 2226- 2235). Pain affects a big portion of the population with an estimated prevalence of 20 % and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly correlated to comorbidities, such as depression, anxiety and insomnia, which leads to important productivity losses and socio-economical burden (Goldberg, D.S., McGee, S.J.; 2011 ; BMC Public Health ; 1 1 ; 770). Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.
Voltage-gated calcium channels (VGCC) are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et al.; Pharmacol. Rev.; 2015; 67; 821-870). The VGCC are assembled through interactions of different subunits, namely a1 (Caval), b (CavP) a2d (Cava23) and g (Cavy). The a1 subunits are the key porous forming units of the channel complex, being responsible for Ca2+ conduction and generation of Ca2+ influx. The a2d, b, and g subunits are auxiliary, although they are very important for the regulation of the channel since they increase the expression of a1 subunits in the plasma membrane as well as modulate their function resulting in functional diversity in different cell types. Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage-activated T-type (Cav3.1 , Cav3.2, and Cav3.3), and high voltage-activated L- (Cav1.1 through Cav1.4), N- (Cav2.2), P/Q-(Cav2.1), and R-(Cav2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo; Neurotherapeutics; 2009; 6; 679-692; Zamponi et al. , 2015; Neumaier et al.; Prog. Neurobiol.; 2015; 129; 1-36). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Cav1.2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Cav3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Cav2.2) calcium channels, has been approved as a treatment of intractable pain.
The Cav1 and Cav2 subfamilies contain an auxiliary a2d subunit which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain (Perret and Luo, 2009; Vink and Alewood; British J. Pharmacol.; 2012; 167; 970- 989). To date, there are four known a2d subunits, each encoded by a unique gene and all possessing splice variants. Each a2d protein is encoded by a single messenger RNA and is post-translationally cleaved and then linked by disulfide bonds. Four genes encoding a2d subunits have now been cloned. The a2d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The a2d-2 and a2d-3 subunits were subsequently cloned from brain. The most recently identified subunit, a2d-4, is largely non-neuronal. The human a2d-4 protein sequence shares 30, 32 and 61 % identity with the human a2d-1 , a2d-2 and a2d-3 subunits, respectively. The gene structure of all a2d subunits is similar. All a2d subunits show several splice variants (Davies et al.; Trends Pharmacol. Sci.; 2007; 28; 220-228; Dolphin, A. C.; Nat. Rev. Neurosci.; 2012; 13; 542-555; Dolphin, A.C.; Biochim. Biophys. Acta; 2013; 1828; 1541- 1549).
The Cava23-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009; Vink and Alewood, 2012). Biochemical data have indicated a significant Cava23-1, but not Cava23-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development. In addition, blocking axonal transport of injury-induced DRG Cav<x25-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Cav<x25-1 subunit contributes to neuropathic allodynia.
The Cav<x25-1 subunit (and the Cav<x25-2, but not Cav<x25-3 and Cav<x25-4, subunits) is the binding site for gabapentin which has anti-allodynic/hyperalgesic properties in patients and animal models. Because injury-induced Cav<x25-1 expression correlates with neuropathic pain, development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability, injury-induced Cav<x25-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn. Intrathecal antisense oligonucleotides against the Cav<x25-1 subunit can block nerve injury-induced Cav<x25-1 upregulation and prevent the onset of allodynia and reserve established allodynia.
As above mentioned, the a2d subunits of VGCC form the binding site for gabapentin and pregabalin which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations. The binding of gabapentin and pregabalin to the Cav<x25-1 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009; Vink and Alewood, 2012, Zamponi et al., 2015).
As mentioned before, there are few available therapeutic classes for the treatment of pain, and opioids are among the most effective, especially when addressing severe pain states. They act through three different types of opioid receptors (mu, kappa and gamma) which are transmembrane G-protein coupled receptors (GPCRs). Still, the main analgesic action is attributed to the activation of the m-opioid receptor (MOR). However, the general administration of MOR agonists is limited due to their important side effects, such as constipation, respiratory depression, tolerance, emesis and physical dependence [Meldrum, M.L. (Ed.). Opioids and Pain Relief: A Historical Perspective. Progress in Pain Research and Management, Vol 25. IASP Press, Seattle, 2003] Additionally, MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain. The finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 113-6 (2005)]. Moreover, prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. Consequently, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.
Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity. The effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect. Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents. In fact, it has been experimentally demonstrated that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities, such selectivity is achieved through differential expression of the drugs’ targets in cell types associated with therapeutic, but not toxic, effects (Lehar et al.; Nat. Biotechnol.; 2009; 27; 659-666).
In the case of chronic pain, which is a multifactorial disease, multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al.; Lancet Neurol.; 2013; 12(1 1); 1084-1095). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al; J. Pharmacol. Exp. Ther.; 2011 ; 337; 312-320; Zhang et al.; Cell Death Dis.; 2014; 5; e1138; Gilron et al., 2013).
Given the significant differences in pharmacokinetics, metabolisms and bioavailability, reformulation of drug combinations (multi-component drugs) is challenging. Further, two drugs that are generally safe when dosed individually cannot be assumed to be safe in combination. In addition to the possibility of adverse drug-drug interactions, if the theory of network pharmacology indicates that an effect on phenotype may derive from hitting multiple targets, then that combined phenotypic perturbation may be efficacious or deleterious. The major challenge to both drug combination strategies is the regulatory requirement for each individual drug to be shown to be safe as an individual agent and in combination (Hopkins, A.L.; Nat. Chem. Biol.; 2008; 4; 682-690).
An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008).
Thus, the compounds of the present invention having affinity for the a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels, additionally have affinity towards the m-receptor and are, thus, more effective to treat chronic pain.
In this way, the present invention relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels) which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin). SUMMARY OF THE INVENTION
The present invention discloses novel compounds with dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltagegated calcium channels, and the m-opiod receptor (MOR or mu-opioid), thus resulting in a dual activity for treating pain and pain related disorders.
The main aspect of the present invention is related to compounds of general formula (I):
Figure imgf000007_0001
wherein:
Wi is -0-, -NRa or -CH2-;
Ra is a hydrogen atom or a branched or unbranched C1-6 alkyl radical; n and m are independently from one another 0 or 1 ;
Ri, Rå and R4 are independently from one another a hydrogen atom; a branched or unbranched C1-6 alkyl radical; a halogen atom; a -C(0)H radical; a branched or unbranched C1-6 alkoxy radical; a -NRbRc radical; a -CN radical; a hydroxyl radical; or a Ci-6 haloalkyl radical;
Rb and Rc are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical;
R3 is selected from: W2 is -C(O)-, -CH2- or bond;
A is C or N; the dotted line represents an optional double bond;
R3a and R3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or
R3a and R3b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;
R3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - CN radical; a Ci-e haloalkyl radical; or a -NR3dR3e radical;
R3d and R3e are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical;
Re is a hydrogen atom or a -C(0)Rsa radical;
Rea is a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(ChbJrNRsbRsc radical; a - 0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR5g-(CH2)s-CH(R5f)-NR5eR5d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
Reb, ec, Red, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-6 alkyl radical;
Ref is a hydrogen atom or a -CORsh radical;
Reh is a hydroxyl radical or a branched or unbranched Ci-6 alkyl radical;
Re is a -C(0)R6a radical; an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
R6a is a hydroxyl radical, a branched or unbranched Ci-6 alkoxy radical; a -(ChhX- NRebRec radical; a -0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR6g-(CH2)v-CH(R6f)- NR6eR6d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
R6b, Rec, R6d, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-6 alkyl radical;
Ref is a hydrogen atom or a -COR6h radical;
Reh is a hydroxyl radical or a branched or unbranched Ci-6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
It is also an aspect of the invention different processes for the preparation of compounds of formula (I).
Another aspect of the invention refers to the use of such compounds of general formula (I) for the treatment and/or prophylaxis of a2d mediated disorders and more preferably for the treatment and/or prophylaxis of disorders mediated by the a2d-1 subunit of voltage-gated calcium channels and the m-receptor. The compounds of the present invention are particularly suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain and pain related or pain derived conditions.
A further aspect of the invention refers to pharmaceutical compositions comprising one or more compounds of general formula (I) with at least one pharmaceutically acceptable excipient. The pharmaceutical compositions in accordance with the invention can be adapted in order to be administered by any route of administration, be it orally or parenterally, such as pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with the invention may be adapted for topical or systemic application, particularly for dermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral application.
DETAILED DESCRIPTION OF THE INVENTION
The invention first relates to compounds of general formula (I)
Figure imgf000010_0001
wherein:
Wi is -0-, -NRa 01- -CH2-;
Ra is a hydrogen atom or a branched or unbranched C1 -6 alkyl radical; n and m are independently from one another 0 or 1 ;
Ri, Rå and R4 are independently from one another a hydrogen atom; a branched or unbranched C1 -6 alkyl radical; a halogen atom; a -C(0)H radical; a branched or unbranched Ci-e alkoxy radical; a -NRbRc radical; a -CN radical; a hydroxyl radical; or a Ci-6 haloalkyl radical;
Rb and Rc are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical;
R3 is selected from
Figure imgf000011_0001
W2 is -C(O)-, -CH2- or bond;
A is C or N; the dotted line represents an optional double bond;
R3a and R3b are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical; or
R3a and R3b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched C1-6 alkyl radical or a branched or unbranched C1-6 alkoxy radical;
R3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched C1-6 alkyl radical; a branched or unbranched C1-6 alkoxy radical; a - CN radical; a C1-6 haloalkyl radical; or a -NRdRe radical;
R3d and R3e are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical; f¾ is a hydrogen atom or a -C(0)Rsa radical;
Rea is a hydrogen atom; a branched or unbranched Ci-6 alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(Chh -NRsbRsc radical; a - 0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR5g-(CH2)s-CH(R5f)-NR5eR5d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
Reb, Rec, Red, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-6 alkyl radical;
Ref is a hydrogen atom or a -CORsh radical;
Reh is a hydroxyl radical or a branched or unbranched Ci-6 alkyl radical;
Re is a -C(0)R6a radical; an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
R6a is a hydroxyl radical, a branched or unbranched Ci-e alkoxy radical; a -(ChhX- NRebRec radical; a -0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR6g-(CH2)v-CH(R6f)- NR6eR6d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
R6b, Rec, R6d, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-6 alkyl radical;
Ref is a hydrogen atom or a -COR6h radical;
Reh is a hydroxyl radical or a branched or unbranched Ci-6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. Unless otherwise stated, the compounds of the invention are also meant to include isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structures except for the replacement of at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by 13C- or 14C-enriched carbon, or the replacement of at least one nitrogen by 15N-enriched nitrogen are within the scope of this invention.
The compounds of general formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
“Halogen” or“halo” as referred in the present invention represents fluorine, chlorine, bromine or iodine. When the term“halo” is combined with other substituents, such as for instance“Ci-e haloalkyl” or“Ci-e haloalkoxy” it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom.
A leaving group is a group that in a heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving groups are well known in the art and include Cl, Br, I and -O- SO2R’, wherein R’ is F, Ci-4-alkyl, Ci-4-haloalkyl, or optionally substituted phenyl. The preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate.
“Protecting group” is a group that is chemically introduced into a molecule to avoid that a certain functional group from that molecule undesirably reacts in a subsequent reaction. Protecting groups are used, among others, to obtain chemoselectivity in chemical reactions. The preferred protecting group in the context of the invention are Boc (te/f-butoxycarbonyl) or Teoc (2-(trimethylsilyl)ethoxycarbonyl).
“C1 -6 alkyl”, as referred to in the present invention, are saturated aliphatic radicals. They may be unbranched (linear) or branched and are optionally substituted. Ci-6-alkyl as expressed in the present invention means an alkyl radical of 1 , 2, 3, 4, 5 or 6 carbon atoms. Preferred alkyl radicals according to the present invention include but are not restricted to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, n-pentyl, 1 , 1- dimethyl propyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl or 1-methylpentyl. The most preferred alkyl radical are C1-4 alkyl, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl or 1 , 1 -dimethylethyl. Alkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci-6-alkoxy radical, a branched or unbranched Ci-6-alkyl radical, a Ci-6-haloalkoxy radical, a Ci-6-haloalkyl radical, CN, a trihaloalkyl radical, hydroxyl group and an amino radical such as -NR’R” wherein R’ and R” are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical .
“Ci-6 alkoxy” as referered to in the present invention, is understood as meaning an alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Examples of alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy or tert-butoxy.
“Heterocycloalkyl” as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), generally 5, 6 or 7 membered cyclic hydrocarbons which can optionally be unsubstituted, mono- or polysubstituted and which have at least one heteroatom in their structure selected from N, O or S. Examples for heterocycloalkyl radical preferably include but are not restricted to pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyrane, tetrahydrofurane, dioxane, dioxolane, oxazolidine, piperidine, piperazine, homopiperazine, morpholine, azepane or diazepane. Heterocycloalkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci-6-alkyl radical, a branched or unbranched Ci-6-alkoxy radical, a Ci-6-haloalkoxy radical, a Ci-6-haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. More preferably heterocycloalkyl in the context of the present invention are 6 or 7-membered ring systems optionally at least monosubstituted.
“Heteroaryl” as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and contain one or more heteroatoms from the group consisting of N, O or S and may optionally be mono- or polysubstituted by substituents independently selected from a halogen atom, a branched or unbranched Ci-6-alkyl radical, a branched or unbranched Ci-6-alkoxy radical, a Ci-e- haloalkoxy radical, a Ci-6-haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. Preferred examples of heteroaryls include but are not restricted to furan, benzofuran, thiophene, thiazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, imidazole, imidazo[4,5-b]pyridine, isoxazole, oxadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole or quinazoline. More preferably heteroaryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.
“Heterocyclic system”, as defined in the present invention, comprise any saturated, unsaturated or aromatic carbocyclic ring systems which are optionally at least mono substituted and which contain at least one heteroatom as ring member. Preferred heteroatoms for these heterocyclyl groups are N, S or O. Preferred substituents for heterocyclyl radicals, according to the present invention, are F, Cl, Br, I, NH2, SH, OH, SO2, CF3, carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, -SO2NH2, C1-6 alkyl and/or Ci-6-alkoxy.
The term“ring system” according to the present invention refers to a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings. The“ring system” thus defined comprises saturated, unsaturated or aromatic carbocyclic rings which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted and may be joined to other carbocyclic ring systems such as aryl radicals, heteroaryl radicals, cycloalkyl radicals etc.
The terms“condensed”,“annulated” or“annelated” are also used by those skilled in the art to designate this kind of join.
The term“room temperature” in the context of this invention is to be understood as temperature between 20 and 25°C.
The term “salt” is to be understood as meaning any form of the active compound according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. The definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to “pharmacologically acceptable salts”.
The term“pharmaceutically acceptable salts” in the context of this invention means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly as a result of the counter-ion) when used in an appropriate manner for a treatment, particularly applied or used in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention - normally an acid (deprotonated) - such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used on humans and/or mammals. Salts with alkali and alkali earth metals are particularly preferred, as well as those formed with ammonium cations (NhV). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e. salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
The term“solvate” is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
The term“prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds of the invention: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (april 2002).
Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
In a particular and preferred embodiment, Wi is -0-.
In another particular embodiment, Wi is -NRa-.
In a particular and preferred embodiment Ra is a branched or unbranched Ci-e alkyl radical; more preferably methyl.
In another particular and preferred embodiment, Wi is -CH2-.
In another particular and preferred embodiment, m is 0.
In another particular and preferred embodiment both, n and m, are 0.
In another particular and preferred embodiment of the invention, Ri, Rå and R4 are independently from one another a hydrogen atom; a branched or unbranched C1 -6 alkyl radical, more preferably methyl; a halogen atom, more preferable fluorine or chlorine; a -C(0)H radical; a branched or unbranched C1 -6 alkoxy radical, more preferably methoxy; a -CN radical; or a Ci-6 haloalkyl radical, more preferably a -CF3 radical.
In another particular and preferred embodiment of the invention R3 is in meta position.
In another particular and preferred embodiment, R3 is selected from: In another particular and preferred embodiment of the invention R3a and R3b are independently from one another a C1 -6 alkyl radical, more preferably methyl.
In another particular and preferred embodiment of the invention R3a and R3b together with the bridging nitrogen form an unsubstituted 4, 5 or 6-membered heterocycloalkyl radical, more preferably azetidine.
In another particular and preferred embodiment of the invention, R3C is a hydrogen atom; a hydroxyl radical; or a halogen atom, more preferably fluorine or chlorine.
In another particular and preferred embodiment of the invention Rs is a hydrogen atom.
In another particular and preferred embodiment of the invention Rsa is a branched C1-6- alkoxy radical; a -(Chh -NRsbRsc radical, more preferably -CH2-NH2; or a - 0CH(CH3)0C(0)CH(CH3)2 radical.
In another particular and preferred embodiment of the invention both Rsb and Rsc are a hydrogen atom.
In another particular and preferred embodiment of the invention R6a is a hydroxyl radical, an unbranched Ci-6 alkoxy radical, more preferably methoxy or ethoxy; or a -NH-(CH2)4- CH(COOH)-NH2 radical.
A particularly preferred embodiment of the invention is represented by compounds of general formula (I’a):
Figure imgf000019_0001
wherein Ri, Rå, R3, R4, Rs, R6 and n are as defined above; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. A still more particularly preferred embodiment of the invention is represented by compounds of general formula (I’a):
Figure imgf000020_0001
wherein:
n is 0 or 1 ;
Ri, are independently from one another a hydrogen atom; a branched or unbranched Ci-6 alkyl radical, more preferably methyl; a halogen atom, more preferable fluorine or chlorine; a -C(0)H radical; a branched or unbranched Ci-6 alkoxy radical, more preferably methoxy; a -CN radical; or a Ci-6 haloalkyl radical, more preferably a -CF3 radical;
R3 is selected from:
R3a and f¾3b are independently from one another a Ci-e alkyl radical, more preferably methyl or R3a and R3b together with the bridging nitrogen form an unsubstituted 4, 5 or 6-membered heterocycloalkyl radical, more preferably azetidine;
R3C is a hydrogen atom; a hydroxyl radical; or a halogen atom, more preferably fluorine or chlorine;
Re is a hydrogen atom;
Rea is a branched Ci-6-alkoxy radical; a -(CH2)r-NR5bR5c radical, more preferably -CH2- NH2; or a -0CH(CH3)0C(0)CH(CH3)2 radical;
Reb and Rsc are a hydrogen atom;
R6a is a hydroxyl radical, an unbranched Ci-6 alkoxy radical, more preferably methoxy or ethoxy; or a -NH-(CH2)4-CH(COOH)-NH2 radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
The compounds of the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of double bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
In a particular and preferred embodiment of the invention, the compounds of general formula (I) are represented by the S,S-isomers according to the following subformula la:
Figure imgf000022_0001
wherein Wi, m, n, Ri, R2, R3, R4, Rs and R6 are as defined before. The preferred compounds of the invention showing dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage gated calcium channels, and the m-opiod receptor (MOR or mu-opioid) are selected from the following group:
[1] (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)benzyl)oxy)pyrrolidine-2- carboxylic acid;
[2] (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)benzyl)(methyl)amino)pyrro lidine-2-carboxylic acid;
[3] (2S,4S)-4-(4-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrrolidine -2-carboxylic acid;
[4] (2S,4S)-4-(3-Chloro-4-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[5] (2S,4S)-4-(3-Chloro-4-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)phenoxy) pyrrolidine-2-carboxylic acid;
[6] (2S,4S)-4-(((4-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)amino) methyl)pyrrolidine-2-carboxylic acid;
[7] (2S,4S)-4-(((4-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)(methyl) amino)methyl)pyrrolidine-2-carboxylic acid;
[8] (2S,4S)-4-(((3-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)(methyl) amino)methyl)pyrrolidine-2-carboxylic acid;
[9] (2S,4S)-4-(3-Chloro-5-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)phenoxy) pyrrolidine-2-carboxylic acid;
[10] (2S,4S)-4-(3-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrrolidi ne-2-carboxylic acid;
[11] (2S,4S)-4-(3-Chloro-5-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[12] (2S,4S)-4-(2-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrroli dine-2-carboxylic acid;
[13] (2S,4S)-4-(3-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)-5-fluorophenoxy) pyrrolidine-2-carboxylic acid;
[14] (2S,4S)-4-(3-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)methyl)phen oxy)pyrrolidine-2-carboxylic acid;
[15] (2S,4S)-4-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)phenoxy)pyrrolidine-2- carboxylic acid;
[16] (2S,4S)-4-(3-((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)phenoxy)pyrrolidine- 2-carboxylic acid; [17] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[18] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[19] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[20] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[21] (2S,4S)-4-(3-Chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)phen oxy)pyrrolidine-2-carboxylic acid;
[22] (2S,4S)-4-(3-Chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[23] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methyl phenoxy)pyrrolidine-2-carboxylic acid;
[24] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methyl phenoxy)pyrrolidine-2-carboxylic acid;
[25] (2S,4S)-4-(5-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[26] (2S,4S)-4-(5-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[27] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[28] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[29] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[30] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[31] (2S,4S)-4-(5-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[32] (2S,4S)-4-(5-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[33] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid;
[34] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid; [35] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methoxy phenoxy)pyrrolidine-2-carboxylic acid;
[36] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methoxy phenoxy)pyrrolidine-2-carboxylic acid;
[37] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,6-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[38] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,6-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[39] (2S,4S)-4-(2-Chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[40] (2S,4S)-4-(2-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[41] (2S,4S)-4-(2-Chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-3- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[42] (2S,4S)-4-(2-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-3- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[43] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[44] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[45] (2S,4S)-4-(3-Cyano-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)phen oxy)pyrrolidine-2-carboxylic acid;
[46] (2S,4S)-4-(3-Cyano-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[47] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[48] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[49] (2S,4S)-4-(5-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,3-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[50] (2S,4S)-4-(5-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,3-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[51] (2S,4S)-4-(2-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[52] (2S,4S)-4-(2-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid; [53] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[54] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[55] (2S,4R)-4-(3-(((1r,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[56] (2S,4R)-4-(3-(((1s,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[57] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid;
[58] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid;
[59] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid;
[60] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-(trifluoro methyl)phenoxy)pyrrolidine-2-carboxylic acid;
[61] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,5-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[62] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,5-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[63] (2S,4S)-4-(3-Chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[64] (2S,4S)-4-(3-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[65] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[66] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-difluoro phenoxy)pyrrolidine-2-carboxylic acid;
[67] (2S,4S)-4-(5-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-2- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[68] (2S,4S)-4-(5-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-2- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[69] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-formylphen oxy)pyrrolidine-2-carboxylic acid;
[70] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-formyl phenoxy)pyrrolidine-2-carboxylic acid; [71] (2S,4S)-4-(4-Chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid;
[72] (2S,4S)-4-(4-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid;
[73] (2S,4S)-4-(3-((1-(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,1'-biphenyl]-4-yl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[74] (2S,4S)-4-(3-(((1s,4R)-4-(Methylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrro lidine-2-carboxylic acid;
[75] Ethyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)phen oxy)pyrrolidine-2-carboxylate;
[76] Ethyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[77] Isopropyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[78] Butyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[79] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)-1- glycylpyrrolidine-2-carboxylic acid;
[80] N6-((2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carbonyl)-L-lysine;
[81] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)-1- ((1-(isobutyryloxy)ethoxy)carbonyl)pyrrolidine-2-carboxylic acid;
[82] 1-(1-(lsobutyryloxy)ethyl)-2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
[83] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[84] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[85] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-2- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[86] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-2- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[87] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[88] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid; [89] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[90] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[91 ] (2S,4S)-4-(4-Chloro-3-(((1 r,4S)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[92] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[93] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(3-chlorophenyl)-4-(dimethylamino)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[94] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(3-chlorophenyl)-4-(dimethylamino)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[95] (2S,4S)-4-(3-(((1r,4S)-4-(3-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)- 4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[96] (2S,4S)-4-(3-(((1s,4R)-4-(3-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)- 4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[97] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(4-chlorophenyl)-4-(dimethylamino)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[98] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(4-chlorophenyl)-4-(dimethylamino)cyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[99] (2S,4S)-4-(3-(((1r,4S)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)- 4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[100] (2S,4S)-4-(3-(((1 s,4R)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)-
4.5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[101] (2S,4S)-4-(3-(((1r,4S)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)-
2.5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[102] (2S,4S)-4-(3-(((1 s,4R)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)- 2,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[103] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) pyrrolidine-2-carboxylic acid;
[104] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) pyrrolidine-2-carboxylic acid;
[105] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro benzyl)pyrrolidine-2-carboxylic acid;
[106] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro benzyl)pyrrolidine-2-carboxylic acid; [107] (2S,4S)-4-((3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenyl)(me thyl)amino)pyrrolidine-2-carboxylic acid
[108] (2S,4S)-4-((3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenyl)(me thyl)amino)pyrrolidine-2-carboxylic acid;
[109] (2S,4S)-4-((3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl)oxy) pyrrolidine-2-carboxylic acid;
[110] (2S,4S)-4-((3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) oxy)pyrrolidine-2-carboxylic acid;
[111] (2S,4S)-4-(3-(((1r,4S)-4-(Azetidin-1-yl)-4-phenylcyclohexyl)methyl)phenoxy)pyrro lidine-2-carboxylic acid;
[112] (2S,4S)-4-(3-(((1s,4R)-4-(Azetidin-1-yl)-4-phenylcyclohexyl)methyl)phenoxy)pyrro lidine-2-carboxylic acid;
[113] (2S,4S)-4-(3-(((1r,3R)-3-(Dimethylamino)-3-phenylcyclobutyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[114] (2S,4S)-4-(3-(((1s,3S)-3-(Dimethylamino)-3-phenylcyclobutyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[115] (2S,4S)-4-(4-Chloro-3-(((1 r,3R)-3-(dimethylamino)-3-phenylcyclobutyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[116] (2S,4S)-4-(4-Chloro-3-(((1s,3S)-3-(dimethylamino)-3-phenylcyclobutyl)methyl)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;
[117] (1 S,4r)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy)benzyl)-N,N-dime thyl-1 -phenylcyclohexan-1 -amine and
[118] (1R,4s)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy)benzyl)-N,N-dime thyl-1 -phenylcyclohexan-1 -amine; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
In another aspect, the invention refers to the processes for the preparation of the compounds of general formula (I).
