Substituted sulfonamide compounds   

This application is a division of co-pending application Ser. No. 11/905,381, filed Sep. 28, 2007. Priority is claimed based on U.S. provisional patent application No. 60/849,438, filed Oct. 5, 2006, the entire disclosure of which is corporated herein by reference. Priority is also claimed based on Federal Republic of Germany patent application no. DE 10 2006 046 743.4, filed Sep. 29, 2006.

The present invention relates to substituted sulfonamide derivatives, to a process for their preparation, to medicaments containing these compounds, and to the use of substituted sulfonamide derivatives in the preparation of pharmaceutical compositions and in treatment and/or inhibition of pain and/or various disease states.

Unlike the constitutive expression of the bradykinin 2 receptor (B2R), the bradykinin 1 receptor (B1R) is not expressed or is expressed only weakly in most tissues. However, the expression of B1R in various cells is inducible. For example, following inflammation reactions there is a rapid and pronounced induction of B1R in neuronal cells but also in various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Accordingly, following inflammation reactions there is a switch from B2R to B1R dominance in the cells that are involved. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) play a substantial part in this B1R up-regulation (Passos et al., J. Immunol. 2004, 172, 1839-1847). Following activation with specific ligands, B1R-expressing cells are then themselves able to secrete inflammation-promoting cytokines such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This results in the immigration of further inflammatory cells, for example neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145). By way of these mechanisms, the bradykinin B1R system can contribute to the chronification of diseases. This is proved by a large number of animal experiments (overviews in Leeb-Lundberg et al., Pharmacol. Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem. 2006, 387, 119-126). In humans too, enhanced expression of B1R is found, for example in enterocytes and macrophages in the affected tissue of patients with inflammatory intestinal diseases (Stadnicki et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G361-366) or on T-lymphocytes of patients with multiple sclerosis (Prat et al., Neurology, 1999; 53, 2087-2092), or activation of the bradykinin B2R-B1R system is found following infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for symptoms ranging from superficial skin infections to septic shock.

Due to the described pathophysiological relationships there is a great therapeutic potential for the use of B1R antagonists in acute and, in particular, chronic inflammatory diseases. These include respiratory diseases (Asthma bronchiale, allergies, COPD/chronic-obstructive pulmonary disease, cystic fibrosis, etc.), inflammatory intestinal diseases (ulcerative colitis, CD/Crohn's disease, etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections, etc.) and mucosa (Behcet's disease, pelvitis, prostatitis, etc.), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock and reperfusion syndrome (following heart attack, stroke).

Moreover, the bradykinin (receptor) system is also involved in regulating angiogenesis (potential as an angiogenesis inhibitor in cancer and macular degeneration of the eye), and B1R knockout mice are protected against the induction of excess weight as a result of a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore suitable also for the treatment of obesity.

B1R antagonists are suitable in particular for the treatment of pain, in particular inflammatory pain and neuropathic pain (Calixto et al., Br. J. Pharmacol. 2004, 1-16), in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). They are also suitable for the treatment of migraine.

When developing B1R modulators there is, however, the problem that the human and the rat B1R receptor are so very different from one another that many compounds that are good B1R modulators on the human receptor exhibit only poor affinity or no affinity for the rat receptor. This makes animal pharmacological studies considerably more difficult, because many studies are normally carried out on the rat. If there is no activity on the rat receptor, however, neither action nor side-effects can be studied on the rat. This has already resulted in the production of transgenic animals having human B1 receptors for animal pharmacological studies (Hess et al., Biol. Chem. 2006; 387(2): 195-201). However, it is more expensive to work with transgenic animals than with the unchanged animals. Nonetheless, because long-term toxicity studies on the rat form part of the standard studies that are carried out when developing medicaments, but such studies are meaningless where there is an absence of activity on the receptor, there is no important, established instrument for checking safety when developing such compounds. There is therefore a need for novel B1R modulators, B1R modulators that bind both to the rat receptor and to the human receptor offering particular advantages.

It is an object of the present invention to provide new pharmaceutically useful compounds.

A particular object of the invention is to provide compounds which a suitable for use in the treatment or inhibition of disorders or diseases which are at least in part related to the B1R-receptor.

Another object of the invention is to provide methods of treating or inhibiting disorders or disease states which are at least in part mediated by the B1R-receptor.

These and other objects are achieved in accordance with the present invention by providing substituted sulfonamide compounds corresponding to the formula I

wherein

• • n represents 0, 1, 2 or 3;
  • m represents 1 or 2;
  • R¹ represents aryl or heteroaryl;
  • R^2a-c, R³ and R⁴ represent H or, with an adjacent radical R^2a-c, R³ or R⁴, form a five- or six-membered ring which can be saturated or unsaturated and mono- or poly-substituted and which can contain hetero atoms from the group N and O,
  • R⁵ and R⁶ together form a 4- to 8-membered ring which can be saturated or unsaturated but not aromatic, wherein the 4- to 8-membered ring can be fused to an aromatic, saturated or unsaturated 4- to 10-membered ring, and the 4- to 8-membered ring and/or the fused 4- to 10-membered ring is substituted by or fused to a basic radical and can be substituted by a further basic radical or radicals from the group C_1-6-alkyl, C_1-3-alkoxy, C_3-8-cycloalkyl, ═O, aralkyl and aryl; or
  • R⁵ and R⁶ together form a 4- to 8-membered ring which contains a further hetero atom from the group N and O and can be substituted by a basic or non-basic radical and, in the case where the basic or non-basic substituent is not bonded via the further hetero atom N to the 4- to 8-membered ring, that further hetero atom N can additionally be substituted by a C_1-6-alkyl group, an aryl or aralkyl group; or
  • R⁵ represents H, C_1-6-alkyl, C_3-8-cycloalkyl, aryl or aralkyl and
  • R⁶ represents aryl or C_3-8-cycloalkyl; or R⁶ represents an aryl radical linked via a C_1-3-alkyl chain, or C_3-8-cycloalkyl, wherein the aryl radical and the C_3-8-cycloalkyl ring can be fused to a 5- to 10-membered saturated or unsaturated ring optionally containing one or more hetero atoms, and the aryl or C_3-8-cycloalkyl ring is substituted by a basic radical or, where appropriate, the substitution with the basic radical takes place on the bridging C_1-3-alkyl chain, or
  • R⁵ represents H, C_1-6-alkyl, C_3-8-cycloalkyl, aryl or aralkyl and R⁶ represents C_4-8-heterocyclyl; or R⁶ represents a C_4-8-heterocyclyl radical linked via a C_1-4-alkyl chain, wherein the heterocyclyl ring can be substituted on one or two ring members by a basic or non-basic radical, or
  • R⁵ and R⁶, independently of one another, represent H, aralkyl or a branched or unbranched, optionally mono- or poly-substituted C_1-100-alkyl radical which contains from one to three nitrogen atoms, wherein R⁵ and R⁶ do not both represent H, or
  • R⁵ represents H, C_1-6-alkyl, C_3-8-cycloalkyl, aralkyl or aryl and R⁶ represents a basic heteroaryl radical which is optionally linked via a C_1-4-alkyl group and can be mono- or poly-substituted, wherein the C_1-4-alkyl chain can be substituted by a basic radical;
    wherein, unless indicated to the contrary, the above-mentioned radicals C_1-6-alkyl, C_1-3-alkoxy, aralkyl, aryl and heteroaryl can be unsubstituted or mono- or poly-substituted and the radical C_3-8-cycloalkyl can be unsubstituted or monosubstituted on one or more ring members, and wherein the compound may be in the form of the racemate; in the form of the enantiomers, diastereoisomers, mixtures of the enantiomers or diastereoisomers or in the form of an individual enantiomer or diastereoisomer; and/or in the form of a free base or a salt thereof with a physiologically acceptable acid.

Within the scope of this invention, the expressions “C_1-3-alkyl”, C_1-6-alkyl” and “C_1-10-alkyl” denote acyclic saturated or unsaturated hydrocarbon radicals which can be branched- or straight-chained as well as unsubstituted or mono- or poly-substituted, having from 1 to 3 carbon atoms or from 1 to 6 carbon atoms or from 1 to 10 carbon atoms, respectively, that is to say C_1-3-alkanyls, C_2-3-alkenyls and C_2-3-alkynyls or C_1-6-alkanyls, C_2-6-alkenyls and C_2-6-alkynyls or C_1-10-alkanyls, C_2-10-alkenyls and C_2-10-alkynyls. Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptanyl, octanyl, nonanyl, decyl, ethylenyl(vinyl), ethynyl, propenyl (—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), propynyl (—CH—C≡CH, —C≡C—CH₃), butenyl, butynyl, pentenyl, pentynyl, hexenyl and hexynyl. Methyl, ethyl, n-propyl and isopropyl are particularly advantageous.

For the purposes of this invention, the term “cycloalkyl” or “C_3-8-cycloalkyl” denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or monosubstituted on one or more ring members. C_3-8-Cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

Within the scope of this invention, the term “heterocyclyl” denotes mono- or poly-cyclic organic radicals in which at least one ring contains one hetero atom or 2, 3, 4 or 5 identical or different hetero atoms selected from the group consisting of N, O and S. Each heterocyclyl radical can be unsubstituted or monosubstituted on one or more ring members. Saturated and unsaturated heterocyclyl are understood as being in particular monocyclic 5- or 6-membered compounds having at least one hetero atom from the group N, O and S, wherein a further 5- or 6-membered, saturated, unsaturated or aromatic ring, which can likewise contain at least one hetero atom from the group N, O and S, can be fused to those compounds. Examples are the benzo- or pyridino-fused analogues of the above-mentioned monocyclic 5- or 6-membered compounds. A saturated or unsaturated heterocyclyl radical is preferably selected from the group comprising pyrrolidinyl, piperidinyl, piperazinyl, pyrazolinyl, morpholinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, indolinyl, isoindolinyl, or

Unless indicated to the contrary, the substitution by a heterocyclyl radical can take place via any desired position of the heterocyclyl radical.

Within the scope of this invention, the term “aryl” denotes aromatic hydrocarbons, including phenyls and naphthyls. The aryl radicals can also be fused to further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical can be unsubstituted or mono- or poly-substituted, wherein the aryl substituents can be identical or different and can be located at any desired and possible position of the aryl. Aryl is advantageously selected from the group comprising phenyl, 1-naphthyl and 2-naphthyl, each of which can be unsubstituted or mono- or poly-substituted.

The term “heteroaryl” is synonymous with “aromatic heterocyclyl” and denotes a 5-, 6- or 7-membered cyclic aromatic radical containing at least one, optionally also 2, 3, 4 or 5, hetero atom(s), the hetero atoms being identical or different and the heterocycle being unsubstituted or mono- or poly-substituted; in the case of substitution on the heterocycle, the substituents can be identical or different and can be located at any desired and possible position of the heteroaryl. The heterocycle can also be part of a bi- or poly-cyclic system, which can then be more than 7-membered in total, preferably up to 14-membered. Preferred hetero atoms are nitrogen, oxygen and sulfur. It is preferred for the heteroaryl radical to be selected from the group comprising pyrrolyl, indolyl, furyl(furanyl), benzofuranyl, thienyl(thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl, it being possible for bonding to the compounds of the general structure I to take place via any desired and possible ring member of the heteroaryl radical. Pyridyl is particularly preferred.

The expression “aryl or heteroaryl bonded via C_1-3-alkyl” means, for the purposes of the present invention, that C_1-3-alkyl and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl radical is bonded to the compound of the general structure I via a C_1-3-alkyl group. Phenyl, benzyl and phenethyl are particularly advantageous within the scope of this invention.

The term “aralkyl” denotes an alkyl group substituted by an aryl group. The aralkyl group is preferably selected from the group consisting of benzyl, phenylethyl and phenylpropyl.

In connection with “alkyl” and “cycloalkyl”, the term “substituted” within the scope of this invention is understood as meaning the substitution of a hydrogen radical by F, Cl, Br, I, —CN, NH₂, NH—C_1-6-alkyl, NH—C_1-6-alkyl-OH, C_1-6-alkyl, N(C_1-6-alkyl)₂, N(C_1-6-alkyl-OH)₂, NO₂, SH, S—C_1-6-alkyl, S-benzyl, O—C_1-6-alkyl, OH, O—C_1-6-alkyl-OH, ═O, O-benzyl, C(═O)C_1-6-alkyl, CO₂H, CO₂—C_1-6-alkyl or benzyl, polysubstituted radicals being understood as being those radicals that are polysubstituted, for example di- or tri-substituted, either on different atoms or on the same atom, for example trisubstituted on the same carbon atom, as in the case of CF₃ or —CH₂CF₃, or at different positions, as in the case of —CH(OH)—CH═CH—CHCl₂. Polysubstitution can be carried out with the same or with different substituents.

In connection with “saturated or unsaturated heterocyclyl”, the term “substituted” is understood as meaning the substitution of a hydrogen radical on one or more ring members by F, Cl, Br, I, —CN, NH₂, NH—C_1-6-alkyl, NH—C_1-6-alkyl-OH, C_1-6-alkyl, N(C_1-6-alkyl)₂, N(C_1-6-alkyl-OH)₂, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH, S—C_1-6-alkyl, S-benzyl, O—C_1-6-alkyl, OH, O—C_1-6-alkyl-OH, ═O, O-benzyl, C(═O)C_1-6-alkyl, CO₂H, CO₂—C_1-6 alkyl or benzyl. The hydrogen bonded to a N hetero atom can be substituted in particular by a C_1-6-alkyl group.

In relation to “aryl” and “heteroaryl” or “aromatic heterocyclyl”, “mono- or poly-substituted” within the scope of this invention means the substitution of one or more hydrogen atoms of the ring system one or more times, for example two, three or four times, by F, Cl, Br, I, CN, NH₂, NH—C_1-6-alkyl, NH—C_1-6-alkyl-OH, N(C_1-6-alkyl)₂, N(C_1-6-alkyl-OH)₂, NHaryl, N(aryl)₂, N(C_1-6-alkyl)aryl, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH, S—C_1-6-alkyl, OH, O—C_1-6-alkyl, O—C_1-6-alkyl-OH, C(═O)C_1-6-alkyl, NHSO₂C_1-6-alkyl, NHCOC_1-6-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C_1-6-alkyl, OCF₃, CF₃,

C_1-6-alkyl, pyrrolidinyl, imidazolyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, in particular benzyl, thienyl or furyl; on one atom or optionally on different atoms, wherein a substituent can itself optionally be substituted. The polysubstitution is carried out with the same or with different substituents. Preferred substituents for “aryl” or “heteroaryl” are —F, —C₁, CF₃, CH₃ or OCH₃.

Within the scope of the present invention, the symbol

used in the formulae denotes a linking of a corresponding radical to the particular higher-order general structure. If this symbol is arranged in a cyclic or polycyclic, for example aromatic or fused aromatic, group in such a manner that a concrete linkage to a specific position is not identifiable, then this means that a linkage at any position of the cyclic or polycyclic group is to be included.

Within the scope of this invention, the expression “a salt formed with a physiologically acceptable acid” is understood as meaning salts of the active ingredient in question with inorganic or organic acids that are physiologically acceptable—in particular when used in humans and/or mammals. The hydrochloride is particularly preferred. Examples of physiologically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1λ⁶-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-liponic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. Citric acid and hydrochloric acid are particularly preferred.

Within the scope of this invention, a basic radical is understood as being a group that is able to react while taking up protons. In particular, it is understood as being a group that contains at least one protonisable nitrogen. A basic radical can in particular represent an optionally fused heterocycle containing at least one nitrogen atom as hetero atom, wherein the heterocycle can optionally be monosubstituted on one or more ring members by C_1-6-alkyl, O—C_1-6-alkyl, heterocyclyl, OH, F, Cl, Br, I, —CN, NH₂, NH(C_1-6-alkyl), N(C_1-6-alkyl)₂, —NH(aryl), —N(C_1-3-alkyl)(aryl), wherein the aryl radicals bonded to these amino groups can be mono- or poly-substituted by F, Cl, Br, CF₃, CN, OH or OMe. Examples of such heterocycles referred to as basic radicals are piperidine, pyrrolidine, azepane, azetidine, azocane, pyrazine, pyridine, imidazole, imidazolidine, 1,2,4-triazole, diazepane, pyrimidine, imidazoline, piperazine, morpholine, quinazoline or quinoxaline. Further basic radicals within the scope of the invention are N(C_1-6-alkyl)₂, NHC_1-6-alkyl, a N(C_1-6-alkyl)₂-substituted aryl radical, in particular phenyl or naphthyl, an aryl or heteroaryl radical, in particular phenyl, naphthyl or pyridinyl, substituted by a 5- to 7-membered heterocyclyl containing at least one N hetero atom, in particular pyrrolidinyl, piperidinyl, 4-methylpiperidinyl or morpholinyl. All the above-mentioned basic radicals can be linked to the structure of the general formula I via a bridging —OH—, —NH—, —NH[(CH₂)_p—] group, —N(C_1-3-alkyl)[—(CH₂)_p—] group, —O—[(CH₂)_p—] group, —O—[—(CH₂)P—O—] group, wherein in each case p=1, 2 or 3, or C_1-3-alkyl group. If the bridging chain contains a terminal O or N atom, then that atom can be bonded to the basic radical or to the structure to be bonded to the basic radical. The bridging —(CH₂)_p— groups or the C_1-3-alkyl chain can optionally be substituted by ═O, F, Cl, Br, I, —CN, phenyl or pyridinyl. Further examples of basic radicals within the scope of the present invention are C_1-6-alkylN(C_1-6-alkyl)₂ or C_1-6-alkylNH(C_1-6-alkyl). If the basic radical is fused to the heterocycle formed from R⁵ and R⁶, it can represent a 6-membered, saturated, unsaturated or aromatic heterocycle containing at least one N hetero atom, preferably pyridine or thiazole. A basic radical is also understood as being in particular a pyridyl, pyrrolyl, imidazolyl, pyrimidinyl or pyrazinyl radical, each of which can be linked via a C_1-3-alkyl chain. Further examples of basic radicals are groups having the structure shown below:

wherein

k represents 0, 1 or 2,

L represents H or C_1-6-alkyl,

K represents C_1-6-alkyl,

M represents C_1-6-alkyl or N(CH₃)₂, and

J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C_1-6-alkyl.

Further examples and/or preferred forms of basic radicals will become apparent from the following descriptions of the preferred substances according to the invention.

A non-basic radical is understood as being a group that does not possess basic properties. In particular, it is understood as being a group that does not carry a protonatable nitrogen. Examples of such non-basic radicals are —CN, C_1-6-alkyl, optionally substituted by methoxy or C_1-3-alkoxy; or aryl, heteroaryl, 3- to 7-membered heterocycles containing at least one oxygen or sulfur atom, in particular tetrahydropyran or thiophene, each unsubstituted or mono- or poly-substituted. Further examples are unsubstituted C_3-8-cycloalkyl or C_3-8-cycloalkyl monosubstituted on one or more ring members. The above-mentioned non-basic groups can be linked to the structure of the general formula I via a —O—, —O—[(CH₂)_q—] or —[(CH₂)_q—]—O group, —O—[—(CH₂)_q—O—] group or a bridging C_1-3-alkyl group, wherein the —(CH₂)_q— chain or the alkyl chain can each be substituted by ═O and q=1, 2 or 3. The substituents of the non-basic groups aryl, heteroaryl, 3- to 7-membered heterocycle and C_3-8-cycloalkyl are preferably selected from F, Cl, Br, I, CN, NO₂, aralkyl, SH, S—C_1-6-alkyl, OH, O—C_1-6-alkyl, O—C_1-6-alkyl-OH, C(═O)C_1-6-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C_1-6alkyl, OCF₃, CF₃,

C_1-6-alkyl.
Preference is given to radicals from the group aryl, heteroaryl, C_3-8-cycloalkyl, each unsubstituted or substituted as described above, which can be linked to the structure of the general formula I via a C_1-3-alkyl chain, wherein the alkyl chain can be substituted by ═O. Preference is further given to C_1-6-alkyl, optionally substituted by methoxy; C_1-3-alkoxy.

In a preferred embodiment of the invention, C_4-8-heterocyclyl in connection with R⁶ represents a saturated or unsaturated, 4- to 8-membered cyclic radical which can contain 1, 2, 3, 4 or 5 identical or different hetero atoms in the ring system, wherein the hetero atoms are preferably selected from the group N, O and S and wherein both the bond of the heterocyclyl radical to the general basic structure of formula I and the optional substitution with the basic or non-basic groups can be present at any desired ring member. The C_4-8-heterocyclyl radical is preferably selected from the group consisting of piperidinyl, 2,6-dimethylpiperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl and tetrahydrofuranyl.

In another preferred embodiment of the invention, a basic heteroaryl radical in connection with R⁶ represents a 5- to 10-membered, fused or non-fused hetero-atom-containing radical which contains at least one nitrogen atom as hetero atom and wherein both the bond of the heteroaryl radical to the general basic structure of formula I, or the bond of the heteroaryl radical to the bridging C_1-4-alkyl group, and the optional substitution can be present at any desired ring member of the heteroaryl radical. The basic heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzoimidazolyl and quinolinyl, quinoxalinyl, quinazolinyl.

In another preferred embodiment of the invention, a 5- to 10-membered, aromatic or unsaturated ring fused to an aryl group and optionally containing one or more hetero atoms represents, in connection with R⁶, a ring selected from the group:

wherein R⁷ represents H or C_1-6-alkyl.

In a further preferred embodiment of the invention, a 5- to 10-membered, saturated or unsaturated ring fused to a C_3-8-cycloalkyl ring and optionally containing one or more hetero atoms represents, in connection with R⁶, a ring selected from the group: phenyl, pyridinyl, cyclopentane, cyclohexane and cycloheptane.

In a further preferred variant of the present invention, an aromatic, unsaturated or saturated 4- to 10-membered ring fused to the 4- to 8-membered ring formed by R⁵ and R⁶ represents a ring selected from the group consisting of C_4-10-cycloalkane, C_4-10-cycloalkene and C_6-10-aromatic compounds and 6-membered heteroaromatic compounds.

Preference is given within the scope of this invention to substituted sulfonamide derivatives of the general formula I wherein R¹ represents phenyl or benzothiophenyl, especially phenyl, unsubstituted or mono- or poly-substituted by C_1-3-alkoxy, C_1-6-alkyl, Cl, F, I, CF₃, OCF₃, OH, SH, aryl or heteroaryl, each unsubstituted or mono- or poly-substituted.

In a preferred embodiment of the invention, R¹ in the substituted sulfonamide derivatives according to the invention represents phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl and dibenzothiophenyl, preferably phenyl, naphthyl, benzothiophenyl, benzoxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl and dibenzofuranyl, particularly preferably phenyl, naphthyl and benzothiophenyl, wherein all those radicals can be unsubstituted or mono- or poly-substituted, preferably by C_1-3-alkoxy, C_1-6-alkyl, Br, Cl, F, I, CF₃, OCF₃, OH, SH, aryl or heteroaryl, each unsubstituted or mono- or poly-substituted.

In a further preferred form of the substituted sulfonamide derivatives according to the invention, R¹ represents phenyl or naphthyl, especially phenyl, optionally mono- or poly-substituted by methyl, methoxy, CF₃, Cl, Br and/or F.

Particular preference is further given to substituted sulfonamide derivatives wherein R¹ represents phenyl substituted in the 4-position by aryl or heteroaryl and in the 2-, 3-, 5- and/or 6-position position by methyl, methoxy, Cl or F, preferably in the 2- and 6-position by methyl.

Most particular preference is given to substituted sulfonamide derivatives wherein R¹ represents 2,6-dimethyl-4-methoxyphenyl, 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dimethyl-4-bromophenyl, 2,6-dichloro-4-bromophenyl, 2,4,6-trichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl.

Preference is given also to substituted sulfonamide derivatives of the general formula I wherein n represents 2, R⁴ and R^2b represent H and R³ and R^2a together form a six-membered aromatic ring, or wherein n represents 1 and R^2a represents H and R⁴ and R³ together form a six-membered aromatic ring.

In a further preferred form of the substituted sulfonamide derivatives according to the invention, R^2a-c, R³ and R⁴ represent H or, with an adjacent radical R^2a-c, R³ or R⁴, form an aromatic ring, preferably a benzene group, which is optionally mono- or poly-substituted, preferably by methyl, methoxy, CF₃, Cl, Br and/or F. Particular preference is given to substituted sulfonamide derivatives wherein R^2a-c, R³ and R⁴ represent H.

In a further form according to the invention of the substituted sulfonamide derivatives, n in the group (CR^2a-c)_n represents 1 or 2, preferably 2.

In a further preferred form of the substituted sulfonamide derivatives, m in the general formula I is 1.

In further preferred embodiments of the present invention:

a) the group NR⁵R⁶ in the general formula I forms a cyclic group according to formula a1, a2, a3 or a4

wherein

• • k=0, 1, 2 or 3, preferably 1 or 2, and
  • w, x, y and z, independently of one another, represent CH or N, with the proviso that not more than two of the groups w, x, y and z simultaneously represent N and that, in the cyclic group according to formula a4, at least one group from w, x, y and z represents N. In formulas a1, a2 and a3, w, x, y and z are preferably all CH or one of w, x, y and z is N and all the others are CH.

In formulas a1, a2 and a3, B represents a basic radical, preferably selected from the group consisting of —NR⁸R⁹, wherein R⁸ and R⁹, independently of one another, can represent H or C_1-6-alkyl, and a radical having the general formula aa1

In the radical aa1, a, b and c, independently of one another, can be 0 or 1, with the proviso that when b is equal to 0, a and c are not simultaneously 1; and
the bridging C_1-3-alkyl can be monosubstituted by ═O.
R¹⁰ represents a 4- to 10-membered, aromatic, unsaturated or saturated, mono- or poly-cyclic heterocyclyl group which can contain 1, 2, 3 or 4 N hetero atoms and optionally O and/or S as further hetero atoms, wherein the heterocyclyl group is unsubstituted or monosubstituted on one or more ring members. R¹⁰ can further represent an aryl group substituted by at least one group —NR¹¹R¹² or a 5- or 6-membered, monocyclic N-containing aromatic, saturated or unsaturated heterocycle containing 1 or 2 N hetero atoms, wherein R¹¹ and R¹², independently of one another, represent H or C_1-6-alkyl, and the aryl group can optionally carry further substituents.
R¹⁰ can further represent a group of the general formula aa2:

wherein
d is 1, 2 or 3,
R¹³ can be H or C_1-3-alkyl, R¹⁴, for each chain member d independently, can be H or an optionally substituted aryl or N-heteroaryl group, preferably phenyl, naphthyl or pyridinyl, wherein R¹⁴ can be H only once within the alkyl chain defined by d, and R¹⁵ is a 5- to 7-membered, saturated or unsaturated heterocyclyl group which is optionally mono-substituted on one or more ring members, contains 1 or 2 N hetero atoms and can contain O or S as further hetero atoms, preferably morpholinyl, piperidinyl or 4-methylpiperazinyl.

In preferred embodiments of the invention, the cyclic group formed by the group NR⁵R⁶ is selected from the group consisting of

particular preference being given to piperidine substituted in the 4-position by the basic radical B,
and the basic radical B is selected from the group comprising: —N(C_1-6-alkyl), preferably —N(CH₃)₂; a radical having the general formula (aa1), wherein R¹⁰ is selected from the group comprising:

wherein those radicals can be unsubstituted or monosubstituted on one or more ring members, preferably by C_1-6-alkyl, especially methyl or ethyl, F, Cl or Br;
or R¹⁰ represents

which can be unsubstituted or mono- or poly-substituted, preferably by C_1-6-alkyl, especially methyl or ethyl, F, Cl, Br, C_1-6-alkoxy, especially methoxy, or phenyl; or
R¹⁰ represents phenyl substituted by —N(C_1-3-alkyl)₂, preferably dimethylamino or diethylamino, or
phenyl substituted by pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, wherein the linkage can take place at any of the ring members of the phenyl and of the substituent, or
R¹⁰ represents a group of the general formula (aa2), d=1 or 2, R¹³ represents H or methyl,
R¹⁴ represents phenyl or pyridinyl, and R¹⁵ represents morpholinyl or 4-methylpiperazinyl.

In further embodiments according to the invention, the cyclic group formed by the group NR⁵R⁶ is

and the basic radical B is a group having the general formula (aa1) wherein i) a=b=c=0,
ii) a=c=0 and b=1, iii) a=b=0 and c=1 or iv) a=b=1 and c=0; or the basic radical B is a group having the general formula (aa2) wherein d=1 or 2, preferably 2, and R¹⁴ is pyridinyl, preferably 3-pyridinyl, and R¹⁵ is morpholinyl.

In further preferred embodiments of the invention,

b) the group NR⁵R⁶ in the general formula I is a cyclic group according to one of the general formulae b1 and b2:

wherein

k=1 or 2, preferably 2,

l=1, 2 or 3, preferably 2,

Z can be NR¹⁷ or O, and R¹⁷ is H or C_1-6-alkyl, and

R¹⁶ represents H or a group of the general formula bb1:

wherein
a and c, independently of one another, are 0 or 1,
b=0, 1, 2 or 3, with the proviso that when b=0, a and c are not simultaneously 1, and wherein in the alkyl chain defined by b, a CH₂ chain member can be replaced by C(═O), R¹⁸ is selected from the group consisting of unsubstituted or mono- or poly-substituted aryl or heteroaryl, wherein the heteroaryl contains at least one N hetero atom, preferably 1, 2 or 3 N hetero atoms, and can contain O and S as further hetero atoms; saturated or unsaturated 5- to 7-membered heterocyclyl, wherein the heterocyclyl contains at least one hetero atom selected from the group N, O and S, preferably 1 or 2 N hetero atoms, and can optionally be monosubstituted or monosubstituted on a plurality of ring members; C_1-6-alkyl, optionally mono- or poly-substituted; C_3-8-cycloalkyl, optionally monosubstituted or monosubstituted on a plurality of ring members; and, apart from the cases where i) c=1 or
ii) b=c=0 and a=1, R¹⁸ can also be selected from the group consisting of —CN and NR¹⁹R²⁰, wherein R¹⁹ and R²⁰, independently of one another, can be H or C_1-6-alkyl but do not simultaneously represent H.