Several procedures have been developed for obtaining all the compounds of the invention. These procedures will be explained below in methods A and B.
METHOD A
Method A represents first processes for synthesizing compounds according to general formula (I). Method A allows the preparation of: • compounds of general formula (A1) that is compounds of general formula (I) where Wi is -CH2-, m is 0 and n is 0, namely Method A1 ;
• compounds of general formula (A2) that is compounds of general formula (I) where Wi is -0-, m is 0 and n is 0, namely Method A2;
• compounds of general formula (A3) that is compounds of general formula (I) where Wi is -0-, m is 0 and n is 1 , namely Method A3;
• compounds of general formula (A4) that is compounds of general formula (I) where Wi is -NRa-, m is 0 and n is 0, namely Method A4;
• compounds of general formula (A5) that is compounds of general formula (I) where Wi is -NRa-, m is 1 and n is 0 namely, Method A5 and
• compounds of general formula (A6) that is compounds of general formula (I) where Wi is -NRa-, m is 0 and n is 1 namely, Method A6.
Method A1
A compound of general formula (A1) as defined above:
Figure imgf000030_0001
wherein Ri, R2, R3, R4, Rs and R6 have the meanings as defined above, can be prepared by means of a Wittig reaction by treating a pyrrolidyl-ketone of general formula (lla):
Figure imgf000030_0002
wherein R5 and R6 have the meanings as defined above and a triphenylphosphonium salt reagent of formula (Ilia):
Figure imgf000030_0003
wherein Ri , R2, R3 and R4 have the meanings as defined above and Z represents triphenylphosphonium salt; in the presence of a suitable base, such as sodium hydride, and with stirring at suitable temperature, for example 70 °C, followed by hydrogenation of the formed alkene with hydrogen and a suitable catalyst, such as platinum(IV)oxide in a suitable solvent, like EtOAc (ethyl acetate), and with heating at a suitable temperature, like 60 °C.
Method A2
A compound of general formula (A2) as defined above:
Figure imgf000031_0001
wherein Ri , R2, R3, R4, Rs, and R6 have the meanings as defined above, can be prepared by treating a pyrrolidinol derivative of general formula (Mb):
Figure imgf000031_0002
wherein R5 and R6 have the meanings as defined above with a suitable derivative of general formula (lllb):
Figure imgf000031_0003
wherein Ri , R2, R3 and R4 have the meanings as defined above; under Mitsunobu conditions, with a suitable coupling agent, such as cyanomethylenetributylphosphorane (CM BP), or diisopropyl azodicarboxylate (DIAD) in the presence of a phosphine, such as triphenylphosphine (PhbP), in a suitable solvent, such as toluene or tetrahydrofuran (THF), at a suitable temperature, between room temperature and 100 °C, preferably room temperature.
Method A3
A compound of general formula (A3) as defined above:
Figure imgf000032_0001
wherein Ri, R2, R3, R4, Rs, and R6 have the meanings as defined above, can be prepared by means of alkylation of a suitable pyrrolidine derivative of general formula (Mb):
Figure imgf000032_0002
wherein Rs and R6 have the meanings as defined above with a suitable halide of general formula (lllc):
Figure imgf000032_0003
wherein Ri , R2, R3 and R4 have the meanings as defined above and X stands for halogen; in the presence of a base such as sodium hydride, in a suitable solvent, for example N,N- dimethylformamide (DMF) or THF, at a suitable temperature, such as between 0 °C and room temperature.
Method A4 A compound of general formula (A4) as defined above:
Figure imgf000033_0001
wherein Ri , R2, R3, R4, Rs, R6 and Ra have the meanings as defined above, can be prepared by means of a Buchwald-Hartwig coupling reaction of a suitable pyrrolidine- amine of general formula (lie):
Figure imgf000033_0002
wherein Ra, Rs and R6 have the meanings as defined above; and a compound of general formula (llld):
Figure imgf000033_0003
wherein Ri , R2, R3 and R4 have the meanings as defined above and X stands for halogen; using suitable reagents, like 2-dicyclohexylphosphino-2',6'-diisopropoxy biphenyl (Ru- Phos), cesium carbonate and a suitable palladium catalyst, for example Pd2(dba)3, with heating under microwave at a suitable temperature, like 60 °C,
Method A5
A compound of general formula (A5) as defined above: wherein Ri , R2, R3, R4, Rs, R6 and Ra have the meanings as defined above, can be prepared by reaction of a suitable amine of general formula (lid):
Figure imgf000034_0001
wherein Ra, Rs and R6 have the meanings as defined above; and a compound of general formula (llld):
Figure imgf000034_0002
wherein Ri , R2, R3 and R4 have the meanings as defined above and X stands for halogen; using suitable reagents, such as Pd2(dba)3 and 2-(dicyclohexylphosphino)-3,6- dimethoxy-2'-4'-6'-tri-i-propyl-1 ,1 '-biphenyl (Brett-Phos) or 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-Phos) in suitable solvents, such as a,a,a-trifluorotoluene or 1 ,4-dioxane, at a suitable temperature between 100 °C to 1 10 °C, and optionally under microwave heating.
Method A6
A compound of general formula (A6) as defined above:
Figure imgf000034_0003
(A6)
wherein Ri, R2, R3, R4, Rs, R6 and Ra have the meanings as defined above, can be obtained by means of reductive amination reactions of a suitable amine of general formula (lie):
Figure imgf000035_0001
wherein Ra, Rs and R6 have the meanings as defined above; and an aldehyde compound of general formula (llle):
Figure imgf000035_0002
wherein Ri, R2, R3 and R4 have the meanings as defined above; using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture, at a suitable temperature, such as room temperature.
METHOD B
Method B represents an alternative process for synthesizing compounds according to general formula (I) from a compound of general formula (V):
Figure imgf000035_0003
wherein Ri, R2, R4, Rs, R6, Wi, m and n have the meanings as defined above and Y represents a group that can be converted into R3, being R3: W2 is -C(O)-, -CH2- or bond;
A is C or N; the dotted line represents an optional double bond;
Method B allows the preparation of:
compounds of general formula (B1 ), that is compounds of general formula (I) wherein W2 is a bond and thus R3 is directly linked to the aryl group;
compounds of general formula (B2), that is compounds of general formula (I) wherein W2 is -CH2-;
compounds of general formula (B3), that is compounds of general formula (I) where W2 is C(O).
Thus, starting from a compound of general formula (V) wherein Y is a halogen atom, preferably a bromine atom or an aldehyde, a compound of general formula (B1 ) wherein W2 is a bond can be obtained: if Y is a halogen atom, preferably a bromine:
by reaction with a compound of general formula (VI):
Figure imgf000036_0001
by means of a Buchwald-Hartwig coupling reaction, using suitable reagents, such as tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3) , 2-dicyclohexyl phosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and sodium te/f-butoxide, in suitable solvents, such as 1 ,4-dioxane, and with conventional heating at a suitable temperature, for example 110 °C and optionally under microwave heating, or
• by a Pd-catalysed reaction using a potassium trifluoroborate salt of general formula (VII), obtainable from a compound of general formula (VI),:
Figure imgf000037_0001
and suitable reagents such as palladium acetate, in the presence of a phosphine ligand, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and cesium carbonate, in suitable solvent mixtures, such as THF and water, and with conventional heating at a suitable temperature, for example 80 °C or
• by means of a Grignard type reaction with a ketone of general formula (VIII) or (IX):
Figure imgf000037_0002
in the presence of magnesium, in a suitable solvent such as tetrahydrofuran, at a suitable temperature, such as 100°C; followed by an elimination reaction of the obtained tertiary alcohol under acidic conditions, like trifluoroacetic acid in dichloromethane as solvent, and subsequent hydrogenation of the formed alkene moiety, using hydrogen and palladium on carbon in methanol as solvent; or if Y is an aldehyde by reaction with a compound of general formula (VI) using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture, at a suitable temperature, such as room temperature.
A compound of general formula (B2) wherein W2 is a -CH2- can be obtained from a compound of general formula (V) wherein Y is a halogen atom, preferably a bromine atom, by reaction with a suitably olefin derivative of general formula (X) or (XI):
Figure imgf000038_0001
(X) (XI)
under a Heck-type conditions, using a suitable catalyst, such as palladium(ll) acetate and phosphine ligand, such as tri-o-tolylphosphine, and an organic base, such as N,N- diisopropylethylamine (DIPEA), in an appropriate solvent, like acetonitrile, with heating at 150 °C under microwave conditions;
starting from an organo-borane derivative obtained in situ by reaction of a compound of general formula (X) or (XI) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF with heating at elevated temperature, by reaction with a compound of general formula (V) wherein Y is a halogen atom, preferably a bromine atom, in a subsequent Pd2(dba)3-catalysed reaction, in a suitable solvent mixture, like a mixture of THF, 1 ,4-dioxane and water, and using suitable reagents, like 4, 5-bis(diphenylphosphino)-9, 9-dimethyl xanthene (XantPhos) and sodium carbonate with heating between 80 °C and 1 10 °C under conventional heating or optionally microwave heating conditions.
A compound of general formula (B3) wherein W2 is a -C(O)- can be obtained from a compound of general formula (V) wherein Y is a carboxylic acid by reaction with a compound of general formula (VI) using for example A/-[(dimethylamino)-1 /-/-1 ,2,3- triazolo-[4,5-Jb]pyridin-1-ylmethylene]-/\/-methylmethanaminium hexafluorophosphate N- oxide (HATU) as coupling reagent in a suitable solvent, like DMF, at a suitable temperature, such as room temperature. The above-described transformations for introducing the group R3 over a compound of general formula (V) can also be applied for introducing the group R3 over a compound of general formula (IV) to give a compound of general formula (III) as shown in Scheme 1 by a dotted arrow.
The intermediate of general formula (V) can be prepared by reaction of a compound of general formula (lla), (Mb), (lie) or (lid):
Figure imgf000039_0001
wherein Ra, Rs and R6 are as defined above, with a compound of general formula (IV):
Figure imgf000039_0002
wherein Ri, R2, R4 and n have the meanings as defined above, Z represents a triphenylphosphonium salt, a hydroxyl radical, an aldehyde or an halogen radical and Y represents a group that can be converted into R3; under the conditions described in Method B. The different reactions of Method A (including from Method A1 to Method A6) and Method B as well as the reactions for preparing the intermediate compounds for such reactions are depicted in Scheme 1 : (lla) W^OH, m:0
(Mb) W-| :NHRa, m:0
(Me) W^NHRg, m:1
Scheme 1 wherein Ra, Ri , R2, R3, R4, Rs, R6, n, m and Wi have the meanings as described above, Y represents a group that can be converted into R3 and Z represents a hydroxyl, an aldehyde, a halogen or a triphenylphosphonium salt.
The functional groups present in the compounds of general formula (I) or any intermediate described in Scheme 1 may be transformed at any stage of the synthesis, as follows:
• A compound where R6 is carboxylic acid can be esterified by reaction with thionyl chloride, in a suitable alcohol solvent, for example n-butanol, at a suitable temperature, such as between 0 °C and room temperature.
• A compound where F¾6 is carboxylic acid can be converted to an amide by reaction with a suitable amine, and using suitable coupling reagents, such as N- (3-dimethylaminopropyl)-/V'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
• A compound where f¾6 is tetrazole can be prepared from a compound where R6 is nitrile by the reaction with sodium azide and ammonium chloride in DMF at elevated temperature, for example 80 °C.
• A compound where f¾ is hydrogen, can be converted to a compound where Rs is an amide group with a suitable carboxylic acid, using suitable coupling reagents, such as A/-(3-dimethylaminopropyl)-/\/'-ethylcarbodiimide (EDC) in a suitable solvent like dichloromethane at room temperature.
• A compound where Rs is hydrogen, can be converted to a compound where Rs is a carbamate, by means of a reaction with a suitable reagent, for example 1- [[(4-nitrophenoxy)carbonyl]oxy]ethyl 2-methylpropanoate, in the presence of a suitable organic base, such as triethylamine, in a solvent such as dichloromethane with stirring at room temperature.
The compounds of general formula (lla), (Mb), (lie), (lid), (Ilia), (lllb), (lllc), (Mid), (llle), (IV), (VI), (VII), (VIII), (IX), (X) and (XI) used in the methods and schemes disclosed above are commercially available or can be synthesized following common procedures described in the literature and exemplified in the synthesis of some intermediates. For example, the compounds of general formula (X) and (XI) can be obtained from the compounds of general formula (VIII) and (IX), respectively, by means of a Wittig type reaction, using a suitable phosphonium salt, for instance methyltriphenylphosphonium bromide, in the presence of a suitable base, for example potassium tert- butoxide, in an appropriate solvent like THF, with stirring at room temperature or elevated temperature, for example 50 °C.
In some of the processes described above it may be necessary to protect the reactive or labile groups present with suitable protecting groups, such as for example Boc ( tert - butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, methyl or tert- butyl ester for the carboxylic acid group and common silyl protecting groups for the protection of the hydroxyl group. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature. In particular, the simultaneous removal of a methyl ester and Boc-group may be carried out in aqueous HCI, optionally in the presence of a suitable co-solvent like acetonitrile, and at a suitable reaction temperature, e.g. heating at 60 °C. In addition, a compound of general formula (I) can be obtained in enantiopure form by resolution of a racemic compound of general formula (I) either by chiral preparative HPLC, or by crystallization of a diastereomeric salt or co-crystal. Alternatively, the resolution step can be carried out at a previous stage, using any suitable protected intermediate.
Compounds of general formula (I) for which R5 and/or
Figure imgf000042_0001
contains a Protecting Group (PG), such as Boc or 2-(trimethylsilyl)ethylcarbamate), or R5 and/or R6 represents a moiety which can be easily converted, can be used as intermediates useful for the preparation of other compounds of general formula (I) as defined above.
In a particular embodiment, these intermediate compounds of general formula (I) are selected from:
• (2S,4S)-1-(te/f-Butoxycarbonyl)-4-((4-(4-(dimethylamino)-4-phenypiperidin-1- yl)benzyl)(methyl)amino)pyrrolidine-2-carboxylic acid;
• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-4-((4-(dimethylamino)-4-phenylpipe ridin-1-yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-((4-(dimethylamino)-4-phenylpiperidin-1- yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
• (2S,4S)-1-(te/f-Butoxycarbonyl)-4-((4-(4-(dimethylamino)-4-phenyl piperidin-1- yl)benzyl)oxy)pyrrolidine-2-carboxylic acid;
• Di-te/f-butyl (2S, 4S)-4-(3-chloro-4-(4-(dimethylamino)-4-phenyl piperidine-1 - carbonyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
• Di-te/f-butyl (2S,4R)-4-(((4-(4-(dimethylamino)-4-phenylpiperidine-1 -carbonyl) phenyl)amino)methyl)pyrrolidine-1 , 2-dicarboxyl ate;
• Di-te/f-butyl (2S,4R)-4-(((4-(4-(dimethylamino)-4-phenylpiperidine-1 -carbonyl) phenyl)(methyl)amino)methyl)pyrrolidine-1 ,2-dicarboxylate;
• Di-te/f-butyl (2S,4R)-4-(((3-(4-(dimethylamino)-4-phenylpiperidine-1 -carbonyl) phenyl)(methyl)amino)methyl)pyrrolidine-1 ,2-dicarboxylate;
• Di-te/f-butyl (2S,4S)-4-(3-chloro-5-(4-(dimethylamino)-4-phenylpiperidine-1- carbonyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
• l-(tert-Butyl) 2-methyl (2S,4S)-4-(3-((4-(dimethylamino)-4-phenylpiperidin-1-yl) methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-chloro-5-((4-(dimethylamino)-4-phenylpiperi din-1 -yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-((4-(dimethylamino)-4-phenylpiperidin-1-yl) ethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((4-(dimethylamino)-4-phenylpiperidin-1-yl) methyl)-5-fluorophenoxy)pyrrolidine-1 , 2-dicarboxyl ate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((4-(dimethylamino)-4-(3-hydroxyphenyl) piperidin-1-yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
(2S,4S)-1-(te/f-Butoxycarbonyl)-4-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl) phenoxy)pyrrolidine-2-carboxylic acid;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethyl amino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethyl amino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-methylphenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-methylphenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl) ethyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-5-methoxyphenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethyl amino)-4-phenylcyclo hexyl)methyl)-5-methoxyphenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,6-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,6-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-cyano-5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-cyano-5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarb oxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4R)-4-(3-(((1r,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1 -(tert- Butyl) 2-methyl (2S,4R)-4-(3-(((1 s,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-4-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-4-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-chloro-3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(5-chloro-3-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-(difluoromethyl)-3-(((1r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-(difluoromethyl)-3-(((1s,4R)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-5-(((1r,4S)-4-(dimethyl amino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-5-(((1s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((1-(dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,T- biphenyl]-4-yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(methylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
Methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylate;
(2S,4S)-1-(te/f-Butoxycarbonyl)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-2-carboxylic acid;
Methyl (2S,4S)-1-((te/f-butoxycarbonyl)glycyl)-4-(3-(((1r,4S)-4-(dimethylamino)-
4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-2-carboxylate;
tert- Butyl (2S,4S)-2-(((S)-5-((te/f-butoxycarbonyl)amino)-6-methoxy-6-oxohexyl) carbamoyl)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-1-carboxylate;
1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-butyl) 2-methyl (2S, 4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-(3-fluoro phenyl)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(dimethylamino)-4-(3- fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4-(3- fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(dimethylamino)-4-(4- fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4-(4- fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(3-chlorophenyl)-4-
(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(3-chlorophenyl)-4-
(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(3-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(3-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(4-chlorophenyl)-4-
(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(4-chlorophenyl)-4-
(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(4-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(4-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(4-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(4-chlorophenyl)-4-(dimethyl amino)cyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 , 2-dicarboxylate; Di-te/f-butyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)benzyl)pyrrolidine-1 ,2-dicarboxylate;
Di-te/f-butyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)benzyl)pyrrolidine-1 ,2-dicarboxylate;
Di-te/f-butyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorobenzyl)pyrrolidine-1 ,2-dicarboxylate;
Di-te/f-butyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorobenzyl)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-((3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenyl)( ethyl)a ino)pyrrolidine-1 ,2-dicarboxylate;
1 -(tert-Butyl) 2-methyl (2S,4S)-4-((3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenyl)(methyl)amino)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-((3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)benzyl)oxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-((3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)benzyl)oxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(azetidin-1-yl)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4R)-4-(azetidin-1-yl)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,3R)-3-(dimethylamino)-3-phenylcyclo butyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,3S)-3-(dimethylamino)-3-phenylcyclo butyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,3R)-3-(di methylamino)-3- phenylcyclobutyl)methyl)-5-fluorophenoxy)pyrrolidine-1 , 2-dicar boxylate;
1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,3S)-3-(dimethylamino)-3- phenylcyclobutyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-di carboxylate;
tert- Butyl (2S,4S)-2-cyano-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)phenoxy)pyrrolidine-1 -carboxylate;
tert- Butyl (2S,4S)-2-cyano-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)phenoxy)pyrrolidine-1 -carboxylate;
tert- Butyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)-2-(2/-/-tetrazol-5-yl)pyrrolidine-1 -carboxylate and
tert- Butyl (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)-2-(2/-/-tetrazol-5-yl)pyrrolidine-1 -carboxylate. Turning to another aspect, the invention also relates to the therapeutic use of the compounds of general formula (I). As mentioned above, compounds of general formula (I) show a strong affinity both to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels as well as to the m-receptor and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments.
They are suitable for the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m-receptor. In this sense, compounds of general formula (I) are suitable for the treatment and/or prophylaxis of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression anxiety and attention-deficit-/hyperactivity disorder (ADHD).
The compounds of general formula (I) are especially suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripferal neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia. PAIN is defined by the International Association for the Study of Pain (IASP) as“an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.
In a preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of allodynia and more specifically mechanical or thermal allodynia.
In another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of hyperalgesia.
In yet another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of neuropathic pain, central neuropathic pain and/or peripferal neuropathic pain, and more specifically for the treatment and/or prophylaxis of hyperpathia. A related aspect of the invention refers to the use of compounds of general formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and the m-receptor, as explained before.