In preferred embodiments of the present invention, the cyclic group formed by the group NR⁵R⁶ is selected from the group consisting of:

wherein R¹⁶ represents a group of the general formula bb1 and in the formula bb1 (i) a=0, b=1, 2 or 3 and c=0 or (ii) a=0, b=1, 2 or 3 and c=0. In formula bb1, R¹⁸ is preferably selected from the group consisting of:

wherein those groups can be unsubstituted or mono- or poly-substituted, preferably by C_1-3-alkyl, especially methyl and/or ethyl; C_1-3-alkoxy, especially methoxy; F, Cl, Br, I; —CN; CF₃; N(C_1-3-alkyl)₂, NH(C_1-3-alkyl), N(C_1-3-alkyl)(aryl), especially N(C_1-3-alkyl)(phenyl or phenethyl), wherein phenyl or phenethyl can be mono- or poly-substituted; benzyl or

and wherein all those substituents can likewise be mono- or poly-substituted, preferably by F, Cl, Br, —CN, —CF₃, C_1-3-alkyl; pyrrolidinyl, piperidinyl, 4-methylpiperidinyl or morpholinyl.

R¹⁸ can further represent a heterocyclyl selected from the group consisting of:

wherein those heterocyclyl groups can be monosubstituted on one or more ring members.

Alternatively, R¹⁸ can represent cyclopentyl, cyclohexyl, optionally monosubstituted on one or more ring members, or C_1-3-alkyl, optionally mono- or poly-substituted.

In further preferred embodiments of the invention, the cyclic group formed by the group NR⁵R⁶ is

and R¹⁶ represents a group according to formula bb1 shown above, wherein a=c=0 and b=0, 1 or 2, and R¹⁸ is selected from

wherein the phenyl group can be substituted, preferably monosubstituted by F, Cl or Br, especially F, preferably in the 4-position.

In further preferred forms of the compounds according to the invention:

c) in the group NR⁵R⁶ from the general formula I, R⁵ is selected from the group consisting of H and C_1-6-alkyl, optionally mono- or poly-substituted, and R⁶ is selected from groups of the general formulae c1 and c2 shown below:

wherein in formula c1:
a=0, 1 or 2;
b=0, 1, 2 or 3;
R²¹ is an unsubstituted or substituted aryl group, preferably phenyl or naphthyl, both substituted or unsubstituted,
R²² and R²³, independently of one another, represent —H or C_1-6-alkyl, or
the group —NR²²R²³ together represents a 5-, 6- or 7-membered, saturated or unsaturated heterocycle which contains at least one N hetero atom and can optionally be monosubstituted or monosubstituted on a plurality of ring members;

wherein in formula c2:
a=0, 1, 2 or 3;
b=0 or 1, with the proviso that when b=0 also c=0;
c=0, 1, 2 or 3,
Y represents aryl or heteroaryl, preferably N-hetero-atom-containing 5- or 6-membered heteroaryl, optionally substituted; C_3-8-cycloalkyl, preferably C_5-6-cycloalkyl; and
Z represents a saturated, unsaturated or aromatic, optionally substituted heterocyclyl group which contains at least one N hetero atom and can contain O and/or S as further hetero atoms; or Z represents a group NR²⁴R²⁵, wherein R²⁴ and R²⁵, independently of one another, represent H, C_1-6-alkyl or —C(═O)—(CH₂)_d—NR²⁶R²⁷, wherein d=1 or 2 and R²⁶ and R²⁷, independently of one another, represent H or C_1-6-alkyl, or NR²⁶R²⁷ forms a 5-, 6- or 7-membered, preferably saturated heterocycle.

In further preferred forms of the substances according to the invention, R⁵ in the group NR⁵R⁶ from the general formula I is selected from the group consisting of H and methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted. R⁵ is a group according to the general formula c1 shown above, wherein:

• • R²¹ is a phenyl or naphthyl group which can be mono- or poly-substituted and is preferably unsubstituted or substituted by F, Cl, Br, I, CN, C_1-3-alkyl, preferably methyl or ethyl;
  • R²² and R²³, independently of one another, represent methyl, ethyl or propyl or isopropyl, or the group NR²²R²³ together represents a N-heterocycle selected from the group consisting of:

wherein those N-heterocycles can be unsubstituted or monosubstituted on one or more ring members, or
R⁶ represents a group of the general formula c2 shown above, wherein
Y represents phenyl, naphthyl, benzooxadiazole, cyclopentyl, cyclohexyl or cycloheptyl, all optionally monosubstituted on one or more ring members, and
Z is selected from the group consisting of:

wherein those radicals can be monosubstituted on one or more ring members, and R³⁰, R³¹ and R⁴⁰ can represent H, methyl, ethyl, propyl or isopropyl, optionally mono- or poly-substituted, or Z is selected from the group consisting of:

wherein R³², R³³ and R³⁴ are selected from H, methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted, and the N-heterocycles can optionally be monosubstituted on one or more ring members; or
Z is a group NR²⁴R²⁵ wherein R²⁴ and R²⁵, independently of one another, represent methyl, ethyl, propyl or isopropyl, or Z represents a group —C(═O)—(CH₂)_d—NR²⁶R²⁷ wherein d is 1 or 2 and NR²⁶R²⁷ together forms a heterocycle selected from

wherein the ring members of those radicals can be monosubstituted on one or more ring members, and R³⁵ and R³⁶ can represent methyl, ethyl, propyl or isopropyl, optionally mono- or poly-substituted.

In further preferred embodiments of the invention, in the group NR⁵R⁶ from the general formula I, R⁵ is selected from the group consisting of H, methyl, ethyl, propyl and isopropyl, preferably methyl, and R⁶ represents a group according to the general formula c2 wherein a=1 or 2, b=1 and c=0, Y represents phenyl or cyclohexyl and Z represents pyrrolidinyl or dihydroimidazolyl.

In further preferred forms of the compounds according to the invention:

d) R⁵ in the group NR⁵R⁶ from the general formula I is selected from the group consisting of H, C_1-6-alkyl, optionally mono- or poly-substituted, C_3-8-cycloalkyl, optionally monosubstituted on one or more ring members. R⁶ is selected from groups of the general formula d1

wherein in formula d1:

• • a=0, 1, 2, 3 or 4;
  • b=0 or 1, with the proviso that when b=0 also c=0;
  • c=0, 1, 2 or 3;
  • J represents a 4- to 7-membered heterocycle which contains at least one N-hetero atom and is preferably saturated or unsaturated and which can optionally be monosubstituted on one or more ring members, and
  • K represents H or an optionally substituted aryl or heteroaryl group.

In further preferred forms of the compounds according to the invention, in the group NR⁵R⁶ from the general formula I, R⁵ is selected from the group consisting of H and methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted, and R⁶ represents a group according to formula d1 shown above wherein J is selected from the group:

and K is selected from the group consisting of H, phenyl, naphthyl, pyridinyl, all optionally mono- or poly-substituted.

In further preferred forms of the compounds according to the invention:

e) in the group NR⁵R⁶ from the general formula I, R⁵ and R⁶ are selected, independently of one another, from the group consisting of H; C_1-6-alkyl; aralkyl; and —(CH₂)_r—NR²⁸R²⁹ wherein r=from 1 to 6 and wherein R²⁸ and R²⁹ are selected, independently of one another, from the group consisting of H and C_1-3-alkyl.

In further preferred embodiments according to the invention, in the group NR⁵R⁶ from the general formula I:

• • R⁵ is selected from the group consisting of H, C_1-3-alkyl, —(CH₂), —NR²⁸R²⁹ wherein r=from 1 to 3 and wherein R²⁸ and R²⁹ can be C_1-3-alkyl, and
  • R⁶ is —(CH₂)_r—NR²⁸R²⁹ wherein r=from 1 to 3 and wherein R²⁸ and R²⁹ can be C_1-3-alkyl, or
  • R⁶ represents a C_1-3-alkyl group substituted by a N(C_1-3-alkyl)(aryl) group, wherein the aryl group can be substituted and aryl preferably represents phenyl or naphthyl.

In further preferred forms of the compounds according to the invention:

f) in the group NR⁵R⁶ from the general formula I, R⁵ is selected from the group consisting of H, C_1-6-alkyl, aryl and aralkyl, and R⁶ is a group of the type —(C_1-4-alkyl)_s-X wherein s=0 or 1 and wherein the group X is a heteroaryl group which contains at least one N hetero atom and is optionally mono- or poly-substituted, and wherein in the C_1-4-alkyl group a hydrogen atom can be replaced by a 5- or 6-membered, saturated heterocyclyl group which contains at least one N hetero atom and can contain, in addition to N, also O and/or S as hetero atom.

In further preferred embodiments according to the invention, in the group NR⁵R⁶ from the general formula I:

• • R⁵ represents H, methyl, ethyl, propyl, isopropyl, phenyl or benzyl; and
  • R⁶ represents a group of the (C_1-3-alkyl)_r-X type, wherein s=0 or 1 and wherein the C_1-3-alkyl group can be substituted by a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group and the radical X is selected from the group consisting of:

wherein R⁴¹, R⁴² and R⁴³ are selected from H, methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted, and the N-heteroaryls can optionally be mono- or poly-substituted.

In further preferred embodiments according to the invention, in general formula I:

• • n represents 0, 1, 2 or 3;
  • m represents 1 or 2;
  • R¹ represents aryl or heteroaryl, unsubstituted or mono- or poly-substituted;
  • R^2a-c, R³ and R⁴ represent H or, with an adjacent radical R^2a-c, R³ or R⁴, form a five- or six-membered ring which can be saturated or unsaturated and mono- or poly-substituted and which can contain hetero atoms from the group N and O,
  • R⁵ and R⁶ together form a 4- to 8-membered ring which can be saturated or unsaturated but not aromatic, is substituted by or fused to a basic radical and can be substituted by a further basic radical or radicals from the group C_1-8-alkyl, C_1-3-alkoxy, C_3-8-cycloalkyl and optionally substituted phenyl; or
  • R⁵ and R⁶ together form a 4- to 8-membered ring which contains a further hetero atom from the group N and O and can be substituted by a basic or non-basic radical, or
  • R⁵ represents H or C_1-5-alkyl and R⁶ represents aryl or C_3-8-cycloalkyl; or an aryl radical linked via a C_1-3-alkyl chain, wherein the aryl or C_3-8-cycloalkyl ring is substituted by a basic radical or, where appropriate, the basic substitution takes place on the bridging C_1-3-alkyl chain, or
  • R⁵ represents H or C_1-5-alkyl and R⁶ represents C_4-8-heterocyclyl; or a C_4-8-heterocyclyl radical linked via a C_1-3-alkyl chain, wherein the heterocyclyl ring is substituted by a basic radical or a non-basic radical, or
  • R⁵ and R⁶, independently of one another, represent H or a branched or unbranched C_1-10-alkyl radical which contains from one to three nitrogen atoms, wherein R⁵ and R⁶ do not both represent H,
    in the form of the racemate; in the form of the enantiomers, diastereoisomers, mixtures of the enantiomers or diastereoisomers or in the form of an individual enantiomer or diastereoisomer; in the form of bases and/or salts of physiologically acceptable acids, wherein preferably
    a substituted aryl or heteroaryl radical is substituted by F, Cl, Br, I, CN, NH₂, NH—C_1-6-alkyl, NH—C_1-6-alkyl-OH, N(C_1-6-alkyl)₂, N(C_1-6-alkyl-OH)₂, NO₂, SH, S—C_1-6-alkyl, OH, O—C_1-6-alkyl, O—C_1-6-alkyl-OH, C(═O)C_1-6-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C_1-6-alkyl, OCF₃, CF₃,

C_1-6-alkyl, phenoxy, phenyl, pyridyl, thienyl or furyl, a substituted cycloalkyl radical or alkyl radical is substituted by F, Cl, Br, I, —CN, NH₂, NH—C_1-6-alkyl, NH—C_1-6-alkyl-OH, C_1-6-alkyl, N(C_1-6-alkyl)₂, N(C_1-6-alkyl-OH)₂, NO₂, SH, S—C_1-6-alkyl, S-benzyl, O—C_1-6-alkyl, OH, O—C_1-6-alkyl-OH, ═O, O-benzyl, C(═O)C_1-6-alkyl, CO₂H, CO₂—C_1-6-alkyl or benzyl,
a basic radical preferably denotes piperidine, pyrrolidine, azepane, azetidine, azocane, pyridine, imidazole, imidazolidine, 1,2,4-triazole, diazepane, pyrimidine, imidazoline, piperazine, N(C_1-6-alkyl)₂, NHC_1-6-alkyl, an aryl radical substituted by N(C_1-6-alkyl)₂; wherein these radicals can all be linked to the structure of the general formula I via a C_1-3-alkyl group, the C_1-3-alkyl chain is optionally substituted by ═O and the remaining radicals can themselves be substituted by C_1-6-alkyl; C_1-6-alkylN(C_1-6-alkyl)₂ or C_1-6-alkylNH(C_1-6-alkyl), and
a non-basic radical preferably denotes aryl, heteroaryl, each unsubstituted or mono- or poly-substituted by F, Cl, Br, I, CN, NO₂, SH, S—C_1-6-alkyl, OH, O—C_1-6-alkyl, O—C_1-6-alkyl-OH, C(═O)C_1-6-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C_1-6-alkyl, OCF₃, CF₃,

C_1-6-alkyl;
which can be linked to the structure of the general formula I via a C_1-3-alkyl chain, wherein the alkyl chain can be substituted by ═O; C_1-6-alkyl optionally substituted by methoxy or C_1-3-alkoxy; or C_3-8-cycloalkyl.

Within the scope of this invention, preference is further given to substituted sulfonamide derivatives of the general formula I wherein R⁵ and R⁶ together form a 4- to 8-membered ring which can be saturated or unsaturated but not aromatic and is substituted by a basic radical selected from the group consisting of

wherein

k represents 0, 1 or 2,

L represents H or C_1-6-alkyl,

K represents C_1-6-alkyl,

M represents C_1-6-alkyl or N(CH₃)₂,

J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C_1-6-alkyl.

Particular preference is given to substituted sulfonamide derivatives wherein the group

represents piperidine, pyrrolidine or azepane, substituted by optionally C_1-3-alkyl-linked piperidine, pyrrolidine, azepane, piperazine or diazepane, unsubstituted or monosubstituted by methyl or ethyl, with the proviso that the linkage takes place between two carbon atoms or between a carbon atom and a nitrogen atom but not between two nitrogen atoms;
in particular a radical selected from the group consisting of:

Preference is given also to substituted sulfonamide derivatives of the general formula I wherein R⁵ and R⁶ together form a 4- to 8-membered ring which contains a further hetero atom from the group N and O and can be substituted by a basic radical from the group

wherein

k represents 0, 1 or 2,

L represents H or C_1-6-alkyl,

K represents C_1-6-alkyl,

M represents C_1-6-alkyl or N(CH₃)₂,

J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C_1-6-alkyl,

or by a non-basic radical from the group aryl, heteroaryl, each unsubstituted or mono- or poly-substituted by F, Cl, Br, I, CF₃, OCH₃, C_1-6-alkyl, C_3-8-cycloalkyl, unsubstituted or monosubstituted by F, Cl, Br, I, CF₃, OCH₃, C_1-6-alkyl; which can be linked to the structure of the general formula I via a C_1-3-alkyl chain, wherein the alkyl chain can be substituted by ═O; C_1-6-alkyl or C_1-3-alkoxy.

Particular preference is given to substituted sulfonamide derivatives wherein the group

represents piperazine or diazepane, substituted by optionally C_1-3-alkyl-linked phenyl, unsubstituted or mono- or poly-substituted by

methyl, methoxy, F, Cl, Br, CF₃ or CN; (CH₂)₂OCH₃; substituted by cyclohexyl or cyclopentyl optionally bonded via C_1-3-alkyl; pyrrolidine, piperazine, piperidine, unsubstituted or monosubstituted by methyl or ethyl, each linked via a C_1-3-alkyl group; or pyrrolidine, piperazine, piperidine, unsubstituted or monosubstituted by methyl or ethyl, with the proviso that the linkage takes place between two carbon atoms or between a carbon atom and a nitrogen atom but not between two nitrogen atoms; or by (CH₂)_aN(CH₃)₂ wherein a=2, 3;
in particular a radical selected from the group consisting of

Preference is additionally given to substituted sulfonamide derivatives of the general formula I wherein R⁵ represents H and R⁶ represents aryl or C_3-8-cycloalkyl; or an aryl radical linked via a C_1-3-alkyl chain, wherein the aryl or C_3-8-cycloalkyl ring is substituted by at least one basic radical from the group

wherein

k represents 0, 1 or 2,

L represents H or C_1-6-alkyl,

K represents C_1-6-alkyl,

M represents C_1-6-alkyl or N(CH₃)₂,

J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C_1-6-alkyl.

Particular preference is given to substituted sulfonamide derivatives of the general formula I wherein R⁵ represents H or CH₃ and R⁶ represents benzyl or phenethyl substituted by pyrrolidine, piperazine, morpholine or piperidine, wherein these radicals are themselves unsubstituted or monosubstituted by methyl or ethyl and are optionally linked via a C_1-3-alkyl chain, wherein the benzyl or phenethyl radical is optionally substituted by a further basic radical,

in particular R⁶ represents

Preference is given also to substituted sulfonamide derivatives wherein R⁵ represents H or C_1-5-alkyl and R⁶ represents C_4-8-heterocyclyl, wherein the heterocyclyl radical is linked to the structure of the general formula I via a carbon atom; or R⁶ represents a C_4-8-heterocyclyl radical linked via a C_1-3-alkyl chain, wherein the heterocyclyl ring is substituted by a basic radical from the group

wherein

k represents 0, 1 or 2,

L represents H or C_1-6-alkyl,

K represents C_1-6-alkyl,

M represents C_1-6-alkyl or N(CH₃)₂, and

J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C_1-6-alkyl,

or by a non-basic radical from the group aryl, heteroaryl, each unsubstituted or mono- or poly-substituted by F, Cl, Br, I, CF₃, OCH₃, C_1-6-alkyl, C_3-8-cycloalkyl, unsubstituted or mono- or poly-substituted by F, Cl, Br, I, CF₃, OCH₃, C_1-6-alkyl; which can be linked to the structure of the general formula I via a C_1-3-alkyl chain, wherein the alkyl chain can be substituted by ═O; C_1-6-alkyl or C_1-3-alkoxy.

Particular preference is given to substituted sulfonamide derivatives wherein R⁵ represents H, methyl or ethyl and R⁶ represents piperidine, pyrrolidine, azepane; piperidine, pyrrolidine, azepane, diazepane or piperazine linked via a C_1-3-alkyl chain; each substituted by phenyl, pyrrolidine, piperazine, morpholine or piperidine linked via a C_1-3-alkyl chain and unsubstituted or monosubstituted by methyl or ethyl.

Very particular preference is given to substituted sulfonamide derivatives wherein the group

represents

Very particular preference is given to substituted sulfonamide compounds selected from the group consisting of