Another related aspect of the invention refers to a method for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d- 1 subunit of voltage-gated calcium channels and the m-receptor, as explained before comprising the administration of a therapeutically effective amount of a compound of general formula (I) to a subject in need thereof.
Another aspect of the invention is a pharmaceutical composition, which comprises at least a compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, isomer or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.
The pharmaceutical composition of the invention can be formulated as a medicament in different pharmaceutical forms comprising at least a compound binding to the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and the m-receptor and optionally at least one further active substance and/or optionally at least one auxiliary substance.
The auxiliary substances or additives can be selected among carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, flavour conditioners such as sugars, antioxidants and/or agglutinants. In the case of suppositories, this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or carriers for parenteral application. The selection of these auxiliary materials and/or additives and the amounts to be used will depend on the form of application of the pharmaceutical composition.
The pharmaceutical composition in accordance with the invention can be adapted to any form of administration, be it orally or parenterally, for example pulmonarily, nasally, rectally and/or intravenously. Preferably, the composition is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.
The composition of the invention can be formulated for oral administration in any form preferably selected from the group consisting of tablets, dragees, capsules, pills, chewing gums, powders, drops, gels, juices, syrups, solutions and suspensions. The composition of the present invention for oral administration may also be in the form of multiparticulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.
Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays.
The compounds of the invention can be formulated as deposits in dissolved form or in patches, for percutaneous application.
In a preferred embodiment, the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in the normal pharmaceutical practice, in particular with an enteric coating.
The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants. The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
The following examples are merely illustrative of certain embodiments of the invention and cannot be considered as restricting it in any way.
EXAMPLES
The following abbreviations are used in the intermediates and EXAMPLES:
Abs: Absolute
ACN: Acetonitrile
AcOH: Acetic acid
Anh: Anhydrous
BOC2O: Di-te/f-butyl dicarbonate
BrettPhos: 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1 ,T-biphenyl Cone: Concentrated
CMBP: Cyanomethylenetributylphosphorane
DIAD: Diisopropyl azodicarboxylate
DIPEA: /V,/V-Diisopropylethylamine
DCM: Dichloromethane
DMF: A/./V-dimethylformamide
EDCI: A/-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
ESI: Electrospray ionization
EtOAc: Ethyl acetate
Et2<D: Diethyl ether
EtOH: Ethanol
Eq: Equivalents
h: Hour/s
HOAt: 1 -Hydroxy-7-azabenzotriazole HPLC: High-performance liquid chromatography
LCMS: Liquid chromatography mass spectrometry
M: Molar
MeOH: Methanol
Min: Minutes
MS: Mass spectrometry
MW: microwave
Pd2(dba)3 : tris(dibenzylideneacetone)dipalladium (0)
Quant: Quantitative
Rt: Retention time
Ru-Phos : 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
rt: Room temperature
Sat: Saturated
SFC: Supercritical fluid chromatography
S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl
f-BuOH: Tertiary butanol
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TEA: EΐbN, Triethylamine
Wt: Weight
XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
The following methods were used to generate the LCMS data:
Method A: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti.emin = 98% A, t3min = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method B: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2. 1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti.emm = 98% A, t3min = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product. Method C: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti.em = 98% A, t4m,n = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method D: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2. 1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti.emm = 98% A, t4min = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method E: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Phenomenex GeminiNX C18, 50 x 2.0 mm, 3m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3.5min = 98% A, temm = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method F: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315D, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000, ELSD Alltech 3300 gas flow 1.5 ml/min, gas temp: 40°C; column: Waters XSelect™ C18, 50 x 2. 1 mm, 3.5m, Temp: 35 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t 3.5m in = 98% A, te m = 98% A, Post time: 2 min; Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water): Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method G: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 50 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3.5min = 98% A, temin = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product. Method H: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 50 x 2. 1 mm, 3.5m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, fcsm/n = 98% A, temin = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method I: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 50 x 2. 1 mm, 3.5m, Temp: 25°C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3.smm = 98% A, temin = 98% A, Post time: 2 min, Eluent A: 250mM ammonia in acetonitrile, Eluent B: 250 mM ammonia in water; Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method J: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Phenomenex GeminiNX C18, 50 x 2.0 mm, 3m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3.smm = 98% A, temin = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.
Method K: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Phenomenex GeminiNX C18, 50 x 2.0 mm, 3m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3.smm = 98% A, temin = 98% A, Post time: 2 min, Eluent A: 250 mM ammonia in acetonitrile, Eluent B: 250 mM ammonia in water; Rt = x.yy min, M+H = xxx.x, xx.x% product.
MS parameters: Source: ESI, Capillary voltage: 3000 V, Drying gas flow: 12 Umin, Nebulizer Pressure 60 psig, Drying Gas Temp: 350 °C, Fragmentor 70, MS scan: MS range 100-1000 (positive and negative mode), scan speed: 0.84 sec/cycle; Flow into MS 0.8 mUmin.
The following methods were used to purify compounds by reverse phase (MPLC) column chromatography: [XSelect] Instrument type: Reveleris™ prep MPLC; column: Waters XSelect CSH C18 (145 x 25 mm, 10p); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammoniumbicarbonate in water; Gradient: t = 0 min 50% B, t = 4 min 50% B, t = 16 min 100% B, t = 21 min 100% B, or Gradient: t = 0 min 5% B, t = 1 min 5% B, t = 2 min 20% B, t = 20 min 60% B, t = 21 min 100% B, t = 26 min 100% B; Detection UV: 220, 254, 340 nm.
[Gemini] Instrument type: Reveleris™ prep MPLC; Column: Phenomenex Gemini C18 (185 x 25 mm, 10p); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammoniumbicarbonate in water; Gradient: t = 0 min 50% B, t = 4 min 50% B, t = 16 min 100% B, t = 21 min 100% B, or Gradient: t = 0 min 5% B, t = 1 min 5% B, t = 2 min 20% B, t = 17 min 60% B, t = 18 min 100% B, t = 23 min 100% B; Detection UV: 220, 254, 340 nm.
Synthesis of Intermediates
Intermediate 1. l -(fert-Butyl) 2-methyl (2S, S)-4-((4-bromobenzyl)amino)pyrrolidi ne-1 ,2-dicarboxylate.
Figure imgf000056_0001
To a suspension of A/-Boc-c/s-4-amino-L-proline methyl ester hydrochloride (250 g, 0.89 mmol) in DCM (3 ml_) were added successively TEA (0.186 ml_, 1.336 mmol) and 4-bromobenzaldehyde (165 mg, 0.89 mmol). The mixture was stirred at rt overnight. Next, sodium triacetoxyborohydride (566 mg, 2.67 mmol) was added and the resulting suspension was stirred at rt for 2 h. Sat aqueous NaHCCh solution (3 ml_) was added and the mixture was stirred vigorously for 10 Min. The layers were separated (phase separator) and the organic layer was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM to 75% DCM/MeOH (9:1) in 30 Min) afforded pure fractions, which were pooled together and concentrated in vacuo. Yield: 253 mg (68%) of 1 as an oil. LCMS (Method B): Rt, 2.22 Min; ESI m/z\ 413.1 & 415.1 [M+H]+, Br-isotope pattern.
Intermediate 2. l -(fert-Butyl) 2-methyl (2S, 4S)-4-((4-bromobenzyl)(methyl) amino)pyrrolidine-1 ,2-dicarboxylate. r
Intermediate 1 (253 mg, 0.612 mmol) was dissolved in ACN (2.5 ml_) / MeOH (2.5 ml_). 10 eq. of formaldehyde (37 wt% in water) (0.46 ml_, 6.12 mmol) and AcOH (0.088 ml_, 1.53 mmol) were added and the reaction mixture was stirred at rt overnight. Sodium triacetoxyborohyride (324 mg, 1.53 mmol) was added in one portion and the brown solution was stirred at rt for 2 h. The reaction mixture was concentrated (60 °C) to afford a white, sticky solid. DCM (10 ml_) was added and the suspension was washed with water (10 ml_). The layers were separated (phase separator) and the organic layer was evaporated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM to 75% DCM/MeOH (9: 1) in 30 Min) afforded 232 mg (89%) of 2 as an oil. LCMS (Method B): Rt, 2.37 Min; ESI m/z\ 427.1 & 429.1 [M+H]+, Br-isotope pattern.
Intermediate 3. (2S,4S)-1 -(fert-Butoxycarbonyl)-4-((4-(4-(dimethylamino)-4-phenyl piperidin-1 -yl)benzyl)(methyl)amino)pyrrolidine-2-carboxylic acid.
Figure imgf000057_0001
A solution of intermediate 2 (100 g, 0.234 mmol), A/,/\/-dimethyl-4-phenylpiperidin-4- amine (52.6 mg, 0.257 mmol) and sodium tert- butoxide (76 mg, 0.796 mmol) in 1 ,4- dioxane (extra dry) (2.5 ml_) was flushed with nitrogen. X-Phos (22.31 mg, 0.047 mmol) and Pd2(dba)3 (10.71 mg, 0.012 mmol) were added. The dark orange solution was stirred at 100 °C under MW-heating for 1 h (Biotage), followed by additional MW-heating at 110 °C for 2 h. After cooling down to rt the mixture was filtered over a small pad of kieselguhr and concentrated to give 139 mg of the title compound. The crude product was used as such for the next step.
Intermediate 4. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-4-formylphenoxy) pyrrolidine-1 ,2-dicarboxylate. A solution of 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (200 g, 0.815 mmol), 2-chloro-4-hydroxybenzaldehyde (1 16 mg, 0.741 mmol) and triphenylphosphine (233 mg, 0.89 mmol) in dry THF (3 ml_) was cooled to 0 °C. A solution of DIAD (0.144 ml_, 0.741 mmol) in dry THF (1 ml_) was added dropwise. The dark solution was stirred at rt for 1 h. The mixture was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 10% EtOAc/heptane to 100% EtOAc in 50 Min, 100% EtOAc for 4 min) afforded 209 mg (34%) of the title compound as an oil. LCMS (Method B): Rt, 2.26 Min; ESI m/z\ 328.1 [M-(C4HS)+H]+, Cl-isotope pattern.
Intermediate 5. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-4-((4-(dimethylamino)-4- phenylpiperidin-1 -yl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000058_0001
Intermediate 5 was prepared from intermediate 4 (209 mg, 0.256 mmol) and N,N- dimethyl-4-phenylpiperidin-4-amine dihydrochloride (71 mg, 0.256 mmol) similar to the preparation of intermediate 1 , using 2.2 eq. of TEA and 2.5 eq. of sodium triacetoxyborohydride. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM to 100% DCM/MeOH (9:1) in 30 Min), followed by 100% DCM / (7 M NH3 in MeOH) (9: 1) for 15 Min) gave 65 mg (44%) of the title compound. LCMS (Method B): Rt, 2.45 Min; ESI m/z\ 572.3 [M+H]+, Cl-isotope pattern.
Intermediate 6. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-formylphenoxy)pyrrolidine-1 ,2- dicarboxylate. Intermediate 6 was prepared according to the synthetic procedure for 4, starting from 1.1 eq. of 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (250 mg, 1.019 mmol) and 4-hydroxybenzaldehyde (113 mg, 0.927 mmol). Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 5% EtOAc/heptane to 100% EtOAc in 54 Min, 100% EtOAc for 4 min) afforded 182 mg (56%) of the title compound as an oil. LCMS (Method B): Rt, 2.1 1 Min; ESI m/z\ 250.1 [M- (Boc)+H]+.
Intermediate 7. l -(fert-Butyl) 2-methyl (2S,4S)-4-(4-((4-(dimethylamino)-4- phenylpiperidin-1 -yl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000059_0001
Intermediate 7 was prepared according to the synthetic procedure for 5 starting from intermediate 6 (182 mg, 0.521 mmol) and A/,/\/-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (144 mg, 0.521 mmol). Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM to 100% DCM/MeOH (9: 1) in 30 Min), followed by 100% DCM / (7 M NH3 in MeOH) (9: 1) for 20 Min) gave 128 mg (45%) of the title compound. LCMS (Method B): Rt, 2.43 Min; ESI m/z\ 538.3 [M+H]+.
Intermediate 8. (2S, 4S)-4-((4-Bromobenzyl)oxy)-1 -(fert-butoxycarbonyl)pyrrolidi ne-2-carboxylic acid.
Figure imgf000059_0002
A solution of (2S, 4S)-1-(te/f-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.865 mmol) in dry THF (6 ml_) was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) (104 mg, 2.59 mmol) was added and the suspension was stirred at 0 °C for 20 min. 1-Bromo-4-(bromomethyl)benzene (476 mg, 1.903 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was cooled to 0 °C and water (2 ml_) was added carefully, followed by 5% aqueous citric acid solution (1 ml_) and sat aqueous NaHCCh solution (4 ml_). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x, each 2 ml_). The organic layers were combined and concentrated in vacuo to afford a mixture of 8 and unreacted 1-bromo-4- (bromomethyl)benzene). The aqueous layer was acidified to pH ~ 2 and extracted with EtOAc (3 x, each 4 ml_). The combined organic layers were washed with brine and concentrated to afford 258 mg of pure 8. DCM (10 ml_) was added to the crude mixture of 8 and unreacted 1-bromo-4-(bromomethyl)benzene) and the solution was washed with water. The layers were separated, and the aqueous layer was acidified to pH ~ 2 and extracted with EtOAc (2 x, each 10 ml_). The combined organic layers were washed with brine and concentrated to dryness to afford an additional batch of pure intermediate 8. Total yield: 358 mg (98%). Purity according to LCMS: 94.9%. LCMS (Method B): Rt, 1.78 Min; ESI m/z\ 300.0 & 302.0 [M-(Boc)+H]+, Br-isotope pattern.
Intermediate 9. (2S,4S)-1 -(fert-Butoxycarbonyl)-4-((4-(4-(dimethylamino)-4-phenyl piperidin-1 -yl)benzyl)oxy)pyrrolidine-2-carboxylic acid.
Figure imgf000060_0001
Intermediate 9 was prepared according to the synthetic procedure for 3 starting from intermediate 8 (308 mg, 0.769 mmol) and A/,/\/-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (213 mg, 0.769 mmol) with conventional heating at 110 °C for 2 h. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 32 mg (7.9%) of the title compound. LCMS (Method B): Rt, 1.81 Min; ESI m/z\ 524.3 [M+H]+.
Intermediate 10. Di-fert-butyl (2S, 4S)-4-(3-chloro-4-(methoxycarbonyl)phenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000060_0002
Intermediate 10 was prepared according to the synthetic procedure for 4 starting from 1.1 eq. of di-te/f-butyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (100 mg, 0.348 mmol) and methyl 2-chloro-4-hydroxybenzoate (59 mg, 0.316 mmol). Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 15 Min) afforded 46 mg (31 %) of the title compound as an oil. LCMS (Method B): Rt, 2.39 Min; ESI m/z\ 478.2 [M+Na]+.
Intermediate 11. 4-(((3S,5S)-1,5-Bis(fert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-2- chlorobenzoic acid.
Figure imgf000061_0001
To a solution of intermediate 10 (46 mg, 0.101 mmol) in MeOH (0.5 ml_) / THF (0.5 ml_) was added a solution of lithium hydroxide monohydrate (16.93 mg, 0.404 mmol) in water (0.5 ml_) and the resulting mixture was stirred at rt overnight. The mixture was diluted with water (~ 5 ml_) and the organic solvents were evaporated. The pH was adjusted to pH ~ 4 by adding aqueous 1 M KHSCL solution and the aqueous phase was extracted with DCM (2 x, each 5 ml_). The combined organic layers were filtered over a phase separator and concentrated to dryness giving 41 mg (92%) of 11 as an oil. Purity according to LCMS: 87.4%. LCMS (Method B): Rt, 1.81 Min; ESI m/z\ 330.1 [M-(2 x C4H8)+H]+.
Intermediate 12. Di-fert-butyl (2S, S)-4-(3-chloro-4-(4-(dimethylamino)-4-phenyl piperidine-1 -carbonyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000061_0002
To a solution of intermediate 11 (41 mg, 0.093 mmol) in dry DMF (2 mL) were added HATU (35.3 mg, 0.093 mmol) and TEA (0.045 mL, 0.325 mmol). After stirring for 15 min A/,/\/-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (25.7 mg, 0.093 mmol) was added and the mixture was stirred at rt overnight. Next, the reaction mixture was concentrated in vacuo , which afforded 64 mg of the title compound. Purity according to LCMS: 79.0%. LCMS (Method B): Rt, 2.45 Min; ESI m/z\ 628.4 [M+H]+. The crude product was used directly for the next step.
Intermediate 13. (4-Bromophenyl)(4-(dimethylamino)-4-phenylpiperidin-1 -yl)me thanone.
Figure imgf000062_0001
Intermediate 13 was prepared according to the method described for intermediate 12 using 4-bromobenzoic acid (150 mg, 0.746 mmol) and A/,/\/-dimethyl-4-phenylpiperidin- 4-amine dihydrochloride (207 mg, 0.746 mmol). After stirring overnight at rt the mixture was concentrated. DCM (20 ml_) was added and the mixture was washed with water (2 x, each 20 ml_). The layers were separated (phase separator) and the organic layer was concentrated. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 15 Min, 100% DCM/MeOH (9: 1) for 20 Min) afforded 256 mg (88%) of intermediate 13 (co-evaporated with DCM) as an oil. LCMS (Method B): Rt, 2.19 Min; ESI m/z\ 387.1 & 389.1 [M+H]+, Br-isotope pattern.
Intermediate 14. Di-fert-butyl (2S,4/?)-4-(((4-(4-(dimethylamino)-4-phenylpiperidine -1 -carbonyl)phenyl)amino)methyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000062_0002
To a solution of di-te/f-butyl (2S,4R)-4-(aminomethyl)pyrrolidine-1 ,2-dicarboxylate (124 mg, 0.336 mmol, purity according to LCMS ~ 81 %) and sodium tert- butoxide (38.7 mg, 0.403 mmol) in a,a,a-trifluorotoluene (3 mL) was added a solution of 13 (130 mg, 0.336 mmol) in dry THF (1 mL). The mixture was flushed with nitrogen, after which BrettPhos (14.41 mg, 0.027 mmol) and Pd2(dba)3 (6.15 mg, 6.71 pmol) were added. The dark yellow solution was stirred at 100 °C under MW-heating (Biotage) for 1 h. After cooling down to rt the mixture was filtered over a small pad of kieselguhr and concentrated. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / 10-100% DCM/MeOH (9: 1)) in 15 Min, 100% DCM/MeOH (9: 1) for 25 Min) afforded 105 mg (51 %) of 14 as a glass-like solid. LCMS (Method B): Rt, 2.38 Min; ESI m/z\ 607.4 [M+H]+.
Intermediate 15. Di-fert-butyl (2S,4/?)-4-((benzylamino)methyl)pyrrolidine-1 ,2-di carboxylate.
Figure imgf000063_0001
Intermediate 15 was prepared from di-te/f-butyl (2S,4R)-4-(aminomethyl)pyrrolidine-1 ,2- dicarboxylate (500 mg, 1.664 mmol), benzaldehyde (0.169 ml_, 1.664 mmol) and 2 eq. of AcOH (0.24 ml_, 4.16 mml) in MeOH (5 ml_) / ACN (5 ml_). After stirring overnight 2.5 eq. of sodium triacetoxyborohydride (882 mg, 4.16 mmol) were added and stirring was continued for 2 h. The reaction mixture was concentrated and partitioned between DCM (15 ml_) and sat aqueous NaHCCh solution (15 ml_). The mixture was stirred vigorously for 30 min, after which the layers were separated (phase separator) and the organic layer was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 30 Min) afforded 426 mg (65%) of the title compound as an oil. LCMS (Method B): Rt, 2.31 Min; ESI m/z\ 391.3 [M+H]+.
Intermediate 16. Di-fert-butyl (2S,4/?)-4-((benzyl(methyl)amino)methyl)pyrrolidine- 1 ,2-dicarboxylate.
Figure imgf000063_0002
Intermediate 16 was obtained from intermediate 15 (400 mg, 1.024 mmol) and 10 eq. of formaldehyde (37 wt% solution in water) (0.491 mL, 6.53 mmol) using 2.5 eq. of AcOH (0.1 13 mL, 1.959 mmol) and sodium triacetoxyborohydride (543 mg, 2.56 mmol) according to the method for the preparation of intermediate 15. For work-up DCM (50 mL) and sat aqueous NaHCCh solution (50 mL) was used. Crude yield: 409 mg (99%). LCMS (Method B): Rt, 2.54 Min; ESI m/z\ 405.3 [M+H]+.
Intermediate 17. Di-fert-butyl (2S,4/?)-4-((methylamino)methyl)pyrrolidine-1 ,2- dicarboxylate. /
-NH
Figure imgf000064_0001
f-BuO Boc
To a solution of intermediate 16 (409 mg, 1.011 mmol) in EtOH (20 ml_) palladium hydroxide on carbon (28.4 mg, 0.202 mmol) was added and the suspension was flushed with nitrogen. Next, the mixture was flushed with hydrogen and stirred under an atmosphere of hydrogen (1 bar, balloon) at rt overnight. The mixture was filtered over kieselguhr and concentrated to dryness to afford 308 mg (97%) of 17 as an oil. The product was used as such. LCMS (Method B): Rt, 2.00 Min; ESI m/z. 315.2 [M+H]+.
Intermediate 18. Di-fert-butyl (2S,4/?)-4-(((4-(4-(dimethylamino)-4-phenylpiperi dine-1 -carbonyl)phenyl)(methyl)amino)methyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000064_0002
Intermediate 18 was prepared according to the synthetic procedure as described for intermediates 3 and 9 starting from intermediates 13 (185 mg, 0.477 mmol) and 17 (150 mg, 0.477 mmol) using 0.08 eq. of X-Phos, 0.02 eq. of Pd2(dba)3, 1.2 eq. of sodium tert- butoxide with conventional heating at 110 °C for 1 h. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5- 100% DCM/MeOH (9: 1)) in 25 Min) afforded 87 mg (19%) of the title compound as a glass-like solid. Purity according to LCMS: 67.5%. LCMS (Method B): Rt, 2.46 Min; ESI m/ . 621.4 [M+H]+.
Intermediate 19. (3-Bromophenyl)(4-(dimethylamino)-4-phenylpiperidin-1 -yl)me thanone.
Figure imgf000064_0003
Intermediate 19 was prepared according to the method as described for intermediates 12 using 3-bromobenzoic acid (300 mg, 1.492 mmol), A/,/\/-dimethyl-4-phenylpiperidin-4- amine dihydrochloride (414 mg, 1.492 mmol), 1 eq. of HATU and 3.5 eq. of TEA with stirring for 1 h. DCM (40 mL) and water (40 mL) were used for work-up/extraction (phase separator). Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 24 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 25 min, 100% DCM/MeOH (9: 1) for 10 min) afforded 541 mg (94%) of the title compound as an oil. LCMS (Method B): Rt, 2.17 Min; ESI m/ 387.1 & 389.1 [M+H]+, Br-isotope pattern.
Intermediate 20. Di-fert-butyl (2S,4/?)-4-(((3-(4-(dimethylamino)-4-phenylpiperidine -1 -carbonyl)phenyl)(methyl)amino)methyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000065_0001
Intermediate 20 was prepared according to the synthetic procedure described for intermediate 18 starting from intermediates 17 (439 mg, 1.397 mmol) and 19 (541 mg, 1.397 mmol) with conventional heating at 110 °C overnight. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 76 mg (8.7%) of the title compound as a glass-like solid. LCMS (Method B): Rt, 2.51 Min; ESI m/z. 621.5 [M+H]+.