• • 1 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-N-(4-piperidin-1-ylmethyl-benzyl)-acetamide
  • 2 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-(4-piperidin-1-ylmethyl-benzyl)-acetamide
  • 3 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-[4-(4-methyl-piperazin-1-yl)-benzyl]-acetamide
  • 4 N-(4-piperidin-1-ylmethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 5 1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-ethanone
  • 6 1-(4-benzyl-[1,4]diazepan-1-yl)-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 7 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-[4-(4-methyl-piperazin-1-ylmethyl)-benzyl]-acetamide
  • 8 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone
  • 9 1-(1,4′-bipiperidin-1′-yl)-2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-yl)methoxy)ethanone
  • 10 N-(4-piperidin-1-ylmethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 11 N-(4-dimethylaminomethyl-benzyl)-2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 12 N-(1-benzyl-piperidin-3-ylmethyl)-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 13 N-[4-(4-methyl-piperazin-1-yl)-benzyl]-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 14 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-(4-piperidin-1-yl-benzyl)-acetamide
  • 15 N-[4-(4-methyl-piperazin-1-ylmethyl)-benzyl]-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 16 N-(1-benzyl-piperidin-3-ylmethyl)-2-[1-(3,4-dichloro-phenylsulfonyl)-2,3-dihydro-1H-indol-2-ylmethoxy]-acetamide
  • 17 2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-pyrrolidin-1-yl)piperidin-1-yl)ethanone
  • 18 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-N-[4-(4-methyl-piperazin-1-yl)-benzyl]-acetamide
  • 19 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)-ethanone
  • 20 2-((1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperidin-1-yl)ethanone
  • 21 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-(4-morpholin-4-yl-benzyl)-acetamide
  • 22 1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-[1-(3-trifluoromethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 23 2-((1-(naphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethanone
  • 24 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-N-(4-morpholin-4-ylmethyl-benzyl)-acetamide
  • 25 1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-ethanone
  • 26 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethanone
  • 27 1-(2-piperidin-1-ylmethyl-pyrrolidin-1-yl)-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 28 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-ethanone
  • 29 N-[4-(4-methyl-piperazin-1-yl)-benzyl]-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 30 N-(4-morpholin-4-ylmethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 31 1-(4-benzyl-[1,4]diazepan-1-yl)-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 32 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone
  • 33 N-[3-(4-methyl-piperazin-1-yl)-benzyl]-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-acetamide
  • 34 N-(1-benzyl-piperidin-3-ylmethyl)-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 35 N-(4-dimethylaminomethyl-benzyl)-2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 36 2-((1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperidin-1-yl)ethanone
  • 37 N-(4-dimethylaminomethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 38 2-((2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethanone
  • 39 1-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 40 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-N-[4-(4-methyl-piperazin-1-ylmethyl)-benzyl]-acetamide
  • 41 N-(1-benzyl-piperidin-3-ylmethyl)-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-acetamide
  • 42 2-((1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperazin-1-yl)ethanone
  • 43 2-[2-(3,4-dichloro-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-N,N-bis-(2-diethylamino-ethyl)-acetamide
  • 44 1-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-[1-(3,4-dichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-ethanone
  • 45 N-[4-(4-methyl-piperazin-1-ylmethyl)-benzyl]-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 46 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(2-methoxy-ethyl)-piperazin-1-yl]-ethanone
  • 47 N-methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 48 N,N-bis-(2-diethylamino-ethyl)-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetra-hydro-isoquinolin-3-ylmethoxy]-acetamide
  • 49 N-(4-morpholin-4-ylmethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 50 N-(3-morpholin-4-yl-benzyl)-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-acetamide
  • 51 2-[2-(2,4-dichloro-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-1-(2-piperidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone
  • 52 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperidin-1-yl)ethanone
  • 53 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(3-methoxy-phenyl)-piperazin-1-yl]-ethanone
  • 54 1-(4-cyclohexylmethyl-piperazin-1-yl)-2-[1-(3,4-dichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-ethanone
  • 55 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-N-(4-morpholin-4-ylmethyl-benzyl)-acetamide
  • 56 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-(4-phenyl-piperazin-1-yl)-ethanone
  • 57 1-(4-benzyl-piperidin-1-yl)-2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 58 1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-[1-(3-trifluoromethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 59 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone
  • 60 2-[1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-N-(4-piperidin-1-yl-benzyl)-acetamide
  • 61 N-(4-morpholin-4-ylmethyl-benzyl)-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 62 2-[1-(3,4-dichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone
  • 63 1-[2-(4-dimethylamino-phenyl)-azepan-1-yl]-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 64 2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylmethoxy]-1-(2-piperidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone
  • 65 2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-morpholinopiperidin-1-yl)ethanone
  • 66 1-(3-dimethylamino-pyrrolidin-1-yl)-2-[1-(naphthyl-1-sulfonyl)-piperidin-2-ylethoxy]-ethanone
  • 67 1-(4-benzyl-[1,4]diazepan-1-yl)-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-ethanone
  • 68 1-(4-cyclohexylmethyl-piperazin-1-yl)-2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 69 2-((2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 70 N-(1-benzyl-piperidin-3-ylmethyl)-2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-yl-methoxy]-acetamide
  • 71 N-(4-piperidin-1-yl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-yl-methoxy]-acetamide
  • 72 2-((1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperazin-1-yl)ethanone
  • 73 N-(4-dimethylaminomethyl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-acetamide
  • 74 N-(4-piperidin-1-yl-benzyl)-2-[1-(2,4,6-trichloro-phenylsulfonyl)-piperidin-2-yl-methoxy]-acetamide
  • 75 N-[2-(4-methyl-piperazin-1-yl)-benzyl]-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-acetamide
  • 76 N-(3-piperidin-1-ylmethyl-phenyl)-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 77 1-[4-(3-methoxy-phenyl)-piperazin-1-yl]-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-ethanone
  • 78 N-(1-benzyl-pyrrolidin-3-yl)-2-[2-(2,4-dichloro-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-N-methyl-acetamide
  • 79 1-(4-benzyl-[1,4]diazepan-1-yl)-2-[2-(2,4-dichloro-phenylsulfonyl)-1,2,3,4-tetra-hydro-isoquinolin-3-ylmethoxy]-ethanone
  • 80 N-[2-(4-methyl-piperazin-1-yl)-benzyl]-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 81 2-[1-(3,4-dichloro-phenylsulfonyl)-2,3-dihydro-1H-indol-2-ylmethoxy]-N-(4-pyrrolidin-1-ylmethyl-benzyl)-acetamide
  • 82 2-[2-(3,4-dichloro-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-1-(2-piperidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone
  • 83 N-(4-pyrrolidin-1-ylmethyl-benzyl)-2-[2-(2,4,6-trimethyl-phenylsulfonyl)-1,2,3,4-tetrahydro-isoquinolin-3-ylmethoxy]-acetamide
  • 84 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(4-methoxy-phenyl)-piperazin-1-yl]-ethanone
  • 85 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-ethanone
  • 86 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-[4-(2-fluoro-phenyl)-piperazin-1-yl]-ethanone
  • 87 N-[4-(2-methyl-imidazol-1-yl)-phenyl]-2-[1-(2,4,6-trimethyl-phenylsulfonyl)-piperidin-2-ylmethoxy]-acetamide
  • 88 2-[1-(3,4-dichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-ethanone
  • 89 2-[1-(3,4-dichloro-phenylsulfonyl)-pyrrolidin-2-ylmethoxy]-1-(4-phenyl-piperazin-1-yl)-ethanone
  • 90 2-(2-(1-(4-methoxyphenylsulfonyl)piperidin-2-yl)ethoxy)-1-(4-(2-(piperidin-1-yl)-ethyl)piperidin-1-yl)ethanone
  • 91 2-(2-(1-(4-methoxyphenylsulfonyl)piperidin-2-yl)ethoxy)-1-(4-phenethylpiperazin-1-yl)ethanone
  • 92 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)-piperazin-1-yl)methyl)benzonitrile hydrochloride
  • 93 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetyl)-piperazin-1-yl)methyl)benzonitrile hydrochloride
  • 94 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone hydrochloride
  • 95 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 96 1-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethylphenyl-sulfonyl)piperidin-2-yl)methoxy)ethanone hydrochloride
  • 97 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 98 1-(4-(dihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 99 1-(4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone dihydrochloride
  • 100 1-(4-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 101 tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-carboxylate
  • 102 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride
  • 103 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone
  • 104 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethanone
  • 105 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylcyclohexyl)piperazin-1-yl)ethanone
  • 106 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone dihydrochloride
  • 107 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 108 2-((1-(2,6-dichloro-4-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 109 2-((1-(2-chloro-6-methylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 110 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(naphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 111 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(naphthalen-2-ylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 112 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone hydrochloride
  • 113 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)ethanone
  • 114 2-((1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 115 2-((1-(4-chloro-3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 116 1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperidin-4-one
  • 117 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 118 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 119 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(2,4,6-triisopropylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 120 2-((1-(2,4-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 121 2-((1-(3-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 122 2-((1-(3-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 123 2-((1-(4-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 124 2-((1-(3-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 125 2-((1-(4-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 126 2-((1-(4-bromophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 127 (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 128 2-((1-(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 129 2-((1-(6-chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 130 1-(4-fluoro-1,4′-bipiperidin-1′-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 131 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(3-(o-tolyloxy)phenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 133 (S)-2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 134 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-(trifluoromethyl)cyclohexyl)piperazin-1-yl)ethanone
  • 135 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)azetidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 136 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-morpholin-2-(pyridin-3-yl)ethylamino)piperidin-1-yl)ethanone
  • 137 2-((1-(benzo[b]thiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 138 2-((1-(2-chloro-4-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 139 2-((1-(2-chlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 140 (R)-2-((1-(4-methoxy-2,3,6-trimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 141 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 142 (S)-2-((2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 143 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)acetamide
  • 144 1-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 145 1-(4-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 146 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-carbonyl)piperidin-1-yl)ethanone
  • 147 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 148 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 149 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 150 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 151 2-((1-(5-chloro-3-methylbenzo[b]thiophen-2-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 152 (R)-2-((1-(2-chloro-6-methylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 153 2-((1-(2,5-bis(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 154 2-((1-(7-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 155 2-((1-(4-methylnaphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 156 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(2,4,5-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone dihydrochloride
  • 157 2-((1-(2-methylnaphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 158 2-((1-(5-(dimethylamino)naphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 159 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(o-tolylsulfonyl)piperidin-2-yl)methoxy)ethanone dihydrochloride
  • 160 2-((1-(4-bromo-2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 161 (S)-2-((1-(2-chloro-6-methylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone hydrochloride
  • 162 (S)-2-((1-(2-chloro-6-methylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 163 (S)-2-((1-(2-chloro-6-methylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone dihydrochloride
  • 164 2-(2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)ethoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 165 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-3-yloxy)piperidin-1-yl)ethanone
  • 166 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(quinoxalin-6-ylmethyl)piperazin-1-yl)ethanone
  • 167 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 168 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-(pyrrolidin-1-yl)quinazolin-7-yl)piperazin-1-yl)ethanone
  • 169 2-((1-(4-fluoro-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 170 2-((1-(2,5-dichlorothiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 171 2-((1-(benzo[b]thiophen-2-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 172 2-((1-(2,5-dimethylthiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 173 2-((1-(2,3-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 174 2-((1-(4-methoxynaphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 175 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(quinolin-8-ylsulfonyl)piperidin-2-yl)methoxy)ethanone dihydrochloride
  • 176 2-((1-(isoquinolin-5-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 177 (R)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 178 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((2-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)ethanone dihydrochloride
  • 179 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)piperidin-2-yl)methoxy)ethanone dihydrochloride
  • 180 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 181 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 182 (S)-2-((2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 183 (S)-2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 184 (S)-2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 185 (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 186 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1-yl)ethanone hydrochloride
  • 187 (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 188 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-((pyridin-4-yloxy)methyl)piperidin-1-yl)ethanone
  • 189 (S)-2-((2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone dihydrochloride
  • 190 (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone hydrochloride
  • 191 2-((1-(2-chloronaphthalen-1-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone dihydrochloride
  • 192 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 193 N-(4-(4,5-dihydro-1H-imidazol-2-yl)benzyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide hydrochloride
  • 194 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methyl-N-(2-(4-(pyrrolidin-1-yl)cyclohexyl)ethyl)acetamide
  • 195 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(pyrazin-2-yloxy)benzyl)acetamide
  • 196 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(pyrazin-2-yloxy)benzyl)acetamide
  • 197 1-(4-((5-chloro-2-phenyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 198 1-(4-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 199 1-(4-((2-(dimethylamino)pyrimidin-5-yl)methyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 200 1-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 201 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperidin-1-yl)ethanone
  • 202 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 203 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)ethanone
  • 204 2-((1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 205 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(pyrazin-2-yloxy)benzyl)acetamide
  • 206 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(1H-pyrrol[3,4-c]pyridin-2(3H)-yl)ethanone
  • 207 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(pyridin-3-yl)morpholin)ethanone
  • 208 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(3-(pyridin-3-ylmethyl)pyrrolidin-1-yl)ethanone
  • 209 N-(2-(4-(dimethylamino)cyclohexyl)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide
  • 210 2-((1-(6-methoxynaphthalen-2-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 211 1-(4-(3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 212 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(1-methylpiperidin-4-yl)ethyl)piperazin-1-yl)ethanone
  • 213 2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)-N-(2-(4-(dimethylamino)cyclohexyl)ethyl)-N-methylacetamide
  • 214 1-(4-((2-((4-fluorophenyl)(methyl)amino)pyrimidin-5-yl)methyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 215 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(6-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone
  • 216 2-((1-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)-N-methyl-N-(2-(4-(pyrrolidin-1-yl)cyclohexyl)ethyl)acetamide
  • 217 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-3-yl)piperidin-1-yl)ethanone
  • 218 N—((S)-1-benzylpyrrolidin-3-yl)-N-methyl-2-((1-(2-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 219 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-methylbenzyl)piperazin-1-yl)ethanone
  • 220 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-phenethylthiazol-2-yl)piperazin-1-yl)ethanone
  • 221 2-(2-(1-(4-methoxyphenylsulfonyl)piperidin-2-yl)ethoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)ethanone
  • 222 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethanone
  • 223 1-(2-((4,6-dimethylpyridin-2-yl)methyl)piperidin-1-yl)-2-((2-(mesitylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)ethanone
  • 224 1-(2-(5-bromopyridin-3-yl)piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 225 1-(1,4′-bipiperidin-1-yl)-2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 226 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(pyridin-2-ylmethyl)pyrrolidin-1-yl)ethanone
  • 227 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(6-methoxypyridin-3-yl)piperidin-1-yl)ethanone
  • 228 1-(2-((5-ethylpyridin-2-yl)methyl)piperidin-1-yl)-2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 229 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(2-((3-methylpyridin-2-yl)methyl)piperidin-1-yl)ethanone
  • 230 1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-((1-(naphthen-1-ylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 231 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 232 2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 233 2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 234 1-(4-(4-benzylthiazol-2-yl)piperazin-1-yl)-2-((1-(mesitylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 235 1-(1,4′-bipiperidin-1′-yl)-2-((1-(naphthen-1-ylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 236 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(3-(pyridin-2-yl)pyrrolidin-1-yl)ethanone
  • 237 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(3-(pyridin-3-yl)pyrrolidin-1-yl)ethanone
  • 238 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(3-(pyridin-4-yl)pyrrolidin-1-yl)ethanone
  • 239 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methyl-N-(2-(pyridin-4-yl)ethyl)acetamide
  • 240 1-(2-((4,6-dimethylpyridin-2-yl)methyl)pyrrolidin-1-yl)-2-((1-(naphthen-1-ylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 241 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methyl-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)acetamide
  • 242 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-methylpiperazin-1-yl)ethanone
  • 243 N-(2-(1H-indol-3-yl)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 244 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-methylquinolin-4-yl)acetamide
  • 245 1-(4-(2-ethoxyethyl)piperazin-1-yl)-2-((2-(mesitylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)ethanone
  • 246 2-((2-(mesitylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-methoxyethyl)piperazin-1-yl)ethanone
  • 247 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(pyridin-2-yl)pyrrolidin-1-yl)ethanone
  • 248 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(4-methylpiperazin-1-yl)ethyl)acetamide
  • 249 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-morpholin-2-(4-(trifluoromethyl)phenyl)ethyl)acetamide
  • 250 N-(5-(dimethylamino)pentyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 251 N-(2-(2-chlorophenyl)-2-morpholinoethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 252 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)ethyl)acetamide
  • 253 1-(4-(3,5-dimethoxyphenyl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 254 1-(4-(2-(diisopropylamino)ethyl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 255 N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 256 N-(2-morpholino-2-(pyridin-3-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 257 N-(1-ethyl-1H-pyrazol-5-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 258 N-(isoquinolin-5-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 259 N-(2-(dimethylamino)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 260 N-(3-(2,6-dimethylpiperidin-1-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 261 N-(2-(dimethylamino)-1-phenylethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 262 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)acetamide
  • 263 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(4-methylpiperazin-1-yl)-1-phenylethyl)acetamide
  • 264 N-(3-morpholinophenyl)-2-((2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)acetamide
  • 265 2-((2-(2,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-N-(3-morpholinophenyl)acetamide
  • 266 2-((1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(piperidin-1-ylmethyl)morpholino)ethanone
  • 267 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 268 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 269 1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 270 1-(4-(2-(diisopropylamino)ethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 271 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(2-(pyridin-2-yl)pyrrolidin-1-yl)ethanone
  • 272 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(3-(pyridin-3-yl)pyrrolidin-1-yl)ethanone
  • 273 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(3-(pyridin-4-yl)pyrrolidin-1-yl)ethanone
  • 274 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 275 2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 276 2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 277 2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(2-((6-methylpyridin-2-yl)methyl)piperidin-1-yl)ethanone
  • 278 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 279 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 280 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)ethanone
  • 281 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(diisopropylamino)ethyl)piperazin-1-yl)ethanone
  • 282 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(3-(pyridin-4-yl)pyrrolidin-1-yl)ethanone
  • 283 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-4-yl)piperazin-1-yl)ethanone
  • 284 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-((6-methylpyridin-2-yl)methyl)piperidin-1-yl)ethanone
  • 285 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 286 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 287 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)ethanone
  • 288 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethanone
  • 289 1-(4-(4-fluorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 290 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methoxyphenyl)piperazin-1-yl)ethanone
  • 291 1-(4-isopropylpiperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 292 2-((2-(mesitylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 293 2-((1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(pyrrolidin-1-ylmethyl)phenyl)acetamide
  • 294 N-(4-(dimethylamino)butyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 295 1-(4-ethylpiperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 296 1-(4-(pyrrolidin-1-yl)piperidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 297 1-(4-morpholinopiperidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 298 1-(1,4′-bipiperidin-1′-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 299 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(pyrrolidin-1-ylmethyl)benzyl)acetamide
  • 300 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 301 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)acetamide
  • 302 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(4-methylpiperazin-1-yl)benzyl)acetamide
  • 303 N—((S)-1-benzylpyrrolidin-3-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-methylacetamide
  • 304 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-methyl-N-(2-morpholino-1-phenylethyl)acetamide
  • 305 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethanone
  • 306 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethanone
  • 307 1-(4-(4-fluorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 308 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methoxyphenyl)piperazin-1-yl)ethanone
  • 309 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethanone
  • 310 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-phenethylpiperazin-1-yl)ethanone
  • 311 1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 312 2-(4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetyl)piperazin-1-yl)nicotinonitrile
  • 313 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(pyrrolidin-1-ylmethyl)benzyl)acetamide
  • 314 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 315 N—((S)-1-benzylpyrrolidin-3-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide
  • 316 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethanone
  • 317 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethanone
  • 318 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-fluorophenyl)piperazin-1-yl)ethanone
  • 319 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methoxyphenyl)piperazin-1-yl)ethanone
  • 320 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-phenethylpiperazin-1-yl)ethanone
  • 321 1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 322 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(pyrrolidin-1-ylmethyl)benzyl)acetamide
  • 323 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 324 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3-methoxyphenyl)piperazin-1-yl)ethanone
  • 325 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methoxyphenyl)piperazin-1-yl)ethanone
  • 326 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-phenethylpiperazin-1-yl)ethanone
  • 327 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 328 1-(4-(4-methoxyphenyl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 329 1-(4-phenethylpiperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 330 1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 331 1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 332 1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 333 1-(4-(2-(diisopropylamino)ethyl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 334 N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 335 1-(4-(pyridin-4-yl)piperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 336 1-(1,4′-bipiperidin-1′-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 337 1-(1,4′-bipiperidin-1′-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 338 N-(2-(piperidin-1-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 339 N-(2-(pyrrolidin-1-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 340 1-(4-(3,5-dimethoxyphenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 341 1-(4-(2-(diisopropylamino)ethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 342 N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 343 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide
  • 344 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-morpholinopropyl)acetamide
  • 345 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(pyridin-3-ylmethyl)acetamide
  • 346 1-(4-(3-chlorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 347 1-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 348 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 349 1-(4-(3,4-dichlorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 350 1-(4-(4-bromobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 351 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2,4,6-trimethylbenzyl)piperazin-1-yl)ethanone
  • 352 1-(4-(4-chlorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 353 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methylbenzyl)piperazin-1-yl)ethanone
  • 354 1-(4-(3-chlorophenyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 355 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3,4-dimethylphenyl)piperazin-1-yl)ethanone
  • 356 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 357 1-(4-(3,4-dichlorobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 358 1-(4-(4-bromobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 359 1-(4-(4-chlorobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 360 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methylbenzyl)piperazin-1-yl)ethanone
  • 361 N-benzyl-N-(2-(dimethylamino)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 362 1-(4-benzyl-1,4-diazepan-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 363 1-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 364 N—((S)-1-benzylpyrrolidin-3-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide
  • 365 N-(1-benzylpyrrolidin-3-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 366 N-(3-(1H-imidazol-1-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 367 N-(4-(dimethylamino)benzyl)-N-isopropyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 368 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methyl-N-(2-morpholino-1-phenylethyl)acetamide
  • 369 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethanone
  • 370 N-(isoquinolin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 371 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(1-methyl-1H-benzo[d]imidazol-2-yl)acetamide
  • 372 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(pyrimidin-4-yl)acetamide
  • 373 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-phenethylpiperazin-1-yl)ethanone
  • 374 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-((S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)ethanone
  • 375 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-methyl-1,4-diazepan-1-yl)ethanone
  • 376 1-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 377 N-benzyl-N-(2-(dimethylamino)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 378 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 379 N-(2-(dimethylamino)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide
  • 380 N-(2-(diethylamino)ethyl)-N-ethyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 381 1-(4-(3,4-dichlorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 382 1-(4-(4-bromobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 383 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2,4,6-trimethylbenzyl)piperazin-1-yl)ethanone
  • 384 1-(4-(4-chlorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 385 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylbenzyl)piperazin-1-yl)ethanone
  • 386 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methoxybenzyl)piperazin-1-yl)ethanone
  • 387 1-(4-(2-fluorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 388 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-methyl-2-phenylpiperazin-1-yl)ethanone
  • 389 1-(3-(pyridin-3-yl)pyrrolidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 390 1-(3-(pyridin-4-yl)pyrrolidin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 391 N-methyl-N-(2-(pyridin-4-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 392 N-methyl-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 393 1-(4-methylpiperazin-1-yl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 394 N-(pyridin-4-ylmethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 395 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-morpholinopyridin-3-yl)acetamide
  • 396 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(6-morpholinopyridin-3-yl)acetamide
  • 397 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethanone
  • 398 1-(2-(4-(dimethylamino)phenyl)pyrrolidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 399 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(piperidin-1-ylmethyl)pyrrolidin-1-yl)ethanone
  • 400 1-(2-(4-(dimethylamino)phenyl)azepan-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 401 N-(2-(4-benzylpiperazin-1-yl)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 402 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-phenylthiazol-2-yl)piperazin-1-yl)ethanone
  • 403 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3,4-dimethylphenyl)piperazin-1-yl)ethanone
  • 404 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 405 1-(4-(3,4-dichlorobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 406 1-(4-(4-bromobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 407 1-(4-(4-chlorobenzyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 408 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylbenzyl)piperazin-1-yl)ethanone
  • 409 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(pyrrolidin-1-yl)phenyl)acetamide
  • 410 3-(4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-yl)propanenitrile
  • 411 N-(3-(4-benzylpiperazin-1-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 412 N-(3-(4-ethylpiperazin-1-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 413 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(piperidin-1-yl)propyl)acetamide
  • 414 N-((1-benzylpyrrolidin-3-yl)methyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 415 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 416 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(5-methyl-1H-pyrazol-1-yl)ethyl)acetamide
  • 417 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)acetamide
  • 418 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(piperidin-1-ylmethyl)phenyl)acetamide
  • 419 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(piperidin-1-ylmethyl)phenyl)acetamide
  • 420 N-(4-((1H-imidazol-1-yl)methyl)phenyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 421 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)acetamide
  • 422 N-((1-benzylpiperidin-3-yl)methyl)-2-((1-(4-methoxyphenylsulfonyl)indolin-2-yl)methoxy)acetamide
  • 423 2-((1-(4-methoxyphenylsulfonyl)indolin-2-yl)methoxy)-N-(3-(piperidin-1-ylmethyl)phenyl)acetamide
  • 424 N-(3-(ethyl(phenyl)amino)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 425 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(pyrazin-2-yl)ethyl)acetamide
  • 426 N-(1-(1H-pyrazol-1-yl)propan-2-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 427 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)acetamide
  • 428 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(piperidin-1-yl)benzyl)acetamide
  • 429 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(piperidin-1-yl)phenyl)acetamide
  • 430 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(piperidin-1-yl)benzyl)acetamide
  • 431 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(4-methylpiperazin-1-yl)phenyl)acetamide
  • 432 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(4-methylpiperazin-1-yl)benzyl)acetamide
  • 433 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(4-methylpiperazin-1-yl)benzyl)acetamide
  • 434 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(4-methylpiperazin-1-yl)benzyl)acetamide
  • 435 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-morpholinobenzyl)acetamide
  • 436 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-morpholinophenyl)acetamide
  • 437 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-morpholinobenzyl)acetamide
  • 438 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-morpholinophenyl)acetamide
  • 439 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-morpholinobenzyl)acetamide
  • 440 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(piperidin-1-yl)ethyl)acetamide
  • 441 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(dimethylamino)butyl)acetamide
  • 442 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-fluorophenyl)piperazin-1-yl)ethanone
  • 443 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethanone
  • 444 1-(4-(2-fluorobenzyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 445 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-methyl-2-phenylpiperazin-1-yl)ethanone
  • 446 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-methyl-N-(2-(4-methylpiperazin-1-yl)-1-phenylethyl)acetamide
  • 447 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(2-(pyridin-2-ylmethyl)pyrrolidin-1-yl)ethanone
  • 448 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(2-((6-methylpyridin-2-yl)methyl)pyrrolidin-1-yl)ethanone
  • 449 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(2-(pyridin-2-ylmethyl)piperidin-1-yl)ethanone
  • 450 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-methyl-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)acetamide
  • 451 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(4-methoxybenzyl)piperazin-1-yl)ethanone
  • 452 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)ethanone
  • 453 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(2-(pyridin-4-ylmethyl)piperidin-1-yl)ethanone
  • 454 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-fluorobenzyl)piperazin-1-yl)ethanone
  • 455 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-methyl-2-phenylpiperazin-1-yl)ethanone
  • 456 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(pyridin-2-ylmethyl)pyrrolidin-1-yl)ethanone
  • 457 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-((4,6-dimethylpyridin-2-yl)methyl)pyrrolidin-1-yl)ethanone
  • 458 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-((6-methylpyridin-2-yl)methyl)pyrrolidin-1-yl)ethanone
  • 459 N-(2-(pyrrolidin-1-yl)ethyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 460 1-(4-benzylpiperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 461 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-phenylpiperazin-1-yl)ethanone
  • 462 1-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 463 N-benzyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-methylpyridin-2-yl)acetamide
  • 464 N-benzyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(6-methylpyridin-2-yl)acetamide
  • 465 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
  • 466 N-ethyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(pyridin-4-ylmethyl)acetamide
  • 467 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-methyl-1,4-diazepan-1-yl)ethanone
  • 468 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethanone
  • 469 1-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 470 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)acetamide
  • 471 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(3-(piperidin-1-ylmethyl)phenyl)acetamide
  • 472 N-(4-(2-(1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 473 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(2-(4-methylpiperazin-1-yl)benzyl)acetamide
  • 474 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethanone
  • 475 1-(2-(4-(dimethylamino)phenyl)azepan-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 476 1-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 477 N-(1-benzylpiperidin-4-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 478 1-(4-benzylpiperazin-1-yl)-2-((1-(2,5-dichlorothiophen-3-ylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 479 2-((2-(4-Methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-phenylpiperazin-1-yl)ethanone
  • 480 1-(4-benzylpiperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 481 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
  • 482 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-ethyl-N-(pyridin-4-ylmethyl)acetamide
  • 483 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-methyl-1,4-diazepan-1-yl)ethanone
  • 484 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethanone
  • 485 1-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 486 N-benzyl-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(pyridin-2-yl)acetamide
  • 487 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethanone
  • 488 N-(1-benzylpiperidin-4-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 489 N-benzyl-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(2-(dimethylamino)ethyl)acetamide
  • 490 1-(2-((5-ethylpyridin-2-yl)methyl)pyrrolidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 491 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(2-methoxyphenyl)piperazin-1-yl)ethanone
  • 492 1-(4-(cyclohexylmethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 493 N-(3-chloro-4-morpholinophenyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 494 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide
  • 495 N-(2-(dimethylamino)-2-(4-(trifluoromethyl)phenyl)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 496 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(2-(pyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)acetamide
  • 497 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(pyridin-3-yl)pyrrolidin-1-yl)ethanone
  • 498 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-methoxyphenyl)piperazin-1-yl)ethanone
  • 499 1-(4-(cyclohexylmethyl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 500 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(2-morpholino-1-phenylethyl)acetamide
  • 501 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(1-methyl-1H-indazol-6-yl)acetamide
  • 502 N-(2-(2-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 503 1-(4-(3,5-dimethoxyphenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 504 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(1-methyl-1H-benzo[d]imidazol-2-yl)acetamide
  • 505 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)acetamide
  • 506 3-(4-(2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-yl)propanenitrile
  • 507 N-benzyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-methylpyridin-2-yl)acetamide
  • 508 N-benzyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(6-methylpyridin-2-yl)acetamide
  • 509 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
  • 510 N-ethyl-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(pyridin-4-ylmethyl)acetamide
  • 511 1-(4-(3-chlorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 512 1-(4-(3,4-dimethylphenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 513 2-(4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-yl)nicotinonitrile
  • 514 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(5-(trifluoro methyl)pyridin-2-yl)piperazin-1-yl)ethanone
  • 515 N-benzyl-2-((1-(2,5-dichlorothiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-N-(6-methylpyridin-2-yl)acetamide
  • 516 1-(4-(2-fluorophenyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 517 1-(4-ethylpiperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 518 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)ethanone
  • 519 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-morpholinopiperidin-1-yl)ethanone
  • 520 1-(1,4′-bipiperidin-1′-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)ethanone
  • 521 N-(3-(4-benzylpiperazin-1-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 522 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(3-(piperidin-1-yl)propyl)acetamide
  • 523 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-(pyrrolidin-1-yl)butyl)acetamide
  • 524 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 525 N-(3-(1H-benzo[d]imidazol-2-yl)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 526 1-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 527 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)acetamide
  • 528 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(4-(dimethylamino)phenyl)pyrrolidin-1-yl)ethanone
  • 529 1-(4-benzyl-1,4-diazepan-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 530 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(dimethylamino)benzyl)-N-isopropylacetamide
  • 531 2-(4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetyl)-1,4-diazepan-1-yl)nicotinonitrile
  • 532 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-methyl-N-(2-(piperidin-1-yl)ethyl)acetamide
  • 533 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 534 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(2-(2-morpholinoethyl)piperidin-1-yl)ethanone
  • 535 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(5-methyl-1H-pyrazol-3-yl)acetamide
  • 536 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(5-phenyl-1H-pyrazol-3-yl)acetamide
  • 537 N-(3-(4-chlorophenyl)-1H-pyrazol-5-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 538 N-(4-(3,4-dimethoxyphenyl)-1H-pyrazol-5-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 539 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-(thiophen-2-yl)-1H-pyrazol-5-yl)acetamide
  • 540 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(5-(2-methoxyphenyl)-1H-pyrazol-3-yl)acetamide
  • 541 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(5-(3-methoxyphenyl)-1H-pyrazol-3-yl)acetamide
  • 542 N-(5-(3-fluorophenyl)-1H-pyrazol-3-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 543 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)acetamide
  • 544 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-p-tolyl-1H-pyrazol-5-yl)acetamide
  • 545 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-phenyl-1H-pyrazol-5-yl)acetamide
  • 546 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-N-(quinolin-2-yl)acetamide
  • 547 2-((1-(4-methoxyphenylsulfonyl)indolin-2-yl)methoxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperidin-1-yl)ethanone
  • 548 1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)-2-((1-(4-methoxyphenylsulfonyl)indolin-2-yl)methoxy)ethanone
  • 549 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-N-(4-(morpholinomethyl)benzyl)acetamide
  • 550 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethanone
  • 551 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3,5-dichloropyridin-2-yl)piperazin-1-yl)ethanone
  • 552 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone
  • 553 1-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 554 1-(4-(6-chlorobenzo[d]thiazol-2-yl)piperazin-1-yl)-2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 555 N-(4-(4-ethylpiperazin-1-yl)phenyl)-2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 556 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-N-(7-morpholinobenzo[c][1,2,5]oxadiazol-4-yl)acetamide
  • 557 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-N-(3-methyl-4-(2-(piperidin-1-yl)acetamideo)phenyl)acetamide
  • 558 2-((1-(4-methoxyphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-phenoxyethyl)piperazin-1-yl)ethanone
  • 559 1-(4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)piperazin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 560 1-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)ethanone
  • 561 N,N-bis(3-(dimethylamino)propyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 562 2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 563 2-((2-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 564 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(3-(dimethylamino)propyl)piperazin-1-yl)ethanone
  • 565 2-((1-(2,6-dichlorophenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 566 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3-(dimethylamino)propyl)piperazin-1-yl)ethanone
  • 567 2-((1-(2,6-dichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 568 1-(4-benzylpiperazin-1-yl)-2-((1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 569 2-((1-(2,6-dichloro-4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(3-(dimethylamino)propyl)piperazin-1-yl)ethanone
  • 570 2-((1-(2,6-dichloro-4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone
  • 571 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-((1-(2-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)ethanone
  • 572 2-((1-(benzo[b]thiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)ethanone
  • 573 2-((1-(benzo[b]thiophen-3-ylsulfonyl)piperidin-2-yl)methoxy)-1-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)ethanone
  • 574 N—((S)-1-benzylpyrrolidin-3-yl)-2-((1-(2,6-dichloro-4-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)methoxy)-N-methylacetamide
  • 575 N-(4-(dimethylamino)benzyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 576 N-(4-(dimethylamino)benzyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 577 N-(4-(dimethylamino)benzyl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 578 N-(4-(dimethylamino)benzyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
  • 579 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)-N-(4-morpholinobenzyl)acetamide
  • 580 N-(4-morpholinobenzyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)pyrrolidin-2-yl)methoxy)acetamide
  • 581 N-(4-morpholinobenzyl)-2-((1-(2,4,6-trichlorophenylsulfonyl)piperidin-2-yl)methoxy)acetamide
    in the form of the racemate; in the form of the enantiomers, diastereoisomers, mixtures of the enantiomers or diastereoisomers or in the form of an individual enantiomer or diastereoisomer; in the form of the bases and/or salts of physiologically acceptable acids.

The numbering of the individual forms of the substances according to the invention that is used above is retained in the explanations of the present invention that follow, in particular in the description of the examples.

The compounds according to the invention exhibit an antagonistic action on the human B1R receptor or the B1R receptor of the rat. In a preferred embodiment of the invention, the substances according to the invention exhibit an antagonistic action both on the human B1R receptor and on the B1R receptor of the rat.

Particular preference is given to compounds which exhibit at least 15%, 25%, 50%, 70%, 80% or 90% inhibition on the human B1R receptor and/or on the B1R receptor of the rat in the FLIPR assay at a concentration of 10 μM. Most particular preference is given to compounds which exhibit at least 70%, especially 80% and particularly preferably 90% inhibition on the human B1R receptor and on the B1R receptor of the rat.

The agonistic or antagonistic action of substances can be quantified on the bradykinin receptor 1 (B1R) of the species human and rat with ectopically expressing cell lines (CHO K1 cells) and with the aid of a Ca²⁺-sensitive dye (Fluo-4) using a fluorescent imaging plate reader (FLIPR). The indication in % activation is based on the Ca²⁺ signal after addition of Lys-Des-Arg⁹-bradykinin (0.5 nM) or Des-Arg⁹-bradykinin (100 nM). Antagonists result in a suppression of the Ca²⁺ influx following administration of the agonist. The % inhibition in comparison with the maximum achievable inhibition is indicated.

The substances according to the invention are active, for example, on B1R, which is relevant in connection with various diseases, so that they are suitable as a pharmaceutical active ingredient in a medicament. The invention therefore further provides pharmaceutical compositions or medicaments comprising at least one substituted sulfonamide derivative according to the invention as well as, optionally, suitable additives and/or auxiliary substances and/or, optionally, further active ingredients.

In addition to comprising at least one substituted sulfonamide derivative according to the invention, the pharmaceutical compositions according to the invention optionally comprise suitable additives and/or auxiliary substances, that is to say carriers, fillers, solvents, diluents, colorings and/or binders, and can be administered as liquid pharmaceutical dosage forms in the form of injection solutions, drops or juices, as semi-solid pharmaceutical dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used depend on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or to the eyes. Preparations suitable for oral administration are in the form of tablets, dragées, capsules, granules, drops, juices and syrups, and those suitable for parenteral and topical administration and administration by inhalation are solutions, suspensions, readily reconstitutable dry preparations and sprays. Substituted sulfonamide derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous forms of administration. Forms of preparation for oral or percutaneous administration can release the substituted sulfonamide derivatives according to the invention in a delayed manner. The substituted sulfonamide derivatives according to the invention can also be administered in parenteral long-term depot forms, such as, for example, implants or implanted pumps. In principle, other further active ingredients known to the person skilled in the art can be added to the medicaments according to the invention.

The amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the manner of administration, the indication and the severity of the disease. Usually, from 0.00005 to 50 mg/kg, preferably from 0.01 to 5 mg/kg, of at least one substituted sulfonamide derivative according to the invention are administered.

In a preferred form of the pharmaceutical composition or medicament, a substituted sulfonamide derivative according to the invention that is present is in the form of a pure diastereoisomer and/or enantiomer, in the form of a racemate or in the form of a non-equimolar or equimolar mixture of the diastereoisomers and/or enantiomers.

B1R has been identified in particular in occurrences of pain. Accordingly, substituted sulfonamide derivatives according to the invention can be used in the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain. The invention accordingly relates further to the use of a substituted sulfonamide derivative according to the invention in the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain. The invention relates further to the use of a substituted sulfonamide derivative according to the invention in the treatment of diabetes, respiratory diseases, inflammatory intestinal diseases, neurological diseases, inflammations of the skin, rheumatic diseases, septic shock, reperfusion syndrome and obesity, and as an angiogenesis inhibitor.

In one of the above uses it can be preferred for a substituted sulfonamide derivative that is used to be in the form of a pure diastereoisomer and/or enantiomer, in the form of a racemate or in the form of a non-equimolar or equimolar mixture of the diastereoisomers and/or enantiomers.

The invention further provides a method of treating, in particular in one of the above-mentioned indications, a non-human mammal or a human requiring treatment for pain, in particular for chronic pain, by administering a therapeutically effective dose of a substituted sulfonamide derivative according to the invention or of a medicament according to the invention.

The invention further provides a process for the preparation of the substituted sulfonamide derivatives according to the invention as set out in the following description, examples and claims. The compounds according to the invention can be obtained according to the following synthesis scheme.

According to method 1, the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acids/acid esters A are converted into an amino alcohol B by means of a reduction, using metal hydrides as reducing agents, such as, for example, LiAlH₄, BH₃×DMS, BH₃×THF or NaBH₄, in an organic solvent, such as THF or diethyl ether, in a temperature range of from −20° C. to +100° C., preferably at from 0° C. to +70° C. The amino alcohols B are converted into the sulfonylated amino alcohols G in a sulfonylation using sulfonyl chlorides, bromides or pentafluorophenolates R₁SO₂X (X═Br, Cl or OPFP) in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, diethylamine or dimethylaminopyridine, or in the presence of tetra-n-butylammonium chloride and in an organic solvent, for example acetonitrile, dichloromethane or N,N-dimethylformamide, in a temperature range of from 0° C. to +120° C.
In method 2, the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acids C are esterified to the amino esters D using water-removing reagents, for example inorganic acids such as H₂SO₄ or phosphorus oxides, or organic reagents, such as thionyl chloride, in organic solvents, such as THF, diethyl ether, methanol, ethanol or dichloromethane, in a temperature range of from 0° C. to the boiling temperature of the solvent in question, preferably at 40° C., and are then converted into the sulfonylated amino esters E in a sulfonylation using sulfonyl chlorides or bromides RSO₂X (X═Br or Cl) in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, pyridine, diethylamine or triethylamine, and in an organic solvent, for example acetonitrile or dichloromethane, in a temperature range of from 0° C. to +25° C., which sulfonylated amino esters E, in an ester cleavage using organic acids, such as trifluoroacetic acid, or aqueous inorganic acids, such as hydrochloric acid, or using aqueous inorganic bases, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, in organic solvents, such as methanol, dioxane, dichloromethane, THF, diethyl ether or those solvents in the form of mixtures, in a temperature range of from −20° C. to +25° C., preferably at room temperature, yield the sulfonylated amino acids F. The sulfonylated amino alcohols G are then converted into the products of the general structure H in an alkylation reaction with halogenated ester derivatives using tetrabutyl-ammonium chloride or bromide or tetrabutylammonium hydrogen sulfate in a phase-transfer reaction using an organic solvent, such as toluene, benzene or xylene, and inorganic base, such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, or in the presence of an organic or inorganic base, conventional inorganic bases are metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium tert-butoxide, lithium or sodium bases, such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methoxide, or metal hydrides, such as potassium hydride, lithium hydride, sodium hydride; conventional organic bases are diisopropylethylamine, triethylamine, in an organic solvent, such as dichloromethane, THF or diethyl ether, in a temperature range of from −20° C. to +25° C., preferably at from 0° C. to +25° C., which products of the general structure H, in an ester cleavage using organic acids, such as trifluoroacetic acid, or aqueous inorganic acids, such as hydrochloric acid, or using aqueous inorganic bases, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, in organic solvents, such as methanol, dioxane, dichloromethane, THF, diethyl ether or those solvents in the form of mixtures, in a temperature range of from 0° C. to +25° C., yield the acid stages of the general formula I. The carboxylic acids I are converted into the end products of the general formula J in an amide formation using primary or secondary amines, in the presence of water-removing agents, such as sodium or magnesium sulfate, phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU, EDCI or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), also in the presence of HOAt or HOBt and of an organic base, for example DIPEA, pyridine or 4-methylmorpholine, in an organic solvent, such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, 0° C. to +40° C., preferably at room temperature.