Intermediate 21. Di-fert-butyl (2S, S)-4-(3-chloro-5-(methoxycarbonyl)phenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000065_0002
Intermediate 21 was prepared according to the synthetic procedure for intermediate 4 starting from di-te/f-butyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (200 mg, 0.696 mmol) and methyl 3-chloro-5-hydroxybenzoate (130 mg, 0.696 mmol), using 1 eq. of DIAD and 1.2 eq. of triphenylphosphine with stirring at rt overnight. Purification (pre packed silica cartridge GraceResolv™ 24 g, gradient 5% EtOAc/heptane to 100% EtOAc in 35 Min) afforded 82 mg (25%) of the title compound as an oil. LCMS (Sc-base 210): Rt, 2.50 Min; ESI m/z. 300.1 [M-(Boc-(C4H8))+H]+, Cl-isotope pattern. Intermediate 22. 3-(((3S,5S)-1,5-Bis(fert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-5- chlorobenzoic acid.
Figure imgf000066_0001
f-BuO Boc
Intermediate 22 was prepared according to the synthetic procedure for intermediate 11 starting from a solution of methyl ester 21 (82 mg, 0.18 mmol) in MeOH (1 ml_) / THF (1 ml_) and 4 eq. of lithium hydroxide monohydrate in water (1 ml_). Work-up involved extraction with EtOAc (3 x, each 10 ml_) and drying over NaaSC o give 73 mg (92%) of the title compound. The product was used as such. LCMS (Method B): Rt, 1.84 Min; ESI m/z. 440.2 [M-H] , Cl-isotope pattern.
Intermediate 23. Di-fert-butyl (2S,4S)-4-(3-chloro-5-(4-(dimethylamino)-4- phenylpiperidine-1 -carbonyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000066_0002
Intermediate 23 was prepared according to the synthetic procedure for intermediate 12 starting from carboxylic acid 22 (73 mg, 0.165 mmol) and A/,/\/-dimethyl-4- phenylpiperidin-4-amine dihydrochloride (45 mg, 0.165 mmol) in DMF (1 ml_), using 1 eq. of HATU and 3.5 eq. of TEA. DCM (5 ml_) and sat aqueous NaHCCh solution (10 ml_) were used for work-up/extraction. The aqueous phase was separated (phase separator) and extracted with DCM (2 x, each 10 ml_). The combined organic phases were concentrated and diluted with EtOAc (20 ml_). The organic layer was washed with a 1 :1 mixture of brine and water (3 x, each 20 ml_), dried over Na2S04, filtered and concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 4 g, gradient DCM / (10-60% DCM/MeOH (9: 1)) to yield 74 mg (71 %) of 23. LCMS (Method B): Rt, 2.54 Min; ESI m/ 628.4 [M+H]+, Cl-isotope pattern.
Intermediate 24. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-bromophenoxy)pyrrolidine- 1 ,2-dicarboxylate. A reaction vial was charged with 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (300 g, 1.223 mmol) and 3-bromophenol (212 mg, 1.223 mmol) in dry toluene (10 ml_) and the dark yellow solution was flushed with nitrogen. 2 eq. of CM BP (0.642 ml_, 2.446 mmol) was added and the light brown solution was stirred in a sealed reaction vial at 100 °C overnight. The mixture was concentrated in vacuo, followed by purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 55 Min). Pure fractions were pooled together and concentrated in vacuo to afford 313 mg (63%) of the title compound as an oil. LCMS (Method B): Rt, 2.27 Min; ESI m/z\ 344.0 & 346 [M- (04Hd)+H]+, Br-isotope pattern.
Intermediate 25. Potassium ((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl) trifluoroborate.
Figure imgf000067_0001
A/,/\/-dimethyl-4-phenylpiperidin-4-amine (196 mg, 0.959 mmol) was suspended in dry THF (2 ml_). Potassium (bromomethyl)trifluoroborate (193 mg, 0.959 mmol) and f-BuOH (500 pl_) were added and the suspension was stirred in a sealed reaction vial at 80 °C for 2 h. After cooling down to rt the mixture was concentrated. DCM (~ 5 ml_) was added and the white suspension was filtered over a nylon microfilter and the filtrate was concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (8-100% DCM/MeOH (9: 1)) in 25 Min, 100% DCM/MeOH (9: 1) for 5 Min) afforded 203 mg (65%) of the title compound as a solid. LCMS (Method B): Rt, 1.71 Min; ESI m/z\ 285.2 [C14H21 BF3N2] .
Intermediate 26. l-(fert-Butyl) 2-methyl (2S, S)-4-(3-((4-(dimethylamino)-4-phenyl piperidin-1 -yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate. A solution of intermediate 25 (100 g, 0.308 mmol) in THF (2 ml_) / water (0.2 ml_) was added to intermediate 24 (95 mg, 0.237 mmol), followed by CS2CO3 (232 mg, 0.712 mmol) and the resulting yellow solution was flushed with nitrogen. Pd(OAc)2 (1.6 mg, 7.12 pmol) and X-Phos (6.79 mg, 0.014 mmol) were added and the mixture was stirred at 80 °C for 4 days. Water (2 ml_) was added and the mixture was extracted with EtOAc (3 x, each 3 ml_). The organic layers were combined, dried over Na2SC>4 and concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (8-100% DCM / (7 M NH3 in MeOH) (9:1) in 30 Min, 100% DCM / (7 M NH3 in MeOH) (9: 1) for 10 Min) afforded 53 mg (41 %) of the title compound. Purity according to LCMS: 86.2%. LCMS (Method B): Rt, 2.30 Min; ESI m/z\ 538.4 [M+H]+.
Intermediate 27. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-chlorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000068_0001
Intermediate 27 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (200 mg, 0.815 mmol) and 3-bromo-5-chlorophenol (169 mg, 0.815 mmol) according to the method as described for the preparation of intermediate 24. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM to 80% DCM/MeOH (9:1)) in 30 Min afforded 268 mg (76%) of the title compound as an oil. LCMS (Method B): Rt, 2.41 Min; ESI m/z\ 334.0 & 336.0 [M- (Boc)+H]+, CI-Br-isotope pattern.
Intermediate 28. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-((4-(dimethylamino)- 4-phenylpiperidin-1 -yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate. Intermediate 28 was obtained from intermediates 25 (200 mg, 0.815 mmol) and 27 (169 mg, 0.815 mmol) according to the method described for the preparation of intermediate 26 with heating overnight at 80 °C. Purification by flash column chromatography (pre- packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM/MeOH (9:1) + 2% Et3N) in 25 Min, 100% DCM / (7 M NH3 in MeOH) (9:1) for 15 Min) afforded 77 mg (53%) of the title compound as an oil. Purity according to LCMS: 88.4%. LCMS (Method B): Rt, 2.43 Min; ESI m/z\ 572.4 [M+H]+, Cl-isotope pattern. Intermediate 29. 2-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenol.
Figure imgf000069_0001
Intermediate 29 was obtained from A/,/\/-dimethyl-4-phenylpiperidin-4-amine (125 mg, 0.612 mmol) and 2-hydroxybenzaldehyde (0.064 ml_, 0.612 mmol) according to the method for the preparation of intermediate 16. For work-up the mixture was concentrated. DCM (10 ml_) was added and the suspension was filtered. The filtrate was concentrated to dryness, followed by purification by preparative LC (XSelect CSH C18, basic eluent gradient). Yield: 91 mg (44%) as a solid. Purity according to LCMS: 93.7%. LCMS (Method B): Rt, 2.27 Min; ESI m/z\ 311.2 [M+H]+. Intermediate 30. l-(fert-Butyl) 2-methyl (2S,4S)-4-(2-((4-(dimethylamino)-4- phenylpiperidin-1-yl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000069_0002
o Boc Intermediate 30 was prepared from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (97 mg, 0.396 mmol) and intermediate 29 (123 mg, 0.396 mmol) according to the method as described for intermediate 24. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 48 mg (22%) of the title compound as an oil. LCMS (Method B): Rt, 2.36 Min; ESI m/z\ 538.4 [M+H]+.
Intermediate 31. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000070_0001
Intermediate 31 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (736 mg, 3.0 mmol) and 3-bromo-5-fluorophenol (573 mg, 3.0 mmol) in dry THF (25 ml_) according to the method described for the preparation of intermediate 4. After stirring for 1 h at rt, additional DIAD (0.1 17 ml_, 0.6 mmol) in THF (5 ml_) was added, and stirring was continued overnight. The solvent was evaporated and purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 5% EtOAc/heptane to 75% EtOAc/heptane in 55 Min) afforded 878 mg (70%) of the title compound as an oil. LCMS (Method B): Rt, 2.31 Min; ESI m/z\ 362.0 & 364.0 [M+H]+, Br-isotope pattern.
Intermediate 32. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((4-(dimethylamino)-4- phenylpiperidin-1 -yl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000070_0002
Intermediate 32 was prepared from intermediates 25 (112 mg, 0.345 mmol) and 31 (1 11 mg, 0.266 mmol) according to the method described for intermediate 26 with heating overnight at 80 °C. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM / (7 M NH3 in MeOH) (9:1) in 25 Min, 100% DCM / (7 M NH3 in MeOH) (9: 1) for 15 Min) afforded 91 mg (61 %) of the title compound as a glass-like solid. Purity according to LCMS: 92.1 %. LCMS (Method B): Rt, 2.36 Min; ESI m/z\ 556.4 [M+H]+. Intermediate 33. Potassium ((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)trifluoroborate.
Figure imgf000071_0001
Intermediate 33 was obtained from 3-(4-(dimethylamino)piperidin-4-yl)phenol dihydrochloride (50 mg, 0.171 mmol), potassium (bromomethyl)trifluoroborate (34.2 mg, 0.171 mmol) and 2.05 eq. of Et3N (0.049 ml_, 0.35 mmol) according to the method as described for the preparation of intermediate 25. For work-up/filtration DCM/MeOH (9:1) (~ 3 ml_) was used. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 4 g, isocratic 100% DCM/MeOH (9: 1) for 20 min gave 42 mg (72%) of the title compound as a solid. LCMS (Method B): Rt, 1.53 Min; ESI m/z\ 301.2 [C14H21 BF3N20]-.
Intermediate 34. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((4-(dimethylamino)-4-(3- hydroxyphenyl)piperidin-1 -yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000071_0002
Intermediate 34 was obtained from intermediate 33 (128 mg, 0.376 mmol) and intermediate 24 (1 16 mg, 0.289 mmol) according to the method described for the preparation of intermediate 26. Purification conditions: flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM / (7 M NHs in MeOH) (9: 1)) in 25 Min, 100% DCM / (7 M NH3 in MeOH (9: 1) for 15 Min). Yield: 57 mg (35%) of the title compound as a glass-like solid. Purity according to LCMS: 92.2%. LCMS (Method B): Rt, 2.16 Min; ESI m/z\ 554.3 [M+H]+.
Intermediate 35. (2S, 4S)-4-(3-Bromophenoxy)-1 -(fert-butoxycarbonyl)pyrrolidine- 2-carboxylic acid.
Figure imgf000071_0003
HO Boc Tesser’s base solution: aqueous 4 M NaOH solution (1 ml_, 4.0 mmol) was diluted with 1 ,4-dioxane (14 ml_) and MeOH (5 ml_). Intermediate 24 (100 mg, 0.250 mmol) was then dissolved in 5 ml_ of this solution and was stirred at rt overnight. The reaction mixture was concentrated until the organic solvents had evaporated. The material was isolated as the corresponding sodium salt, which was used as such for the next step. LCMS (Method B): Rt, 1.66 Min; ESI m/z\ 384.0 & 386.0 [M-H] , Br-isotope pattern.
Intermediate 36. (2S,4S)-1 -(fert-Butoxycarbonyl)-4-(3-(4-(dimethylamino)-4-phenyl piperidin-1 -yl)phenoxy)pyrrolidine-2-carboxylic acid.
Figure imgf000072_0001
Intermediate 36 was prepared according to the synthetic procedure for intermediate 3 from intermediate 35 (97 mg, 0.251 mmol) and A/,/\/-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (77 mg, 0.276 mmol), using 0.2 eq. of X-Phos, 0.05 eq. of Pd (dba) and 3 eq. of sodium tert- butoxide with conventional heating at 1 10 °C for 3 h. After cooling down to rt the mixture was concentrated to give the crude title compound which was used as such in the next step.
Intermediate 37. 1 -(3-(Benzyloxy)phenyl)-4-(dimethylamino)-4-phenylcyclohexan- 1 -ol.
Figure imgf000072_0002
In a 50 ml_ three-necked reaction flask, fitted with stirring bean, septum, reflux condenser with nitrogen flow setup and stopper, magnesium turnings (112 mg, 4.60 mmol; first grinded with a mortar and pestle to obtain gleaming metallic magnesium turnings) was suspended in dry THF (10 ml_). The resulting mixture was heated to 60 °C and iodine (crushed grain; 5 mg, 0.020 mmol) was added (not stirred for 5 min after the addition of the iodine). The reaction mixture was stirred for 1 h at 60 °C. A suspension of 3- benzyloxybromobenzene (605 mg, 2.301 mmol) in dry THF (2 ml_) was slowly added and stirring at reflux temperature was continued for 2 h. After this time, the reaction mixture was cooled down to -10 °C (salt/ice bath) and a solution of 4-(dimethylamino)-4- phenylcyclohexan-1-one (500 mg, 2.301 mmol) in dry THF (2 ml_) was slowly added. After stirring for 3 h at -10 °C the reaction mixture was quenched with sat aqueous NhUCI solution, followed by the addition of Et2<D. The aqueous phase was separated (including the solid residues) and extracted with Et2<D (2 x). The combined organic phases were washed with brine, dried with Na2SC>4, filtered and concentrated to dryness. The crude material (1.1 1 g,‘120%’) was used as such for the next step.
Intermediate 38. 3"-(Benzyloxy)-A/,A/-dimethyl-3,,6,-dihydro-[1 ,1,:4,,1 "-terphenyl]- 1 '(2'H)-amine.
Figure imgf000073_0001
Crude intermediate 37 (601 mg, 1.497 mmol) was dissolved in DCM (10 ml_). TFA (0.5 ml_, 6.53 mmol) was added and stirring was continued at rt overnight. More TFA (0.5 ml_, 6.53 mmol) was added and stirring was continued for 2 h. The reaction mixture was quenched with sat aqueous NaHCCh solution (10 ml_) and diluted with additional DCM. The aqueous phase was separated and extracted with DCM (2 x, each 20 ml_). The combined organic phases were washed with brine, dried with Na2SC>4, filtered and concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 173 mg (30% over 2 steps) of the title compound. LCMS (Method B): Rt, 2.44 Min; ESI m/z\ 384.3 [M+H]+.
Intermediate 39. 3-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)phenol.
Figure imgf000073_0002
Intermediate 38 (170 mg, 0.443 mmol) was dissolved in MeOH (8 ml_) and the solution was subjected to hydrogenation (H-cube hydrogenation flow reactor: 1 mL/min; 60 °C; atmospheric H2 pressure; 10% Pd/C Cat Cart™ cartridge; rinsed with additional MeOH (~ 10 ml_); collection started as soon as the reaction solution was applied, no delay). This solution was concentrated to dryness followed by co-evaporating with EtOH (3 x) and DCM (2 x) to yield 1 15 mg of the title compound. This crude material was used as such in the next reaction. Intermediate 40. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-((1 ,4S)-4-(dimethylamino)-4- phenylcyclohexyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000074_0001
Intermediate 40 was prepared from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (95 mg, 0.389 mmol) and crude phenol 39 (max. 0.443 mmol) according to the synthesis method described for intermediate 24 in dry toluene (2 ml_) and using 1.5 eq. of CMBP (0.642 ml_, 2.446 mmol). Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 69 mg (33%) of the title compound. LCMS (Method B): Rt, 2.23 Min; ESI m/z 523.3 [M+H]+.
Aryl ether intermediates 41-64 were prepared from 1-(te/f-butyl) 2-methyl (2S,4R)-4- hydroxypyrrolidine-1 ,2-dicarboxylate or 1-(te/f-butyl) 2-methyl (2S,4S)- 4- hydroxypyrrolidine-1 ,2-dicarboxylate and suitable phenol starting materials similar to the synthesis and purification method as described for intermediate 4 (Mitsunobu conditions, using DIAD and triphenylphosphine, Method M) and described for the preparation of intermediate 24, using CMBP (Method C). For LCMS analysis method B was used.
Intermediate 41. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-methylphenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000074_0002
Method M. Yield: 468 mg (92%). LCMS: Rt, 2.38 Min; ESI m/z 358.0 & 360.0 [M- (C4H8)+H]+ Br isotope pattern. Purity according to LCMS: 97.6%.
Intermediate 42. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate. Method M. Yield: 325 mg (63%). LCMS: Rt, 2.28 Min; ESI m/z\ 318.0 & 320.0 [M- (04Hd)+H]+ Br isotope pattern. Purity according to LCMS: 98.0%. Intermediate 43. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000075_0001
Method M. Yield: 672 mg (83%). LCMS: Rt, 2.28 Min; ESI m/z\ 318.0 & 320.0 [M- (C H )+H]+ Br isotope pattern. Purity according to LCMS: 100.
Intermediate 44. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-4-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000075_0002
Boc
Method M. Yield: 635 g (78%). LCMS: Rt, 2.28 Min; ESI m/z\ 318.0 & 320.0 [M- (C H )+H]+ Br isotope pattern. Purity according to LCMS: 99.7%.
Intermediate 45. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2,4-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000075_0003
Method M. Yield: 380 mg (72%). LCMS: Rt, 2.30 Min; ESI m/z\ 336.0 & 338.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 97.7%. Intermediate 46. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-(trifluoromethyl) phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000076_0001
Method M. Yield: 476 g (52%). LCMS: Rt, 2.41 ; ESI m/z 368.1 & 370.1 [M-(Boc)+H]+ Br isotope pattern. Purity according to LCMS: 99.2%.
Intermediate 47. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-methoxyphenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000076_0002
Method M. Yield: 664 g (79%). LCMS: Rt, 2.30 Min; ESI m/ 330.1 & 332.1 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 99.8%.
Intermediate 48. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2,6-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000076_0003
Method C. Yield: 414 mg (49%). LCMS: Rt, 2.28 Min; ESI m/z 336.0 & 338.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 98.9%. Intermediate 49. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2-chlorophenoxy) pyrrolidine-1 ,2-dicarboxylate. Method C. Yield: 649 mg (92%). LCMS: Rt, 2.34 Min; ESI m/z\ 334.0 & 336.0 [M- (Boc)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 99.6%.
Intermediate 50. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2-chloro-3-fluorophen oxy)pyrrolidine-1,2-dicarboxylate.
Cl \ F
Figure imgf000077_0001
Ό Boc
Method C. Yield: 448 g (88%). LCMS: Rt, 2.36 Min; ESI m/z\ 352.0 & 354.0 [M- (Boc)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 99.5%.
Intermediate 51. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-4-chlorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000077_0002
Boc
Method M. Yield: 447 mg (50%). LCMS: Rt, 2.33 Min; ESI m/z\ 334.0 & 336.0 [M- (Boc)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 99.8%.
Intermediate 52. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-cyanophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000077_0003
Method M. Yield: 409 mg (62%). LCMS: Rt, 2.26 Min; ESI m/z. 325.0 & 327.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 100%. Intermediate 53. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-4-chloro-5-fluoro phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000078_0001
Method M. Yield: 1.08 g (72%). LCMS: Rt, 2.27 Min; ESI m/z 396.0 & 397.9. [M- (04Hd)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 99.8%.
Intermediate 54. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2,3-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000078_0002
Method C. Yield: 654 g (92%). LCMS: Rt, 2.34 Min; ESI m/z 336.0 & 338.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 98.9%.
Intermediate 55. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2-chlorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000078_0003
Method C. Yield: 629 g (89%). LCMS: Rt, 2.30 Min; ESI m/ 334.0 & 336.0 [M- (Boc)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 99.9%.
Intermediate 56. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2,4-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
F
rf" Br
/O Boc
Method C. Yield: 626 mg (75%). LCMS: Rt, 2.29 Min; ESI m/z 336.0 & 338.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 99.5%. Intermediate 57. 1 -(fert-Butyl) 2-methyl (2S,4R)-4-(3-bromophenoxy)pyrrolidine- 1 ,2-dicarboxylate.
Figure imgf000079_0001
Method C. Yield: 569.8 g (69%). LCMS: Rt, 2.35 Min; ESI m/z 300.1 & 302.1 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 97.8%.
Intermediate 58. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2-(trifluoromethyl) phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000079_0002
Method C. Yield: 680 g (71 %). LCMS: Rt, 2.35 Min; ESI m/ 368.0 & 370.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 98.1 %.
Intermediate 59. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-4-(trifluoromethyl) phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000079_0003
Method M. Yield: 661 mg (69%). LCMS: Rt, 2.42 Min; ESI m/z 368.0 & 370.0 [M- (Boc)+H]+ Br isotope pattern. Purity according to LCMS: 99.2%.
Intermediate 60. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-2,5-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000079_0004
Method C. Yield: 734 mg (83%). LCMS: Rt, 2.32 Min; ESI m/z\ 380.0 & 382.0 [M- (C H )+H]+ Br isotope pattern. Purity according to LCMS: 91.4%.
Intermediate 61. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-chloro-4- fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000080_0001
Method C. Yield: 754 g (82%). LCMS: Rt, 2.41 Min; ESI m/z\ 396.0 & 398.0 [M- (04Hd)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 94.2%.
Intermediate 62. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-chloro-2- fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000080_0002
Ό Boc
Method C. Yield: 755 g (91 %). LCMS: Rt, 2.31 Min; ESI m/z\ 395.9 & 397.9 [M- (C H )+H]+ Cl-Br isotope pattern. Purity according to LCMS: 96.4%.
Intermediate 63. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-4-formylphenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000080_0003
Method M. Yield: 400 mg (37%). LCMS: Rt, 2.15 Min; ESI m/z\ 372.0 & 374.0 [M- (C H )+H]+ Br isotope pattern. Purity according to LCMS: 99.2%.
Intermediate 64. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-bromo-4-chloro-2,3-difluoro phenoxy)pyrrolidine-1,2-dicarboxylate. F F
Cl
Figure imgf000081_0001
Method C. Yield: 552 mg (82%). LCMS: Rt, 2.28 Min; ESI m/z\ 413.9 & 415.9 [M- (04Hd)+H]+ Cl-Br isotope pattern. Purity according to LCMS: 94.8%.
Intermediate 65. 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-A/,A/-dimethyl-1 -phe nylcyclohexan-1 -amine.
Figure imgf000081_0002
A capped reaction vial containing A/,/\/-dimethyl-4-methylene-1-phenylcyclohexan-1- amine (1 g, 4.64 mmol) was flushed with nitrogen. A solution of 9-BBN in THF (0.5 M, 13.0 mL, 6.5 mmol) was added and the mixture was stirred at 75 °C for 3 h. Complete conversion of the starting material was observed on TLC (EtOAc/heptane, 1 :1). The solution was used as such for the next step.