Commercially available amino alcohols are used as structural units B in the synthesis process and are converted into the end products of the general formula J in the manner described in methods 1 and 2.

Compounds corresponding to formula I in which m represents 2 can be prepared according to the same methods from starting materials of the general formula K

The synthesis preferably begins at the stage of the starting materials Ga.

Compounds of the general formula J_a can be prepared, as described in method 1 and 2, from commercially available amino alcohols which are used as the structural units B and are finally reacted, in the last step, in an amide formation, with tert-butyl piperazine-1-carboxylate and are converted into the products of the general structure J_b under acid conditions, in the presence of, for example, trifluoroacetic acid, hydrogen chloride or chlorotrimethylsilane/water in an organic solvent, such as ethyl acetate, methanol, diethyl ether, methyl ethyl ketone or 1,4-dioxane or those solvents in the form of mixtures, in a temperature range of from 0° C. to +100° C., preferably at from +25° C. to +80° C. The amines or the corresponding hydrochlorides of the general formula J_b can be converted into compounds of the general formula J_c using aldehydes or ketones in a reductive amination, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine, and in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium diacetoxyborohydride, or those or similar reducing agents in the form of polymer-bonded variants, optionally in the presence of acetic acid, in an organic solvent, for example tetrahydrofuran, dichloromethane, 1,2-dichloroethane or those solvents in the form of mixtures, in a temperature range of from −0° C. to +25° C.

Compounds of the general formula J_d can be prepared, as described in method 1 and 2, from commercially available amino alcohols which are used as structural units B and are finally reacted, in the last step, in an amide formation, with piperidin-4-one. The ketones of the general formula J_d can be converted into compounds of the general formula J_e using amines in a reductive amination, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine, and in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium diacetoxy-borohydride, or those or similar reducing agents in the form of polymer-bonded variants, optionally in the presence of acetic acid, in an organic solvent, for example tetrahydrofuran, dichloromethane, 1,2-dichloroethane or those solvents in the form of mixtures, in a temperature range of from −0° C. to +25° C.

The commercially available, protected amino alcohols of the general formula J_f can be converted into the products of the general structure J_g in an alkylation reaction with halogenated ester derivatives using tetrabutylammonium chloride or bromide or tetra-butylammonium hydrogen sulfate in a phase-transfer reaction using an organic solvent, such as toluene, benzene or xylene, and an inorganic base, such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, or in the presence of an organic or inorganic base, conventional inorganic bases are metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium tert-butoxide, lithium or sodium bases, such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methoxide, or metal hydrides, such as potassium hydride, lithium hydride, sodium hydride; conventional organic bases are diisopropylethylamine, triethylamine, in an organic solvent, such as dichloromethane, THF or diethyl ether, in a temperature range of from −20° C. to +25° C., preferably at from 0° C. to +25° C., which products of the general structure J_g, in an ester cleavage using organic acids, such as trifluoroacetic acid, or aqueous inorganic acids, such as hydrochloric acid, or using aqueous inorganic bases, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, in organic solvents, such as methanol, dioxane, dichloromethane, THF, diethyl ether or those solvents in the form of mixtures, in a temperature range of from 0° C. to +110° C., preferably at from +25° C. to +90° C., yield the acid stages of the general formula J_h. The carboxylic acids J_h can be converted into the products of the general formula J_l, in an amide formation using primary or secondary amines, in the presence of water-removing agents, such as sodium or magnesium sulfate, phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU, EDCI or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), also in the presence of HOAt or HOBt and an organic base, for example DIPEA, pyridine or 4-methylmorpholine, in an organic solvent, such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, at from 0° C. to +40° C., preferably at room temperature. The compounds J_l can be deprotected in the presence of an inorganic or organic acid, such as HCl, trifluoroacetic acid or formic acid, in an organic solvent, such as THF, dichloro-methane, diethyl ether, dioxane, MeOH or chloroform, at from 0° C. to +40° C., preferably at from +25 to +40° C., to form the products of the general formula J_j. The amines J_j are converted into the sulfonamides J_k in a sulfonylation using sulfonyl chlorides, bromides or pentafluorophenolates R₁SO₂X (X═Br, Cl or OPFP) in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, diethylamine, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) and/or dimethylaminopyridine, or in the presence of tetra-n-butylammonium chloride and in an organic solvent, for example acetonitrile, dichloromethane, THF or N,N-dimethylformamide, in a temperature range of from 0° C. to 120° C., preferably at from +25° C. to +70° C.

The separation of diastereoisomers and/or enantiomers is carried out according to methods known to the person skilled in the art, for example by recrystallization, chromatography or, in particular, HPLC chromatography or crystallization using an optionally chiral acid or base and with separation of the salts, or chiral HPLC chromatography (Fogassy et al., Optical resolution methods, Org. Biomol. Chem. 2006, 4, 3011-3030).

In the following examples the yields of the prepared compounds are not optimized, and all temperatures are uncorrected. The term “ether” means diethyl ether, “EE” means ethyl acetate, “DCM” means dichloromethane, “DMF” means dimethylformamide, “DME” means dimethoxyethane, “DMSO” means dimethyl sulfoxide and “THF” means tetrahydrofuran. The term “equivalents” means equivalent amounts, “m.p.” means melting point or melting range, “decomp.” means decomposition, “RT” means room temperature, “abs.” means absolute (anhydrous), “rac.” means racemic, “conc.” means concentrated, “min.” means minutes, “h” means hours, “d” means days, “vol. %” means percent by volume, “wt. %” means percent by weight, and “M” is the concentration in mol/l. The chemicals and solvents used were obtained commercially from the conventional suppliers (ABCR, Acros, Acocado, Aldrich, ApolloScientific, Bachem, Bionet, Chempur, Fluka, Lancaster, Maybridge, Merck, Sigma, TCi TygerScientific, etc.) or were synthesized. Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as the stationary phase for the column chromatography. Thin-layer chromatographic investigations were carried out using precoated HPTLC plates, silica gel 60 F 254, from E. Merck, Darmstadt. The mixing ratios of eluants for chromatographic investigations are always given as volume/volume. Analysis was carried out by means of HPLC-MS, precursors were confirmed by NMR. Other abbreviations used in the examples include:

TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,

CDI=1,1′-carbonyldiimidazole,

DCC=dicyclohexylcarbodiimide,

EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,

HOAt 1-hydroxy-7-azabenzotriazole,

DIPEA=N,N-diisopropylamine,

HOBt=1-hydroxybenzotriazole, and

PFP=pentafluorophenyl.

1. LiAlH₄ (100 ml, 1.0 M in diethyl ether) was added successively with stirring, at a temperature of from −10° C. to RT, under an inert gas atmosphere, to a suspension of the cyclic amino acid (100 mmol) in THF (150 ml). The reaction mixture was stirred for 16 h and thereby warmed to RT. It was then cooled to 0° C. again, and ethyl acetate (20 ml), water (8 ml), 15% aqueous NaOH (8 ml) and water (20 ml) were added, with stirring. After filtration, the residue was washed with diethyl ether. The solvent from the combined organic phases was removed in vacuo, and the product was used in the next step without being purified further.
2. Et₃N (125 mmol) was added to a solution of the amino alcohol (100 mmol) in CH₂Cl₂ (200 ml), and the mixture was cooled to 0° C. using an ice-bath. The particular sulfonyl chloride (50 mmol), undiluted or in the form of a solution in CH₂Cl₂ (100 ml), was then added, and stirring was carried out for 3 h at RT. After addition of 0.5 M hydrochloric acid (100 ml), the organic phase was separated off, washed with water, dried over Na₂SO₄ and filtered, and the solvent was removed in vacuo. The crude product was used in the next step without being purified further or was purified by column chromatography.
3. n-Bu₄NCl (10 mmol) was added to a solution of the product from step 2 (31 mmol) in toluene (200 ml); the mixture was cooled to 0° C., and first aqueous 35% NaOH (200 ml) and then bromoacetic acid tert-butyl ester (46 mmol) were added dropwise. The reaction mixture was stirred for 3 h and then washed with water until neutral and dried over Na₂SO₄, and the organic solvent was removed in vacuo. The crude product was used in the next step without being purified further or was purified by column chromatography.
4. The product from step 3 (30 mmol) was dissolved in CH₂Cl₂ (200 ml); TFA (30 ml) was added, and stirring was carried out for 2 h at RT. The solvent was largely removed in vacuo, and the crude product was purified by recrystallization or chromatography.

1. A solution of the amino acid (153 mmol) in methanol (500 ml) was cooled to 0° C., and thionyl chloride (168 mmol, 12 ml) was added dropwise. After warming to RT, the reaction solution was heated overnight at 40° C. Removal of the solvent by distillation yielded the crude product, which was used in the next step without being purified further.
2. Pyridine (459 mmol) and a solution of the sulfonyl chloride (153 mmol) in CH₂Cl₂ (100 ml) were added to a solution of the methyl ester from step 1 (152 mmol) in CH₂Cl₂ (400 ml). The reaction solution was stirred overnight at RT. The solution was diluted with a small amount of CH₂Cl₂ and washed, in succession, with 0.5 M KHSO₄, saturated aqueous NaHCO₃ solution and saturated aqueous NaCl solution. The organic phase was separated off and dried over Na₂SO₄, the solvent was removed in vacuo, and the crude product was purified by means of column chromatography.
3. 4 M NaOH (153 ml, 610 mmol, 4.5 equivalents) was added, with stirring, to a solution of the product from step 2 (136 mmol) in a methanol/dioxane/4 M NaOH mixture in a ratio of 15/4/1 (1020 ml, 203 mmol NaOH, 1.5 equivalents), and stirring was carried out overnight at RT. The solvent was removed in vacuo. The residue was dissolved with ethyl acetate and washed with 0.5 M KHSO₄. The organic phase was washed with saturated aqueous NaCl solution, and the separated organic phase, after filtration, was dried over Na₂SO₄. After removal of the solvent in vacuo and washing with diethyl ether, the purified product from step 3 was obtained.
4. BH₃×DMS (2.0 M in THF, 31.2 ml, 63 mmol) was slowly added dropwise at 0° C., with stirring, to a solution of the product from step 3 (31 mmol) in THF (250 ml). After stirring for 30 minutes at RT, the solution was allowed to warm slowly to RT overnight. Methanol was then added slowly until no more gas was liberated, and the solvent was reduced in vacuo. The crude product was filtered over silica and washed with CH₂Cl₂/methanol in a ratio of 9/1.
5. n-Bu₄NCl (10 mmol, 2.9 g) was added to a solution of the product from step 4 (31 mmol) in toluene (175 ml), and the mixture was cooled to 0° C.; aqueous 35% NaOH (200 ml) was added first, and then bromoacetic acid tert-butyl ester (48 mmol, 7 ml) was added dropwise. The reaction mixture was stirred for 3 hours and then washed with water until neutral and dried over Na₂SO₄, and the organic solvent was removed in vacuo. The crude product was used in the next step without being purified further.
6. The product from step 5 (30 mmol) was dissolved in a mixture of MeOH/dioxane/4 M NaOH in a ratio of 15/4/1 (236 ml, 47 mmol NaOH); further NaOH (4 M, 35 ml, 141 mmol) was added, and stirring was carried out overnight at RT. The solvent was reduced in vacuo, and the residue was diluted with ethyl acetate and washed with 0.5 M KHSO₄. The organic phase was separated off, washed with saturated aqueous NaCl solution and dried over Na₂SO₄. After filtration, the solvent was removed in vacuo. The crude product was purified by coevaporation with diethyl ether and CH₂Cl₂.

1. K₂CO₃ (148 mmol) and the sulfonyl chloride (82 mmol) were added at RT to a solution or suspension of the amino alcohol (74 mmol) in acetone (350 ml), and stirring was carried out overnight at 40-50° C. The reaction mixture was cooled to RT and filtered. The solvent of the filtrate was then removed in vacuo. The crude product was used in the next step without being purified further.
2. n-Bu₄NCl (10 mmol) was added to a solution of the product from step 1 (31 mmol) in toluene (200 ml); the mixture was cooled to 0° C., and first aqueous 35% NaOH (200 ml) and then bromoacetic acid tert-butyl ester (46 mmol) were added dropwise. The reaction mixture was stirred for 3 h and then washed with water until neutral and dried over Na₂SO₄, and the organic solvent was removed in vacuo. The crude product was used in the next step without being purified further or was purified by column chromatography.

a. 6 M NaOH (200 ml, 1200 mmol) was added to a solution of the tert-butyl ester (63 mmol) in THF (200 ml) and methanol (200 ml). The reaction mixture was stirred at RT. After 15 min. to 1 h, the organic solvent was removed, the residue was cooled to 0° C., and 6 M HCl (210 ml) was added. The aqueous phase was extracted with CH₂Cl₂ (200 ml) and ethyl acetate (200 ml). The combined organic phases were dried over Na₂SO₄. After filtration, the solvent was removed in vacuo and the residue was coevaporated twice with i-propyl ether.
b. Dioxane (30 ml) was added to a suspension of the tert-butyl ester (38 mmol) in 6 M NaOH (64 ml, 384 mmol) and methanol (64 ml) until a solution was obtained. The reaction solution was stirred at RT. After 15 min. to 3 h, the organic solvent was removed, the residue was cooled to 0° C., and 6 M HCl (200 ml) was added. The aqueous phase was extracted with CH₂Cl₂ (200 ml). The combined organic phases were dried over Na₂SO₄. After filtration, the solvent was removed in vacuo and the residue was coevaporated twice with i-propyl ether.
c) The tert-butyl ester (7 mmol) was stirred overnight at RT in 4 M HCl in dioxane (7 ml, 27 mmol). After removal of the solvent, the residue was coevaporated twice with i-propyl ether.

1. Et₃N (95 mmol) was added to a suspension of DL-piperidine-2-carboxylic acid ethyl ester (38 mmol) in CH₂Cl₂ (150 ml). The solution was cooled to 0° C., the sulfonyl chloride (42 mmol) in a solution of CH₂Cl₂ (30 ml) was slowly added dropwise, and stirring was carried out for 2 h at RT. The organic phase was extracted with 1 M HCl (250 ml) and H₂O (250 ml). The organic phase was separated off and dried over Na₂SO₄. The solvent was removed in vacuo. The residue was coevaporated with i-propyl ether and the product was used in the next step without being purified further.
2. 4 M NaOH (113 mmol) was added at RT, with stirring, to a solution of the ester (38 mmol) in a solvent mixture of methanol/dioxane/4 M NaOH (15/4/1) (57 mmol NaOH), and stirring was carried out for 2 h. The organic solvent was removed in vacuo, and the residue was diluted with ethyl acetate (300 ml) and extracted with 1 M KHSO₄ (300 ml). The organic phase was washed with saturated NaCl solution (200 ml). The organic phase was separated off and dried over Na₂SO₄; filtration was carried out, and the solvent was removed in vacuo. The product was used in the next step without being purified further.
3. 2 M BH₃×DMS in THF (82 mmol) was added slowly at 0° C., with stirring, to a solution of the carboxylic acid (27 mmol) in THF (135 ml). After further cooling for 30 min., stirring was carried out overnight at RT. After removal of the solvent, the crude product was obtained, which was used in the next step without being purified further.
4. n-Bu₄NCl (8.8 mmol) was added to a solution of bromoacetic acid tert-butyl ester (40 mmol) in toluene (100 ml). The reaction mixture was cooled to 0° C., and 35% NaOH (150 ml) and then, dropwise, the alcohol (27 mmol) dissolved in toluene (50 ml) were added. After stirring for 1.5 h at RT, the organic phase was separated off and extracted with water (4×150 ml) and with saturated NaCl solution (150 ml). The organic phase was separated off and dried over Na₂SO₄; filtration was carried out, and then the solvent was removed in vacuo. The crude product was purified by column chromatography.
5. The tert-butyl ester (16 mmol) was stirred overnight at RT in 4 M HCl in dioxane (70 ml, 27 mmol). After removal of the solvent, the crude product was purified by column chromatography.

1. Et₃N (181 mmol) was added to a suspension of DL-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (36 mmol) in CH₂Cl₂ (180 ml). The solution was cooled to 0° C., the sulfonyl chloride (40 mmol) in a solution of CH₂Cl₂ (30 ml) was slowly added dropwise, and stirring was carried out for 2 h at RT. The organic phase was extracted with 1 M HCl (250 ml), H₂O (250 ml). The organic phase was separated off and dried over Na₂SO₄. The solvent was removed in vacuo. The residue was coevaporated with i-propyl ether and the product was used in the next step without being purified further.
2. 4 M NaOH (108 mmol) was added at RT, with stirring, to a solution of the ester (36 mmol) in a solvent mixture of methanol/dioxane/4 M NaOH (15/4/1) (54 mmol NaOH), and stirring was carried out for 2 h. The organic solvent was removed in vacuo, and the residue was diluted with ethyl acetate (300 ml) and extracted with 1 M KHSO₄ (300 ml). The organic phase was washed with saturated NaCl solution (200 ml). The organic phase was separated off and dried over Na₂SO₄; filtration was carried out, and the solvent was removed in vacuo. The product was used in the next step without being purified further.
3. 2 M BH₃×DMS in THF (86 mmol) was slowly added at 0° C., with stirring, to a solution of the carboxylic acid (28 mmol) in THF (140 ml). After further cooling for 30 min., stirring was carried out overnight at RT. After removal of the solvent, the crude product was obtained, which was used in the next step without being purified further.
4. n-Bu₄NCl (9 mmol) was added to a solution of bromoacetic acid tert-butyl ester (42 mmol) in toluene (100 ml). The reaction mixture was cooled to 0° C., and 35% NaOH (150 ml) and then, dropwise, the alcohol (28 mmol) dissolved in toluene (50 ml) were added. After stirring for 1.5 h at RT, the organic phase was separated off and extracted with water (4×150 ml) and with saturated NaCl solution (150 ml). The organic phase was separated off and dried over Na₂SO₄; filtration was carried out, and then the solvent was removed in vacuo. The crude product was purified by column chromatography.
5. The tert-butyl ester (16 mmol) was stirred overnight at RT in 4 M HCl in dioxane (70 ml, 27 mmol). After removal of the solvent, the crude product was purified by column chromatography.

1. 1,2,3,4-tetrahydroquinolin-2-carboxylic acid ethyl ester (25 mmol) in THF (5 ml/mol) was added dropwise at 0° C. to a suspension of LAH (2 eq.) in THF (50 ml). The reaction mixture was stirred for 1 h at RT and then heated under reflux for 4 h. After addition of aqueous saturated Na₂SO₄ solution, filtration was carried out and the organic solvent was removed in vacuo. The product was purified by column chromatography (3:7 ethyl acetate/hexane). Yield: 50%.
2. Pyridine (5 eq.), DMAP (0.5 eq.) and 3,4-dichlorobenzenesulfonyl chloride (1.2 eq.) dissolved in CH₂Cl₂ (50 ml) were added to a suspension, cooled to 0° C., of the alcohol (16 mmol) in CH₂Cl₂ (5 ml/mmol). After stirring for 5 h at 0° C., CH₂Cl₂ was added and the mixture was washed with aqueous copper sulfate solution, water and saturated NaCl solution. After drying over sodium sulfate and filtration, the solvent was removed in vacuo. The product was purified by column chromatography (5:95 ethyl acetate/CH₂Cl₂). Yield: 80%.
3. A solution of the sulfonamide (16 mmol) dissolved in THF (100 ml) was added dropwise, with stirring, to a suspension, cooled to 0° C., of NaH (2 eq.) in THF (300 ml). After stirring for 45 min. at that temperature, a solution of bromoacetic acid tert-butyl ester (1.5 eq.) in THF (50 ml) was added. The reaction mixture was heated for 20 h at 50° C. It was then cooled to 0° C., ice was added, and extraction with ethyl acetate was carried out. The organic phase was washed with aqueous saturated NaCl solution and dried over Na₂SO₄. After filtration, the solvent was removed in vacuo. The product was purified by column chromatography (1:9 ethyl acetate/hexane). Yield: 50%.
4. TFA (13 eq.) was added at a temperature of 0° C., with stirring, to a solution of the tert-butyl ester (1 eq.) in CH₂Cl₂ (10 ml/mmol). After stirring for 3 h at 0° C., the solvent was removed in vacuo. The crude product was used without being worked up further.

Chlorosulfonic acid (251 ml, 3763 mmol) in CH₂Cl₂ (250 ml) was added dropwise to a solution of 3,5-dimethylanisole (102.5 g, 753 mmol) in CH₂Cl₂ (1 l), cooled to 0° C. After 10 min., the reaction mixture was poured onto ice (1 l) and extracted with CH₂Cl₂ (1×250 ml). The organic phase was washed with water (1 l) and with aqueous saturated NaCl solution (1 l). After drying over Na₂SO₄ and filtration, the solvent was removed in vacuo. The product was purified by column chromatography (silica, heptane/CH₂Cl₂, 5:1). Yield: 63.5 g, 36%.

The following structural units were prepared according to these methods:

Structural unit Structure Synthesis method S1 1  S2 1  S3 1  S4 1  S5 1  S6 1  S7 1  S8 1  S9 1  S10 1  S11 1  S12 1  S13 1  S14 1  S15 1  S16 2  S17 1  S18 1  S19 1b S20 1c S21 1c S22 2  S23 — S24 — S25 1b S26 1c S27 3a S28 1  S29 3a S30 1  S31 3b S32 3a S33 3a S34 3a S35 —
S18 was prepared from structural unit

according to method 1.

The amines used were commercially available or were prepared according to methods known to the person skilled in the art or as described below. The following amine structural units were used for the syntheses:

1. 4-bromomethylbenzonitrile (500 mg, 2.55 mmol), K₂CO₃ (388 mg, 2.8 mmol), amine (2.8 mmol) and DMF (6 ml) were stirred for 0.5 to 3 h at RT and then heated for 2 to 6 h at 80-90° C. The reaction mixture was cooled to RT, water (18 ml) was added, and stirring was carried out for 0.5 h at 0-5° C. The precipitates were filtered off, washed with cold water (2×10 ml) and dried in vacuo. The filtrates were extracted with ethyl acetate (3×15 ml) and dried over Na₂SO₄. The organic solvent was removed.
2. A solution of step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml). The reaction mixture was stirred at 25° C.; after 16 to 20 h, it was cooled with ice, and aqueous saturated Na₂SO₄ solution was added dropwise. After filtration and washing the residue with ethyl acetate (3×10 ml), the solvent was largely removed and HCl gas was introduced at 0-5° C. The precipitate was filtered off and washed with ether. The amine hydrochlorides were obtained in the form of products which were used without being worked up further.

1. A reaction mixture of 4-benzonitrile (2 mmol), amine (3 mmol), K₂CO₃ (4 mmol), CuI (0.2 mmol) and L-proline (0.4 mmol) in DMSO (4 ml) was heated for 40 h at 80-90° C., with stirring. After addition of water, extraction with ethyl acetate was carried out. The organic phase was washed with aqueous saturated NaCl solution and dried over Na₂SO₄. After filtration and removal of the solvent, the residue was purified by column chromatography (30% ethyl acetate/CH₂Cl₂).
2. A solution of step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml). The reaction mixture was heated under reflux for 6 h and cooled with ice, and aqueous saturated Na₂SO₄ solution was added dropwise. After filtration, the residue was washed with a solvent mixture (ethyl acetate and 10% methanol, 3×10 ml). After removal of the solvent, the amines were obtained, which were used without being worked up further.

1. Me₂SO₄ (1.01 ml, 10.57 mmol) was added dropwise at 0° C. to a stirred suspension of 4-aminobenzonitrile (0.5 g, 4.23-mmol) in 10% aqueous Na₂CO₃ solution (18 ml). The reaction mixture was stirred for 1 h at 25° C. Further Me₂SO₄ (1.01 ml, 10.57 mmol) and 10% aqueous Na₂CO₃ solution (18 ml) were then added. After addition of water, extraction with ethyl acetate was carried out. The organic phase was separated off, washed with aqueous saturated NaCl solution and dried over Na₂SO₄. After filtration and removal of the solvent, the residue was purified by column chromatography (5% ethyl acetate/hexane).
2. A solution of step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml). The reaction mixture was heated under reflux for 6 h and cooled with ice, and aqueous saturated Na₂SO₄ solution was added dropwise. After filtration, the residue was washed with a solvent mixture (ethyl acetate and 10% methanol, 3×10 ml). The solvent was largely removed in vacuo and the amine was obtained in the form of the hydrochloride by introduction of HCl gas.

1. A reaction mixture of 4-morpholinebenzoic acid (0.5 g) and methanolic HCl solution (6 ml, 4%) was heated under reflux for 6 h, with stirring. After removal of the solvent in vacuo, water (10 ml) was added to the residue and the mixture was neutralized with aqueous saturated NaHCO₃ solution. The solution was extracted with ethyl acetate (3×20 ml). The organic phase was separated off and dried over Na₂SO₄. After filtration and removal of the solvent, the product was obtained, which was used in the next step without being worked up further.
2. A reaction mixture of product step 1 (4 g), NH₃ (25 ml) and methanol (20 ml) was heated for 4 d at 120° C. in an autoclave (pressure 50 kg/cm²). After removal of the solvent in vacuo, the product was purified by column chromatography (50% ethyl acetate/hexane).
3. BH₃×DMS (1.86 ml, 19.4 mmol) was added at 0° C., with stirring, under a nitrogen atmosphere, to a solution of the amide from step 2 (1 g, 4.84 mmol) in THF (15 ml). The reaction mixture was heated under reflux for 18 h and cooled, and methanol was added. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with aqueous saturated NaCl solution. After filtration and drying over Na₂SO₄, the solvent was removed in vacuo and the product was used in the next step without being worked up further.
4. (Boc)₂O (0.82 ml, 3.83 mmol) was added to a solution of the amine from step 3 (0.67 g) dissolved in THF (12 ml), and stirring was carried out for 18 h. The solvent was then removed in vacuo and the product was purified by column chromatography (10% ethyl acetate/hexane).
5. A solution of HCl gas in ethyl acetate (4%) was added to the Boc-protected product from step 4 (280 mg), and stirring was carried out for 2 h at RT. The solvent was removed in vacuo and the residue was taken up in a small amount of ethyl acetate. After filtration and drying in vacuo, the product was obtained in the form of the amine hydrochloride.

1. A solution of triethyl phosphonoacetate (11 mmol) in THF (50 ml) was added slowly to a suspension, cooled to 0° C., of NaH (10 mmol) in THF (50 ml), and the reaction mixture was stirred for 30 min. 1,4-Dioxa-spiro[4.5]decan-8-one (10 mmol) in THF (50 ml) was then added dropwise at 0° C., and stirring was carried out for 16 h. After addition of ice and aqueous saturated NaCl solution, the aqueous phase was washed with ethyl acetate and the organic phase with water and aqueous saturated NaCl solution. The combined organic phases were dried over Na₂SO₄ and, after filtration, the solvent was removed in vacuo. The product was purified by column chromatography (20% ethyl acetate/hexane). Yield: 90%.
2. A solution of the ester (10 mmol) in MeOH (30 ml) was hydrogenated with hydrogen for 16 h under argon with 10% Pd/C (50%). After filtration over Celite, the residue was washed with MeOH and the solvent of the combined organic phases was removed in vacuo. The product was used in the next step without being worked up further.
3. A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)acetic acid ethyl ester (10 mmol) in THF (50 ml) was slowly added over a period of 30 min. to a suspension, cooled to 0° C., of LaH (10 mmol) in THF (30 ml). When the reaction of the ester was complete, the solution was cooled to 0° C., aqueous saturated Na₂SO₄ solution was added, and filtration over Celite was carried out. The solvent was removed in vacuo and the product was used in the next step without being worked up further.
4. Methanesulfonyl chloride (11 mmol) was added dropwise at 0° C., under nitrogen, to a solution of the alcohol (10 mmol) in CH₂Cl₂ (50 ml). The reaction mixture was stirred for a further 2 h and then diluted with CH₂Cl₂. After extraction with aqueous saturated NaCl solution, drying over Na₂SO₄ was carried out. After filtration and removal of the solvent, the crude product was obtained in a yield of 80%.
5. A 2 M solution of methylamine in CH₂Cl₂ (10 ml) was added to a solution of the Ms-protected alcohol (5 mmol) in THF (5 ml), and the reaction solution was heated for 16 h at 100° C. After removal of the solvent in vacuo, the crude product was used in the next step without being worked up further. Yield of crude product: 90%.
6. 6 N HCl (20 ml) was added at 0° C. to [2-(1,4-dioxa-spiro[4.5]dec-8-yl)-ethyl]-methylamine (10 mmol), and stirring was carried out for 16 h at 25° C. The aqueous solution was extracted with ethyl acetate and then adjusted to pH 14 with 6N NaOH. The aqueous phase was extracted with CH₂Cl₂ and the organic phase was washed with water and aqueous saturated NaCl solution. The organic phase was dried over Na₂SO₄ and, after filtration, the solvent was removed. The crude product was used in the next step without being worked up further. Yield of crude product: 80%.
7. Diisopropylamine (37.5 mmol) and di-tert-arylbutyl dicarbonate (22.5 mmol) were added at 0° C. to a solution of 4-(2-methylamino-ethyl)-cyclohexanone (15 mmol) in CH₂Cl₂ (45 ml). The reaction mixture was stirred for 16 h at 25° C. After addition of CH₂Cl₂, extraction with water and aqueous saturated NaCl solution was carried out. The organic phase was separated off and dried over Na₂SO₄. After filtration, the solvent was removed in vacuo and the product was purified by column chromatography (5% methanol/CH₂Cl₂). Yield: 70%.
8. To a solution of the ketone (1 eq.) in methanol (10 ml/mmol) there were added the corresponding amine (1.5 eq.), sodium cyanoborohydride (2 eq.) and acetic acid (2 eq.). The reaction mixture was stirred for 16 h at 25° C. Ice was then added thereto, and the solvent was removed in vacuo. After addition of ethyl acetate, extraction was carried out first with aqueous saturated Na₂CO₃ solution and then with aqueous saturated NaCl solution. The organic phase was separated off, dried over Na₂SO₄ and filtered, and the solvent was removed in vacuo. The product was purified by column chromatography (3% methanol/CH₂Cl₂).
9. 20% TFA in CH₂Cl₂ (5 ml/mmol) was added at 0° C. to the Boc-protected precursor, and the reaction mixture was stirred for 3 h. The solvent was removed in vacuo and the amine was used in the form of the TFA salt in the further synthesis.