Intermediate 66. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000081_0003
To a solution of intermediate 24 (1.5 g, 3.75 mmol) in 1 ,4-dioxane (12 mL), a solution of Na2CC>3 (0.794 g, 7.49 mmol) in water (4 mL) was added. The mixture was flushed with N2 after which XantPhos (0.130 g, 0.225 mmol), Pd2(dba)3 (0.103 g, 0.1 12 mmol) and a freshly prepared solution of intermediate 65 (1.517 g, 4.50 mmol) in THF (~ 13 mL) were added. The mixture was stirred at 80 °C under MW-heating for 4.5 h (in two separate batches). The mixture was filtered over a small pad of kieselguhr, rinsed with 1 ,4-dioxane and concentrated in vacuo. DCM (25 mL) was added and the suspension was washed with water. The layers were separated using a phase separator and the organic layer was concentrated. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient DCM to 50% DCM/MeOH (9: 1)) in 15 Min, 50% to 100% DCM/MeOH (9: 1) in 5 min, 100% DCM/MeOH (9: 1) for 83 Min) afforded 584 g (26%) of the title compound. LCMS (Method B): Rt, 2.58 Min; ESI m/z\ 537.4 [M+H]+. Purity according to LCMS: 90.6%.
Intermediate 67. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000082_0001
Intermediate 67 was obtained together with its diastereoisomer 66. Yield: 989 mg (45%) of the title compound. LCMS (Method B): Rt, 2.77 Min; ESI m/z\ 537.4 [M+H]+. Purity according to LCMS: 92.1 %.
The synthesis method as described for intermediates 66 and 67 was followed for the preparation of intermediates 68-119 using suitable starting materials:
Intermediate 68. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000082_0002
Yield: 133 mg (18%). LCMS (Method B): Rt, 2.79 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 98.4%.
Intermediate 69. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000082_0003
Yield: 251 mg (37%). LCMS (Method B): Rt, 2.65 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 93.2%.
Intermediate 70. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-chloro-5-(((1 r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate. Yield: 155 g (21 %). LCMS (Method B): Rt, 2.69 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 98.1 %. Intermediate 71. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-chloro-5-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000083_0001
Yield: 275 g (37%). LCMS (Method B): Rt, 2.90 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 97.1 %.
Intermediate 72. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-methylphenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000083_0002
Yield: 132 mg (21 %). LCMS (Method B): Rt, 2.72 Min; ESI m/z\ 551.3 [M+H]+. Purity according to LCMS: 92.9%.
Intermediate 73. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-5-methylphenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000083_0003
Yield: 263 mg (42%). LCMS (Method B): Rt, 2.86 Min; ESI m/z. 551.3 [M+H]+. Purity according to LCMS: 89.7%.
Intermediate 74. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1,2-dicarboxylate. Yield: 82 g (19%). LCMS (Method B): Rt, 2.60 Min; ESI m/z\ 555.3 [M+H]+. Purity according to LCMS: 80.2%.
Intermediate 75. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000084_0001
Yield: 101 mg (23%). LCMS (Method B): Rt, 2.76 Min; ESI m/z\ 555.3 [M+H]+. Purity according to LCMS: 99.2%.
Intermediate 76. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000084_0002
Yield: 110 mg (20%). LCMS (Method B): Rt, 2.53 Min; ESI m/z\ 555.3 [M+H]+. Purity according to LCMS: 99.4%.
Intermediate 77. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000084_0003
Yield: 164 g (30%). LCMS (Method B): Rt, 2.74 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 99.7%.
Intermediate 78. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate. Yield: 117 mg (21 %). LCMS (Method B): Rt, 2.57 Min; ESI m/z\ 555.3 [M+H]+. Purity according to LCMS: 95.7%.
Intermediate 79. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000085_0001
Yield: 198 g (36%). LCMS (Method B): Rt, 2.70 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 99.0%.
Intermediate 80. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000085_0002
Yield: 44 mg (8.8%). LCMS (Method B): Rt, 2.59 Min; ESI m/z\ 573.3 [M+H]+. Purity according to LCMS: 96.9%.
Intermediate 81. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000085_0003
Yield: 85 mg (17.0%). LCMS (Method B): Rt, 2.78 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 95.2%.
Intermediate 82. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxy late. Yield: 94 mg (15.0%). LCMS (Method B): Rt, 2.70 Min; ESI m/z\ 605.4 [M+H]+. Purity according to LCMS: 79.1 %. Intermediate 83. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-(trifluoromethyl)phenoxy)pyrrolidine-1 ,2-dicarboxyla te.
Figure imgf000086_0001
Yield: 130 g (21.0%). LCMS (Method B): Rt, 2.88 Min; ESI m/z\ 605.4 [M+H]+. Purity according to LCMS: 90.2%.
Intermediate 84. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-methoxyphenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000086_0002
Yield: 86 mg (9.7%). LCMS (Method B): Rt, 2.55 Min; ESI m/z\ 567.4 [M+H]+. Purity according to LCMS: 94.6%.
Intermediate 85. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-methoxyphenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000086_0003
Yield: 224 mg (25.0%). LCMS (Method B): Rt, 2.71 Min; ESI m/z\ 567.4 [M+H]+. Purity according to LCMS: 90.8%. Intermediate 86. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,6-difluorophenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000087_0001
Yield: 207 g (24.0%). LCMS (Method B): Rt, 2.63 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 98.7%.
Intermediate 87. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,6-difluorophenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000087_0002
Yield: 401 g (49.0%). LCMS (Method B): Rt, 2.83 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 96.1 %.
Intermediate 88. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-5-(((1 ,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000087_0003
Yield: 230 mg (27.0%). LCMS (Method B): Rt, 2.71 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 78.1 %.
Intermediate 89. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-5-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
ci.
rf-M
°9 N
O Boc
Figure imgf000087_0004
Yield: 424 mg (50.0%). LCMS (Method B): Rt, 2.83 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 84.6%. Intermediate 90. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-5-(((1 r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxy late.
Figure imgf000088_0001
Yield: 171 mg (29.0%). LCMS (Method B): Rt, 2.70 Min; ESI m/z\ 589.3 [M+H]+. Purity according to LCMS: 97.0%.
Intermediate 91. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-5-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxy late.
Figure imgf000088_0002
Yield: 309 g (53.0%). LCMS (Method B): Rt, 2.83 Min; ESI m/z\ 589.3 [M+H]+. Purity according to LCMS: 99.1 %.
Intermediate 92. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-(((1 r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000088_0003
Yield: 120 g (17.0%). LCMS (Method B): Rt, 2.64 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 85.1 %.
Intermediate 93. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000088_0004
Yield: 226 mg (28.0%). LCMS (Method B): Rt, 2.84 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 74.5%. Intermediate 94. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-cyano-5-(((1 r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000089_0001
Yield: 119 mg (22.0%). LCMS (Method B): Rt, 2.47 Min; ESI m/z\ 562.4 [M+H]+. Purity according to LCMS: 94.3%.
Intermediate 95. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-cyano-5-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000089_0002
Yield: 227 g (42.0%). LCMS (Method B): Rt, 2.62 Min; ESI m/z\ 562.4 [M+H]+. Purity according to LCMS: 94.2%.
Intermediate 96. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-(((1 r,4S)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxy late.
Figure imgf000089_0003
Yield: 165 mg (17.0%). LCMS (Method B): Rt, 2.69 Min; ESI m/z\ 589.3 [M+H]+. Purity according to LCMS: 91.2%.
Intermediate 97. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-(((1s,4/?)-4-(dimethyl amino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxy late.
Figure imgf000089_0004
Yield: 282 g (30.0%). LCMS (Method B): Rt, 2.88 Min; ESI m/z\ 589.3 [M+H]+. Purity according to LCMS: 84.9%. Intermediate 98. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000090_0001
Yield: 178 g (20.0%). LCMS (Method B): Rt, 2.65 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 98.6%.
Intermediate 99. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000090_0002
Yield: 325 mg (37.0%). LCMS (Method B): Rt, 2.76 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 97.7%.
Intermediate 100. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((1 ,4S)-4- (dimethyl amino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000090_0003
Yield: 146 g (17.0%). LCMS (Method B): Rt, 2.67 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 98.5%.
Intermediate 101. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((1s,4/?)-4-
(dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarb oxylate.
Figure imgf000090_0004
Yield: 318 mg (38.0%). LCMS (Method B): Rt, 2.82 Min; ESI m/z\ 571.4 [M+H]+. Purity according to LCMS: 96.7%. Intermediate 102. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000091_0001
Yield: 56 mg (6.8%). LCMS (Method B): Rt, 2.55 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 97.6%.
Intermediate 103. l-(fert-Butyl) 2-methyl (2S, 4S)-4-(3-(((1s,4R)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-2,4-difluorophenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000091_0002
Yield: 149 g (18.0%). LCMS (Method B): Rt, 2.74 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 80.7%.
Intermediate 104. l-(fert-Butyl) 2-methyl (2S,4R)-4-(3-(((1r,4R)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000091_0003
Yield: 156 mg (20.0%). LCMS (Method B): Rt, 2.64 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 85.4%.
Intermediate 105. l-(fert-Butyl) 2-methyl (2S,4R)-4-(3-(((1s,4S)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000091_0004
Yield: 191 g (25.0%). LCMS (Method B): Rt, 2.81 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 91.4%. Intermediate 106. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-
4-phenylcyclohexyl)methyl)-2-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000092_0001
Yield: 143 mg (16.0%). LCMS (Method H): Rt, 4.82 Min; ESI m/z\ 605.5 [M+H]+. Purity according to LCMS: 94.7%.
Intermediate 107. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-2-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000092_0002
Yield: 300 g (34.0%). LCMS (Method H): Rt, 4.88 Min; ESI m/z\ 605.5 [M+H]+. Purity according to LCMS: 81.7%.
Intermediate 108. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-
4-phenylcyclohexyl)methyl)-4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000092_0003
Yield: 100 mg (11.0%). LCMS (Method D): Rt, 2.53 Min; ESI m/z\ 605.3 [M+H]+. Purity according to LCMS: 77.6%.
Intermediate 109. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-4-(trifluoromethyl)phenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000092_0004
Yield: 409 g (47.0%). LCMS (Method D): Rt, 2.69 Min; ESI m/z\ 605.3 [M+H]+. Purity according to LCMS: 91.8%. Intermediate 110. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000093_0001
Yield: 195 mg (20.0%). LCMS (Method A): Rt, 2.60 Min; ESI m/z\ 573.2 [M+H]+. Purity according to LCMS: 96.2%.
Intermediate 111. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000093_0002
Yield: 276 mg (28.0%). LCMS (Method A): Rt, 2.76 Min; ESI m/z. 573.2 [M+H]+. Purity according to LCMS: 92.6%.
Intermediate 112. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((1 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000093_0003
Yield: 223 g (22.0%). LCMS (Method A): Rt, 2.72 Min; ESI m/z\ 589.2 [M+H]+. Purity according to LCMS: 95.0%. Intermediate 113. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((1s,4f?)-4-
(dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000093_0004
Yield: 315 g (32.0%). LCMS (Method A): Rt, 2.87 Min; ESI m/z\ 589.2 [M+H]+. Purity according to LCMS: 96.0%.
Intermediate 114. l -(fert-Butyl) 2-methyl (2S,4S)-4-(5-chloro-3-(((1 r,4S)-4-
(dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000094_0001
Yield: 102 mg (14.0%). LCMS (Method A): Rt, 2.53 Min; ESI m/z\ 589.2 [M+H]+. Purity according to LCMS: 93.3%.
Intermediate 115. l -(fert-Butyl) 2-methyl (2S,4S)-4-(5-chloro-3-(((1s,4/?)-4-
(dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000094_0002
Yield: 208 g (28.0%). LCMS (Method A): Rt, 2.70 Min; ESI m/z\ 589.2 [M+H]+. Purity according to LCMS: 94.1 %.
Intermediate 116. l -(fert-Butyl) 2-methyl (2S,4S)-4-(4-(difluoromethyl)-3-(((1 r,4S)-
4-(dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxy late.
Figure imgf000094_0003
Yield: 18 mg (3.4%). LCMS (Method A): Rt, 2.36 Min; ESI m/z\ 587.3 [M+H]+. Purity according to LCMS: 76.1 %.
Intermediate 117. l -(fert-Butyl) 2-methyl (2S,4S)-4-(4-(difluoromethyl)-3-(((1s,4/?)-
4-(dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxy late. Yield: 44 mg (10.0%). LCMS (Method A): Rt, 2.53 Min; ESI m/z\ 587.3 [M+H]+. Purity according to LCMS: 91.7%.
Intermediate 118. l-(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-5-(((1 ,4S)-4- (dimethyl amino)-4-phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine- 1 ,2-dicarboxylate.
Figure imgf000095_0001
Yield: 87 g (11.0%). LCMS (Method A): Rt, 2.50 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 92.0%.
Intermediate 119. l-(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-5-(((1s,4/?)-4-
(dimethylamino)-4-phenylcyclohexyl)methyl)-2,3-difluorophenoxy)pyrrolidine-1,2- dicarboxylate.
Figure imgf000095_0002
Yield: 125 mg (16.0%). LCMS (Method A): Rt, 2.65 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 93.0%.
Intermediate 120. l-(fert-Butyl) 2-methyl (2S, 4S)-4-(3-(benzyloxy)-4,5-difluoro phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000095_0003
o Boc
Intermediate 120 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4- hydroxypyrrolidine-1 ,2-dicarboxylate (500 mg, 2.039 mmol) and 3-(benzyloxy)-4,5- difluorophenol (482 mg, 2.039 mmol) according to the method described for the preparation of intermediate 24, using 1.6 eq. of CMBP. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 80 g, gradient 3% to 50% EtOAc/heptane in 30 Min) afforded 1.26 g (67%) of the title compound as a crystalline solid. LCMS (Method B): Rt, 2.37 Min; ESI m/z\ 408.1 [M-(C4H8)+H]+.
Intermediate 121. l-(fert-Butyl) 2-methyl (2S, 4S)-4-(3,4-difluoro-5-hydroxy phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000096_0001
Intermediate 120 (1.26 g, 2.72 mmol) was dissolved in EtOH (30 ml_) upon gentle heating and the reaction flask was flushed with nitrogen under vacuum suction (3 x). Next, 10 wt% Pd/C (150 mg) was added and the reaction mixture was flushed with hydrogen (3 x) under vacuum suction. The reaction mixture was then stirred under a hydrogen atmosphere (balloon) overnight. Next, the suspension was filtered over a small pad of kieselguhr and the filtrate was concentrated in vacuo and co-evaporated with DCM (1 x) to afford 1.028 g (Ί 01 %') of the title compound as a foam. The product was used directly for the next step. LCMS (Method A): Rt, 1.92 Min; ESI m/z\ 372.1 [M-H]\
Intermediate 122. l-(fert-Butyl) 2-methyl (2S, S)-4-(3,4-difluoro-5-(((trifluo romethyl)sulfonyl)oxy)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000096_0002
Intermediate 121 (max. 2.72 mmol) was dissolved in DCM (15 mL) and the solution was cooled with an ice-bath. Next, pyridine (286 pL, 3.54 mmol, 1.3 eq.) was added, followed by the dropwise addition of triflic anhydride (587 pL, 3.54 mmol, 1.3 eq.) and the reaction mixture was allowed to warm to rt. After stirring for 1 h the organic solvent was evaporated and water (70 mL) was added. The aqueous layer was extracted with EtOAc (2 x, each 70 mL). The organic layers were combined, washed with brine (100 mL), dried over Na2SC>4, filtered and the filtrate was concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 3% to 40% EtOAc/heptane in 25 Min) afforded 992 mg (72% yield over two steps) of the title compound as an oil. LCMS (Method A): Rt, 2.35 Min; ESI m/z\ 450.0 [M-(C4H8)+H]+. Intermediate 123. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000097_0001
Intermediate 123 was prepared from triflate 122 (450 mg, 0.89 mmol) and 1.2 eq. of intermediate 65 according to the method described for intermediate 66 (MW-heating for 4 h at 80 °C). Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient 15% DCM to 100% DCM/MeOH (9: 1)) in 40 Min) gave 130 mg (25%) of the title compound. LCMS (Method A): Rt, 2.43 Min; ESI m/z\ 573.3 [M+H]+.
Intermediate 124. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000097_0002
Intermediate 124 was obtained together with its diastereoisomer 123. Yield: 204 g (40%) of the title compound. LCMS (Method A): Rt, 2.61 Min; ESI m/z\ 573.3 [M+H]+.
Intermediate 125. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((1 -(dimethylamino)-1 ,2,3,6- tetrahydro-[1 ,1 '-biphenyl]-4-yl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000097_0003
The reaction was carried out in two batches: intermediate 24 (929 mg, 2.322 mmol) and A/,/\/-dimethyl-4-methylene-1-phenylcyclohexan-1 -amine (500 mg, 2.322 mmol) were dissolved in anh ACN (10 ml_) and the solution was flushed with nitrogen for 10 Min. Tri- o-tolylphosphine (70.7 mg, 0.232 mmol), palladium(ll) acetate (26.1 mg, 0.116 mmol) and DIPEA (0.809 ml, 4.64 mmol) were added and the mixture was flushed with nitrogen again for 10 min, followed by MW-heating at 150 °C for 1 h. After cooling down the crude mixtures were combined and diluted with DCM. The organic layer was washed with sat aqueous NaHCCh solution (2 x) and brine. The organic layer was then filtered over a phase separator and the filtrate was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 80 g, gradient DCM to 100% DCM/MeOH (9: 1) in 33.7 Min) afforded 1.7 g of an oil. Trituration with n-heptane gave the title compound as a white solid (1 g). The mother liquor was concentrated in vacuo and triturated with n-heptane giving an additional amount of 200 mg. Total yield: 1.2 g (48%) of 125 as a solid. LCMS (Method A): Rt, 2.59 Min; ESI m/ 535.2 [M+H]+.
Intermediate 126. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(methylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000098_0001
Under a nitrogen atmosphere, intermediate 67 (250 mg, 0.466 mmol) was dissolved in anh ACN (3 ml_). The solution was cooled to 0 °C and 1.2 eq. of /V-iodosuccinimide (126 mg, 0.559 mmol) was added. The reaction mixture was then allowed to reach rt and stirring was continued for 20 h. The reaction mixture was diluted with EtOAc (40 ml_) and quenched by the addition of aqueous 5% sodium metabisulfite solution (50 ml_). The layers were separated, and organic phase was washed with sat aqueous Na2C03 solution (40 ml_), then dried with Na2S04, filtered and the solvent evaporated. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 65 mg (26%) of the title compound. LCMS (Method A): Rt, 2.63 Min; ESI m/z. 523.3 [M+H]+. Purity according to LCMS: 86.5%.
Intermediate 127. Methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-2-carboxylate.
Figure imgf000098_0002
Intermediate 66 (150 mg, 0.279 mmol) was dissolved in DCM (2 ml_). TFA (1.0 ml_, 13.06 mmol) was added and the reaction mixture was stirred at rt overnight. The crude reaction mixture was concentrated to dryness. Purification by preparative LC (Gemini C18, basic eluent gradient), followed by additional purification by flash column chromatography (pre packed silica cartridge GraceResolv™ 4 g, isocratic 2% (7 M NH3 in MeOH)/DCM afforded 52 mg (46%) of the title compound. LCMS (Method I): Rt, 4.30 Min; ESI m/z\ 437.3 [M+H]+.
Intermediate 128. (2S,4S)-1 -(fert-Butoxycarbonyl)-4-(3-(((1 r,4S)-4-(dimethylamino) -4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-2-carboxylic acid.
Figure imgf000099_0001
Aqueous 4 M NaOH solution (1 mL, 4.0 mmol) was diluted with 1 ,4-dioxane (14 mL) and MeOH (5 mL) giving Tesser’s base. Intermediate 66 (150 mg, 0.279 mmol) was dissolved in Tesser's base (5 mL, 14.3 eq. of NaOH) and the reaction mixture was stirred overnight at rt. Next, the reaction mixture was concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 132 mg (90%) of the title compound. LCMS (Method A): Rt, 1.89 Min; ESI m/z\ 523.2 [M+H]+.
Intermediate 129. Methyl (2S,4S)-1 -((fert-butoxycarbonyl)glycyl)-4-(3-(((1 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-2-carboxylate.
Figure imgf000099_0002
Intermediate 127 was dissolved in DCM (2 ml_). EDCI (119 g, 0.623 mmol), HOAt (4.24 mg, 0.031 mmol) and Boc-glycine (65.5 mg, 0.374 mmol) were added, resulting in a turbid solution. After stirring overnight at rt the reaction mixture was concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 158 mg (85%) of the title compound, which was used as such in the next reaction. LCMS (Method A): Rt, 2.38 Min; ESI m/z\ 594.4 [M+H]+.
Intermediate 130. fert-Butyl (2S,4S)-2-(((S)-5-((fert-butoxycarbonyl)amino)-6- methoxy-6-oxohexyl)carbamoyl)-4-(3-(((1 ,4S)-4-(dimethylamino)-4-phenylcyclo hexyl)methyl)phenoxy)pyrrolidine-1 -carboxylate. Intermediate 130 was obtained from intermediate 128 (crude sodium salt, max 0.335 mmol) and A/-Boc-Lys(H)-OH methyl ester hydrochloride (144 mg, 0.485 mmol) and purified according to the method described for the preparation of intermediate 129. Yield: 135 mg (52%). LCMS (Method A): Rt, 2.54 Min; ESI m/z\ 765.4 [M+H]+.
Intermediate 131. 1 -(3-Fluorophenyl)-A/,A/-dimethyl-4-methylenecyclohexan-1 - amine.
Figure imgf000100_0001
Under a nitrogen atmosphere, methyltriphenylphosphonium bromide (1.594 g, 4.46 mmol) was suspended in dry THF (10 ml_). The mixture was cooled to 0 °C, then 1.6 M n-butyllithium in hexanes (2.79 ml_, 4.46 mmol) was slowly added dropwise. The resulting orange suspension was stirred at rt for 60 min, forming a slightly turbid solution. Then at rt, a solution of 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexan-1-one (0.7 g, 2.97 mmol) in dry THF (5 ml_) was added, once more forming a thick suspension. The resulting reaction mixture was heated to reflux temperature overnight, giving an almost clear solution. The crude reaction mixture was quenched with water (20 ml_), and after the addition of EtOAc (10 ml_) the organic phase was separated. The aqueous phase (pH ~ 9) was extracted once more with EtOAc (20 ml_). The combined organic phases were extracted with aqueous 1 M KHSO4 solution (2 x, each 20 ml_). The combined aqueous phases (pH ~ 1) were basified with aqueous 2 M NaOH solution and sat aqueous NaHCOs solution to pH ~ 10, forming a thick white precipitate. The aqueous phase was extracted with EtOAc (2 x, each 50 ml_). The combined organic phases were dried with sodium sulfate, filtered and the solvent evaporated. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 511 mg (73%) of the title compound. LCMS (Method B): Rt, 2.31 Min; ESI m/z\ 234.2 [M+H]+. Intermediate 132. 1 -(4-Fluorophenyl)-A/,A/-dimethyl-4-methylenecyclohexan-1 - amine.
Figure imgf000101_0001
Intermediate 132 was obtained from 4-(dimethylamino)-4-(4-fluorophenyl)cyclohexan-1- one (500 mg, 2.125 mmol) and methyltriphenylphosphonium bromide (1.139 g, 3.19 mmol) according to the method for intermediate 131 , using 1.5 eq. of 2.5 M n-butyllithium in hexanes (1.3 ml_, 3.25 mmol) and heating at 70 °C overnight. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 372 mg (75%) of the title compound. LCMS (Method B): Rt, 2.26 Min; ESI m/z 234.2 [M+H]+.
Intermediate 133. 1 -(3-Chlorophenyl)-A/,A/-dimethyl-4-methylenecyclohexan-1 - amine.
Figure imgf000101_0002
A suspension of methyltriphenylphosphonium bromide (1064 mg, 2.98 mmol) in dry THF (20 ml_) was cooled to 0 °C. A 2.5 M solution of n-butyllithium in hexanes (1.192 ml_, 2.98 mmol) was added dropwise keeping the internal temperature < 10 °C, and the orange suspension was stirred at rt for 2 h. A solution of 4-(3-chlorophenyl)-4- (dimethylamino)cyclohexan-l-one (500 mg, 1.986 mmol) in dry THF (5 ml_) was added dropwise and the resulting mixture was stirred at reflux temperature overnight. The mixture was diluted with EtOAc (20 ml_) and washed with water (20 ml_). The layers were separated and the organic layer was concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 129 mg (26%) of the title compound as an oil. LCMS (Method A): Rt, 2.36 Min; ESI m/z. 250.1 [M+H]+, Cl-isotope pattern.
Intermediate 134. 1 -(4-Chlorophenyl)-A/,A/-dimethyl-4-methylenecyclohexan-1 - amine. Intermediate 134 was prepared from 4-(3-chlorophenyl)-4-(dimethylamino)cyclohexan- 1-one (500 mg, 1.986 mmol) and 1.5 eq. of methyltriphenylphosphonium bromide (1064 mg, 2.98 mmol) according to the method described for intermediate 131. After cooling down to rt water (40 ml_) was added and the mixture was extracted with EtOAc (2 x, each 40 ml_). The organic layer of the first extraction was concentrated (to remove most of the THF) before combining with the organic layer from the second extraction. The combined organic layers were washed with aqueous 1 M KHSCU solution (2 x, each 30 ml_). The combined aqueous layers (pH ~ 1) were basified with 2 M aqueous NaOH solution (30 ml_) until pH ~ 10, forming a thick white precipitate. The aqueous phase was extracted with EtOAc (2 x, each 50 ml_). The combined organic layers were dried over Na2S04 and concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 373 mg (75%) of the title compound as an oil. LCMS (Method A): Rt, 2.36 Min; ESI m/z\ 250.1 [M+H]+, Cl-isotope pattern.
Intermediate 135. 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(3-fluorophenyl)- A/,A/-dimethylcyclohexan-1 -amine.
Figure imgf000102_0001
Intermediate 135 was prepared from intermediate 131 (500 mg, 2.143 mmol) and a solution of 9-BBN in THF (0.5 M, 6.5 ml_, 3.25 mmol) according to the method described for intermediate 65, and the solution was used directly for the next step.
Intermediate 136. 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(4-fluorophenyl)- A/,A/-dimethylcyclohexan-1 -amine. Intermediate 136 was prepared from intermediate 132 (372 mg, 1.594 mmol) and a solution of 9-BBN in THF (0.5 M, 5.1 ml_, 2.55 mmol) according to the method described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step.
Intermediate 137. 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(3-chlorophenyl)- A/,A/-dimethylcyclohexan-1 -amine.
Figure imgf000103_0001
Intermediate 137 was prepared from a solution of intermediate 133 (129 mg, 0.516 mmol) in 1 ,4-dioxane (0.5 ml_) and a solution of 9-BBN in THF (0.5 M, 1.446 ml_, 0.723 mmol) according to the procedure described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step. Intermediate 138. 4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1-(4-chlorophenyl)- A/,A/-dimethylcyclohexan-1 -amine.
Figure imgf000103_0002
Intermediate 138 was prepared from intermediate 134 (373 mg, 1.493 mmol) and a solution of 9-BBN in THF (0.5 M, 4.18 ml_, 2.091 mmol) according to the procedure as described for intermediate 65 with heating at 75 °C for 2 h, and the solution was used directly for the next step. Intermediate 139. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- (3-fluorophenyl)cyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000104_0001
Intermediate 139 was obtained from bromide 24 (780 mg, 1.948 mmol) and 1.1 eq. of intermediate 135 according to the synthesis method as described for the preparation of intermediate 66, using a solution of sodium carbonate (516 mg, 4.87 mmol) in water (2 ml_), XantPhos (67.6 mg, 0.117 mmol), Pd2(dba)3 (53.5 mg, 0.058 mmol) and with MW- heating for 5.5 h at 80 °C. The crude reaction mixture was diluted with 1 ,4-dioxane and filtered over a pad of kieselguhr, which was rinsed with additional 1 ,4-dioxane. The filtrate was concentrated to dryness (at 50 °C) and the residue was partitioned between water and DCM. The aqueous phase was separated (phase separator) and extracted once more with DCM. The filtrates were concentrated to dryness and the residue was purified by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM to 100% DCM/MeOH (9:1)) in 60 Min, 100% DCM/MeOH (9: 1) for 40 Min) to give 252 mg (23%) of the title compound. LCMS (Method B): Rt, 2.52 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 88.8%.
Intermediate 140. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)- 4-(3-fluorophenyl)cyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000104_0002
Intermediate 140 was obtained together with its diastereoisomer 139. Yield: 480 mg (44%) of the title compound. LCMS (Method B): Rt, 2.72 Min; ESI m/z\ 555.4 [M+H]+. Purity according to LCMS: 88.5%.
The method as described for the preparation of intermediates 139 and 140 was followed for the preparation of intermediates 141-158 using suitable starting materials with heating under microwave conditions and subsequent purification: Intermediate 141. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-
(3-fluorophenyl)cyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000105_0001
Yield: 82 g (14.0%). LCMS (Method B): Rt, 2.53 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 90.2%.
Intermediate 142. 1 -(fert-butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-
4-(3-fluorophenyl)cyclohexyl)methyl)-2-fluorophenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000105_0002
Yield: 88 mg (16.0%). LCMS (Method B): Rt, 2.75 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 100.0%.
Intermediate 143. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4-(dimethylamino)-4-
(3-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1,2-dicarboxy late.
Figure imgf000105_0003
Yield: 1 19 mg (20.0%). LCMS (Method B): Rt, 2.57 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 88.9%.
Intermediate 144. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-
4-(3-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1,2-dicarboxy late. Yield: 219 mg (37.0%). LCMS (Method B): Rt, 2.77 Min; ESI m/z\ 573.4 [M+H]+. Purity according to LCMS: 90.0%. Intermediate 145. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1 ,4S)-4-
(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000106_0001
Yield: 91 g (18.0%). LCMS (Method A): Rt, 2.51 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 92.8%.
Intermediate 146. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4f?)-4-
(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000106_0002
Yield: 175 mg (36.0%). LCMS (Method A): Rt, 2.69 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 94.8%.
Intermediate 147. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1 ,4S)-4- (dimethylamino)-4-(4-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000106_0003
Yield: 72 mg (7.4%). LCMS (Method A): Rt, 2.50 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 94.7%.
Intermediate 148. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4/?)-4-
(dimethylamino)-4-(4-fluorophenyl)cyclohexyl)methyl)-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000107_0001
Yield: 160 g (16.0%). LCMS (Method A): Rt, 2.68 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 85.7%.
Intermediate 149. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1 ,4S)-4-(3-chloro phenyl)-4-(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000107_0002
Yield: 55 mg (17.0%). LCMS (Method A): Rt, 2.63 Min; ESI m/z\ 623.2 [M+H]+. Purity according to LCMS: 97.9%.
Intermediate 150. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4/?)-4-(3-chloro phenyl)-4-(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.
Figure imgf000107_0003
Yield: 51 mg (15.0%). LCMS (Method A): Rt, 2.82 Min; ESI m/z\ 623.2 [M+H]+. Purity according to LCMS: 97.9%.
Intermediate 151. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4-(3-chlorophenyl)-
4-(dimethylamino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1 ,2-dicarb oxylate.
Figure imgf000108_0001
Yield: 104 mg (26.0%). LCMS (Method A): Rt, 2.43 Min; ESI m/z 607.2 [M+H]+. Purity according to LCMS: 92.1 %.
Intermediate 152. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(3-chlorophenyl)- 4-(dimethylamino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000108_0002
Yield: 89 g (22.0%). LCMS (Method A): Rt, 2.57 Min; ESI m/ 607.3 [M+H]+. Purity according to LCMS: 98.8%. Intermediate 153. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1 ,4S)-4-(4- chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine- 1 ,2-dicarboxylate.
Figure imgf000108_0003
Yield: 60 mg (12.0%). LCMS (Method A): Rt, 2.61 Min; ESI m/z 623.2 [M+H]+. Purity according to LCMS: 93.1 %.
Intermediate 154. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,4f?)-4-(4- chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine- 1 ,2-dicarboxylate. Yield: 100 mg (21.0%). LCMS (Method A): Rt, 2.79 Min; ESI m/z\ 623.2 [M+H]+. Purity according to LCMS: 94.3%.
Intermediate 155. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4-(4-chlorophenyl)-
4-(dimethylamino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000109_0001
Yield: 34 mg (7.5%). LCMS (Method A): Rt, 2.44 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 96.2%.
Intermediate 156. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(4-chlorophenyl)-
4-(dimethylamino)cyclohexyl)methyl)-4,5-difluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000109_0002
Yield: 106 g (23.0%). LCMS (Method A): Rt, 2.58 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 98.5%.
Intermediate 157. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4-(4-chlorophenyl)-
4-(dimethylamino)cyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000109_0003
Yield: 12 mg (2.4%). LCMS (Method A): Rt, 2.51 Min; ESI m/z\ 607.3 [M+H]+. Purity according to LCMS: 94.3%. Intermediate 158. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(4-chlorophenyl)-
4-(dimethylamino)cyclohexyl)methyl)-2,5-difluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000110_0001
Yield: 52 g (10.0%). LCMS (Method A): Rt, 2.69 Min; ESI m/z\ 607.2 [M+H]+. Purity according to LCMS: 88.7%.
Intermediate 159. Di-fert-butyl (S)-4-(3-bromobenzylidene)pyrrolidine-1, 2-dicar boxy I ate.
Figure imgf000110_0002
To a suspension of NaH (60% dispersion in mineral oil; 352 mg, 8.80 mmol) in dry THF (30 mL) was added a suspension of (3-bromobenzyl)triphenylphosphonium bromide (4.51 g, 8.80 mmol) in dry THF (20 mL). Dimethyl sulfoxide (dry) (25 mL) was added to the yellow suspension, which resulted in an orange solution (a solid formed after a few minutes, which dissolved again after ~ 10 min). The solution was stirred at 70 °C for 4 h. The mixture was cooled to 50 °C and a solution of A/-Boc-4-oxo-L-proline tert- butyl ester (400 mg, 1.402 mmol) in dry THF (10 mL) was added dropwise and the mixture was stirred at 70 °C overnight. The solvent was evaporated and the residue was dissolved in DCM (150 mL). The mixture was washed with water (150 mL) and the aqueous layer was extracted with DCM (150 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 1 % EtOAc/heptane to 40% EtOAc/heptane in 54 Min) afforded 382 mg (62%) of the title compound as an oil. LCMS (Method B): Rt, 2.66 Min; ESI m/z\ 326.0 & 328.0 [M-(2 x C4HS)+H]+, Br-isotope pattern.
Intermediate 160. Di-fert-butyl (2S,4S)-4-(3-bromobenzyl)pyrrolidine-1,2-dicar boxy I ate. f-BuO Boc
To a solution of intermediate 159 (382 g, 0.871 mmol) in EtOAc (15 ml_) platinum(IV)oxide (59.4 mg, 0.261 mmol) was added under an atmosphere of nitrogen. The nitrogen atmosphere was replaced with hydrogen (balloon) and the mixture was stirred at 60 °C for 4 h. After cooling down the mixture was filtered over a small pad of kieselguhr and the filtrate was concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient 2% EtOAc/heptane to 25% EtOAc/heptane in 30 Min), followed by purification by preparative SFC afforded 151 mg (39%) of the title compound. LCMS (Method B): Rt, 2.59 Min; ESI m/z. 328.0 & 330.0 [M-(q4Hd)+H]+, Br-isotope pattern. Purity according to LCMS: 88.8%.
Intermediate 161. Di-fert-butyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)benzyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000111_0001
Intermediate 161 was obtained from bromide 160 (407 mg, 0.924 mmol) and a freshly prepared solution of intermediate 65 (374 mg, 1.109 mmol) in THF (4 mL) according to the method described for the preparation of intermediate 66, using 2.5 eq. of Na2CC>3. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (15-100% DCM/MeOH (9:1)) in 55 Min), 100% DCM/MeOH (9: 1) for 45 Min), followed by additional purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 101 mg (18%) of the title compound as an oil. LCMS (Method B): Rt, 3.34 Min; ESI m/ 577.5 [M+H]+.
Intermediate 162. Di-fert-butyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)benzyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000111_0002
Intermediate 162 was obtained together with its diastereoisomer 161. Yield: 98 mg (15%) of the title compound. LCMS (Method C): Rt, 3.40 Min; ESI m/z\ 577.5 [M+H]+. Purity according to LCMS: 84.5%.
Intermediate 163. Di-fert-butyl (S)-4-(3-bromo-5-fluorobenzylidene)pyrrolidine-1 ,2- dicarboxylate.
F
Figure imgf000112_0001
f-BuO Boc
To a suspension of NaH (60% dispersion in mineral oil; 0.762 g, 19.05 mmol) in dry THF (75 ml_) a suspension of (3-bromo-5-fluorobenzyl)-triphenylphosphonium bromide (10.1 g, 19.05 mmol) in dry THF (50 ml_) was added. Dimethyl sulfoxide (dry) (60 ml_) was added and the yellow suspension was stirred at 70 °C for ~ 4 h. The resulting solution was allowed to cool down to ~ 40 °C giving a thick suspension. Next, a solution of N- Boc-4-oxo-L-proline tert- butyl ester (2.72 g, 9.52 mmol) in dry THF (25 ml_) was added dropwise and the mixture was heated to 70 °C overnight. The solvent was evaporated and the residue was dissolved in DCM (300 ml_). The organic layer was washed with water (300 ml_) and the aqueous layer was extracted with DCM (300 ml_). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The crude material was suspended in DCM (~ 20 ml_, with a few additional drops of EtOAc) and the solids were removed by filtration. The filtrate was concentrated to dryness and dissolved in DCM for purification by means of flash column chromatography (pre-packed silica cartridge GraceResolv™ 220 g, gradient 1 % EtOAc/heptane to 25% EtOAc/heptane in 80 Min). Yield: 1.93 g (44%) as an oil. LCMS (Method B): Rt, 2.59 Min; ESI m/z\ 344.0 & 346.0 [M-(C4HS)+H]+, Br-isotope pattern.
Intermediate 164. Di-fert-butyl (2S,4S)-4-(3-bromo-5-fluorobenzyl)pyrrolidine-1 ,2- dicarboxylate.
F
Figure imgf000112_0002
f-BuO Boc
Intermediate 164 was obtained from intermediate 163 (1.93 g, 4.23 mmol) by means of hydrogenation with platinum(IV)oxide (59.4 mg, 0.261) and hydrogen (balloon) at 60 °C overnight. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient heptane to 15% EtOAc/heptane in 44 Min), followed by purification by preparative SFC afforded 1.21 g (62%) of the title compound as a paste. LCMS (Method C): Rt, 2.61 Min; ESI m/z\ 346.0 & 348.0 [M-(2 x C4H8)+H]+, Br-isotope pattern.
Intermediate 165. Di-fert-butyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorobenzyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000113_0001
Intermediate 165 was obtained from intermediate 164 (600 mg, 1.309 mmol) and a freshly prepared solution of 1.0 eq. of intermediate 65 (442 mg, 1.309 mmol) in THF (5 mL) according to the method described for the preparation of intermediate 66. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM to 100% DCM/MeOH (9:1) in 40 Min) afforded 188 mg (24%) of the title compound. LCMS (Method C): Rt, 3.17 Min; ESI m/z\ 595.4 [M+H]+. Purity according to LCMS: 92.0%.
Intermediate 166. Di-fert-butyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)-5-fluorobenzyl)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000113_0002
Intermediate 166 was obtained together with its diastereoisomer 165. Yield: 512 mg (65%). LCMS (Method C): Rt, 3.33 Min; ESI m/z\ 595.4 [M+H]+. Purity according to LCMS: 94.5%.
Intermediate 167. l -(fert-Butyl) 2-methyl (2S, 4S)-4-((3-bromophenyl)(methyl) amino)pyrrolidine-1 ,2-dicarboxylate. A glass vial (20 mL) was dried using a heat gun under a flow of argon and charged with 1-(te/f-butyl) 2-methyl (2S, 4S)-4-(methylamino)pyrrolidine-1 ,2-dicarboxylate (0.050 g, 0.194 mmol), followed by the addition of dry 1 ,4-dioxane (2.5 mL) and 3- bromoiodobenzene (0.271 mL, 2.129 mmol). The reaction mixture was flushed with argon using an ultrasonic bath (5 min). Subsequently, CS2CO3 (0.189 g, 0.581 mmol), Ru-Phos (9.03 mg, 0.019 mmol) and Pd2(dba)3 (8.86 mg, 9.68 pmol) were added with stirring under an atmosphere of argon for 5 Min. The reaction mixture was heated under MW-conditions at 60 °C for 6 h in total. After cooling down the reaction mixture was filtered over a small pad of kieselguhr, which was rinsed with DCM and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient heptane to 100% EtOAc in 50 Min) afforded 41 mg (51 %) of the title compound as an oil. LCMS (Method B): Rt, 2.38 Min; ESI m/z\ 413.0 & 415.0 [M+H]+, Br-isotope pattern.
Intermediate 168. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-((3-(((1 r,4S)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)phenyl)(methyl)amino)pyrrolidine-1 ,2-dicarboxylate.
Figure imgf000114_0001
Intermediate 168 was obtained from bromide 167 (72 mg, 0.174 mmol) and a freshly prepared solution of 1.2 eq. of intermediate 65 (70.5 mg, 0.209 mmol) in THF, according to the method as described for the preparation of intermediate 66, using 2.15 eq. of Na2CC>3. Purification by flash column chromatography (pre-packed silica GraceResolv™ 40 g, gradient DCM to 100% DCM/MeOH (9:1) in 75 Min), afforded 38.8 mg (26%) of the title compound. LCMS (Method B): Rt, 2.85 Min; ESI m/z\ 550.4 [M+H]+. Purity according to LCMS: 90.2%.
Intermediate 169. 1 -(tert-Butyl) 2-methyl (2S,4S)-4-((3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)phenyl)(methyl)amino)pyrrolidine-1 ,2-dicarboxylate. Intermediate 169 was obtained together with its diastereoisomer 168. Yield: 51.4 mg (34%) of the title compound. LCMS (Method C): Rt, 2.85 Min; ESI m/z\ 550.4 [M+H]+. Purity according to LCMS: 83.3%.
Intermediate 170. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-((3-(((1r,4S)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)benzyl)oxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000115_0001
Intermediate 170 was obtained from 1-(te/f-butyl) 2-methyl (2S,4S)- 4-((3- bromobenzyl)oxy)pyrrolidine-1 ,2-dicarboxylate (614 mg, 1.482 mmol) and 1.0 eq. of intermediate 65 (500 mg, 1.482 mmol) according to the method as described for intermediate 66. Purification by flash column chromatography (pre-packed silica GraceResolv™ 40 g, gradient DCM / (5-100% DCM/MeOH (9:1)) in 80 Min) afforded 172 mg (21%) of the title compound. LCMS (Method A): Rt, 2.75 Min; ESI m/z\ 551.2 [M+H]+. Purity according to LCMS: 91.2%.
Intermediate 171. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-((3-(((1s,4/?)-4-(dimethylamino)- 4-phenylcyclohexyl)methyl)benzyl)oxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000115_0002
Intermediate 171 was obtained together with its diastereoisomer 170. Yield: 373 g (45%). LCMS (Method A): Rt, 2.79 Min; ESI m/z\ 551.4 [M+H]+.
Intermediate 172. 1-(4-Methylene-1-phenylcyclohexyl)azetidine. Methyltriphenylphosphonium bromide (1.168 g, 3.27 mmol) was suspended in dry THF (10 ml_) and cooled to 0 °C under an atmosphere of nitrogen. Next, 2.5 M n-butyllithium in hexanes (1.4 ml_, 3.50 mmol) was added slowly while keeping the internal temperature < 10 °C. The resulting orange suspension was stirred at rt for 2 h, forming a clear solution. More THF (dry) (10 ml_) was added, followed by the addition of a solution of 4- (azetidin-1-yl)-4-phenylcyclohexan-1-one (500 mg, 2.180 mmol) in dry THF (5 ml_) and the mixture was heated to reflux temperature overnight. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with EtOAc (3 x). The combined organic layers were acidified with 1 M aqueous KHSCL solution. The organic phase was separated and extracted twice more with aqueous 1 M KHSCL solution. The combined aqueous phases were basified with aqueous 4 M NaOH solution and extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried with Na2S04 and filtered. The filtrate was concentrated in vacuo. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded pure fractions, which were pooled together and concentrated in vacuo to obtain the product as an oil (192.9 mg, 39%). LCMS (Method A): Rt, 2.34 Min; ESI m/z\ 228.2 [M+H]+.
Intermediate 173. 1 -(4-((9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-1 -phenylcyclo hexyl)azetidine.
Figure imgf000116_0001
A solution of 9-BBN in THF (0.5 M, 2.365 ml_, 1.18 mmol) was added to intermediate
172 (192 mg, 0.845 mmol) and the solution was flushed with nitrogen. The capped reaction vial was stirred at 75 °C for 3 h. Incomplete conversion was observed (TLC: EtOAc/heptane, 1 : 1). More of a solution of 9-BBN in THF (0.5 M, 1 ml_, 0.5 mmol) was added and heating was continued for 3 h. More, of a (fresh) solution of 9-BBN in THF (0.5 M, 2.365 ml_, 1.18 mmol) was added and heating was continued for 2 h. Complete conversion of the starting material was observed on TLC. The solution of intermediate
173 was used as such for the next step. Intermediate 174. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4-(azetidin-1-yl)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000117_0001
Intermediate 24 (282 g, 0.704 mmol) was dissolved in 1 ,4-dioxane (6 ml_), followed by the addition of a solution of Na2CC>3 (187 mg, 1.760 mmol) in water (2 ml_) and was then flushed with nitrogen for > 15 Min. Next, a solution of 1.2 eq. of intermediate 173 (0.845 mmol) in THF (5.73 ml_), Pd2(dba)3 (19.34 mg, 0.021 mmol) and XantPhos (24.45 mg, 0.042 mmol) were successively added and the mixture was stirred at 100 °C under MW- heating for 4 h. The reaction mixture was diluted with 1 ,4-dioxane and filtered over a nylon microfilter. The filtrate was concentrated in vacuo and co-evaporated with ACN. Purification of the residue by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 66 mg (17%) of the title compound. LCMS (Method A): Rt, 2.70 Min; ESI m/z\ 549.3 [M+H]+. Purity according to LCMS: 93.1%. Intermediate 175. l-(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,4/?)-4-(azetidin-1-yl)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000117_0002
Intermediate 175 was obtained together with its diastereoisomer 174. Yield: 118 mg (30%). LCMS (Method A): Rt, 2.86 Min; ESI m/z\ 549.4 [M+H]+.