Structural Synthesis unit Structure method A1 1 A2 1 A3 1 A4 1 A5 — A6 2 A7 — A8 2 A9 — A10 —

Acid solution (0.05 M in CH₂Cl₂, 2 ml) was added to 105 μmol of CDI solution (0.105 M in CH₂Cl₂, 1 ml), and the mixture was agitated for 1 h at RT. 100 μmol of the amine solution (0.1 M in CH₂Cl₂) were then added at RT, and the mixture was agitated for a further 12 h at RT. 3 ml of water were then added to the reaction mixture, agitation was carried out for 15 min., and the organic phase was separated off. After removal of the solvent by distillation, the crude products were analysed by LC-MS and purified by HPLC.

At RT, 100 μmol of acid solution (0.05 M in CH₂Cl₂, 2 ml) were placed in a vessel, and 105 μmol of CDI solution (0.105 M in CH₂Cl₂, 1 ml) were added. After stirring for 1 h at RT, 100 μmol of the corresponding amine (0.1 M in CH₂Cl₂) were pipetted into the reaction solution. The reaction solution was stirred for 16 h at RT. 3 ml of water were then added, and vortexing and thorough mixing were carried out for 30 min. The magnetic stirrer bar was filtered off, and the vessel was flushed with 1.5 ml of CH₂Cl₂.

The aqueous phase was removed and discarded. 3 ml of H₂O and 0.5 ml of CH₂Cl₂ were added to the organic phase; vortexing was carried out, followed by intensive mixing for 15 min. After centrifugation, the aqueous phase was separated off and discarded. The organic phase was extracted in an analogous manner for a second time with 3 ml of saturated NaCl solution. The organic phase was then removed, introduced into a test glass and dried over a MgSO₄ cartridge. After removal of the solvent by distillation, the crude products were analysed by means of LC-MS and purified by HPLC.

The acids (50 mg, 1 eq.) were reacted with the amine (50-70 mg, 1.2 eq.) in CH₂Cl₂ (3 ml/mmol) using the coupling reagents EDCI (1.5 eq.), HOBt (1 eq.) and DIPEA (2 eq.). After removal of the solvent, the products were purified by column chromatography.

The acids (50 mg, 1 eq.) in CH₂Cl₂ (3 ml/mmol) were stirred for 15 min. at 25° C. with EDCI (1.5 eq.), HOBt (1 eq.) and DIPEA (1.5 eq.). DIPEA (4 eq.) was added at 0° C. to a solution of the amine-TFA salt (1.2 eq.) in CH₂Cl₂ (1 ml/mmol), and the whole was added to the solution of the acid. The reaction mixture was stirred for 16 h at 25° C. and then diluted with CH₂Cl₂. The organic phase was separated off, extracted with aqueous NH₄Cl solution, Na₂CO₃ solution, NaCl solution and then dried over Na₂SO₄. After filtration and removal of the solvent, the products were purified by column chromatography.

The following compounds were prepared according to one of these methods of parallel synthesis.

Example Method Mass 1 1 543.28 2 1 557.29 3 1 558.29 4 1 601.13 5 2 568.31 6 1 535.25 7 1 572.30 9 2 579.17 10 1 587.12 11 1 517.26 12 1 541.30 13 1 602.13 14 1 543.28 15 1 616.14 16 2 601.16 17 1 565.16 18 1 544.27 19 1 491.28 20 1 559.20 21 1 545.26 22 2 546.25 23 2 499.25 24 1 559.27 25 2 556.31 26 1 517.16 27 2 505.30 28 1 546.18 29 1 588.11 30 1 603.11 31 2 527.28 32 1 546.18 33 2 590.29 34 1 549.27 35 1 503.25 36 1 545.19 37 1 561.10 38 1 565.16 39 1 583.13 40 1 558.29 41 2 589.30 42 1 560.20 43 1 626.25 44 1 569.12 45 1 602.13 46 1 507.14 47 1 565.26 48 2 600.37 49 1 589.10 50 2 577.26 51 1 579.17 52 1 521.29 53 1 555.14 54 1 531.17 55 1 545.26 56 1 525.13 57 1 538.15 58 2 534.25 59 1 543.12 60 1 529.26 61 1 551.25 62 1 532.17 63 1 563.28 64 1 513.27 65 2 581.15 66 1 459.22 67 2 575.28 68 1 545.19 69 1 569.29 70 1 567.17 71 1 573.10 72 1 546.18 73 1 547.09 74 1 587.12 75 2 590.29 76 1 527.28 77 2 529.26 78 1 601.16 79 1 601.16 80 1 542.29 81 2 587.14 82 1 579.17 83 2 575.28 84 1 555.14 85 1 534.18 86 1 543.12 87 1 510.23 88 1 520.17 89 1 511.11 90 2 535.30 91 2 529.26 194 4 563.3 209 4 537.3 213 4 595.2 216 4 621.2 218 2 553.2 219 1 515.3 220 1 598.2 221 1 536.3 222 2 552.3 223 2 589.3 224 2 603.1 225 2 505.3 226 2 499.3 227 2 529.3 228 2 541.3 229 2 527.3 230 2 528.3 231 2 520.3 232 2 534.3 233 2 594.2 234 2 596.3 235 2 513.3 236 2 501.2 237 2 501.2 238 2 501.2 239 2 489.2 240 2 535.3 241 2 557.3 242 2 453.2 243 2 513.2 244 2 511.2 245 2 543.3 246 2 529.3 247 2 501.2 248 2 496.3 249 2 627.3 250 2 483.3 251 2 593.2 252 2 573.3 253 2 619.1 254 2 610.2 255 2 627.2 256 2 604.1 257 2 463.2 258 2 496.2 259 2 440.2 260 2 522.3 261 2 516.3 262 2 542.3 263 2 571.3 264 2 521.2 265 2 589.1 266 1 547.2 267 2 522.3 268 2 535.3 269 2 546.3 270 2 552.3 271 2 487.2 272 2 487.2 273 2 487.2 274 2 502.2 275 2 598.3 276 2 611.3 277 2 605.3 278 2 546.2 279 2 559.2 280 2 570.2 281 2 576.2 282 2 511.1 283 2 526.1 284 2 553.2 285 2 532.2 286 2 545.2 287 2 556.2 288 2 545.3 289 2 533.2 290 2 545.3 291 2 481.3 292 2 568.3 293 1 539.1 294 2 613.3 295 2 497.1 296 2 537.1 297 2 553.1 298 2 551.1 299 2 529.3 300 2 543.3 301 2 530.3 302 2 544.3 303 2 529.3 304 2 559.3 305 2 502.2 306 2 531.2 307 2 519.2 308 2 531.2 309 2 503.2 310 2 529.3 311 2 549.2 312 2 527.2 313 2 553.2 314 2 567.2 315 2 553.2 316 2 526.1 317 2 555.1 318 2 543.1 319 2 555.1 320 2 553.2 321 2 573.1 322 2 539.1 323 2 553.2 324 2 541.1 325 2 541.1 326 2 539.1 327 2 587.1 328 2 575.1 329 2 573.1 330 2 566.1 331 2 579.2 332 2 590.1 333 2 596.2 334 2 613.1 335 2 546.1 336 2 531.2 337 2 517.2 338 2 511.1 339 2 497.1 340 2 575.3 341 2 566.4 342 2 583.3 343 2 467.3 344 2 497.3 345 2 461.2 346 2 535.2 347 2 529.3 348 2 569.2 349 2 583.2 350 2 593.2 351 2 557.3 352 2 549.2 353 2 529.3 354 2 545.1 355 2 539.1 356 2 579 357 2 593.1 358 2 603 359 2 559.1 360 2 539.1 361 2 531.3 362 2 543.3 363 2 467.3 364 2 543.3 365 2 529.3 366 2 478.2 367 2 545.3 368 2 573.3 369 2 516.2 370 2 497.2 371 2 500.2 372 2 448.2 373 2 543.3 374 2 507.3 375 2 467.3 376 2 618.2 377 2 531.3 378 2 583.2 379 2 455.3 380 2 497.3 381 2 597.2 382 2 607.2 383 2 571.3 384 2 563.2 385 2 543.3 386 2 559.3 387 2 547.3 388 2 529.3 389 2 545.1 390 2 545.1 391 2 533.1 392 2 601.1 393 2 497.1 394 2 505 395 2 532.2 396 2 532.2 397 2 568.3 398 2 543.3 399 2 521.3 400 2 571.3 401 2 572.3 402 2 598.2 403 2 553.2 404 2 593.1 405 2 607.1 406 2 617.1 407 2 573.1 408 2 553.2 409 2 515.3 410 2 492.2 411 2 586.3 412 2 524.3 413 2 495.3 414 2 543.3 415 2 557.3 416 2 478.2 417 2 604.3 418 2 543.3 419 2 543.3 420 2 526.2 421 2 557.3 422 2 563.3 423 2 549.2 424 2 531.3 425 2 476.2 426 2 478.2 427 2 526.2 428 2 543.3 429 2 529.3 430 2 543.3 431 2 544.3 432 2 558.3 433 2 558.3 434 2 558.3 435 2 545.3 436 2 531.2 437 2 545.3 438 2 531.2 439 2 545.3 440 2 591.1 441 2 593.3 442 2 543.1 443 2 517.2 444 2 533.2 445 2 515.3 446 2 572.3 447 2 501.2 448 2 515.3 449 2 515.3 450 2 543.3 451 2 555.1 452 2 506.2 453 2 525.1 454 2 557.1 455 2 539.1 456 2 525.1 457 2 553.2 458 2 539.1 459 2 511.1 460 2 515.3 461 2 501.2 462 2 559.2 463 2 537.2 464 2 537.2 465 2 569.2 466 2 475.2 467 2 453.2 468 2 570.2 469 2 604.2 470 2 589.3 471 2 528.3 472 2 574.2 473 2 543.3 474 2 553.3 475 2 557.3 476 2 453.2 477 2 528.3 478 2 531.1 479 2 577.3 480 2 539.1 481 2 593.1 482 2 499.1 483 2 477.1 484 2 594.1 485 2 528.1 486 2 547.1 487 2 577.1 488 2 552.2 489 2 541.2 490 2 529.3 491 2 531.2 492 2 521.3 493 2 550.2 494 2 485.2 495 2 570.2 496 2 596.2 497 2 511.1 498 2 555.1 499 2 545.2 500 2 544.3 501 2 485.2 502 2 562.2 503 2 561.3 504 2 486.2 505 2 529.3 506 2 502.1 507 2 551.3 508 2 551.3 509 2 583.2 510 2 489.2 511 2 549.2 512 2 543.3 513 2 541.2 514 2 584.2 515 2 567.1 516 2 519.2 517 2 453.2 518 2 493.3 519 2 509.3 520 2 507.3 521 2 572.3 522 2 481.3 523 2 481.3 524 2 536.3 525 2 526.2 526 2 572.2 527 2 536.1 528 2 553.2 529 2 553.2 530 2 555.2 531 2 541.2 532 2 495.3 533 2 549.3 534 2 551.3 535 2 450.2 536 2 512.2 537 2 546.2 538 2 572.2 539 2 518.2 540 2 542.2 541 2 542.2 542 2 530.2 543 2 542.2 544 2 526.2 545 2 512.2 546 2 497.2 547 2 555.3 548 2 566.3 549 2 569.2 550 2 593.1 551 2 594 552 2 493.1 553 2 582.1 554 2 616.1 555 1 530.3 556 1 545.2 557 1 572.3 558 1 531.2 559 2 560.3 560 2 586.3 561 2 540.3 562 2 598.3 563 2 612.3 564 2 534.2 565 2 546.2 566 2 520.2 567 2 532.2 568 2 533.2 569 2 588.2 570 2 600.2 571 2 546.3 572 2 534.3 573 2 548.3 574 2 621.1 575 3 533.1 576 3 489.2 577 3 503.3 578 3 547.1 579 3 531.2 580 3 575.1 581 3 589.1

N,N′-Carbonyldiimidazole (114 mg, 0.706 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (250 mg, 0.673 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (123 mg, 0.673 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was then extracted with water (20 ml) and saturated sodium chloride solution (20 ml), and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using dichloromethane/methanol (97:3→90:10).

Yield: 296 mg (82%), brown resin

¹H-NMR (600 MHz, DMSO-d₆): 1.27 (1H); 1.42 (1H); 1.55 (4H); 1.69 (2H); 1.79 (1H); 1.89 (2H); 2.18 (3H); 2.40 (4H); 2.53 (6H); 2.83 (2H); 2.95 (1H); 3.26 (4H); 3.38 (3H); 3.50 (1H); 3.66 (1H); 3.80 (4H); 4.05 (2H); 6.79 (2H).

N,N′-Carbonyldiimidazole (272 mg, 1.696 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (600 mg, 1.615 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (293 mg, 1.615 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (20 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic phases were extracted with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using dichloromethane/methanol (5:1). 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone (590 mg, 1.105 mmol) was dissolved in methyl ethyl ketone/ethanol (1:1) (20 ml) [plus a few drops of acetone], and chlorotrimethylsilane (168 μl, 1.326 mmol) was added slowly. Diethyl ether (20 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.

Yield: 430 mg (44%), white solid

HPLC-MS, m/z 537.2 (MH⁺)

N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 3-(piperazin-1-ylmethyl)benzonitrile (81 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/hexane (20:1). 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazin-1-yl)methyl)benzonitrile (100 mg, 0.180 mmol) was dissolved in methyl ethyl ketone (3 ml), and chlorotrimethylsilane (27 μl, 0.216 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.

Yield: 100 mg (42%), white solid

¹H-NMR (400 MHz, DMSO-d₆): 1.24 (1H); 1.54 (4H); 1.79 (1H); 2.53 (6H); 2.79 (3H); 2.94 (2H); 3.10 (1H); 3.28 (3H); 3.36 (5H); 3.55 (1H); 3.69 (1H); 3.85 (1H); 4.12 (2H); 4.39 (2H); 6.79 (2H); 7.69 (1H); 7.95 (2H); 8.10 (1H); 11.65 (1H).

N,N′Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 3-(piperazin-1-ylmethyl)benzonitrile (84 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/hexane/ammonia solution (25% aq.) (100:10:1). 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetyl)piperazin-1-yl)methyl)benzonitrile (190 mg, 0.351 mmol) was dissolved in acetone/diethyl ether (1:1; 8 ml), and chlorotrimethylsilane (89 μl, 0.702 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.

Yield: 200 mg (83%), white solid

HPLC-MS, m/z 541.2 (MH⁺)

N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (73 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol/ammonia solution (25% aq.) (400:100:5). 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(4-(2-(pyrrolidin-1-yl)ethyl)piperidin-1-yl)ethanone (160 mg, 0.299 mmol) was dissolved in methyl ethyl ketone (3 ml), and trimethylchlorosilane (75 μl, 0.358 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.

Yield: 100 mg (43%), white solid

¹H-NMR (400 MHz, DMSO-d₆): 1.25 (1H); 1.60 (10H); 1.84 (4H); 1.97 (2H); 2.53 (6H); 2.92 (5H); 3.11 (2H); 3.30 (2H); 3.50 (1H); 3.66 (3H); 3.80 (5H); 4.03 (2H); 4.29 (1H); 6.80 (2H); 10.69 (1H).

N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (76 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol/ammonia solution (25% aq.) (400:100:5).

Yield: 190 mg (87%), colorless oil

HPLC-MS, m/z 522.3 (MH⁺)

N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1,2,3,4-tetrahydro-2,6-naphthyridine (54 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol (20:1). 1-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone (197 mg, 0.404 mmol) was dissolved in methyl ethyl ketone (5 ml), and trimethylchlorosilane (61 μl, 0.516 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.

Yield: 135 mg (64%), white solid

¹H-NMR (400 MHz, DMSO-d₆): 1.25 (1H); 1.55 (4H); 1.80 (1H); 2.52 (6H); 2.96 (3H); 3.27 (2H); 3.58 (2H); 3.72 (2H); 3.77 (3H); 3.84 (1H); 4.20 (2H); 4.85 (2H); 6.77 (2H); 7.85 (1H); 8.69 (1H); 8.79 (1H); (OH masked).

The example compounds listed in the following table were prepared from acid structural unit S27 by reaction with the corresponding amines (R⁵R⁶NH) closely following the processes described for Examples 8 and 92-96. The amines used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes. Instead of the solvent dichloromethane, the solvent N,N-dimethylformamide was used in the synthesis of the following example compounds: Example 113, 143 and 146. For the preparation of example compounds in which amines were used which were not in the form of the free base but in the form of the corresponding hydrochlorides (×HCl), a corresponding amount of triethylamine was added to the reaction (eq. Et₃N=×HCl). For Example 99, the formation of the hydrochloride was carried out analogously to the process described for Example 97. Examples 106 and 112 were converted into the corresponding hydrochlorides (×HCl) by the following general process: The free bases were in each case dissolved in a small amount of methyl ethyl ketone, and 2 M hydrogen chloride solution in diethyl ether (4-5 eq.) was added. Where appropriate, the mixture was cooled to 0° C. and/or diethyl ether was added before the hydrochloride (×HCl) was filtered out.

Example No. Amine (R⁵R⁶NH) Yield (%) MS, m/z (MH⁺)  98 2-(piperidin-4-yl)octahydro-1H-pyrido[1,2-a]pyrazine 94 577.3 trihydrochloride  99 2-(piperidin-4-yl)octahydro-1H-pyrido[1,2-a]pyrazine 30 577.3 trihydrochloride 100 2-(piperidin-4-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine 82 571.3 trihydrochloride 101¹ tert-butyl piperazine-1-carboxylate 89 540.3 103 5-(piperidin-4-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole 89 584.3 106 1-((1-methylpiperidin-4-yl)methyl)piperazine 87 551.3 112 1-methyl-4-(piperidin-4-yl)piperazine 69 537.3 113 4-(piperazin-1-yl)thieno[3,2-d]pyrimidine 78 574.2 143 2-(1-(pyridin-4-yl)piperidin-4-yl)ethanamine 55 559.2 dihydrochloride² 146 (4-methylpiperazin-1-yl)(piperidin-4-yl)methanone 66 565.2 hydrochloride (xHCl) 147 1-(pyridin-4-yl)piperazine 62 517.2 165 3-(piperidin-4-yloxy)pyridine hydrochloride 23 532.2 168 7-(piperazin-1-yl)-4-(pyrrolidin-1-yl)quinazoline 63 637.3 dihydrochloride (C) 188 4-(piperidin-4-ylmethoxy)pyridine dihydrochloride 82 546.3 ¹This compound was additionally also obtained in a smaller yield of 80% by reaction in the presence of ECDI/HOBt in dichloromethane. ²The amine can be prepared analogously to the synthesis described in WO 2006/071775.

(i) Pd(PPh₃)₂Cl₂ (1.07 g, 1.52 mmol), trimethylsilylacetylene (18.9 ml, 133 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (17.1 g, 152 mmol) and copper(I) iodide (145 mg, 0.76 mmol) were added in succession, under nitrogen, to a solution of 3-bromo-4-pyridine carboxaldehyde (14.16 g, 76.1 mmol) in dry tetrahydrofuran (140 ml). The reaction mixture was stirred for 1 h, filtered off over Celite, washed with tetrahydrofuran and concentrated. The residue was purified by column chromatography (heptane/ethyl acetate, 9:1→9:2).

Yield: 14.62 g (94%)

(ii) A solution of 3-((trimethylsilyl)ethynyl)isonicotinaldehyde (13.22 g, 65.0 mmol) in ethanol (300 ml), under nitrogen, was refluxed for 7.5 h with the simultaneous continuous addition of ammonia. The mixture was then concentrated, and the residue was taken up in ethyl acetate and filtered over silica gel. The crude product was dissolved in hot hexane and decanted off twice. The filtrate was concentrated and crystallized from hexane/diisopropyl ether.

Yield: 3.29 g (39%)

(iii) Platinum(IV) oxide (223 mg, 0.984 mmol) was added to a suspension of calcium oxide (758 mg, 13.5 mmol) and 2,6-naphthyridine (1.60 g, 12.3 mmol) in 2-methoxyethanol (15 ml), under nitrogen. The reaction mixture was stirred overnight under a hydrogen atmosphere and then filtered over Celite, washed with ethanol, concentrated in vacuo and coevaporated with dichloromethane. The residue was taken up in ethyl acetate, filtered over a microfilter, washed with ethyl acetate and concentrated again. The residue was combined with a second batch, which was prepared analogously (from 1.66 g (12.8 mmol) of 2,6-naphthyridine), and coevaporated with toluene (2×) and dichloromethane (2×). The crude product was then dried overnight in vacuo. Purification was carried out by means of column chromatography (heptane/dichloromethane/7 M ammonia solution in methanol, 10:30:2). Coevaporation with dichloromethane was then carried out.

Yield: 2.83 g (84%)

(iv) 1,2,3,4-tetrahydro-2,6-naphthyridine (1.16 g, 8.65 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.72 g, 8.65 mmol) were dissolved in 1,2-dichloroethane (20.5 ml). Sodium triacetoxyborohydride (2.56 g, 12.10 mmol) and acetic acid (0.49 ml, 8.65 mmol) were added to this solution at room temperature. The reaction mixture was stirred for 15 h at room temperature, and then saturated sodium hydrogen carbonate solution (20 ml) was added and stirring was carried out for 30 min. The aqueous phase was extracted with diethyl ether (2×30 ml) and the organic phase was in turn washed with saturated sodium chloride solution (20 ml). The organic phase was dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/hexane/methanol/ammonia solution (25% aq.) (100:10:10:1).

Yield: 2.26 g (82%)

(v) Hydrogen chloride (28.48 ml, 35.60 mmol, 1.25 M solution in methanol) was added at room temperature to a solution of tert-butyl 4-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-piperidine-1-carboxylate (2.26 g, 7.12 mmol) in methanol (10 ml). The reaction mixture was refluxed for 30 min. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol, and diethyl ether was added. The mixture was then cooled in an ice bath for 30 min., and the resulting solid was filtered off and dried.

Yield: 2.09 g (90%)

The amine was prepared analogously to 2-(piperidin-4-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine trihydrochloride from octahydro-1H-pyrido[1,2-a]pyrazine and tert-butyl 4-oxopiperidine-1-carboxylate (steps iv and v).

(i) 1-methylpiperazine (2.20 ml, 19.84 mmol) and 4-methylmorpholine (4.37 ml, 39.68 mmol) were added to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.82 mmol) in N,N-dimethylformamide (76.3 ml). Benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (11.44 g, 25.79 mmol) was then added to the mixture, and stirring was carried out for 15 h at room temperature. Concentration in vacuo was then carried out. The residue was taken up in ethyl acetate (100 ml) and saturated sodium hydrogen carbonate solution (100 ml), and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with saturated sodium chloride solution (30 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (40:10:0.5).

Yield: 5.61 g (83%)

(ii) Hydrogen chloride (49.46 ml, 61.83 mmol, 1.25 M solution in methanol) was added at room temperature to tert-butyl 4-(4-methylpiperazine-1-carbonyl)piperidine-1-carboxylate (4.81 g, 15.46 mmol), and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, and the residue was taken up in a small amount of ethanol; methyl ethyl ketone and diethyl ether were added, and refluxing was carried out for 40 min. The mixture was then cooled slowly to room temperature and then cooled for 30 min. in an ice bath. The resulting solid was filtered off and dried.

Yield: 3.83 g (88%)

(i) tert-butyl-4-hydroxypiperidine-1-carboxylate (1.85 g, 9.20 mmol) and triphenylphosphine (2.41 g, 9.20 mmol) were added at room temperature to a solution of 3-pyrrolidinol (700 mg, 7.36 mmol) in tetrahydrofuran (10 ml). Diisopropyl-azodicarboxylate (1.79 ml, 125.1 mmol) was then added dropwise, and the mixture was then stirred for 15 h at 55° C. The solvent was removed in vacuo, and the residue was taken up in 1 M hydrochloric acid (20 ml) and extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with 1 M hydrochloric acid (20 ml) and water (20 ml). The aqueous phases were combined, adjusted to pH 12 with 1 M sodium hydroxide solution and then extracted with dichloromethane (4×20 ml). The organic phase was then washed with saturated sodium chloride solution (20 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was then purified by column chromatography (silica gel) using ethyl acetate/hexane (10:1).

Yield: 410 mg (20%)

[analogous process see: J. Chao et al., Tetrahedron Lett., 2007, 48, 791]

(ii) Hydrogen chloride (4.71 ml, 5.89 mmol, 1.25 M solution in methanol) was added at room temperature to a solution of tert-butyl 4-(pyridin-3-yloxy)piperidine-1-carboxylate (410 mg, 1.473 mmol) in methanol (2-5 ml), and the reaction mixture was refluxed for 30 min. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol, and diethyl ether was added. Cooling in an ice bath was then carried out for 30 min., and the resulting solid was filtered off and dried.

Yield: 270 mg (85%)

The amine was prepared analogously to 3-(piperidin-4-yloxy)pyridine hydrochloride from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 3-pyrrolidinol.

7-Chloro-4-(pyrrolidin-1-yl)quinazoline (A) was prepared from 2-amino-4-chlorobenzoic acid analogously to the following procedure, known from the literature, for the preparation of aminoquinazolines: H. Hayashi et al., Bioorg. Med. Chem., 2003, 11, 383. [Review zur Synthese von Chinazolinen: P. J. Guiry et al., Tetrahedron, 2005, 61, 10153.]

Potassium tert-butoxide (998 mg, 8.99 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropyl-biphenyl (X-Phos) (79 mg, 0.18 mmol) and tris-(dibenzylideneacetone)-dipalladium [Pd₂(dba)₃] (36 mg, 0.036 mmol) were added, under nitrogen, to a mixture of 7-chloro-4-(pyrrolidin-1-yl)quinazoline (A) (840 mg, 3.59 mmol) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.39 mmol) in toluene (49 ml). The reaction mixture was then heated for 15 h at 100° C. The reaction mixture was cooled to room temperature, and water (25 ml) and ethyl acetate (25 ml) were added. The aqueous phase was extracted with ethyl acetate (2×25 ml), and the combined organic phases were washed with saturated sodium chloride solution (20 ml). The organic phase was then dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/dichloromethane/ammonia solution (25% aq.) (50:10:0.5) and ethyl acetate/dichloro-methane/methyl tert-butyl ether/ammonia solution (25% aq.) (50:10:10:0.7).

Yield: 700 mg (51%)

tert-butyl 4-(4-(pyrrolidin-1-yl)quinazolin-7-yl)piperazine-1-carboxylate (B) (130 mg, 0.339 mmol) was dissolved at room temperature in methanol (2 ml), and then hydrogen chloride (2.71 ml, 3.39 mmol, 1.25 M solution in methanol) was added. The reaction mixture was refluxed for 1 h and then stirred for 15 h at room temperature. Concentration in vacuo was carried out, and the residue was taken up in a small amount of ethanol and heated. Diethyl ether was then added, the mixture was cooled in an ice bath, and finally the resulting solid was filtered off.

Yield: 103 mg (85%)

Example Compound 137 was prepared from acid structural unit S32 in a yield of 79% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96. MS, m/z 535.2 (MH⁺)

Example compound 164 was prepared from the corresponding acid structural unit in a yield of 80% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96. The acid structural unit was prepared analogously to the process described under Method 1 for the preparation of acid structural units for parallel synthesis.

MS, m/z 551.2 (MH⁺)

Example Compound 178 was prepared from the corresponding acid structural unit in a yield of 29% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96. The acid structural unit was prepared analogously to the process described under Method 1 for the preparation of acid structural units for parallel synthesis. The hydrochloride precipitation of the free base relating to Example 178 was carried out from a methyl ethyl ketone/diethyl ether solution of the base with addition of 2 M hydrogen chloride solution in diethyl ether.

MS, m/z 577.2 (MH⁺)

Step (i): tert-butyl 2-bromoacetate (4.1 ml, 27.88 mmol) was added at room temperature to a mixture of tetra-n-butylammonium hydrogen sulfate (625 mg, 1.859 mmol), aqueous sodium hydroxide solution (18.58 g, 464.69 mmol in water (20 ml)) and toluene (15 ml), and then the mixture was cooled to 0° C. A solution of tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (4.0 g, 18.587 mmol) in toluene (10 ml) was then added slowly. The reaction mixture was heated to room temperature and stirred for 1 h at that temperature. The phases were separated and the aqueous phase was extracted with diethyl ether (2×25 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using hexane/diethyl ether (3:1).

Yield: 3.53 g (58%)

Step (ii): tert-butyl 2-((2-tert-butoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (3.53 g, 10.717 mmol) was dissolved in tetrahydrofuran (20 ml), and sodium hydroxide solution (1.71 g, 42.87 mmol in water (2 ml)) was added. The reaction mixture was heated for 3 h at 90° C. and then cooled to room temperature again. The pH value of the mixture was adjusted to pH 2 with 2M hydrochloric acid, and extraction with ethyl acetate (3×30 ml) was then carried out. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next synthesis step without being purified further.

Yield: 3.28 g (>99%)

Step (iii): N,N′-Carbonyldiimidazole (2.02 g, 12.563 mmol) was added to a solution of 2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methoxy)acetic acid (3.27 g, 11.965 mmol) in dichloromethane (15 ml), and stirring was carried out for 1.5 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (2.19 g, 11.965 mmol) in dichloromethane (15 ml) was then added, and the reaction mixture was stirred for 3 d at room temperature. Saturated sodium hydrogen carbonate solution (30 ml) was added to the mixture, and then the aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with saturated sodium chloride solution (30 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/dichloromethane/ammonia solution (25% aq.) (400:100:100:5).

Yield: 4.57 g (87%)

Step (iv): Hydrogen chloride (26.0 ml, 52.10 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of tert-butyl 2-((2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)methyl)piperidine-1-carboxylate (4.57 g, 10.42 mmol) in a mixture of ethyl acetate (15 ml) and diethyl ether (50 ml). The reaction mixture was stirred for 2 h at 45° C. Then the resulting white solid was filtered off and dried.

Yield: 3.59 g (77%)

Step (v): Triethylamine (0.221 ml, 1.608 mmol) and then 2,4,6-trimethylbenzenesulfonyl chloride (105 mg, 0.482 mmol) were added at 0° C. to a solution of 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride (180 mg, 0.402 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated slowly to room temperature, stirred for 15 h at that temperature and then refluxed for 1 h. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the mixture, and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (300:100:5). Yield: 90 mg (43%), yellow oil; MS, m/z 520.3 (MH⁺)

Step (v): 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride (150 mg, 0.335 mmol) was dissolved at room temperature in a mixture of dichloromethane (5 ml) and triethylamine (0.208 ml, 1.507 mmol), and 2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl chloride (156 mg, 0.503 mmol) in dichlormethane (5 ml) was added. The reaction mixture was stirred for 3 d at that temperature, and then saturated sodium hydrogen carbonate solution (5 ml) was added thereto. The aqueous phase was extracted with dichloromethane (2×20 ml), and the combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was then purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (200:100:3). Yield: 120 mg (58%), yellow oil; MS, m/z 614.2 (MH⁺)

The example compounds listed in the following table were prepared from 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride by reaction with the corresponding sulfonyl chlorides (R¹SO₂Cl) closely following the process described for Example 108 (step (v)). The progress of the reaction was monitored by thin-layer chromatography; the reaction time was in most cases from 15 h to 3 d. The amounts of the reagents used varied as follows: sulfonyl chloride (from 0.9 to 1.5 eq.), triethylamine (3.5-4.5 eq.). The reactions were in some cases carried out in tetrahydrofuran as an alternative to dichloromethane. The sulfonyl chlorides used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes. Furthermore, for Examples 141, 155, 156, 158, 159, 169 and 170, the bases were converted into the corresponding dihydrochlorides (2×HCl) according to the following general process: The free bases were in each case dissolved in a small amount of dichloromethane or methyl ethyl ketone, and 2 M hydrogen chloride solution in diethyl ether (4-5 eq.) was added. In some cases, the mixture was cooled to 0° C. and/or diethyl ether was added thereto, before the dihydrochloride was filtered out.

Example No. Sulfonyl chloride (R¹SO₂Cl) Yield (%) MS, m/z (MH⁺) 109 2-Chloro-6-methylbenzene-1-sulfonyl 85 527.2 chloride 110 Naphthalene-1-sulfonyl chloride 79 529.3 111 Naphthalene-2-sulfonyl chloride 79 529.3 114 4-Chloro-2,5-dimethylbenzene-1-sulfonyl 24 541.2 chloride 115 4-Chloro-3-(trifluoromethyl)benzene-1- 51 581.2 sulfonyl chloride 118 2,4,6-Trichlorobenzene-1-sulfonyl chloride 46 583.1 119 2,4,6-Triisopropylbenzene-1-sulfonyl chloride 54 605.4 120 2,4-dichlorobenzene-1-sulfonyl chloride 60 547.2 128 5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl 39 531.3 chloride 129 6-Chloroimidazo[2,1-b]thiazole-5-sulfonyl 37 559.2 chloride 131 3-(o-Tolyloxy)benzene-1-sulfonyl chloride 71 585.3 138 2-Chloro-4-(trifluoromethyl)benzene-1- 48 581.2 sulfonyl chloride 139 2-Chlorobenzene-1-sulfonyl chloride 38 513.1 141 2,6-dichlorobenzene-1-sulfonyl chloride 43 547.1 151 5-Chloro-3-methylbenzo[b]thiophene-2- 41 583.1 sulfonyl chloride 153 2,5-Bis(trifluoromethyl)benzene-1-sulfonyl 58 615.1 chloride 154 7-Chlorobenzo[c][1,2,5]oxadiazole-4-sulfonyl 27 555.1 chloride 155 4-methylnaphthalene-1-sulfonyl chloride 44 543.2 156 2,4,5-Trichlorobenzene-1-sulfonyl chloride 21 581.0 158 5-(Dimethylamino)naphthalene-1-sulfonyl 56 572.2 chloride 159 2-methylbenzene-1-sulfonyl chloride 55 493.2 169 4-Fluoro-2,6-dimethylbenzene-1-sulfonyl 47 525.2 chloride 170 2,5-dichlorothiophene-3-sulfonyl chloride 54 553.1 171 Benzo[b]thiophene-2-sulfonyl chloride 59 535.2 172 2,5-Dimethylthiophene-3-sulfonyl chloride 57 513.2

Chlorosulfonic acid (54.3 ml, 4 eq.) was added dropwise at 0° C., over a period of 45 min., to a solution of 1-fluoro-3,5-dimethylbenzene (25 g) in dichloromethane (250 ml). The reaction mixture was then stirred for 1 h at room temperature, and the progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was poured onto ice, and the aqueous phase was extracted with dichloromethane (3×150 ml). The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was then purified by column chromatography. Yield: 19.5 g (44%), white solid.

Step (i): Hydrogen chloride (1.15 ml, 2.30 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazine-1-carboxylate (Example 101) (310 mg, 0.574 mmol) in diethyl ether (2-5 ml). The reaction mixture was stirred for 2 h at room temperature and then refluxed for 10 min. The resulting solid was filtered off and dried. Yield: 210 mg (77%), white solid

Reaction with Ketones:

Step (ii): 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) (90 mg, 0.189 mmol) and dihydro-2H-pyran-4(3H)-one (0.017 ml, 0.189 mmol) were dissolved in a mixture of 1,2-dichloroethane (4 ml) and triethylamine (0.026 ml, 0.189 mmol). Sodium triacetoxyborohydride (56 mg, 0.265 mmol) and acetic acid (0.011 ml, 0.189 mmol) were added at room temperature to that solution. The reaction mixture was stirred for 1 h at room temperature, and then saturated sodium hydrogen carbonate solution (5 ml) was added thereto. The aqueous phase was extracted with diethyl ether (2×20 ml), and the organic phase was in turn washed with saturated sodium chloride solution (10 ml). The organic phase was dried (MgSO₄) and concentrated in vacuo, and the crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol (10:1). Yield: 90 mg (91%), yellow oil; MS, m/z 524.3 (MH⁺)

The example compounds listed in the following table were prepared from 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) by reaction with the corresponding ketones (R^aR^bC═O) closely following the process described for Example 104 (step (ii)). The reactions were monitored by thin-layer chromatography and had reaction times of from 1 to 15 h. The ketones used are commercially available.

Example MS, m/z No. Ketone (R^aR^bC═O) Yield (%) (MH⁺) 105 4-methylcyclohexanone 20 536.3 134 4-(trifluoromethyl)cyclohexanone 19 590.3
Reaction with Aldehydes:

Step (ii): 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) (150 mg, 0.315 mmol) was suspended in a mixture of tetrahydrofuran (3 ml) and triethylamine (0.052 ml, 0.378 mmol). 1H-benzo[d]-imidazole-2-carbaldehyde (55 mg, 0.378 mmol) was added at room temperature to the suspension, and the resulting mixture was stirred for 10 min. at room temperature. Sodium triacetoxyborohydride (267 mg, 1.26 mmol) was then added, and stirring was carried out for a further 3 d at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was added to the reaction mixture, and extraction with ethyl acetate (4×10 ml) was carried out. The organic phase was dried (MgSO₄) and concentrated in vacuo, and the crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (100:1:1). Yield: 60 mg (33%), yellow solid; MS, m/z 570.3 (MH⁺)

The example compound shown in the following table was prepared from 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) by reaction with the corresponding aldehyde (R^aR^bC═O) closely following the process described for Example 117 (step (ii)). The aldehyde used is commercially available.

Example MS, m/z No. Aldehyde (R^aR^bC═O) Yield (%) (MH⁺) 166 Quinoxaline-6-carbaldehyde 90 582.2

Step (i): Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperazine-1-carboxylate (Example 101) (1 eq.) in dichloromethane (10 ml/mmol). The reaction mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The crude product was used in the next synthesis step without being purified further.

Step (ii): 4-Chloro-2-phenyl-1H-imidazole-5-carbaldehyde (1.5 eq.) and acetic acid (cat.) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone (1 eq.) in dichloromethane (25 ml/mmol). The reaction mixture was stirred for 30 min. at 25° C., then sodium triacetoxyborohydride (4 eq.) was added and stirring was carried out for a further 16 h at 25° C. The mixture was diluted with dichloromethane and washed with saturated bicarbonate solution and saturated sodium chloride solution. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography using 3% methanol in ethyl acetate. Yield: 50%; MS, m/z 630.2 (MH⁺)

The example compounds listed in the following table were prepared from 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone by reaction with the corresponding aldehydes (R^aHC═O) closely following the process described for Example 197 (step (ii)). The aldehydes used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes.

Example Yield MS, m/z No. Aldehyde (R^aHC═O) (%) (MH⁺) 198 1,5-Dimethyl-1H-pyrazole-4-carbaldehyde 40 548.2 199 2-(Dimethylamino)pyrimidine-5- 30 575.2 carbaldehyde 212 2-(1-methylpiperidin-4-yl)acetaldehyde 40 565.3 214 2-((4- 10 655.3 Fluorophenyl)(methyl)amino)pyrimidine- 5-carbaldehyde

Step (i): To a solution of 5-bromo-2-chloropyrimidine (2.5 mmol) in dimethyl sulfoxide (6.5 ml) there was added 4-fluoro-N-methylaniline, followed by potassium carbonate (5 mmol). The resulting solution was heated for 2 h at 120° C., and the progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in hexane). Yield: 35%

Step (ii): Copper cyanide (2 eq.) was added to a solution of 5-bromo-N-(4-fluorophenyl)-N-methylpyrimidine-2-amine (1 mmol) in dimethylformamide (3 ml/mmol). The resulting solution was heated for 18 h at 100° C., and the progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by column chromatography (20% ethyl acetate in hexane). Yield: 25%

Step (iii): Diisobutylaluminium hydride (1 M solution, 0.75 mmol) was added to a cold solution of 2-((4-fluorophenyl)(methyl)amino)pyrimidine-5-carbonitrile (0.5 mmol) in benzene (8 ml). The resulting solution was stirred for 4 h at 25° C. The reaction mixture was then cooled to 0° C. again, and 10% hydrochloric acid (5 ml) was added dropwise. The mixture was then heated slowly to 25° C. and stirred for 2 h. The reaction mixture was neutralized with saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was used directly in the next synthesis step.

Step (i): A solution of potassium tert-butoxide (13.27 mmol) in tetrahydrofuran (2 ml/mmol) was added dropwise at 0° C., under argon, to a solution of methoxy-methyl-triphenyl-phosphine (8.84 mmol) in dry tetrahydrofuran (2 ml/mmol). The resulting solution was stirred for 30 min. at 25° C. The reaction mixture was then cooled to 0° C., and a solution of 1-methylpiperidin-4-one (4.42 mmol) in dry tetrahydrofuran (2 ml/mmol) was added dropwise. The mixture was stirred for 16 h at 25° C. until the reaction was complete. The mixture was then cooled to 0° C., 6 N hydrochloric acid (22 ml) was added dropwise, and stirring was carried out for 1 h. The aqueous phase was washed with diethyl ether (10 ml) and then rendered basic with 5 N sodium hydroxide solution and extracted with dichloromethane (4×75 ml). The organic phase was washed with saturated sodium chloride solution, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was used directly in the next synthesis step. Yield: 95%

Step (ii): A solution of potassium tert-butoxide (11.7 mmol) in dry tetrahydrofuran (2 ml/mmol) was added dropwise at 0° C., under argon, to a solution of methoxy-methyl-triphenylphosphine (7.8 mmol) in dry tetrahydrofuran (2 ml/mmol). The resulting solution was stirred for 30 min. at 25° C. The reaction mixture was then cooled to 0° C., and a solution of 1-methylpiperidine-4-carbaldehyde (3.9 mmol) in dry tetrahydrofuran (2 ml/mmol) was added dropwise. The mixture was stirred for 16 h at 25° C. until the reaction was complete. The mixture was then cooled to 0° C., 6 N hydrochloric acid (22 ml) was added dropwise, and stirring was carried out for 1 h. The aqueous phase was washed with diethyl ether (10 ml) and then rendered basic with 5 N sodium hydroxide solution and extracted with dichloromethane (4×75 ml). The organic phase was washed with saturated sodium chloride solution, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was used directly in the next synthesis step. Yield: 95%

Step (i): 4-piperidone monohydrate hydrochloride (260 mg, 2.692 mmol), triethylamine (0.560 ml, 4.038 mmol) and then 4-methylmorpholine (1.62 ml, 14.805 mmol) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (acid structural unit S27) (1.0 g, 2.692 mmol) in N,N-dimethylformamide (20 ml). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.42 g, 3.230 mmol) was then added to the mixture, and stirring was carried out for 3 d at room temperature. The mixture was then concentrated in vacuo, and the residue was taken up in ethyl acetate (30 ml) and saturated sodium hydrogen carbonate solution (20 ml); the aqueous phase was extracted with ethyl acetate (4×10 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (20 ml) and saturated sodium chloride solution (20 ml), dried (MgSO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using diethyl ether/dichloromethane/ammonia solution (25% aq.) (100:100:2). Yield: 430 mg (35%); MS, m/z 540.3 (MH⁺)

Step (ii): 1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)-piperidin-4-one (Example 116) (100 mg, 0.221 mmol) and 4-fluoropiperidine hydrochloride (30 mg, 0.221 mmol) were dissolved in a mixture of 1,2-dichloroethane (4 ml) and triethylamine (0.036 ml, 0.265 mmol). Sodium triacetoxyborohydride (66 mg, 0.309 mmol) and acetic acid (0.013 ml, 0.221 mmol) were added at room temperature to the mixture. The reaction mixture was stirred for 15 h at room temperature, and then saturated sodium hydrogen carbonate solution (5 ml) was added thereto. The aqueous phase was extracted with diethyl ether (2×20 ml), and the organic phase was in turn washed with saturated sodium chloride solution (10 ml). The organic phase was dried (MgSO₄) and concentrated in vacuo, and the crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol (20:1). Yield: 70 mg (59%); MS, m/z 540.3 (MH⁺)

The example compounds listed in the following table were prepared from 1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperidin-4-one (Example 116) by reaction with the corresponding amines (R^cR^dNH) closely following the process described for Example 130 (step (ii)). The reactions were monitored by thin-layer chromatography and had reaction times of about 15 h. In some cases, additional sodium triacetoxyborohydride was added subsequently. If the amine was not present in the form of the hydrochloride (×HCl), no triethylamine was added. The amines used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized by described processes.

Example Yield MS, m/z No. Amines (R^cR^dNH) (%) (MH⁺) 136 2-Morpholino-2-(pyridin-3-yl)ethanamine 79 644.4 144 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 70 560.2 145 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- 75 561.2 a]pyrazine

Step (i): A mixture of 2-aminopyrazine (25 g, 262.9 mmol) and chloroacetaldehyde (50% solution in water, 50 ml, 394 mmol) was heated for 2 d at 100° C. in the presence of sodium hydrogen carbonate (33.1 g, 394 mmol). The reaction mixture was cooled to room temperature, and saturated potassium carbonate solution (100 ml) was added thereto. Extraction with dichloromethane was then carried out, and the organic phase was dried (Na₂SO₄) and concentrated. Purification was carried out by column chromatography (dichloromethane/methanol 95:5+5% NH₄OH [35%]). Yield: 7.6 g (24%)

Step (ii): Imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmol) was dissolved in 2-methoxyethanol (100 ml). Platinum(IV) oxide (1.2 g, 5.13 mmol) was added, and the mixture was stirred overnight at room temperature, under a hydrogen atmosphere of 4 bar, in an autoclave. The reaction mixture was flooded with nitrogen, filtered over Celite, concentrated and coevaporated with toluene. Purification was carried out by column chromatography dichloromethane/7 N ammonia in methanol 95:5). Yield: 5.7 g (76%)

Step (i): N,N-Dimethylformamide dimethyl acetal (29.5 ml, 220 mmol) was added to a solution of pyrazine-2-amine (18.98 g, 200 mmol) in toluene (110 ml), and the mixture was refluxed for 2.25 h. The reaction mixture was cooled to room temperature, concentrated and coevaporated with toluene. Yield: 32.89 g (100%)

Step (ii): A solution of hydroxylamine hydrochloride (17.0 g, 245 mmol) in methanol (150 ml) was added dropwise, while cooling with ice, to a suspension of (E)-N,N-dimethyl-N′-(pyrazin-2-yl)formamide amide (38.27 g, 233 mmol) and sodium acetate (20.1 g, 245 mmol) in methanol (450 ml). The reaction mixture was stirred for 4 h at 0° C. and then heated to room temperature and concentrated. The residue was triturated with dichloromethane/7 M ammonia solution in methanol (˜9:1), and the desired solid was filtered off and washed with dichloromethane/7 M ammonia solution in methanol (˜9:1). The filtrate was concentrated, coevaporated with ethanol and then crystallized from ethanol. Further recrystallization of the resulting solids from ethanol finally yielded the purified product. Yield: 24.55 g (76%)

Step (iii): Polyphosphoric acid (250 g) was added to (Z)-N′-hydroxy-N-(pyrazin-2-yl)-formimide amide (25.07 g, 181 mmol), and the reaction mixture was then immediately heated to 90° C. The mixture was stirred for 4 h, and the hot reaction mixture was poured into ice-water and rendered basic with sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane (1 l, 3×0.5 l), and the combined organic phases were dried (Na₂SO₄) and concentrated. The crude product was crystallized from ethanol in several batches. Yield: 18.10 g (83%)

Step (iv): Platinum(IV) oxide (2.75 g, 12.1 mmol) was added, under nitrogen, to a suspension of calcium oxide (9.30 g, 166 mmol) and [1,2,4]triazolo[1,5-a]pyrazine (18.10 g, 151 mmol) in 2-methoxyethanol (150 ml). The reaction mixture was stirred for 21.5 h under a hydrogen atmosphere, filtered over Celite, and washed with dichloromethane/ethanol (9:1). The filtrate was concentrated, coevaporated with toluene and diisopropyl ether, and then dissolved in ethyl acetate, filtered over Celite, washed with ethyl acetate and concentrated again. The residue was dissolved in hot diisopropyl ether, filtered, washed with diisopropyl ether, and concentrated for 7 h in vacuo. Yield: 17.12 g (92%)

Step (a): Chlorosulfonic acid (7.3 ml, 110.13 mmol) in dichloromethane (60 ml) was slowly added dropwise, over a period of 10 min., to a solution, cooled to 0° C., of 3,5-dimethylanisole (3.1 g, 22.03 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for a further 10 min. and then slowly added dropwise to ice-water (300 ml) and stirred until the ice had melted. The phases were separated, and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with saturated sodium chloride solution (50 ml), dried (Na₂SO₄) and concentrated in vacuo. A solution of pentafluorophenol (4.1 g, 22.03 mmol) and triethylamine (6.1 ml, 44.05 mmol) in dichloromethane (50 ml) was stirred for 30 min. at room temperature. A solution of the sulfonyl chloride that had been prepared in dichloromethane (50 ml) was then slowly added dropwise. The reaction mixture was stirred for 1 h at room temperature. Saturated sodium hydrogen carbonate solution (50 ml) was added to the mixture, and the organic phase was washed with saturated sodium chloride solution (50 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using hexane/diethyl ether/dichloromethane (20:1:2). Yield: 6.1 g (72%). [The undesired regioisomer was isolated in a yield of 14%.]

Step (b): Perfluorophenyl 4-methoxy-2,6-dimethylbenzenesulfonate (1.5 g, 3.92 mmol) and tetra-n-butylammonium chloride (2.18 g, 7.85 mmol) were added to a solution of the amino alcohol (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (960 mg, 5.89 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was heated for 1 h at 120° C. It was then concentrated in vacuo, and the residue was taken up in ethyl acetate (50 ml) and washed with 10% aqueous ammonium chloride solution (20 ml). The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using hexane/diethyl ether/dichloromethane (3:2:2). Yield: 1.2 g (85%)

Step (c): tert-butyl 2-bromoacetate (1.02 ml, 6.07 mmol) was added at room temperature to a mixture of tetra-n-butylammonium hydrogen sulfate (113 mg, 0.332 mmol), aqueous sodium hydroxide solution (6.64 g, 165.98 mmol in water (7 ml)) and toluene (5 ml), and the mixture was then cooled to 0° C. A solution of (S)-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (1.2 g, 3.32 mmol) in toluene (5 ml) was then added slowly. The reaction mixture was heated to room temperature and then stirred for 1 h at that temperature. The phases were separated, and the aqueous phase was extracted with diethyl ether (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next step without being purified further. Yield: 1.79 g (>99%)

Step (d): (S)-tert-butyl 2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)acetate (1.58 g, 3.32 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium hydroxide solution (531 mg, 13.28 mmol in water (0.5 ml)) was added. The reaction mixture was refluxed for 2 h and then cooled to room temperature again, and water (20 ml) was added. The pH value of the aqueous phase was adjusted to pH 2 with 2 M hydrochloric acid, and extraction with ethyl acetate (3×20 ml) was carried out. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next step without being purified further. Yield: 580 mg (42%)

Step (e): 1-(1-methylpiperidin-4-yl)piperazine (65 mg, 0.358 mmol) and 4-methylmorpholine (0.117 ml, 1.073 mmol) were added to a solution of (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)acetic acid (150 mg, 0.358 mmol) in N,N-dimethylformamide (5 ml). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (188 mg, 0.429 mmol) was added to the mixture, and stirring was carried out for 15 h at room temperature. The mixture was then concentrated in vacuo, the residue was taken up in ethyl acetate (20 ml) and saturated sodium hydrogen carbonate solution (10 ml), and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using diethyl ether/dichloromethane/methanol/ammonia solution (25% aq.) (20:10:10:0.4). Yield: 90 mg (43%), orange oil; MS, m/z 595.2 (MH⁺).

Step (e): N,N′-Carbonyldiimidazole (131 mg, 0.813 mmol) was added to a solution of (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-acetic acid (step d, Example 127) (325 mg, 0.775 mmol) in dichloromethane (5 ml), and stirring was carried out for 2 h at 30° C. A solution of 1-((1-methylpiperidin-4-yl)methyl)piperazine (152 mg, 0.775 mmol) in dichloromethane (5 ml) was then added at room temperature, and the reaction mixture was stirred for 15 h at that temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added to the mixture, and the aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (40:10:0.5). Yield: 263 mg (57%); MS, m/z 599.3 (MH⁺).

The example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 185. The progress of the reaction was monitored in each case by thin-layer chromatography and, on the basis thereof, the reaction times for analogous reactions were adapted accordingly. The reaction temperatures and the equivalent amounts of the reagents used can differ slightly in analogous reactions. The starting materials used are commercially available or were prepared in the manner described.

Yield (%) MS, m/z Example No. Amino alcohol Amine (R⁵R⁶NH) (over 5 steps) (MH⁺) 186³ (S)-piperidin-2- 4-(piperidin-4-yloxy)pyridine 14 532.2 ylmethanol⁴ dihydrochloride⁵ 187 (S)-(1,2,3,4- 4-(2-(pyrrolidin-1-yl)ethyl)- 18 584.3 tetrahydroisoquino- piperidine lin-3-yl)methanol ³The hydrochloride precipitation was carried out from a methyl ethyl ketone solution of the free base, with addition of 2 M hydrogen chloride solution in diethyl ether (5 eq.). ⁴The (S)-amino alcohol used was prepared as follows: Hydrogen bromide-tetrahydrofuran complex (3 eq., 1 M solution in tetrahydrofuran) was added dropwise to a suspension, cooled to 0° C., of the carboxylic acid (1 eq.) in tetrahydrofuran (4 ml/mmol), and the mixture was then stirred for 1 h at room temperature. The reaction mixture was then refluxed for 4 h and stirred for a further 15 h at room temperature. The mixture was cooled to 0° C. and 3 M sodium hydroxide solution was added, and then refluxing was carried out for 6 h. The mixture was extracted with dichloromethane (4×), and the combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next synthesis step without being purified. ⁵The amine R⁵R⁶NH was prepared analogously to 3-(piperidin-4-yloxy)pyridine hydrochloride (used in the synthesis of Example compound 165) [analogous process see also: J. Chao et al., Tetrahedron Lett., 2007, 48, 791]

The synthesis of this compound was for the most part carried out analogously to the synthesis described for Example 185. However, synthesis step (a) was omitted and synthesis step (b) was carried out as follows:

Step (b): Triethylamine (1.27 ml, 9.19 mmol) was added to a solution of (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (1.0 g, 6.13 mmol) in dichloromethane (10 ml), and the mixture was stirred for 5 min. at room temperature. A solution of 2,4-dichlorobenzene-1-sulfonyl chloride (1.35 g, 5.51 mmol) in dichloromethane (10 ml) was then added dropwise at 0° C. The reaction mixture was heated to room temperature and stirred for 1 h at that temperature. Saturated sodium hydrogen carbonate solution (20 ml) was then added to the mixture, and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using hexane/diethyl ether/dichloromethane (1:1:1). Yield: 1.59 g (70%).

Synthesis steps (c) to (e) were carried out analogously to the processes described for Example 185. Example 133 (clear oil) was obtained in this manner in a yield of 85% over 3 steps. MS, m/z 585.3 (MH⁺)

The example compounds listed in the following table were prepared analogously to Example 133 from (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol, the corresponding sulfonyl chloride (R¹SO₂Cl) and the corresponding amine (R⁵R⁶NH).

Sulfonyl chloride Amine Yield (%) MS, m/z Example No. (R¹SO₂Cl) (R⁵R⁶NH) (over 4 steps) (MH⁺) 142 4-methoxybenzene-1- 1-(1-methyl- 62 557.2 sulfonyl chloride piperidin-4-yl)- piperazine 182 4-methoxybenzene-1- 4-(2-(pyrrolidin-1- 56 556.2 sulfonyl chloride yl)ethyl)piperidine 183 2,4-dichlorobenzene-1- 4-(2-(pyrrolidin-1- 20 594.1 sulfonyl chloride yl)ethyl)piperidine 184 2,4-dichlorobenzene-1- 1-((1-methyl- 28 609.2 sulfonyl chloride piperidin-4-yl)- methyl)piperazine 189⁶ 4-methoxybenzene-1- 1-((1-methyl- 14 571.3 sulfonyl chloride piperidin-4-yl)- methyl)piperazine ⁶The corresponding base was converted into the corresponding dihydrochloride (2 × HCl) as follows: The free base was dissolved in a small amount of dichloromethane/diethyl ether (1:5); 2 M hydrogen chloride solution in diethyl ether (3 eq.) was added, and the resulting dihydrochloride was filtered off.

Step (i): tert-butyl 2-bromoacetate (0.799 ml, 5.45 mmol) was added at room temperature to a mixture of tetra-n-butylammonium hydrogen sulfate (122 mg, 0.363 mmol), aqueous sodium hydroxide solution (7.27 g, 181.7 mmol in water (7 ml)) and toluene (5 ml), and the mixture was then cooled to 0° C. A solution of (S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (680 mg, 3.63 mmol) in toluene (5 ml) was then added slowly. The reaction mixture was heated to room temperature and stirred for 1 h at that temperature. The phases were separated, and the aqueous phase was extracted with diethyl ether (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using hexane/diethyl ether/dichloromethane (2:1:1). Yield: 910 mg (83%)

Step (ii): (S)-tert-butyl 2-((2-tert-butoxy-2-oxoethoxy)methyl)azetidine-1-carboxylate (890 mg, 2.95 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium hydroxide (708 mg, 17.72 mmol in water (1 ml)) was added. The reaction mixture was refluxed for 2 h and then cooled to room temperature again, and water (20 ml) was added. The pH value of the aqueous phase was adjusted to pH 2 with 2 M hydrochloric acid, and extraction with ethyl acetate (3×20 ml) was carried out. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next synthesis step without being purified further. Yield: 700 mg (97%)

Step (iii): 1-(1-methylpiperidin-4-yl)piperazine (433 mg, 2.39 mmol) and 4-methylmorpholine (0.798 ml, 7.95 mmol) were added to a solution of (S)-2-((1-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)acetic acid (650 mg, 2.65 mmol) in N,N-dimethylformamide (20 ml). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.39 mg, 3.18 mmol) was added to the mixture, and stirring was carried out for 15 h at room temperature. The mixture was then concentrated in vacuo, the residue was taken up in ethyl acetate (20 ml) and saturated sodium hydrogen carbonate solution (10 ml), and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using diethyl ether/dichloromethane/methanol/ammonia solution (25% aq.) (20:10:10:0.4). Yield: 580 mg (53%).