Intermediate 176. fert-Butyl (3-oxo-1-phenylcyclobutyl)carbamate.
Figure imgf000117_0003
tert- Butyl (1-(4-bromophenyl)-3-oxocyclobutyl)carbamate (560 mg, 1.646 mmol) was dissolved in dry 1 ,4-dioxane (10 mL) in a heat-gun dried reaction vial and under an atmosphere of argon. TEA (0.413 mL, 2.96 mmol) was added and the solution was flushed with argon for 15 Min. Then, Pd2(dba)3 (75 mg, 0.082 mmol) and S-Phos (67.6 mg, 0.165 mmol) were added, followed by the addition of triethylsilane (1.329 mL, 8.23 mmol). The dark red reaction mixture was heated to 100 °C (hot start conditions) for 1.5 h. After cooling down to rt the crude reaction mixture was filtered over a small pad of kieselguhr. The residue was rinsed with DCM (50 ml_) and the filtrate was successively washed with aqueous 1 M KHSCU solution (75 ml_) and sat aqueous NaHCCh solution (75 ml_). Each time the aqueous layer was extracted with additional DCM (20 ml_). The combined organic layers were washed with brine (75 ml_), dried over Na2SC>4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 5% EtOAc/heptane to 50% EtOAc in 24 Min) afforded 360 mg (84%) of the title compound as an oil. LCMS (Method A): Rt, 2.06 Min; ESI m/z\ 206.0 [M-(C4H8)+H]+.
Intermediate 177. fert-Butyl (3-methylene-1 -phenylcyclobutyl)carbamate.
Figure imgf000118_0001
Methyltriphenylphosphonium bromide (1589 mg, 4.45 mmol) was suspended in dry THF (6 ml_) in a heat-gun dried reaction vial and under an atmosphere of argon. Potassium tert- butoxide (483 mg, 4.31 mmol) was added in one portion giving a yellow suspension. After stirring at rt for 1 h the suspension (4 ml_, 1.0 eq.) was added dropwise to a solution of intermediate 176 (750 mg, 2.87 mmol) in dry THF (6 ml_) and the resulting (orange/red) mixture was stirred at rt for 1 h. The reaction mixture was quenched with water and diluted with Et2<D. The aqueous phase was separated and extracted with additional Et2<D (2 x). The organic layers were combined, washed with brine, dried with Na2SC>4, filtered and the solvents were evaporated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 5% EtOAc/heptane to 40% EtOAc in 40 Min) afforded 305 mg (84%) of the title compound. LCMS (Method A): Rt, 2.13 Min; ESI m/z\ 204.0 [M-(C4H8)+H]+.
Intermediate 178. A/,A/-Dimethyl-3-methylene-1 -phenylcyclobutan-1 -amine.
Figure imgf000118_0002
Intermediate 177 (305 mg, 1.176 mmol) was dissolved in DCM (10 ml_). TFA (6 ml_, 78 mmol) was added in one portion and the red solution formed was stirred for 1 h. The reaction mixture was concentrated to dryness and co-evaporated with DCM (2 x). The residue was dissolved in DCM (15 ml_) and water (10 ml_) was added. The aqueous layer was basified using solid Na2CC>3 until pH ~ 12. The layers were separated, and the aqueous layer was extracted with DCM (3 x, each 5 mL). The combined organic layers were dried with Na2SC>4, filtered and concentrated to dryness. The residue was dissolved in MeOH (10 L). Formaldehyde, 37 wt% solution in water (0.9 mL, 1 1.98 mmol) was added, followed by the addition of AcOH (0.2 mL, 3.46 mmol). The reaction mixture was stirred for a few min at rt, after which sodium triacetoxyborohydride (748 mg, 3.53 mmol) was added to form a clear solution. After stirring overnight at rt the reaction mixture was concentrated to dryness. The residue was partitioned between DCM (10 mL) and sat aqueous NaHCCh solution (10 mL). The aqueous layer (pH ~ 9) was separated (phase separator) and extracted with DCM (2 x, each 10 mL). The combined organic phases were concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 4 g, gradient 5% EtOAc/heptane to 60% EtOAc in 40 Min) afforded 122 mg (55% over 2 steps) of the title compound. LCMS (Method A): Rt, 1.95 Min; ESI m/z\ 188.1 [M+H]+.
Intermediate 179. 3-(((1S,5S)-9-Borabicyclo[3.3.1]nonan-9-yl)methyl)-A/,A/-dime thyl-1 -phenylcyclobutan-1 -amine.
Figure imgf000119_0001
Intermediate 178 (122 mg, 0.651 mmol) was dissolved in dry THF (0.5 mL) in a heat-gun dried reaction vial and under an atmosphere of argon. A solution of 9-BBN in THF (0.5 M, 1.824 mL, 0.912 mmol) was added and the mixture was stirred at 75 °C for 3 h (hot- start conditions). More 9-BBN solution in THF (0.5 M, 0.4 mL, 0.2 mmol) was added and stirring at 75 °C was continued for 1 h. The reaction was complete according to TLC analysis (EtOAc/heptane, 1 : 1) and the solution of intermediate 179 was used as such for the next step.
Intermediate 180. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1 r,3/?)-3-(dimethylamino)- 3-phenylcyclobutyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000119_0002
Intermediate 24 (288 mg, 0.720 mmol) was dissolved in 1 ,4-dioxane (4.5 mL) in a heat- gun dried reaction vial. Solid sodium carbonate (164 mg, 1.547 mmol) and water (1.5 mL) were added, followed by the addition of a solution of intermediate 179 (289 g, 0.935 mmol) in THF (~ 3 mL). The resulting suspension was flushed with argon for 10 Min. XantPhos (26.6 mg, 0.046 mmol) and Pd2(dba)3 (21.74 mg, 0.024 mmol) were added and the resulting mixture was stirred at 80 °C under MW-heating for 4 h. The reaction mixture was filtered through a short pad of kieselguhr; the residue was rinsed with DCM and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 24 g, gradient DCM to 60% DCM/MeOH (9:1) in 25 Min) afforded 71 mg (19%) of the title compound as an oil. LCMS (Method A): Rt, 2.46 Min; ESI m/z\ 509.2 [M+H]+. Purity according to LCMS: 94.7%.
Intermediate 181. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((1s,3S)-3-(dimethylamino)- 3-phenylcyclobutyl)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.
Figure imgf000120_0001
Intermediate 181 was obtained together with its diastereoisomer 180 Yield: 63 mg (17%). LCMS (Method A): Rt, 2.46 Min; ESI m/z\ 509.2 [M+H]+.
Intermediate 182. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1r,3F?)-3-(di methylamino)-3-phenylcyclobutyl)methyl)-5-fluorophenoxy)pyrrolidine-1,2-dicarb oxylate.
Figure imgf000120_0002
Intermediate 182 was obtained from intermediate 53 (295 mg, 0.651 mmol) and 1 eq. of a solution of intermediate 179 (0.651 mmol) in THF (~ 3 mL) according to the method as described for the preparation of intermediate 180. The crude material was dissolved in DCM and the residual solid was removed by filtration over a paper filter. The filtrate (clear yellow solution) was concentrated to a volume of ~ 1 mL and subjected to purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-60% DCM/MeOH (9: 1)) in 45 Min). Mixed fractions were pooled together and subjected to additional purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 4 g, gradient DCM to 60% DCM/MeOH (9: 1) in 60 Min) giving a combined total yield of 40 mg (10%). LCMS (Method A): Rt, 2.42 Min; ESI m/z: 561.2 [M+H]+, Cl-isotope pattern.
Intermediate 183. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((1s,3S)-3-
(dimethylamino)-3-phenylcyclobutyl)methyl)-5-fluorophenoxy)pyrrolidine-1 ,2-di carboxylate.
Figure imgf000121_0001
Intermediate 183 was obtained together with its diastereoisomer 182. Yield: 87 mg (23%). LCMS (Method A): Rt, 2.42 Min; ESI /z: 561.2 [M+H]+, Cl-isotope pattern.
Intermediate 184. fert-Butyl (2S,4S)-4-(3-bromophenoxy)-2-cyanopyrrolidine-1 - carboxylate.
Figure imgf000121_0002
Boc
Intermediate 184 was prepared from (2S,4R)-1-Boc-2-cyano-4-hydroxypyrrolidine (700 mg, 3.3 mmol) and 3-bromophenol (571 mg, 3.3 mmol) and 1.4 eq. of CMBP 1.211 ml_, 4.62 mmol) following the procedure as described for intermediate 24. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 3% EtOAc/heptane to 50% EtOAc/heptane in 27 Min) afforded 666 mg (55%) of the title compound as an oil, which solidified upon standing. LCMS (Method E): Rt 3.77 Min; ESI m/z: 384.0 & 386.0 [M+IMH4G, Br-isotope pattern.
Intermediate 185. fert-Butyl (2S,4S)-2-cyano-4-(3-(((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 -carboxylate.
Figure imgf000121_0003
To a solution of te/f-butyl (2S, 4S)-4-(3-bromophenoxy)-2-cyanopyrrolidine-1-carboxylate (650 mg, 1.770 mmol) in 1 ,4-dioxane (6 ml_) a solution of sodium carbonate (375 mg, 3.54 mmol) in water (2 ml_) was added. The mixture was flushed with nitrogen, after which XantPhos (61.4 mg, 0.106 mmol), Pd2(dba)3 (48.6 mg, 0.053 mmol) and a solution of intermediate 65 (597 mg, 1.77 mmol) in THF (~ 5 ml_) were added. The mixture was stirred at 80 °C under MW heating for 4 h. Next, the mixture was filtered over a small pad of kieselguhr, which was washed with 1 ,4-dioxane, and the filtrate was concentrated to dryness. DCM (25 ml_) was added and the suspension was washed with water (25 ml_). The layers were separated (separation filter) and the organic layer was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (15-100% DCM/MeOH (9:1)) afforded 221 mg (24%) of the title compound. LCMS (Method A): Rt, 2.48 Min; ESI m/z\ 504.4 [M+H]+. Purity according to LCMS: 94.6%. Intermediate 186. fert-Butyl (2S,4S)-2-cyano-4-(3-(((1s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1-carboxylate.
Figure imgf000122_0001
Intermediate 186 was obtained together with its diastereoisomer 185. Yield: 394 mg (44%). LCMS (Method A): Rt, 2.67 Min; ESI m/z\ 504.2 [M+H]+. Purity according to LCMS: 79.6%.
Intermediate 187. fert-Butyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)phenoxy)-2-(2H-tetrazol-5-yl)pyrrolidine-1-carboxylate.
Figure imgf000122_0002
Intermediate 185 (221 mg, 0.439 mmol) was dissolved in dry DMF (3 mL), followed by the addition of 1.2 eq. of NaN3 (34.2 mg, 0.527 mmol) and 1.2 eq. of NFUCI (28.2 mg, 0.527 mmol, 1.2 eq). The mixture was heated at 80 °C for 45 h. More NaN3 (11.4 mg, 0.176 mmol, 0.4 eq.) and NFUCI (9.39 mg, 0.176 mmol, 0.4 eq.) were added and stirring was continued overnight. Aqueous 1 M KHSCL solution (10 mL) was added, followed by brine (20 mL). The aqueous phase was extracted with EtOAc (2 x, each 30 mL). The organic layers were combined, dried over Na2SC>4, filtered and concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 19.7 Min), 100% DCM/MeOH (9: 1) for 24.6 Min) afforded 92 mg (38%) of the title compound. LCMS (Method A): Rt, 1.92 Min; ESI m/z\ 547.4 [M+H]+. Purity according to LCMS: 86.6%.
Intermediate 188. fert-Butyl (2S,4S)-4-(3-(((1s,4/?)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)phenoxy)-2-(2H-tetrazol-5-yl)pyrrolidine-1 -carboxylate.
Figure imgf000123_0001
Intermediate 188 was prepared from intermediate 186 (394 mg, 0.782 mmol), according to the method described for intermediate 187. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 24 g, gradient DCM / (20- 100% DCM/MeOH (9: 1)) in 25 Min, 100% DCM/MeOH (9:1) for 20 Min) afforded 213 mg (49%) of the title compound. LCMS (Method A): Rt, 2.00 Min; ESI m/z\ 547.4 [M+H]+.
Synthesis of EXAMPLES
EXAMPLE 1. (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)benzyl)oxy) pyrrolidine-2-carboxylic acid.
Figure imgf000123_0002
To a solution of intermediate 9 (32 mg, 0.061 mmol) in DCM (2 mL) TFA (0.094 mL, 1.222 mmol) was added and the resulting orange solution was stirred at rt for 6 h. The mixture was concentrated in vacuo and the residue was purified by preparative LCMS (XSelect CSH C18, basic eluent gradient) to afford 16.3 mg (63%) as a solid. LCMS (Method H): Rt, 2.77 Min; ESI m/z\ 424.3 [M+H]+.
EXAMPLE 2. (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)benzyl)(me thyl)amino)pyrrolidine-2-carboxylic acid. Aqueous 1 M HCI solution (5 ml_, 5 mmol) was added to crude intermediate 3 (126 mg, max. 0.235 mmol) and the resulting solution was stirred at 60 °C for 1 h. The mixture was concentrated in vacuo (60 °C) and the residue was purified by preparative LCMS (XSelect CSH C18, basic eluent gradient). Pure fractions were pooled together and concentrated in vacuo (60 °C), followed by co-evaporation with ACN to afford 22 mg (21% over 2 steps) of the title compound as a solid. LCMS (Method H): Rt, 2.75 Min; ESI m/z\ 437.3 [M+H]+. The method as described for the preparation of EXAMPLE 2 was used for the preparation of EXAMPLES 3-16. If needed, ACN was added additionally to solubilise the starting material. Purification was performed by preparative LC(MS) (XSelect CSH C18, basic eluent):
Figure imgf000124_0001
Figure imgf000125_0001
EXAMPLES 17-72 were prepared from the corresponding intermediates using aqueous HCI (1 M or 2 M) according to the method for EXAM PLE 2 with heating at 60 °C overnight. If needed, ACN was added to solubilise the starting material. Purification by preparative LC(MS) (XSelect CSH C18, basic eluent) afforded the corresponding EXAMPLES as free base.
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0003
EXAMPLE 73. (2S,4S)-4-(3-((1 -(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,1’-biphenyl]- 4-yl)methyl)phenoxy)pyrrolidine-2-carboxylic acid.
Figure imgf000132_0001
Intermediate 125 (230 g, 0.430 mmol) was dissolved in ACN (2.5 mL), followed by the addition of aqueous 2 M HCI solution (20 mL, 40 mmol) and the resulting solution was heated at 60 °C overnight. The reaction mixture was then concentrated in vacuo and co evaporated with ACN. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 67.3 mg (37%) of the title compound. LCMS (Method G): Rt, 2.87 Min; ESI m/z\ 421.2 [M+H]+.
EXAMPLE 74. (2S,4S)-4-(3-(((1s,4f?)-4-(Methylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid.
Figure imgf000132_0002
EXAMPLE 74 was prepared according to the method as described for EXAMPLE 2, starting from intermediate 126 (65 mg, 0.124 mmol). Yield after purification: 14.6 mg (28%). LCMS (Method G): Rt, 2.91 Min; ESI m/z\ 409.2 [M+H]+.
EXAMPLE 75. Ethyl (2S,4S)-4-(3-(((1 ,4S)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)phenoxy)pyrrolidine-2-carboxylate. Intermediate 128 (130 g, 0.249 mmol) was dissolved in EtOH (3 mL) and cooled to 0 °C under a nitrogen atmosphere. Thionyl chloride (27.1 pL, 0.373 mmol) was added slowly, the reaction mixture was allowed to slowly reach rt and stirred overnight. The solution was then cooled down to 0 °C again, and a second batch of thionyl chloride (100 pL, 1.379 mmol) was added and stirring was continued overnight at rt. The reaction mixture was concentrated to dryness. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 57.8 mg (51%) of the title compound. LCMS (Method I): Rt, 3.80 Min; ESI m/z\ 451.3 [M+H]+.
EXAMPLE 76. Ethyl (2S,4S)-4-(4-chloro-3-(((1s,4F?)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate.
Figure imgf000133_0001
A suspension of EXAMPLE 48 (114 mg, 0.194 mmol) in EtOH (3 mL, 51.4 mmol) was cooled to 0 °C. Thionyl chloride (0.282 mL, 3.89 mmol) was added dropwise and the resulting solution was stirred at rt overnight. Next, the mixture was concentrated to dryness and the residue was purified by preparative LC (XSelect CSH C18, basic eluent gradient) to afford 77 mg (79%) of the title compound as an oil. LCMS (Method F): Rt, 2.65 Min; ESI m/z\ 503.2 [M+H]+, Cl-isotope pattern.
EXAMPLE 77. Isopropyl (2S,4S)-4-(4-chloro-3-(((1s,4F?)-4-(dimethylamino)-4- phenyl cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate.
Figure imgf000133_0002
A suspension of EXAMPLE 48 (108 mg, 0.227 mmol) in iso- propanol (3 mL, 39.4 mmol) was reacted with 20 eq. of thionyl chloride (0.330 mL, 4.55 mmol) according to the procedure for EXAMPLE 76. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 67 mg (57%) of the title compound. LCMS (Method F): Rt, 2.48 Min; ESI m/z\ 517.2 [M+H]+, Cl-isotope pattern.
EXAMPLE 78. Butyl (2S,4S)-4-(4-chloro-3-(((1s,4F?)-4-(dimethylamino)-4-phenyl cyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate.
Figure imgf000134_0001
A suspension of EXAMPLE 48 (108 mg, 0.227 mmol) in 1-butanol (3 mL, 39.4 mmol) was reacted with 20 eq. of thionyl chloride (0.330 mL, 4.55 mmol) according to the procedure for EXAMPLE 76. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 64 mg (53%) of the title compound. LCMS (Method F): Rt, 2.55 Min; ESI m/z\ 531.2 [M+H]+, Cl-isotope pattern.
EXAMPLE 79. (2S,4S)-4-(3-(((1 ,4S)-4-(Dimethylamino)-4-phenylcyclohexyl) methyl)phenoxy)-1 -glycylpyrrolidine-2-carboxylic acid.
Figure imgf000134_0002
EXAMPLE 79 was prepared according to the method as described for EXAMPLE 2, starting from intermediate 129 (158 mg, 0.266 mmol). The reaction mixture was evaporated to dryness at 45 °C. Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) afforded pure fractions, which were pooled together and lyophilized. Yield after purification: 45.4 mg (35%). LCMS (Method G): Rt, 2.73 Min; ESI m/z\ 480.2 [M+H]+. Purity according to LCMS: 94.3%.
EXAMPLE 80. A/6-((2S,4S)-4-(3-(((1 ,4S)-4-(Dimethylamino)-4-phenylcyclohexyl) methyl)phenoxy)pyrrolidine-2-carbonyl)-L-lysine. Intermediate 130 (135 g, 0.176 mmol) was dissolved in ACN (1 ml_) and aqueous 2 M HCI solution (5 ml_, 10 mmol) was added, forming a slightly turbid solution. The reaction temperature was raised to 60 °C and stirring was continued for 40 h. The reaction mixture was concentrated to dryness and the residue was stripped twice with ACN (2 x, each 3 ml_). The material was suspended in DCM (2 ml_), followed by the addition of TFA (2 ml_, 26.1 mmol) giving a clear, colourless solution. This reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to dryness and the residue stripped with DCM (1 x) and ACN (2 x). Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) afforded 53.9 mg (55%) of the title compound. Purity according to LCMS: 92.6%. LCMS (Method I): Rt, 2.62 Min; ESI m/z\ 551.3 [M+H]+.
EXAMPLE 81. (2S,4S)-4-(3-(((1 ,4S)-4-(Dimethylamino)-4-phenylcyclohexyl) me thyl)phenoxy)-1 -((1 -(isobutyryloxy)ethoxy)carbonyl)pyrrolidine-2-carboxylic acid, mixture of diastereoisomers.
Figure imgf000135_0001
To a white suspension of EXAMPLE 17 (116 mg, 0.275 mmol) and TEA (0.114 mL, 0.824 mmol) in DCM (4 mL) was added a solution of 1-[[(4-nitrophenoxy)carbonyl]oxy]ethyl 2- methylpropanoate (82 mg, 0.275 mmol) in DCM (2 mL). The resulting yellow solution was stirred at rtfor 2 h. More 1-[[(4-nitrophenoxy)carbonyl]oxy]ethyl 2-methylpropanoate (8.16 mg, 0.027 mmol) in DCM (1 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated to dryness. The residue was purified by preparative LC (Gemini C18, basic eluent gradient) to afford 127 mg (47%) of EXAMPLE 81 (mixture of diastereoisomers) as a glass-like solid. LCMS (Method G): Rt, 3.04 & 3.09 Min; ESI m/z\ 581.3 [M+H]+.
EXAMPLE 82. 1 -(1 -(lsobutyryloxy)ethyl) 2-methyl (2S,4S)-4-(3-(((1 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxy late (mixture of diastereoisomers).
Figure imgf000136_0001
To a white suspension of intermediate 127 (47 mg, 0.108 mmol) and TEA (0.045 mL, 0.323 mmol) in DCM (1 mL), a solution of 1-[[(4-nitrophenoxy)carbonyl]oxy]ethyl 2- methylpropanoate (48.0 mg, 0.161 mmol) in DCM (1 mL) was added and the resulting yellow solution was stirred at rt overnight. More 1-[[(4-nitrophenoxy)carbonyl]oxy]ethyl 2- methylpropanoate (48.0 mg, 0.161 mmol) in DCM (0.5 mL) was added and stirring was continued for 4 h. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 20 Min), 100% DCM/MeOH (9: 1) for 30 Min) to afford 43 mg (67%) of the title compound. LCMS (Method F): Rt, 2.98 Min; ESI m/z\ 595.3 [M+H]+.
EXAMPLES 83-116 were prepared by means of acidic hydrolysis of the corresponding intermediates using aqueous HCI (1 M or 2 M) according to the method for EXAMPLE 2 with heating at 60 °C overnight. If needed, ACN was added additionally to solubilise the starting material. Purification by preparative LC(MS) (XSelect CSH C18, basic eluent) afforded the corresponding compounds as free base.
Figure imgf000136_0002
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0003
EXAMPLE 117. (1 S,4r)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy) benzyl)-A/,A/-dimethyl-1 -phenylcyclohexan-1 -amine.
Figure imgf000140_0001
Intermediate 187 (92 g, 0.168 mmol) was dissolved in DCM (2.5 mL). TFA (387 pL, 5.05 mmol, 30 eq.) was added and the solution was stirred at rt overnight. Next, the solution was concentrated in vacuo and co-evaporated with DCM (2 x, 25 mL). Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) afforded 24 mg (31%) of the title compound. LCMS (Method G): Rt, 2.88 Min; ESI m/z\ 447.2 [M+H]+.