Step (iv): Hydrogen chloride (3.47 ml, 6.94 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of (S)-tert-butyl 2-((2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)methyl)azetidine-1-carboxylate (570 mg, 1.39 mmol) in ethyl acetate/diethyl ether (2 ml; 2:5). The reaction mixture was stirred for 2 h at 40° C., and the resulting solid was filtered off and dried. Yield: 520 mg (89%)

Step (v): 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (0.15 ml, 0.993 mmol) and perfluoro-phenyl 4-methoxy-2,6-dimethylbenzenesulfonate (123 mg, 0.298 mmol) [for synthesis see Example 127]were added to a solution of (S)-2-(azetidin-2-ylmethoxy)-1-(4-(1-methyl-piperidin-4-yl)piperazin-1-yl)ethanone trihydrochloride (100 mg, 0.238 mmol) in tetrahydrofuran (10 ml). The reaction mixture was refluxed for 1 h and stirred for 3 d at room temperature. Then saturated sodium hydrogen carbonate solution (20 ml) and ethyl acetate (30 ml) were added to the mixture. The aqueous phase was extracted with ethyl acetate (2×15 ml), and the combined organic phases were washed with saturated sodium chloride solution (20 ml). The organic phase was then dried (Na₂SO₄) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using diethyl ether/dichloromethane/methanol/ammonia solution (25% aq.) (20:10:10:0.4). Yield: 40 mg (33%), yellow resin; MS, m/z 509.3 (MH⁺).

Step (i): tert-butyl 2-bromoacetate (2.19 ml, 14.91 mmol) was added at room temperature to a mixture of tetra-n-butylammonium hydrogen sulfate (334 mg, 0.994 mmol), aqueous sodium hydroxide solution (9.93 g, 248.43 mmol in water (10 ml)) and toluene (7.5 ml), and then the mixture was cooled to 0° C. A solution of the amino alcohol (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 9.94 mmol) in toluene (7.55 ml) was then added slowly. The reaction mixture was heated to room temperature and then stirred for 2 h at that temperature. The phases were separated, and the aqueous phase was extracted with diethyl ether (2×30 ml). The combined organic phases were washed with saturated sodium chloride solution (30 ml), dried (Na₂SO₄) and concentrated in vacuo. The crude product was filtered over silica gel using ethyl acetate and was used in the next step. Yield: 3.2 g (>99%).

Step (ii): (R)-tert-butyl 2-((2-tert-butoxy-2-oxoethoxy)methyl)pyrrolidine-1-carboxylate (3.2 g, 10.15 mmol) was dissolved in tetrahydrofuran (25 ml), and sodium hydroxide solution (2.44 g, 60.88 mmol in water (2.5 ml)) was added. The reaction mixture was refluxed for 2 h and then cooled to room temperature again, and water (20 ml) was added. The pH value of the aqueous phase was adjusted to pH 2 with 2 M hydrochloric acid, and extraction with ethyl acetate (3×30 ml) was carried out. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next synthesis step without being purified further. Yield: 2.0 g (76%)

Step (iii): N,N′-Carbonyldiimidazole (328 mg, 1.93 mmol) was added to a solution of (R)-2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)acetic acid (500 mg, 1.93 mmol) in dichloromethane (5 ml), and stirring was carried out for 30 min. at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (353 mg, 1.93 mmol) in dichloromethane (5 ml) was then added at room temperature, and the reaction mixture was stirred for 15 h at that temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the mixture, and the aqueous phase was then extracted with dichloromethane (20 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using diethyl ether/dichloromethane/methanol/ammonia solution (25% aq.) (20:10:10:0.4). Yield: 540 mg (66%)

Step (iv): Hydrogen chloride (6.24 ml, 12.48 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of (R)-tert-butyl 2-((2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)methyl)pyrrolidine-1-carboxylate (530 mg, 1.25 mmol) in ethyl acetate/diethyl ether (30 ml; 1:2). The reaction mixture was stirred for 2 h at 40° C., and the resulting solid was filtered off and dried. Yield: 440 mg (81%)

Step (v): Triethylamine (0.172 ml, 1.25 mmol) was added to a solution of (R)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(pyrrolidin-2-ylmethoxy)ethanone trihydrochloride (120 mg, 0.277 mmol) in dichloromethane (5 ml). A solution of 4-methoxy-2,3,6-trimethylbenzene-1-sulfonyl chloride¹⁰ (58 mg, 0.249 mmol) in dichloromethane (5 ml) was then added dropwise at 0° C. The reaction mixture was heated to room temperature and stirred for 3 d at that temperature. Saturated sodium hydrogen carbonate solution (5 ml) was added to the mixture, and the aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo, and the crude product was then purified by column chromatography (silica gel) using diethyl ether/dichloromethane/methanol/ammonia solution (25% aq.) (20:10:10:0.4). The crude product was dissolved in a small amount of dichloromethane/diethyl ether, and chlorotrimethylsilane (2.5 eq.) was added slowly. The resulting precipitate was filtered off and dried. Yield: 80 mg (47%), white solid; MS, m/z 537.2 (MH⁺).

The example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 140. The progress of the reaction was in each case monitored by thin-layer chromatography and, on the basis thereof, the reaction times in analogous reactions were adapted accordingly. The reaction temperatures and equivalent amounts of the reagents used can differ in analogous reactions. The amount of triethylamine used in step (v) in each case was adapted according to the stoichiometry of the amine hydrochloride (×HCl) used. The starting materials used are commercially available or were prepared in the manner described.

Amine Sulfonyl chloride Yield (%) MS, m/z Example No. Amino alcohol (R⁵R⁶NH) (R¹ SO₂Cl) (over 5 steps) (MH⁺) 152⁷ (R)-tert-butyl 2- 1-(1-methylpiperidin- 2-Chloro-6-methylbenz- 34 513.1 (hydroxymethyl)pyrrol- 4-yl)piperazine 1-sulfonyl chloride idine-1-carboxylate 161⁸ (S)-tert-butyl 2- 4-(2-(pyrrolidin-1- 2-Chloro-6-methylbenz- 27 512.1 (hydroxymethyl)pyrrol- yl)ethyl)piperidine 1-sulfonyl chlorid idine-1-carboxylate 162⁸ (S)-tert-butyl 2- 1-(1-methylpiperidin- 2-Chloro-6-methylbenz- 20 513.1 (hydroxymethyl)pyrrol- 4-yl)piperazine 1-sulfonyl chloride idine-1-carboxylate 163⁸ (S)-tert-butyl 2- 1-((1-methylpiperidin- 2-Chloro-6-methylbenz- 11 527.1 (hydroxymethyl)pyrrol- 4-yl)methyl)- 1-sulfonyl chloride idine-1-carboxylate piperazine 167 (S)-tert-butyl 2- 1-(1-methylpiperidin- 4-methoxy-2,6- 53 537.3 (hydroxymethyl)piperi- 4-yl)piperazine dimethylbenzene-1- dine-1-carboxylate⁹ sulfonyl chloride¹⁰ 177⁸ (R)-tert-butyl 2- 1-(1-methylpiperidin- 4-methoxy-2,6- 16 537.3 (hydroxymethyl)piperi- 4-yl)piperazine dimethylbenzene-1- dine-1-carboxylate⁹ sulfonyl chloride¹⁰ 180 (S)-tert-butyl 2- 1-(1-methylpiperidin- 4-methoxy-2,6- 10 523.2 (hydroxymethyl)pyrrol- 4-yl)piperazine dimethylbenzene-1- idine-1-carboxylate sulfonyl chloride¹⁰ 181 (S)-tert-butyl 2- 4-(2-(pyrrolidin-1- 4-methoxy-2,6- 8 537.3 (hydroxymethyl)pyrrol- yl)ethyl)piperidine dimethylbenzene-1- idine-1-carboxylate sulfonyl chloride¹⁰ 190⁸ (S)-tert-butyl 2- 1-((1-methylpiperidin- 4-methoxy-2,6- 20 522.3 (hydroxymethyl)pyrrol- 4-yl)methyl)- dimethylbenzene-1- idine-1-carboxylate piperazine sulfonyl chloride^{10 7}The hydrochloride precipitation was carried out from a dichloromethane solution of the free base with addition of 2 M hydrogen chloride solution in diethyl ether (10 eq.). ⁸The hydrochloride precipitation was carried out from a methyl ethyl ketone/(optional) diethyl ether solution of the free base with addition of 2 M hydrogen chloride solution in diethyl ether (3-5 eq.). ⁹The Boc-protected (R)- or (S)-amino alcohol used was prepared as follows: Hydrogen bromide-tetrahydrofuran complex (1.5 eq., 1 M solution in tetrahydrofuran) was added dropwise to a solution, cooled to 0° C., of the Boc-protected carboxylic acid (1 eq.) in tetrahydrofuran (50 ml/mmol), and the mixture was then stirred for 3 h at room temperature. Water and potassium carbonate were added to the mixture, cooled to 0° C., and stirring was carried out for 30 min. The aqueous phase was then extracted with diethyl ether (3×), and the combined organic phases were washed with saturated sodium chloride solution (1×) and then dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel). [see also Timothy J. Wilkinson et al.; Org. Lett.; 2000; 155-158] ¹⁰4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride was prepared as follows: Chlorosulfonic acid (5 eq.) in dichloromethane (25 ml/mmol) was slowly added dropwise over a period of 10 min. to a solution, cooled to 0° C., of 3,5-dimethylanisole (1 eq.) in dichloromethane (25 ml/mmol). The reaction mixture was stirred for a further 10 min. and then slowly added dropwise to ice-water and stirred until the ice had melted. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried (Na₂SO₄) and concentrated in vacuo. The crude product was used in the next synthesis step without being purified further.

Diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.) were added to a solution of the acid structural unit S27 (1 eq.) in dichloromethane (5 ml/mmol). The resulting reaction mixture was stirred for 15 min. at 25° C. Cooling to 0° C. was then carried out, and 4-(piperidin-4-yl)pyridine (1.2 eq.) was added. The mixture was stirred for 16 h at 25° C. until the reaction was complete. It was diluted with dichloromethane (30 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (2% methanol in dichloromethane). Yield: 40%; MS, m/z 516.2 (MH⁺).

The example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 201. 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (acid structural unit S27) was synthesized analogously to the process described for Examples 202 and 210 for the preparation of the corresponding carboxylic acid from the corresponding amino alcohol, 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride being prepared analogously to the process described for Example 167 (except that 2 eq. of chlorosulfonic acid were used).

MS, m/z Example No. Amine (R⁵R⁶NH) Yield (%) (MH⁺) 200 6-Fluoro-2-(piperidin-4-yl)-1,2,3,4- 50 588.2 tetrahydroisoquinoline  211* 2-(piperidin-4-yl)-1,2,3,4- 11 559.3 tetrahydropyrrolo[1,2-a]pyrazine 217 3-(piperidin-4-yl)pyridine 50 516.2 *The reaction was carried out in N,N-dimethylformamide instead of dichloromethane.

Step (i): To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.12 mmol) and 6-fluoro-1,2,3,4-tetrahydroisoquinoline (2.6 mmol) in methanol (15 ml) there was added, under nitrogen, at 25° C., a catalytic amount of acetic acid followed by sodium cyanoborohydride (2.5 eq.). The resulting solution was stirred for 16 h at that temperature until the reaction was complete (TLC monitoring). Ice was added to the reaction mixture, and concentration in vacuo was then carried out. The residue was taken up in dichloromethane (100 ml) and washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product so obtained was used directly in the following synthesis step. Yield: 50%.

Step (ii): Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (1 eq.) in dichloromethane (10 ml/mmol), and the reaction mixture was then stirred for 2 h at 25° C. The solvent was removed, and the crude product was dried in vacuo. The amine so obtained was reacted further without being purified.

Step (i): Sodium hydroxide (9.4 g, 0.23 mol; powder) and tetrabutylammonium hydrogen sulfate (0.8 g, 2.36 mmol) were added to a solution of 1H-pyrrole (4 g, 0.06 mol) in acetonitrile (33 ml). The mixture was stirred for 30 min. at 25° C., and then 2-chloroethylamine hydrochloride (8.2 g, 0.07 mol) was added. The reaction mixture was refluxed for 24 h, the solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by distillation in vacuo. Yield: 30%

Step (ii): Trifluoroacetic acid (0.5 ml) was added to a solution of 1-(2-aminoethyl)pyrrole (9 mmol) and 37% aqueous formaldehyde solution (9 mmol) in ethanol (20 ml), and the resulting reaction mixture was stirred for 15 min. at 50° C. It was then cooled to 25° C. and stirred for a further 4 h at that temperature. The solvent was removed in vacuo, and the residue was taken up in ethyl acetate, rendered basic with aqueous sodium carbonate solution. The organic phase was dried (Na₂SO₄) and concentrated. The crude product was used in the next synthesis step without being purified further. Yield: 40%.

Step (iii): To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.68 mmol) and 1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine (3.9 mmol) in methanol (15 ml) there was added, under nitrogen, at 25° C., a catalytic amount of acetic acid, followed by sodium cyanoborohydride (2.5 eq.). The resulting solution was stirred for 16 h at that temperature until the reaction was complete (TLC monitoring). Ice was added to the reaction mixture, and then concentration in vacuo was carried out. The residue was taken up in dichloromethane (100 ml) and washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product so obtained was used directly in the following synthesis step. Yield: 40%.

Step (iv): A solution of tert-butyl 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (1.8 mmol) and hydrogen chloride in ethyl acetate (30 ml, saturated solution) was stirred for 2 h at room temperature until the reaction was complete (TLC monitoring). The solvent was removed, and the crude product was dried in vacuo. The amine so obtained was used in the next synthesis step without being purified further.

Step (i): n-butyllithium (2 eq.) was added dropwise over a period of 2 hours at −78° C. to a solution of 3-bromopyridine (1 eq.) in dry tetrahydrofuran (250 ml). The reaction mixture was then stirred for 1 h at −78° C. N-benzyl-piperidone (3 g, in 50 ml of tetrahydrofuran) was slowly added dropwise to the solution over a period of 30 min. at −78° C. The reaction mixture was stirred for 1 h at −78° C., and the progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, water was added and extraction with ethyl acetate (3×100 ml) was carried out. The combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (4% methanol in dichloromethane). Yield: 20%.

Step (ii): 80% sulfuric acid was added dropwise at 0° C. to a solution of 1-benzyl-4-(pyridin-3-yl)piperidin-4-ol (1 g) in methanol (10 ml). The reaction mixture was maintained for 4 d at 90° C., and the progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, excess methanol was removed and the mixture was then adjusted to pH 14 by addition of sodium hydroxide solution and extracted with dichloro-methane (4×100 ml). The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product so obtained was used directly in the next synthesis step. Yield: quantitative.

Step (iii): 10% Pd/C (600 mg) was added, under argon, to a solution of 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyridine (950 mg) in methanol (10 ml), and the resulting mixture was stirred for 16 h at 23° C. under a hydrogen atmosphere. The progress of the reaction was monitored by LC-MS analysis and, when the reaction was complete, the mixture was filtered over Celite and washed with methanol. The filtrate was concentrated in vacuo, and the crude product was used directly in the next synthesis step. Yield: quantitative

Step (iv): To a solution of 3-(1-benzylpiperidin-4-yl)pyridine (650 mg) in methanol (10 ml) there was added, under argon, Pd(OH)₂ (600 mg), followed by a catalytic amount of acetic acid. The resulting mixture was stirred for 16 h at 23° C. under a hydrogen atmosphere. The progress of the reaction was monitored by LC-MS analysis and, when the reaction was complete, the mixture was filtered over Celite and washed with methanol. The filtrate was concentrated in vacuo, and the crude product was used directly in the following synthesis step. Yield: quantitative

Step (i): To a solution of the acid structural unit S27 (1.5 g) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 23° C. It was then cooled to 0° C., and 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.2 eq., dissolved in dichloromethane) was added dropwise. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. The mixture was diluted with dichloromethane (100 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in dichloromethane). Yield: 80%

Step (ii): Cesium carbonate (2.5 eq.) was added to a solution of N-methylpiperazine (3.6 mmol) and 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)piperidin-2-yl)methoxy)ethanone (3 mmol) in dioxane (20 ml), and the resulting solution was degassed for 30 min. with argon. Xanthphos (2 mmol), followed by palladium tris(dibenzylideneacetone)dipalladium (0.15 mmol) were then added, under argon, and the mixture was heated for 16 h at 120° C. The progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was filtered and washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was taken up in dichloromethane and washed with water and saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The product was purified by column chromatography (4% methanol in dichloromethane). Yield: 10%; MS, m/z 585.3 (MH⁺).

Step (i): 1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester (25 mmol) in tetrahydrofuran (5 ml/mol) was added dropwise at 0° C. to a suspension of lithium aluminium hydride (2 eq.) in tetrahydrofuran (50 ml). The reaction mixture was stirred for 1 h at 25° C. and then refluxed for 4 h. The progress of the reaction was monitored by thin-layer chromatography. Saturated sodium sulfate solution was added to the reaction mixture, and the mixture was then filtered over Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (3:7 ethyl acetate/hexane). Yield: 50%

Step (ii): To a solution of (1,2,3,4-tetrahydro-quinolin-2-yl)-methanol (0.67 mmol) in dichloromethane (5 ml) there was added at 0° C. pyridine (5 eq.) followed by a catalytic amount of dimethylaminopyridine (0.01 eq.). 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (1.2 eq.) in dichloromethane (2 ml) was then added dropwise. The reaction mixture was stirred for 1 h at 25° C. until the reaction was complete (TLC monitoring) and then diluted with dichloromethane (50 ml) and washed with saturated copper sulfate solution (4×15 ml) and saturated sodium chloride solution. The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in dichloromethane).

[4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride was prepared analogously to the process described for Example 167 (except that 2 eq. of chlorosulfonic acid were used).] Yield: 75%

Step (iii): Tetrabutylammonium chloride (0.33 eq.) and 35% sodium hydroxide solution (3 ml) were added at 0° C. to a cold solution of (1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methanol (0.47 mmol) in toluene (3 ml). tert-butyl bromoacetate (1.5 eq.) was added dropwise at 0° C. to this cold reaction mixture. The mixture was then stirred for 90 min. at 25° C. until the reaction was complete (TLC monitoring). The mixture was extracted with ethyl acetate (50 ml), and the organic phase was washed with water until the pH value was neutral. Extraction with saturated sodium chloride solution was then carried out, and the organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (20% ethyl acetate in hexane). Yield: 66%

Step (iv): Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetate (1 eq.) in dichloormethane (10 ml/mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was then concentrated in vacuo, and the crude product was used in the next synthesis step without being purified further.

Step (v): To a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl)methoxy)acetic acid (1 eq.) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 25° C. It was then cooled to 0° C., and 1-(1-methylpiperidin-4-yl)piperazine (1.2 eq.) was added. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. It was diluted with dichloromethane (30 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (2% methanol in dichloromethane). Yield: 60%; MS, m/z 585.3 (MH⁺)

The example compounds listed in the following table were prepared from the corresponding sulfonyl chlorides closely following the process described for Example 202 (step (v)).

Yield (%) MS, m/z Example No. Sulfonyl chloride (R¹SO₂Cl) (over 5 steps) (MH⁺) 203 Naphthalene-2- 18 577.2 sulfonyl chloride 204 4-methoxybenzene-1- 10 557.2 sulfonyl chloride

Step (i): Sodium hydroxide (0.7 g) was added to a solution of sodium 6-hydroxynaphthalene-2-sulfonate (9 mmol) in water (20 ml). To this solution there was added over a period of 1 h at 50-55° C. dimethyl sulfate (1.1 eq.), followed by sodium chloride (3.3 g). The solid was filtered off and washed with saturated sodium chloride solution and toluene. The crude product was then dried. Yield: 75%.

Step (ii): Thionyl chloride (0.25 ml) was added at 0° C., under nitrogen, to a solution of sodium 6-methoxynaphthalene-2-sulfonate (2 mmol) in dry N,N-dimethylformamide (1 ml). The reaction mixture was stirred for 3 h at 0° C., and then ice-water (20 ml) was added thereto. The solid was filtered off and washed with cold water. The solid was then taken up in dichloromethane (25 ml), dried (Na₂SO₄) and concentrated in vacuo. Yield: 75%

Step (iii): Triethylamine (2.5 eq.) was added to a cold solution of piperidin-2-ylmethanol

(1.5 mmol) in dichloromethane (10 ml). A solution of 6-methoxynaphthalene-2-sulfonyl chloride (1.5 mmol) in dichloromethane (5 ml) was then added dropwise, and the mixture was stirred for 90 min. at 25° C. until the reaction was complete (TLC monitoring). Dichloromethane (100 ml) was added to the reaction mixture, and extraction with water was carried out. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (5% methanol in dichloromethane). Yield: 50%

Step (iv): Tetrabutylammonium chloride (0.33 eq.) and 35% sodium hydroxide solution (4.5 ml) were added at 0° C. to a cold solution of (1-(6-methoxynaphthalen-2-ylsulfonyl)-piperidin-2-yl)methanol (0.75 mmol) in toluene (4.5 ml). tert-butyl bromoacetate (1.5 eq.) was added dropwise at 0° C. to this cold reaction mixture. The mixture was then stirred for 90 min. at 25° C. until the reaction was complete (TLC monitoring). The mixture was extracted with ethyl acetate (100 ml), and the organic phase was washed with water until the pH value was neutral. Extraction with saturated sodium chloride solution was then carried out, and the organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (50% ethyl acetate in hexane). Yield: 90%.

Step (v): Trifluoroacetic acid (13 eq.) was added at 0° C. to a solution of tert-butyl 2-((1-(6-methoxynaphthalen-2-ylsulfonyl)piperidin-2-yl)methoxy)acetate (1 eq.) in dichloromethane (10 ml/mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was then concentrated in vacuo, and the crude product was used in the following synthesis step without being purified further.

Step (vi): To a solution of 2-((1-(6-methoxynaphthalen-2-ylsulfonyl)piperidin-2-yl)methoxy)-acetic acid (1 eq.) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 25° C. It was then cooled to 0° C., and 1-(1-methylpiperidin-4-yl)piperazine (1.2 eq.) was added. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. It was diluted with dichloromethane (100 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography (2% methanol in dichloromethane). Yield: 50%; MS, m/z 559.3 (MH⁺)

Five equivalents of the corresponding amino alcohol are dissolved in dichloromethane (about 1.5 ml/mmol), and the corresponding sulfonyl chloride (1 equivalent) dissolved in dichloromethane (about 1.5 ml/mmol) is added at room temperature. When the sulfonyl chloride has dissolved completely (TLC monitoring), the batch is washed 3 times with 5% HCl. The organic phase is dried over sodium sulfate and concentrated to dryness in vacuo.

The corresponding alcohol (1 equivalent) is dissolved in THF (about 5.5 ml/mmol) and cooled to 0° C., and sodium hydride (1.2 equivalents) is added in portions. The reaction mixture is stirred for 15 min. at 0° C. before tert-butyl bromoacetate (2.5 equivalents) is added. The reaction mixture is stirred for 16 hours at room temperature. For working up, the batch is quenched with saturated ammonium chloride solution, the aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated to dryness in vacuo, and the residue is purified by column chromatography.

The corresponding tert-butyl ester is dissolved in dichloromethane (about 15 ml/mmol), and trifluoroacetic acid (about 3.25 ml/mmol) is added at room temperature. The reaction mixture is stirred at room temperature until the tert-butyl ester has reacted completely (TLC monitoring) and is then concentrated to dryness in vacuo. Finally, toluene is added 3 times to the residue, and concentration to dryness is carried out.

The corresponding carboxylic acid (1 equivalent) is dissolved in dichloromethane (about 8 ml/mmol); 1,1′-carbonyldiimidazole (about 1.05 equivalents) is added, and stirring is carried out for 1 hour at room temperature. The corresponding amine (1 equivalent), dissolved in dichloromethane (about 8 ml/mmol), is then added, and the reaction mixture is stirred for 16 hours at room temperature. For working up, the batch is washed 3 times with saturated ammonium chloride solution and 3× with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulfate, and finally concentration to dryness in vacuo is carried out.

According to AAV 1,4-bromobenzene-1-sulfonyl chloride (58.7 mmol) was reacted with 2-(hydroxymethyl)-piperidine in 77% yield to form (1-(4-bromophenylsulfonyl)piperidin-2-yl)-methanol. This was reacted further according to AAV2, yielding tert-butyl 2-((1-(4-bromo-phenylsulfonyl)piperidin-2-yl)methoxy)acetate in a yield of 38% (17.3 mmol). Finally, tert-butyl ester cleavage according to MV 3 yielded 2-((1-(4-bromophenylsulfonyl)piperidin-2-yl)methoxy)acetic acid without losses.

According to AAV 1,3-bromobenzene-1-sulfonyl chloride (58.7 mmol) was reacted with 2-(hydroxymethyl)-piperidine in 80% yield to form (1-(4-bromophenylsulfonyl)piperidin-2-yl)-methanol. This was reacted further according to AAV2, yielding tert-butyl 2-((1-(3-bromo-phenylsulfonyl)piperidin-2-yl)methoxy)acetate in a yield of 31% (14.9 mmol). Finally, tert-butyl ester cleavage according to MV 3 yielded 2-((1-(3-bromophenylsulfonyl)piperidin-2-yl)methoxy)acetic acid without losses.

4-bromo-2,6-dimethylbenzene-1-sulfonyl chloride: A solution of 42 g of sodium nitrite in 150 ml of water is added to a mixture, cooled to −5° C., of 200 ml of 48% HBr and 50 g of 3,5-dimethylaniline. The reaction mixture is stirred for 1 hour at from −5° C. to 0° C. Finally, this reaction mixture is slowly added to a mixture, heated to 80° C., of 88.3 g of copper(I) bromide and 150 ml of 48% HBr. The reaction mixture is stirred for 2 hours at 80° C. and observed by TLC monitoring (silica; hexane). When the reaction is complete, the product is obtained by water-vapour distillation and is purified by column chromatography (silica; hexane). In this manner, 1-bromo-3,5-dimethylbenzene was obtained in a yield of 60% (30 g).

The bromide obtained above, dissolved in 150 ml of dichloromethane, was added dropwise at 0° C., in the course of 20 minutes, to 90 ml of chlorosulfonic acid. When the addition is complete, stirring is carried out for 1 hour at room temperature. The progress of the reaction is monitored by means of TLC (hexane). When the reaction is complete, the reaction mixture is agitated on ice and extracted 3× with dichloromethane (200 ml each time). The combined organic phases are dried over Na₂SO₄, concentrated in vacuo and purified by column chromatography (silica; hexane). The desired 4-bromo-2,6-dimethylbenzene-1-sulfonyl chloride was obtained in a yield of 65% (29.8 g).

(1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol: Potassium carbonate is added to a solution of (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol (22.5 g) in dichloromethane (290 ml), and the mixture is cooled to 0° C. A suspension of the hydrochloride of piperidin-2-ylmethanol (39 g, commercially available, CAS No.: 3433372) in dichloromethane (300 ml) was added to the sulfonyl chloride suspension in the course of 45 minutes at 0° C. When the addition was complete, the reaction mixture was stirred for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (silica; 10% EtOAc/heptane). When the reaction was complete, filtration was carried out, followed by washing with water and drying over Na₂SO₄. The solvent was removed in vacuo, and the crude product was purified by column chromatography (silica; 10% EtOAc/hexane). (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol was obtained in a yield of 61.2% (30 g).

tert-butyl 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate: 180 ml of 50% sodium hydroxy solution and 180 ml of tert-butyl bromoacetate were added to a solution of 18 g of (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol, and stirring was carried for 10 minutes. 1.815 g of tetra-n-butylammonium hydrogen sulfate were then added, and stirring was carried out for a further 45 minutes at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% EtOAc/hexane). When the reaction was complete, 400 ml of ethyl acetate were added, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; 5% EtOAc/hexane). tert-butyl 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate was obtained in a yield of 78.2% (18 g).

The tert-butyl ester cleavage of 40 g of 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)-piperidin-2-yl)methoxy)acetate according to AAV 3 resulted in 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid in a yield of 76%.

Acid structural unit (Ib) (6.4 mmol) was reacted according to AAV4 with 1-(1-methyl-4-piperidinyl)piperazine. The desired product was obtained in a yield of 57%. HPLC-MS, m/z 557.2 (MH⁺)

Acid structural unit (Ib) (4 mmol) was reacted according to AAV4 with 1-(4-pyridyl)piperazine. The desired product was obtained in a yield of 97%. HPLC-MS, m/z 537.1 (MH⁺)

Acid structural unit (Ia) (7.6 mmol) was reacted according to AAV4 with 1-(1-methyl-4-piperidinyl)piperazine. The desired product was obtained in a yield of 73%. HPLC-MS, m/z 557.2 (MH⁺)

Acid structural unit (Ib) (5 mmol) was reacted according to AAV4 with 4-(2-pyrrolidinoethyl)piperidine. The desired product was obtained in a yield of 69%. HPLC-MS, m/z 556.2 (MH⁺)

Acid structural unit (Ia) (7.6 mmol) was reacted according to AAV4 with 4-(2-pyrrolidinoethyl)piperidine. The desired product was obtained in a yield of 71%. HPLC-MS, m/z 556.2 (MH⁺)

Acid structural unit (Ia) (5 mmol) was reacted according to AAV4 with 1-(4-pyridyl)piperazine. The desired product was obtained in a yield of 70%. HPLC-MS, m/z 537.1 (MH⁺)

Acid structural unit (Ic) (7.1 mmol) was reacted according to AAV4 with 1-(1-methyl-4-piperidinyl)piperazine. The desired product was obtained in a yield of 70%. HPLC-MS, m/z 585.1 (MH⁺)

Acid structural unit (Ic) (7.1 mmol) was reacted according to AAV4 with 4-(2-pyrrolidionoethyl)-piperidine. The desired product was obtained in a yield of 70%. HPLC-MS, m/z 584.0 (MH⁺)

Acid structural unit (Ic) (7.1 mmol) was reacted according to AAV4 with 1-(4-pyridyl)piperazine. The desired product was obtained in a yield of 79%. HPLC-MS, m/z 565.0 (MH⁺)

Commercially available 1-naphthylsulfonyl chloride (21.5 g) was added in portions at −5° C. to a mixture of 2-propanol (7.3 ml) and pyridine (25 ml). The reaction mixture was stirred for 15 h at 0° C. For working up, DCM (75 ml) and 1 M HCl (75 ml) were added at that temperature, and the organic phase was separated off. The aqueous phase was extracted with DCM (3×75 ml), and the combined organic phases were washed with 1 M HCl (2×50 ml) and sat. NaCl solution (50 ml). After drying over MgSO₄, complete concentration was carried out and the desired product was obtained in the required purity. 22.8 g, 96%.

The title compound from step A (18.6 g) was dissolved in THF (190 ml), and the mixture was cooled to −78° C. under a protecting gas atmosphere. Then 1.6 M n-BuLi in n-hexane (51 ml) was added sufficiently slowly that the temperature did not rise above −70° C. The reaction mixture was stirred for 2 h at −70° C., and then MeI (9.7 ml) was added. The reaction mixture was allowed to warm to 0° C. and was stirred for 3 h at that temperature. For working up, sat. NH₄Cl (80 ml) was added at that temperature, and then the mixture was diluted with EtOAc (500 ml). The organic phase was separated off and the aqueous phase was extracted with EtOAc (2×120 ml), and the combined organic phases were washed with water (50 ml) and sat. NaCl solution (50 ml). After drying over MgSO₄, complete concentration was carried out, and the residue was purified by column chromatography on silica gel (hexane/EtOAc). The desired product was obtained. 12.4 g, 63%.

The title compound from step B (0.8 g) was suspended in 4 M HCl (31 ml), and the mixture was heated for 1-2 h at 110° C. It was then cooled to room temperature over a period of 15 h and concentrated completely; the residue obtained after coevaporation twice with DCM (2×30 ml) was dried under a high vacuum. The product so obtained was used in the next step without being purified further. 0.47 g, 70%.

The title compound from step C (0.46 g) was suspended in toluene (2.2 ml), and SOCl₂ (0.75 ml) and DMF (0.010 ml) were added to the resulting mixture. Heating was then carried out for 1 h at 90° C. until a solution was present. The solution was concentrated completely, and the residue was dried under a high vacuum. The product so obtained was used in the next step without being purified further.

The title compound from the preparation of 2-methylnaphthalene-1-sulfonyl chloride, step A (20 g) was dissolved in THF (213 ml), and the mixture was cooled to −78° C. under a protecting gas atmosphere. Then 1.6 M n-BuLi in n-hexane (55 ml) was added sufficiently slowly that the temperature did not rise above −70° C. The reaction mixture was stirred for 2 h at −70° C., and then hexachloroethane (21 g) was added. The reaction mixture was allowed to warm to 0° C. and was stirred for 15 h at that temperature. For working up, sat. NH₄Cl (100 ml) was added at that temperature, and then the mixture was diluted with EtOAc (350 ml). The organic phase was separated off and the aqueous phase was extracted with EtOAc (2×120 ml), and the combined organic phases were washed with water (50 ml) and sat. NaCl solution (50 ml). After drying over MgSO₄, complete concentration was carried out, and the residue was purified by column chromatography on silica gel (hexane/EtOAc). The desired product was obtained. 19.8 g, 87%.

The title compound from step A (3 g) was dissolved in EtOH (15.4 ml), and TFA (0.04 ml) was added. The resulting solution was refluxed for 5 h. After cooling, the mixture was concentrated and the residue was dissolved in DCM (20 ml) and washed with water (10 ml). After drying over MgSO₄, complete concentration was carried out. The resulting product was used in the next step without being purified further. 2.2 g, 87%.

Commercially available sodium 4-methoxynaphthyl-1-sulfonate (2.5 g) was added at RT to a mixture of water (5.2 ml) and conc. HCl (22 ml). The mixture was extracted several times with MeOH/EtOAc 1:15 (a total of 400 ml), and the combined organic phases were washed with sat. NaCl solution (50 ml). After drying over MgSO₄, complete concentration was carried out. The resulting product was used in the next step without being purified further. 1.2 g, 52%.

The preparation of the following examples was carried out closely following the process described for 2-methylnaphthalene-1-sulfonyl chloride, except that the sulfonic acids mentioned in the following table were used.

Sulfonic acid Sulfonyl chloride

Commercially available 1,2,3,4-tetrahydronaphthalene (50 ml) was placed in chloroform (110 ml). At from −5 to −10° C., chlorosulfonic acid (73 ml) was added dropwise, with stirring, in the course of 30 min. The cooling was removed, and the solution was heated to RT in the course of 1 h. The reaction solution was poured onto ice, and the organic phase was separated off. The aqueous phase is extracted with DCM/MeOH 9:1 (3×150 ml), and the combined organic phases are washed with ice-water (2×50 ml). After drying over MgSO₄, complete concentration was carried out, and the residue was purified by column chromatography on silica gel (hexane/EtOAc). The desired product is obtained. 8.4 g, 10%.

The title compound from Example 107, step 4 (1.0 g) was placed in DCM (19 ml); cooling to 0° C. was carried out, and Et₃N (1.8 ml) was added. The title compound from step A (0.5 g) was then added rapidly at that temperature. Stirring was carried out at RT until TLC monitoring indicated that the reaction was complete. For working up, NH₄Cl solution (10 ml) and water (10 ml) were added, and the organic phase was separated off. The aqueous phase was extracted with DCM (3×15 ml), and the combined organic phases were washed with water (10 ml) and sat. NaCl solution (10 ml). After drying over MgSO₄, complete concentration was carried out, and the residue was purified by column chromatography on silica gel (DCM/MeOH/NH₃). 638 mg of the base were obtained, which was precipitated from acetone (10 ml)/ether (10 ml) by addition of H₂O (21 μl) and TMSCl (302 μL). 598 mg, 46%, 533 (MH⁺).

Examples 157, 160, 173-176 and 191 were prepared closely following the process described for Example 179, except that the sulfonyl chlorides and amines mentioned in the following table were used. The preparation of sulfonyl chlorides that are not commercially available was carried out as described above.

Yield MS No. Sulfonyl chloride Amine (%) (MH+) 157 8 543 191 27 563 174 30 559 176 57 530 175 3 530 173 61 547 160 69 627

A suspension of the acid (500 mg, 1.4 mmol), amine (256 mg, 1.4 mmol) and HOAt (19 mg, 0.14 mmol) in CH₂Cl₂ (10 ml) was cooled to 0° C. After addition of EDCI (296 mg, 1.54 mmol), the reaction mixture was stirred for 30 min. at 0° C. and overnight at RT under a nitrogen atmosphere. After addition of CH₂Cl₂ (20 ml), the organic phase was extracted with aqueous saturated NaHCO₃ solution (30 ml), and then the aqueous phase was separated off and extracted with CH₂Cl₂ (15 ml). The combined organic phases were dried over Na₂SO₄. After filtration and removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol) 4/6-93/7). Yield: 331 mg, 45%.

EDCI (402 mg, 2.1 mmol) was added to a solution of the acid (520 mg, 1.4 mmol), 3-(pyrrolidin-3-ylmethyl)pyridine dioxalate (527 mg, 1.54 mmol), HOAt (28.6 mg, 0.21 mmol) and DIPEA (0.98 ml, 5.6 mmol) in CH₂Cl₂ (10 ml), and the mixture was stirred overnight at RT. After removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 99/1-96/4). Yield: 378 mg, 52%

EDCI (486 mg, 2.53 mmol) was added to a solution of the acid (627 mg, 1.69 mmol), 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (291 mg, 1.86 mmol), HOAt (34.5 mg, 0.25 mmol) and DIPEA (0.89 ml, 5.07 mmol) in CH₂Cl₂ (10 ml), and the mixture was stirred overnight at RT. After removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 99/1-97/3). Yield: 481 mg, 60%

EDCI (497 mg, 2.59 mmol) was added to a solution of the acid (642 mg, 1.73 mmol), 2-(pyridin-3-yl)morpholine oxalate (483 mg, 1.90 mmol), HOAt (35.3 mg, 0.26 mmol) and DIPEA (0.91 ml, 5.18 mmol) in CH₂Cl₂ (10 ml), and the mixture was stirred overnight at RT. After removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 99/1-96/4). Yield: 453 mg, 51%

EDCI (580 mg, 3.02 mmol) was added to a solution of the acid (749 mg, 2.02 mmol), (2-(pyrazin-2-yloxy)phenyl)methanamine hydrochloride (527 mg, 2.22 mmol), HOAt (41.2 mg, 0.30 mmol) and DIPEA (1.06 ml, 6.05 mmol) in CH₂Cl₂ (10 ml), and the mixture was stirred overnight at RT. After removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 99/1-97/3). Yield: 977 mg, 87%

Oxalyl chloride (3.68 ml, 42.8 mmol) and a catalytic amount of DMF were added to a solution of the acid (5.3 g, 14.3 mmol) in CH₂Cl₂ (100 ml), and the mixture was stirred overnight at RT. After removal of the solvent in vacuo, the residue was coevaporated with CH₂Cl₂ (3×50 ml). Yield: 5.38 g, 96%

4-(pyrazin-2-yloxy)-benzylamine hydrochloride (439 mg, 1.85 mmol) was added to a solution of the acid chloride (600 mg, 1.54 mmol) and Et₃N (535 μl, 3.85 mmol) in CH₂Cl₂ (10 ml). The reaction mixture was stirred for 4 h at RT. The solvent was then removed in vacuo. The product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 95/5). Yield: 468 mg, 55%

EDCI (387 mg, 2.0 mmol) was added at 0° C. to a solution of the acid (500 mg, 1.35 mmol), (3-(pyrazin-2-yloxy)phenyl)methanamine hydrochloride (320 mg, 1.35 mmol), HOAt (27.5 mg, 0.20 mmol) and DIPEA (705 μl, 4.1 mmol) in CH₂Cl₂ (10 ml), and the mixture was stirred for 30 min. at 0° C. and overnight at RT. After removal of the solvent in vacuo, the product was purified by column chromatography (silica, CH₂Cl₂/(7 M NH₃ in methanol), 99/1-95/5). Yield: 412 mg, 55%

Methylamine (350 ml of a 40% aqueous solution, 4.06 mol) was added to a solution of 4-(bromomethyl)benzonitrile (51.3 g, 262 mmol) in EtOH (500 ml). After 2 h, the solvent was removed in vacuo and CH₂Cl₂ (500 ml) and aqueous saturated NaHCO₃ solution (400 ml) were added. The organic phase was separated off and extracted with aqueous saturated NaCl solution (250 ml), over Na₂SO₄, and the solvent was removed after filtration in vacuo. The residue was taken up in 1 M HCl in Et₂O (300 ml) and stirred for 30 min., then filtered off and washed with Et₂O. The residue was taken up in H₂O (500 ml), rendered basic with aqueous 6 M NaOH and extracted with CH₂Cl₂ (500 ml). The organic phase was dried over Na₂SO₄ and filtered off, and the solvent was removed in vacuo. Yield: 31.17 g, 81%

Et₃N (35.96 ml, 256 mmol) was added to a solution of the amine (31.17 g, 213 mmol) in CH₂Cl₂ (150 ml). Benzyl chloroformate (36.37 ml, 256 mmol) in CH₂Cl₂ (50 ml) was then added dropwise at a temperature of 0° C. The reaction mixture was stirred overnight at RT and washed with aqueous 0.1 M HCl (150 ml) and H₂O (150 ml), dried over Na₂SO₄ and filtered out, and the solvent was removed in vacuo.

Sulfur (3.41 g, 107 mmol) was added to a reaction mixture of the carbamate (62.1 g, max. 213 mmol) and ethylenediamine (192 ml, 2.87 mol), and stirring was carried out for 2 h at 100° C. After cooling to RT, H₂O (250 ml) was added, and extraction with ethyl acetate (2×250 ml) was carried out. The combined organic phases were extracted with H₂O (250 ml) and dried over Na₂SO₄, and the solvent was removed after filtration in vacuo. Yield: 67.6 g, 98%

A solution of (Boc)₂O (50.2 g, 230 mmol) in CH₂Cl₂ (500 ml) was added dropwise to a solution of the imidazoline (67.6 g, 209 mmol) and DMAP (28.1 g, 230 mmol) in CH₂Cl₂ (500 ml), and stirring was carried out overnight at RT. 0.5 M HCl (300 ml) and H₂O (300 ml) were then added. The organic phase was separated off and dried over Na₂SO₄. After filtration, the solvent was removed in vacuo and product was purified by column chromatography (silica, CH₂Cl₂/MeOH, 98:2). Yield: 50.7 g, 57%

The Boc-protected imidazoline (3.03 g, 7.15 mmol) was dissolved in absolute EtOH (60 ml) and hydrogenated under nitrogen for 10 min. with Pd/C (10%, 381 mg, 0.36 mmol) and hydrogen. After stirring for 2 h at RT, filtration over kieselguhr was carried out, followed by washing with EtOH. After removal of the solvent in vacuo, the product was used in the next step without being worked up further.

A reaction mixture of the carboxylic acid (683 mg, 1.84 mmol), amine (2.10 g, 1.93 mmol), DIPEA (608 μl, 3.68 mmol) and HOAt (38 mg, 0.28 mmol) in CH₂Cl₂ (100 ml) was cooled to 0° C. EDCI (388 mg, 2.02 mmol) was then added, and stirring was carried out overnight at RT. After addition of aqueous saturated NaCl solution (25 ml), the aqueous phase was separated off and extracted with CH₂Cl₂ (25 ml). The combined organic phases were dried over Na₂SO₄ and, after filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica, CH₂Cl₂/MeOH, 95:5). Yield: 750 mg, 63%

TFA (4.3 ml, 58 mmol) was added to a solution of the Boc-protected derivative (750 mg, 1.16 mmol) in CH₂Cl₂ (10 ml), and stirring was carried out for 4 h at RT. The solvent was removed in vacuo, and the residue was dissolved in CH₂Cl₂ (20 ml) and washed with aqueous saturated NaHCO₃ solution (25 ml). The organic phase was separated off, dried over Na₂SO₄ and filtered off, and the solvent was removed in vacuo. The product was purified by column chromatography (silica, CH₂Cl₂/MeOH/Et₃N, 95:5:2). The free amine was stirred for 1 h in 1 M HCl in Et₂O (10 ml), and the solvent was removed in vacuo. The product was obtained in the form of the hydrochloride in a yield of 641 mg, 95%.

The agonistic or antagonistic action of substances can be determined on the bradykinin receptor 1 (B1R) of the species human and rat using the following assay. According to this assay, the Ca²⁺ influx through the channel is quantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, Netherlands) using a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA).

Chinese hamster ovary cells (CHO K1 cells) which have been stably transfected with the human B1R gene (hB1R cells, Euroscreen s.a., Gosselies, Belgium) or with the B1R gene of the rat (rB1R cells, Axxam, Milan, Italy) are used. For functional studies, the cells are plated out on black 96-well plates having a clear base (BD Biosciences, Heidelberg, Germany) in a density of 20,000-25,000 cells/well. The cells are incubated overnight at 37° C. and with 5% CO₂ in culture medium (hB1R cells: Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH, Karlsruhe, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen GmbH, Karlsruhe, Germany), with 10 vol. % FBS (fetal bovine serum, Gibco Invitrogen GmbH, Karlsruhe, Germany). On the following day, the cells are loaded for 60 minutes at 37° C. with 2.13 μM Fluo-4 (Molecular Probes Europe BV, Leiden, Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) with 2.5 M probenecid (Sigma-Aldrich, Taufkirchen, Germany) and 10 mM HEPES (Sigma-Aldrich, Taufkirchen, Germany). The plates are then washed twice with HBSS buffer, and HBSS buffer additionally containing 0.1% BSA (bovine serum albumin; Sigma-Aldrich, Taufkirchen, Germany), 5.6 mM glucose and 0.05% gelatin (Merck KGaA, Darmstadt, Germany) is added to the plates. After incubation for a further 20 minutes at room temperature, the plates are inserted into the FLIPR for Ca²⁺ measurement. The Ca²⁺-dependent fluorescence is measured before and after the addition of substances (λ_ex=488 nm, λ_em=540 nm). Quantification is carried out by measuring the highest fluorescence intensity (FC, fluorescence counts) over time.

The FLIPR protocol consists of 2 substance additions. Test substances (10 μM) are first pipetted onto the cells and the Ca²⁺ influx is compared with the control (hB1R: Lys-Des-Arg⁹-bradykinin 0.5 nM; rB1R: Des-Arg⁹-bradykinin 100 nM). This gives the activation in %, based on the Ca²⁺ signal after addition of Lys-Des-Arg⁹-bradykinin (0.5 nM) or Des-Arg⁹-bradykinin (100 nM).

After 10 minutes' incubation, 0.5 nM Lys-Des-Arg⁹-bradykinin (hB1R) or 100 nM Des-Arg⁹-bradykinin (rB1R) are applied, and the influx of Ca²⁺ is likewise determined. Antagonists lead to suppression of the Ca²⁺ influx. The % inhibition compared with the maximum achievable inhibition is calculated. The compounds exhibit good activity on the human and the rat receptor.

B1R Antagonism, B1R Antagonism, rat human [10 μM] [10 μM] Example % Inhibition % Inhibition 1 104.68 106.8 2 104.12 87.41 3 103.84 108.97 4 103.63 106.31 5 102.96 102.66 6 102.21 94.88 7 101.85 99.28 8 101.66 106.6 9 101.53 85.33 10 100 91.84 11 99.62 105.97 12 99.1 74.91 13 97.67 112.52 14 96.97 104.22 15 96 92.47 16 95.89 25.53 17 95.53 96.94 18 95.33 109.83 19 95.03 98.89 20 94.86 86.42 21 93.47 107.92 22 92.64 21.4 23 92.35 85.35 24 92.25 106.89 25 91.03 80.59 26 86.78 4.56 27 85.41 97.69 28 84.73 0 29 84.37 109.8 30 83.97 108.46 31 83.75 94.69 32 83.26 63.28 33 82.71 47.69 34 79.9 39.48 35 79.7 99 36 79.43 45.71 37 78.23 102.66 38 74.95 65.36 39 73.21 0 40 72.7 88.65 41 72.61 16.38 42 70.57 57.85 43 69.88 24.16 44 69.62 0 45 69.07 92.41 46 68.25 0 47 68.07 48.84 48 66.59 30.49 49 65.88 92.34 50 65.71 50.31 51 65.06 87.91 52 65.01 92.83 53 64.83 0 54 63.8 0 55 63.23 88.78 56 62.66 0 57 62.39 0 58 62.23 10.18 59 61.48 0 60 59.89 108.64 61 59.7 30.54 62 59.58 33.97 63 58.57 26.41 64 57.92 25.48 65 55.41 93.17 66 55.38 38.64 67 55.03 80.49 68 54.11 0 69 53.64 82.89 70 53.27 42.16 71 53.19 95.22 72 52.58 13.25 73 51.02 105.54 74 50.42 102.6 75 50.14 9.11 76 48.94 40.3 77 47.95 104.71 78 45.73 35.22 79 45.47 54.49 80 45.26 22.47 81 44.9 34.14 82 44.86 4.42 83 43.94 30.77 84 43.73 0 85 43.69 40.84 86 43.22 0 87 42.69 44.38 88 42.06 7.33 89 41.34 0 90 49.96 99.55 91 48.78 92 103.49 101.34 93 105.57 99.12 94 105.3 103.1 95 106.86 100.63 96 104.91 91.35 97 98.05 98.2 98 104.09 101.37 99 103.76 100.08 100 103.71 101.69 101 100.27 100.47 102 103.94 99.95 103 105.15 100.39 104 105.3 100.57 105 105.66 100.37 106 102.6 102.64 107 102.05 102.39 108 102.41 102.31 109 102.82 101.69 110 102.5 101.77 111 91.86 101.4 112 102.43 101.88 113 99.23 97.07 114 102.24 102.56 115 102.47 58.09 116 74.25 100.94 117 100.65 100.53 118 103.54 102.07 119 95.94 61.85 120 103.28 102.56 121 70.47 52.72 122 12.11 13.04 123 43.88 79.94 124 76.28 63.16 125 50.56 95.36 126 46.36 81.06 127 102.31 93.69 128 90.8 94.47 129 0.03 31.23 130 103.2 96.3 131 82.09 95.37 133 103.01 98.08 134 102.44 98.25 135 102.68 98.31 136 103.97 98.94 137 102.25 98.75 138 103.55 98.45 139 99.91 98.83 140 100.08 80.7 141 100.51 100.7 142 89.91 62.99 143 99.91 99.3 144 100.57 98.16 145 99.4 98.64 146 97.26 99.64 147 99.95 99.96 148 100.09 99.97 149 99.41 100.05 150 98.31 99.06 151 106.94 103.01 152 100.06 90.83 153 81.64 40.58 154 83.21 84.36 155 107.43 89.64 156 108.3 102.71 157 98.2 99.97 158 98.49 99.3 159 99.17 100.6 160 98.97 99.04 161 98.53 99.25 162 99.53 99.51 163 95.05 100.8 164 99.63 100.63 165 97.13 96.78 166 99.44 99.28 167 101.53 100.86 168 93.83 98.38 169 100.44 101.1 170 101.02 97.85 171 101.89 82.78 172 101.45 85.19 173 100.61 100.68 174 101.35 97.95 175 103.24 86.31 176 −24.81 36.52 177 103.86 100.43 178 101.6 99.82 179 104.26 100.13 180 104 98.6 181 105.03 98.54 182 91.1 99.72 183 100.16 96.92 184 104.83 99 185 105.43 97.93 186 105.87 97.13 187 100.41 101.8 188 101.92 102.25 189 70.72 86.37 190 101.56 101.94 191 — — 192 105.69 100.29 193 103.95 98.28 194 103.08 100.27 195 85.11 98.81 196 100.47 98.8 197 103.6 100 198 105.4 99.75 199 104.01 100.83 200 102.44 98.73 201 103.19 98.19 202 103.84 99.79 203 103.19 98.78 204 104.58 98.98 205 49.98 99.71 206 53.94 99.49 207 101.93 100.16 208 104.84 100.76 209 103.97 99.93 210 106.17 96.03 211 106.08 100.06 212 106.74 100.18 213 59.72 94.53 214 101.16 101.91 215 99.94 100.96 216 −10.12 4.48 217 — — 218 100.43 — 219 5.04 96.23 220 15.27 86.34 221 38.04 89.58 222 7.55 113.93 223 26.23 86.37 224 72.06 52.77 225 104.47 84.08 226 76.38 96.87 227 26.87 94.52 228 88.56 99.82 229 101.09 100.53 230 95.42 62.33 231 102.03 83.34 232 102.37 90.03 233 101.96 86.74 234 51.96 103.02 235 102.3 83.46 236 95.86 99.58 237 99.72 99.45 238 99.93 99.35 239 94.7 99.7 240 78.48 97.3 241 103.76 99.26 242 102.04 87.99 243 24.76 80.63 244 70.16 97.28 245 69.86 80.5 246 56.38 72.1 247 70.78 96.75 248 95.6 89.86 249 59.22 92.36 250 96.85 90.55 251 45.81 98.51 252 101.72 97.94 253 59.31 101.11 254 105.08 97.8 255 104.91 100.81 256 50.23 91.02 257 34.31 99.94 258 75.25 99.75 259 66.06 99.3 260 101.6 60.62 261 78.92 98.87 262 81.81 99.65 263 100.01 97.85 264 103.07 31.71 265 99.95 51.3 266 102.46 2.12 267 103.79 95.16 268 103.88 101.64 269 103.6 99 270 103.77 93.42 271 59.08 85.9 272 97.14 84.61 273 96.05 84.87 274 103.75 98.08 275 101.73 93.06 276 98.92 94.16 277 85.55 81.59 278 103.71 96.94 279 103.74 95.39 280 103.9 92.04 281 103.69 92.37 282 102.79 85.95 283 103.46 92.9 284 102.93 93.55 285 103.77 90.97 286 103.72 97.93 287 101.02 89.25 288 101.83 93.34 289 102.52 95.5 290 104.09 92.91 291 104.28 92.99 292 105.83 99.22 293 90.51 −6.96 294 105.91 100 295 96.67 103.18 296 105.85 99.28 297 105.76 102.53 298 105.09 103.58 299 106.32 102.79 300 105.73 103.1 301 106.36 100.99 302 100.69 102.41 303 106.27 100.4 304 71.12 101.52 305 76.41 95.47 306 103.75 99.16 307 105.47 98.38 308 104.85 100.95 309 52.02 101.11 310 106.11 102.07 311 94.88 103.15 312 98.52 98.68 313 103.46 102.58 314 105.18 103.91 315 105.13 100.59 316 82.66 98.17 317 92.19 100.22 318 101.58 101.55 319 104.47 100.08 320 105.66 101.93 321 41.19 100.13 322 101.81 98.72 323 104.72 88.06 324 83.97 98.44 325 101.91 100.88 326 103.59 101.04 327 104.27 100.52 328 103.86 101.85 329 104.89 98.16 330 104.39 100.44 331 105.94 100.52 332 105.29 100.79 333 107.07 100.76 334 106.56 100.58 335 106.11 99.82 336 103.22 104.8 337 103.65 104.4 338 92.57 92.22 339 77.54 41.63 340 104.92 100.73 341 104.72 102.33 342 104.5 100.29 343 79.97 100.23 344 48.77 88.4 345 22.26 95.94 346 95.54 100.91 347 56.56 102.91 348 87.09 102.94 349 100.78 102.8 350 103.91 103.72 351 44.01 103.99 352 103.57 103.63 353 102.72 102.17 354 62.46 102.22 355 83.39 101.52 356 43.04 103.33 357 79.38 104.35 358 101.48 102.53 359 98.56 102.84 360 96.66 103.03 361 93.42 100.74 362 103.34 101.91 363 90.7 101.09 364 104.69 101.44 365 55.61 99.85 366 14.76 99.03 367 20.1 102.67 368 62.06 100.94 369 82.34 100.93 370 18.72 98.83 371 0.38 100.72 372 −2.76 83.81 373 104.41 98.85 374 80.78 101.66 375 98.74 99.85 376 67.07 99.02 377 87.21 99.56 378 63.42 98.75 379 67.92 101.75 380 91.51 100.9 381 77.88 100.15 382 103.44 101.03 383 40.17 101.54 384 104.56 98.56 385 101.05 99.45 386 100.74 97.86 387 90.98 100.56 388 22.88 100.66 389 100.51 100.49 390 102.87 99.78 391 97.78 101.54 392 100.93 99.09 393 103.77 101.49 394 31.48 99.08 395 12.63 100.41 396 24.69 80.61 397 97.25 101.46 398 59.84 98 399 93.05 102.16 400 62.01 102.17 401 90.84 95.62 402 47.09 101.25 403 100.68 100.41 404 55.06 98.55 405 98.59 100.41 406 102.96 100.21 407 102.44 99.02 408 102.22 99.79 409 28.09 81.39 410 102.43 102.85 411 101.07 100.19 412 101.44 102.89 413 99.93 102.79 414 100.97 100.12 415 99.23 97.52 416 50.22 100.96 417 96.16 103.38 418 101.28 103.53 419 99.98 101.17 420 100.33 92.05 421 97.3 93.36 422 48.04 98.61 423 58.71 80.13 424 35.11 97.61 425 −0.97 98.84 426 −4.95 94.38 427 101.54 98.83 428 23.84 101.75 429 14.33 99.48 430 38.56 100.57 431 28.42 96.18 432 94.03 100.3 433 103.47 99.97 434 103.69 101.47 435 6.23 99.56 436 39.2 101.6 437 36.08 101.67 438 22.12 99.98 439 48.25 100.94 440 98.07 95.62 441 103.96 98.36 442 101.8 98.56 443 103.85 99.33 444 92.79 98.58 445 102.23 98.61 446 95.03 99.75 447 66.5 94.21 448 85.75 99.78 449 90.75 99.72 450 87.36 99.66 451 80.68 99.23 452 104.82 95.19 453 40.51 74.44 454 101.91 100.32 455 102.81 99.34 456 100.44 100.76 457 102 99.65 458 102.65 100.43 459 57.14 102.04 460 96.59 100.78 461 100.64 99.1 462 101.3 98.25 463 97.39 100.72 464 56.56 101.94 465 101.95 98.82 466 92.52 99.72 467 101.34 100.88 468 84.49 101.4 469 92.34 101.61 470 92.67 98.07 471 102.93 98.79 472 92.06 101.17 473 94.59 99.49 474 96.7 96.3 475 90.42 101.75 476 90.06 100.14 477 94.46 98.77 478 36.16 90.24 479 32.3 99.07 480 100.76 102.62 481 72.64 103.71 482 97.92 102.46 483 102.72 104.43 484 75.57 100.57 485 65.25 103.41 486 70.44 101.22 487 100.93 99.13 488 100.99 101.64 489 99.28 99.96 490 93.52 103.22 491 96.35 97.94 492 102.54 103.95 493 40.64 99.47 494 26.16 73.41 495 30.7 95.72 496 68.19 103.02 497 66.04 101.25 498 94.25 96.7 499 103.35 100.58 500 41.81 93.22 501 65.06 89.7 502 96.74 103.44 503 103.07 97.92 504 24.18 90.61 505 74.02 100.82 506 98.27 98.91 507 −10.08 102.4 508 31.93 102.55 509 92.72 102.13 510 51.42 101.9 511 86.96 102.91 512 93.03 102.26 513 73.53 101.16 514 85.25 99.02 515 30.9 100.15 516 101.34 99.39 517 98.85 101.92 518 102.58 99.69 519 81.88 102.71 520 102.91 102.07 521 85.17 99.34 522 54.17 98.7 523 66.38 101.41 524 101.62 100.66 525 15.41 102.31 526 73.35 101.65 527 97.16 97.33 528 88.22 101.57 529 105.85 101.47 530 93.08 101.41 531 92.59 96.17 532 96.4 107.74 533 105.76 107.71 534 104.14 107.17 535 48.36 107.33 536 63.12 107.33 537 12.53 98.72 538 −11.76 105.77 539 38.81 107.39 540 7.17 100.18 541 103.13 107.61 542 49.24 107.2 543 21.14 104.54 544 11.72 106.99 545 39.81 106.41 546 7.44 104.05 547 77.44 99.97 548 24.68 95.44 549 75.84 99.05 550 57.78 101.12 551 52.7 101.87 552 46.78 101.41 553 54.09 100.52 554 25.2 101.97 555 62.48 102.09 556 12.13 85.58 557 29.73 87.56 558 −3.53 102.69 559 99.91 100.17 560 101.72 99.35 561 102.13 101.17 562 102.46 100.03 563 101.86 100.42 564 104.58 102.33 565 104.82 102.52 566 103.44 102.51 567 104.25 102.19 568 38.49 81.34 569 90.04 92.89 570 97.65 98.06 571 103.97 100.34 572 — 98.98 573 — 101.21 574 89.99 — 575 23.44 96.83 576 1.85 107.17 577 17.34 107.05 578 8.96 87.13 579 39.4 107.07 580 39.09 88.5 581 27.54 76.31