EXAMPLE 118. (1 F?,4s)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy) benzyl)-A/,A/-dimethyl-1 -phenylcyclohexan-1 -amine.
Figure imgf000140_0002
EXAMPLE 118 was obtained from intermediate 188 (213 mg, 0.39 mmol) using 30 eq. of TFA according to the method as described for the preparation of EXAMPLE 117. Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) afforded 72.8 mg (41.8%) of the title compound as a white glass-like solid. LCMS (Method G): Rt, 3.02 Min; ESI m/z\ 447.2 [M+H]+.
Examples of biological activity
Binding assay to human a2d-1 subunit of Cav2.2 calcium channel.
Human a2d-1 enriched membranes (2.5 pg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10 mM, pH 7.4.
NSB (non specific binding) was measured by adding 10 mM pregabalin. The binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). After 60 min incubation at 27 °C, binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5 % polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCI, pH 7.4.
Filter plates were dried at 60 °C for 1 h and 30mI of scintillation cocktail were added to each well before radioactivity reading.
Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).
Binding assay to human m-opioid receptor
Transfected CHO-K1 cell membranes (20 pg) were incubated with [3H]-DAMGO (1 nM) in assay buffer containing Tris-HCI 50 mM, MgCL 5 mM at pH 7.4.
NBS (non-specific binding) was measured by adding 10 pM naloxone. The binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). Plates were incubated at 27 °C for 60 min. After the incubation period, the reaction mixture was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice- cold 10 mM Tris-HCI (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.
The following scale has been adopted for representing the binding to the a2d-1 subunit of the voltage-gated calcium channel, expressed as Ki:
+ Ki (a2d-1) >= 3000 nM
++ 500nM < Ki (a2d-1) <3000 nM
+++ 100nM < Ki (a2d-1) <500 nM
++++ Ki (a2d-1) <100 nM
Preferably, when K(a2d-1) > 3000 nM, the following scale has been adopted for representing the binding to the a2d-1 subunit of voltage-gated calcium channels:
+ K(a2d-1) > 3000 nM or inhibition ranges between 1 % and 50 %
For the m-opioid receptor, the following scale has been adopted for representing the binding, expressed as Ki:
+ (m) >= 500 nM
++ 100 nM <= K (m) < 500 nM
+++ K (m) < 100 nM
Preferably, when K (m) > 500 nM, the following scale has been adopted for representing the binding to the m -receptor:
+ K (m) > 500 nM or inhibition ranges between 1 % and 50 %.
The K results for the a2d-1 subunit of the voltage-gated calcium channel and the m- opioid receptor are shown in Table 1 :
Table 1
Figure imgf000142_0001
2
Figure imgf000143_0001
3
Figure imgf000144_0001
4
Figure imgf000145_0001

Claims

1. A compound of general formula (I):
Figure imgf000146_0001
wherein:
Wi is -0-, -NRa or -CH2-;
Ra is a hydrogen atom or a branched or unbranched Ci-e alkyl radical; n and m are independently from one another 0 or 1 ;
Ri, Rå and R4 are independently from one another a hydrogen atom; a branched or unbranched alkyl radical; a halogen atom; a C(0)H radical; a branched or unbranched C alkoxy radical; a -NRbRc radical; a -CN radical; a hydroxyl radical; or a C haloalkyl radical;
Rb and Rc are independently from one another a hydrogen atom or a branched or unbranched C alkyl radical;
R is selected from:
Figure imgf000146_0002
W2 is -C(O)-, -CH2- or bond;
A is C or N; the dotted line represents an optional double bond;
R3a and R3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or
R3a and R3b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;
R3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -CN radical; a Ci-e haloalkyl radical; or a -NR3CR3d radical;
R3d and R3e are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical;
Re is a hydrogen atom or a -C(0)Rsa radical;
Rea is a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(ChbJrNRsbRsc radical; a 0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR5g-(CH2)s-CH(R5f)-NR5eR5dradical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
Reb, Rec, Red, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-e alkyl radical;
Ref is a hydrogen atom or a -CORsh radical; Reh is a hydroxyl radical or a branched or unbranched C1 -6 alkyl radical;
Re is a -C(0)R6a radical; an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
R6a is a hydroxyl radical, a branched or unbranched C1 -6 alkoxy radical; a -(ChhX- NRebRec radical; a -0CH(CH3)0C(0)CH(CH3)2 radical; or a -NR6g-(CH2)v-CH(R6f)- NR6eR6d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
R6b, Rec, R6d, Ree, Reg are independently from one another a hydrogen atom; or a branched or unbranched C1 -6 alkyl radical;
Ref is a hydrogen atom or a -COR6h radical;
R6h is a hydroxyl radical or a branched or unbranched C1 -6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
2. A compound according to claim 1 wherein Ri, Rå and R4 are independently from one another a hydrogen atom; a branched or unbranched C1 -6 alkyl radical, more preferably methyl; a halogen atom, more preferable fluorine or chlorine; a -C(0)H radical; a branched or unbranched C1 -6 alkoxy radical, more preferably methoxy; a - CN radical; or a Ci-6 haloalkyl radical, more preferably a -CF3 radical.
3. A compound according to claim 1 wherein R3 is in meta position.
4. A compound according to claim 1 wherein R3 is selected from:
wherein R3a, R3b and R3c are as defined in claim 1.
5. A compound according to claim 1 having the general formula (la): wherein Wi, m, n, Ri, Rå, R3, R4, Rs and R6 are as defined In claim 1 ; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
6. A compound according to claim 1 having the formula general (I’a):
Figure imgf000150_0001
wherein Ri, Rå, R3, R4, Rs, R6 and n are as defined in claim 1 ;
or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
7. A compound according to claim 1 selected from the following list:
[1] (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)benzyl)oxy)pyrrolidine- 2-carboxylic acid;
[2] (2S,4S)-4-((4-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)benzyl)(methyl)amino) pyrrolidine-2-carboxylic acid;
[3] (2S,4S)-4-(4-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrro lidine-2-carboxylic acid;
[4] (2S,4S)-4-(3-Chloro-4-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phen oxy)pyrrolidine-2-carboxylic acid;
[5] (2S,4S)-4-(3-Chloro-4-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)phen oxy)pyrrolidine-2-carboxylic acid; [6] (2S,4S)-4-(((4-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)amino) methyl)pyrrolidine-2-carboxylic acid;
[7] (2S,4S)-4-(((4-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)(me thyl)amino)methyl)pyrrolidine-2-carboxylic acid;
[8] (2S,4S)-4-(((3-(4-(Dimethylamino)-4-phenylpiperidine-1-carbonyl)phenyl)(me thyl)amino)methyl)pyrrolidine-2-carboxylic acid;
[9] (2S,4S)-4-(3-Chloro-5-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)phen oxy)pyrrolidine-2-carboxylic acid;
[10] (2S,4S)-4-(3-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrro lidine-2-carboxylic acid;
[11] (2S,4S)-4-(3-Chloro-5-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phen oxy)pyrrolidine-2-carboxylic acid;
[12] (2S,4S)-4-(2-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenoxy)pyrroli dine-2-carboxylic acid;
[13] (2S,4S)-4-(3-((4-(Dimethylamino)-4-phenylpiperidin-1-yl)methyl)-5-fluorophen oxy)pyrrolidine-2-carboxylic acid;
[14] (2S,4S)-4-(3-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[15] (2S,4S)-4-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)phenoxy)pyrrolidine-2- carboxylic acid;
[16] (2S,4S)-4-(3-((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)phenoxy)pyrro lidine-2-carboxylic acid;
[17] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[18] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[19] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[20] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[21] (2S,4S)-4-(3-Chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[22] (2S,4S)-4-(3-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[23] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methyl phenoxy)pyrrolidine-2-carboxylic acid;
[24] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-methyl phenoxy)pyrrolidine-2-carboxylic acid;
[25] (2S,4S)-4-(5-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[26] (2S,4S)-4-(5-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[27] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[28] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[29] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[30] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-fluoro phenoxy)pyrrolidine-2-carboxylic acid;
[31 ] (2S,4S)-4-(5-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[32] (2S,4S)-4-(5-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[33] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[34] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[35] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-meth oxyphenoxy)pyrrolidine-2-carboxylic acid;
[36] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-meth oxyphenoxy)pyrrolidine-2-carboxylic acid;
[37] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,6-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[38] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,6-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[39] (2S,4S)-4-(2-Chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[40] (2S,4S)-4-(2-Chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[41] (2S,4S)-4-(2-Chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 3-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[42] (2S,4S)-4-(2-Chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 3-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[43] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[44] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[45] (2S,4S)-4-(3-Cyano-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[46] (2S,4S)-4-(3-Cyano-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[47] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[48] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[49] (2S,4S)-4-(5-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,3-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[50] (2S,4S)-4-(5-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,3-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[51] (2S,4S)-4-(2-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[52] (2S,4S)-4-(2-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[53] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[54] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,4-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[55] (2S,4R)-4-(3-(((1r,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[56] (2S,4R)-4-(3-(((1s,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[57] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[58] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[59] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[60] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-(trifluo romethyl)phenoxy)pyrrolidine-2-carboxylic acid;
[61] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,5-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[62] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-2,5-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[63] (2S,4S)-4-(3-Chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 4-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[64] (2S,4S)-4-(3-Chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 4-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[65] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[66] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-difluo rophenoxy)pyrrolidine-2-carboxylic acid;
[67] (2S,4S)-4-(5-Chloro-3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 2-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[68] (2S,4S)-4-(5-Chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 2-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[69] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-formyl phenoxy)pyrrolidine-2-carboxylic acid;
[70] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4-formyl phenoxy)pyrrolidine-2-carboxylic acid;
[71] (2S,4S)-4-(4-Chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 2,3-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[72] (2S,4S)-4-(4-Chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)- 2,3-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[73] (2S,4S)-4-(3-((1-(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 , 1 '-biphenyl]-4-yl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[74] (2S,4S)-4-(3-(((1 s,4R)-4-(Methylamino)-4-phenylcyclohexyl) methyl) phenoxy) pyrrolidine-2-carboxylic acid;
[75] Ethyl (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)phen oxy)pyrrolidine-2-carboxylate;
[76] Ethyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) ethyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[77] Isopropyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclo hexyl) ethyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[78] Butyl (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl) methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylate;
[79] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)- 1-glycylpyrrolidine-2-carboxylic acid;
[80] N6-((2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phen oxy)pyrrolidine-2-carbonyl)-L-lysine;
[81] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenoxy)-
1-((1-(isobutyryloxy)ethoxy)carbonyl)pyrrolidine-2-carboxylic acid;
[82] 1-(1-(lsobutyryloxy)ethyl)-2-methyl (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;
[83] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[84] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl) phenoxy)pyrrolidine-2-carboxylic acid;
[85] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)-
2-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[86] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)- 2-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[87] (2S,4S)-4-(3-(((1r,4S)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[88] (2S,4S)-4-(3-(((1s,4R)-4-(Dimethylamino)-4-(3-fluorophenyl)cyclohexyl)methyl)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[89] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[90] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[91 ] (2S,4S)-4-(4-Chloro-3-(((1 r,4S)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[92] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[93] (2S,4S)-4-(4-Chloro-3-(((1r,4S)-4-(3-chlorophenyl)-4-(dimethylamino)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[94] (2S,4S)-4-(4-Chloro-3-(((1s,4R)-4-(3-chlorophenyl)-4-(dimethylamino)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[95] (2S,4S)-4-(3-(((1r,4S)-4-(3-Chlorophenyl)-4-(dimethylamino)cyclohexyl)me thyl)-4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[96] (2S,4S)-4-(3-(((1 s,4R)-4-(3-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl) -4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[97] (2S,4S)-4-(4-Chloro-3-(((1 r,4S)-4-(4-chlorophenyl)-4-(dimethylamino)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[98] (2S,4S)-4-(4-Chloro-3-(((1 s,4R)-4-(4-chlorophenyl)-4-(dimethylamino)cyclohe xyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[99] (2S,4S)-4-(3-(((1 r,4S)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)methyl) -4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[100] (2S,4S)-4-(3-(((1 s,4R)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)me thyl)-4,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[101] (2S,4S)-4-(3-(((1 r,4S)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)me thyl)-2,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[102] (2S,4S)-4-(3-(((1 s,4R)-4-(4-Chlorophenyl)-4-(dimethylamino)cyclohexyl)me thyl)-2,5-difluorophenoxy)pyrrolidine-2-carboxylic acid;
[103] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) pyrrolidine-2-carboxylic acid;
[104] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) pyrrolidine-2-carboxylic acid;
[105] (2S,4S)-4-(3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro benzyl)pyrrolidine-2-carboxylic acid;
[106] (2S,4S)-4-(3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluoro benzyl)pyrrolidine-2-carboxylic acid;
[107] (2S,4S)-4-((3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenyl) (methyl)amino)pyrrolidine-2-carboxylic acid
[108] (2S,4S)-4-((3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)phenyl) (methyl)amino)pyrrolidine-2-carboxylic acid;
[109] (2S,4S)-4-((3-(((1 r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) oxy) pyrrolidine-2-carboxylic acid;
[1 10] (2S,4S)-4-((3-(((1 s,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl)benzyl) oxy)pyrrolidine-2-carboxylic acid;
[11 1] (2S,4S)-4-(3-(((1 r,4S)-4-(Azetidin-1-yl)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[112] (2S,4S)-4-(3-(((1 s,4R)-4-(Azetidin-1-yl)-4-phenylcyclohexyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[1 13] (2S,4S)-4-(3-(((1 r,3R)-3-(Dimethylamino)-3-phenylcyclobutyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[114] (2S,4S)-4-(3-(((1s,3S)-3-(Dimethylamino)-3-phenylcyclobutyl)methyl)phenoxy) pyrrolidine-2-carboxylic acid;
[115] (2S,4S)-4-(4-Chloro-3-(((1 r,3R)-3-(dimethylamino)-3-phenylcyclobutyl)methyl) -5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[116] (2S,4S)-4-(4-Chloro-3-(((1s,3S)-3-(dimethylamino)-3-phenylcyclobutyl)methyl)
-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;
[117] (1 S,4r)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy)benzyl)-N,N-di methyl-1 -phenylcyclohexan-1 -amine and
[118] (1R,4s)-4-(3-(((3S,5S)-5-(2H-Tetrazol-5-yl)pyrrolidin-3-yl)oxy)benzyl)-N,N-di methyl-1 -phenylcyclohexan-1 -amine; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
8. Process for the preparation of a compound of general formula (I) according to
claim 1 :
Figure imgf000157_0001
wherein Ri , R2, R3, R4, Rs, R6, Wi, m and n are as defined in claim 1 , from a compound of general formula (V):
Figure imgf000157_0002
wherein Ri , R2, R4, Rs, R6, Wi, m and n have the meanings as defined in claim 1 and Y represents a group that can be converted into R3, wherein R3 has the meaning as defined in claim 1.
9. Process according to claim 8 wherein Y is a halogen atom, preferably a bromine atom, or an aldehyde for the preparation of a compound of general formula (B1 ), particular case of compounds of formula (I) according to claim 1 for which W2 is a bond, comprising: if Y is a halogen atom, preferably a bromine:
• a reaction with a compound of general formula (VI):
Figure imgf000158_0001
by means of a Buchwald-Hartwig coupling reaction, using suitable reagents, such as tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3) , 2-dicyclohexyl phosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and sodium tert- butoxide, in suitable solvents, such as 1 ,4-dioxane, and with conventional heating at a suitable temperature, for example 110 °C and optionally under microwave heating, or
a Pd-catalysed reaction using a potassium trifluoroborate salt of general formula (VII), obtainable from a compound of general formula (VI),:
Figure imgf000158_0002
and suitable reagents such as palladium acetate, in the presence of a phosphine ligand, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and cesium carbonate, in suitable solvent mixtures, such as THF and water, and with conventional heating at a suitable temperature, for example 80 °C or
• a Grignard type reaction with a ketone of general formula (VIII) or (IX):
Figure imgf000159_0001
in the presence of magnesium, in a suitable solvent such as tetrahydrofuran, at a suitable temperature, such as 100 °C; followed by an elimination reaction of the obtained tertiary alcohol under acidic conditions, like trifluoroacetic acid in dichloromethane as solvent, and subsequent hydrogenation of the formed alkene moiety, using hydrogen and palladium on carbon in methanol as solvent; or if Y is an aldehyde, a reaction with a compound of general formula (VI) using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol mixture, at a suitable temperature, such as room temperature.
10. Process according to claim 8 wherein Y is a halogen atom, preferably a bromine atom, for the preparation of a compound of general formula (B2), particular case of compounds of formula (I) according to claim 1 for which W2 is a -CH2-, comprising: • the reaction with a suitably olefin derivative of general formula (X) or (XI):
Figure imgf000159_0002
(X) (XI)
under a Heck-type conditions, using a suitable catalyst, such as palladium(ll) acetate and phosphine ligand, such as tri-o-tolylphosphine, and an organic base, such as A/,A/-diisopropylethyiamine (DIPEA), in an appropriate solvent, like acetonitrile, with heating at 150 °C under microwave conditions; or
• the reaction with an organo-borane derivative of a compound of general formula (X) or (XI), obtained in situ by reaction with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF with heating at elevated temperature, in a subsequent Pd2(dba)3- catalysed reaction, in a suitable solvent mixture, like a mixture of THF, 1 ,4- dioxane and water, and using suitable reagents, like 4,5-bis(diphenylphosphino)- 9, 9-dimethyl xanthene (XantPhos) and sodium carbonate with heating between 80 °C and 110 °C under conventional heating or optionally microwave heating conditions.
11. Process according to claim 8 wherein Y is a carboxylic acid, for the preparation of a compound of general formula (B3), particular case of compounds of formula (I) according to claim 1 for which W2 is a -C(O)-, comprising a reaction with a compound of general formula (VI) using for example A/-[(dimethylamino)-1/-/-1 ,2,3- triazolo-[4,5-Jb]pyridin-1-ylmethylene]-/\/-methylmethanaminium
hexafluorophosphate /V-oxide (HATU) as coupling reagent in a suitable solvent, like DMF, at a suitable temperature, such as room temperature.
12. Process for the preparation of a compound of general formula (A1), particular case of compounds of formula (I) according to claim 1 for which Wi is -CH2-, m is 0 and n is 0 or (A2), particular case of compounds of formula (I) according to claim 1 for which Wi is -0-, m is 0 and n is 0:
Figure imgf000160_0001
(A1) (A2) wherein Ri, R2, R3, R4, Rs and R6 are as defined in claim 1 comprising: a) a Wittig reaction by treating a pyrrolidyl-ketone of general formula (lla):
Figure imgf000161_0001
wherein R4 and R5 have the meanings as defined in claim 1 and a triphenylphosphonium salt reagent of formula (Ilia):
Figure imgf000161_0002
wherein Ri , R2, Rs and R4 have the meanings as defined in claim 1 and Z represents triphenylphosphonium salt; in the presence of a suitable base, such as sodium hydride, and with stirring at elevated temperature, for example 70 °C, followed by hydrogenation of the formed alkene with hydrogen and a suitable catalyst, such as platinum(IV)oxide and hydrogen in a suitable solvent, like EtOAc, and with heating at a suitable temperature, like 60 °C; or b) by treating a pyrrolidinol derivative of general formula (Mb):
Figure imgf000161_0003
wherein R5 and R6 have the meanings as defined in claim 1 with a suitable derivative of general formula (lllb): wherein Ri, R2, R3 and R4 have the meanings as defined in claim 1 ; under Mitsunobu conditions, with a suitable coupling agent, such as cyanomethylenetributylphosphorane (CMBP), or diisopropyl azodicarboxylate (DIAD) in the presence of a phosphine, such as triphenylphosphine (PhbP), in the presence of a suitable solvent, such as toluene or tetrahydrofuran (THF), at a suitable temperature, between room temperature and 100 °C, preferably room temperature. 13. Process for the preparation of a compound of general formula (A3), particular case of compounds of formula (I) according to claim 1 for which Wi is -0-, m is 0 and n is 1 or (A4), particular case of compounds of formula (I) according to claim 1 for which Wi is -NRa-, m is 0 and n is 0:
Figure imgf000162_0001
wherein Ri, R2, R3, R4, Rs and R6 are as defined in claim 1 comprising: a) an alkylation of a suitable pyrrolidinyl-ketone derivative of general formula
(lla):
Figure imgf000162_0002
wherein R5 and R6 have the meanings as defined in claim 1 with a suitable halide of general formula (lllc):
Figure imgf000163_0001
wherein Ri, R2, R3 and R4 have the meanings as defined in claim 1 and X stands for halogen; in the presence of a base such as sodium hydride, in a suitable solvent, for example A/./V-dimethylformamide (DMF) or THF, at a suitable temperature, such as between 0 °C and room temperature; or b) a Buchwald-Hartwig coupling reaction of a suitable pyrrolidine-amine of general formula (lie):
Figure imgf000163_0002
wherein Ra, R5 and R6 have the meanings as defined in claim 1 ; and a compound of general formula (Mid):
Figure imgf000163_0003
wherein Ri, R2, R3 and R4 have the meanings as defined in claim 1 and X stands for halogen; using suitable reagents, like 2-dicyclohexylphosphino- 2',6'-diisopropoxy biphenyl (Ru-Phos), cesium carbonate and a suitable palladium catalyst, for example Pd2(dba)3, with heating at a suitable temperature, like 60 °C, under microwave heating.
14. Process for the preparation of a compound of general formula (A5), particular case of compounds of formula (I) according to claim 1 for which Wi is -NRa-, m is 1 and n is 0 or (A6), particular case of compounds of formula (I) according to claim 1 for which Wi is -NRa-, m is 0 and n is 1 :
Figure imgf000164_0001
wherein Ri, R2, R3, R4, Rs and R6 are as defined in claim 1 comprising: a) the reaction of a suitable pyrrolidina-amine of general formula (lid):
Figure imgf000164_0002
wherein Ra, R5 and R6 have the meanings as defined in claim 1 ; and a compound of general formula (llld):
Figure imgf000164_0003
wherein Ri, R2, R3 and R4 have the meanings as defined in claim 1 and X stands for halogen; using suitable reagents, such as Pd2(dba)3 and 2- (dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1 ,1 '-biphenyl (Brett-Phos) or 2-dicyclohexylphosphi no-2',4',6'-triisopropylbiphenyl (X- Phos) in suitable solvents, such as a,a,a-trifluorotoluene or 1 ,4-dioxane, at a suitable temperature between 100 °C to 110 °C, and optionally under microwave heating; or b) a reductive amination of a suitable pyrrolidina-amine of general formula (lie):
Figure imgf000165_0001
wherein Ra, Rs and R6 have the meanings as defined in claim 1 ; and an aldehyde compound of general formula (I lie):
Figure imgf000165_0002
wherein Ri , R2, R3 and R4 have the meanings as defined in claim 1 ; using a reducing reagent, such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, or acetonitrile and methanol, at a suitable temperature, such as room temperature.
15. A compound according to any of claims 1 to 7 for use as a medicament.
16. A compound according to any of claims 1 to 7, for use in the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m-opioid receptor.
17. A compound for use according to claim 16, where the disease or disorder is pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression, anxiety and attention-deficit-/hyperactivity disorder.
18. A pharmaceutical composition comprising a compound of general formula (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.
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