# Patent

## Title
Sulfonylated 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine compounds and their use as pharmaceuticals

## Abstract

Sulfonylated tetrahydroazolopyrazine compounds corresponding to the formula I




wherein R1, R2a, R2b, R3a, R3b, R4, R8, R9a, R9b, R10, R11, A, B, W1, W2 and W3 have the meanings defined herein, pharmaceutical compositions containing such compounds, a method for the preparation of such compounds, and the use of such compounds for treating or inhibiting various types of pain and/or other conditions mediated at least in part by the bradykinin 1 receptor (B1R).

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. provisional patent application No. 61/157,393, filed Mar. 4, 2009, the entire disclosure of which is incorporated herein by reference. Priority is also claimed based on European patent application no. EP 09003075.0, filed Mar. 4, 2009.


BACKGROUND OF THE INVENTION
The present invention relates to sulfonylated tetrahydroazolopyrazines, methods for the preparation thereof, pharmaceutical compositions containing these compounds and the use thereof for the preparation of pharmaceutical compositions.
In contrast to the constitutive expression of the bradykinin 2 receptor (B2R), the bradykinin 1 receptor (B1R) is not expressed or is only weakly expressed in most tissues. Nevertheless, expression of the B1R can be induced on various cells. By way of example, in the course of inflammation reactions a rapid and pronounced induction of the B1R takes place on neuronal cells, but also on various peripheral cells, such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Thus, in the course of inflammation reactions a switch from a B2R to a B1R dominance occurs on the cells involved. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) are substantially involved in this B1R up-regulation (Passos et al. J. Immunol. 2004, 172, 1839-1847). After activation with specific ligands, B1R-expressing cells can subsequently themselves secrete inflammation-promoting cytokines, such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This leads to inwards migration of further inflammation cells, for example neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145). The bradykinin B1R system can contribute to the chronification of diseases via these mechanisms. This is demonstrated by a large number of animal studies (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, an increased expression of the B1R is seen, for example on enterocytes and macrophages in the affected tissue of patients with inflammatory bowel diseases (Stadnicki et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G361-366) and on T lymphocytes of patients with multiple sclerosis (Prat et al., Neurology. 1999; 53, 2087-2092), or an activation of the bradykinin B2R-B1R system is seen in the course of infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for disease profiles such as superficial infections of the skin through to septic shock.
Based on the pathophysiological relationships described, there is great therapeutic potential for the use of B1R antagonists against acute and in particular chronic inflammatory diseases. They include diseases of the respiratory tract (bronchial asthma, allergies, COPD/chronic obstructive pulmonary disease, cystic fibrosis, etc.), inflammatory bowel 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 mucous membranes (Behcet's disease, chronic pelvic pain, prostatitis, etc.), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock and reperfusion syndrome (following heart attack or stroke).
The bradykinin (receptor) system is moreover also involved in the regulation of angiogenesis (potential as an angiogenesis inhibitor in cases of cancer and macula degeneration in the eye), and B1R-knockout mice are protected from the induction of obesity by a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore also suitable for the treatment of obesity.
B1R antagonists are particularly suitable for the treatment of pain, in particular inflammatory pain and neuropathic pain (Calixto et al., Br. J. Pharmacol 2004, 1-16), and here in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). They are also suitable for the treatment of migraine.
In the development of B1R modulators there is the problem, however, that the human and the rat B1R receptor differ so widely that many compounds which are good B1R modulators on the human receptor have only a poor or no affinity for the rat receptor. This makes animal pharmacology studies considerably more difficult, since many studies are usually conducted on the rat. However, if there is no activity on the rat receptor, neither action nor side-effect can be investigated on the rat. This has already meant that transgenic animals with human B1 receptors have been produced for animal pharmacology studies (Hess et al., Biol. Chem. 2006; 387(2):195-201). Working with transgenic animals is, however, more expensive than working with the unmodified animals.
The patent applications WO 2008/040492 and WO 2008/046573 describe compounds which in in-vitro assays exhibit an antagonistic action both on the human B1 receptor and on the B1 receptor of the rat.
The patent applications WO 2007/140383 and WO 2007/101007 describe compounds which in in-vitro assays exhibit an antagonistic action on the macaque B1 receptor. Experimental data on the activity on the human B1 receptor or the B1 receptor of the rat is not disclosed.
Despite the efforts of the prior art, there remains a need for new B1R modulators, wherein B1R modulators which bind both to the rat receptor and to the human receptor offer particular advantages.
SUMMARY OF THE INVENTION
An object of the present invention was therefore to provide novel compounds which are suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment of disorders or diseases which are at least partly mediated by B1R receptors.
This object is achieved by the sulfonylated tetrahydroazolopyrazines according to the invention.
The invention therefore provides compounds having the general formula I




wherein

    a stands for 1 or 2;
    b stands for 0, 1 or 2;
    B stands for C(R6a)(R6b), NR7, O or a single bond, with the proviso that if b stands for 0 then B does not stand for NR7;
    W1, W2 and W3 each independently stand for CR5 or N, with the proviso that at least one of W1, W2 and W3 stands for CR5;
    R1 stands for aryl, heteroaryl, CH(aryl)2 or an aryl or heteroaryl bound by a C1-3 alkylene group;
    R2a, R2b, R3a, R3b, R6a and R6b each independently stand for H, F, Cl, Br, I, —CF3, OH, SH, O—C1-6 alkyl, C1-6 alkyl, C3-8 cycloalkyl, aryl or heteroaryl; or for a C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group or C2-6 alkenylene group; and/or
    R2a and R2b and/or R3a and R3b can together denote ═O;
    R4 stands for 0 to 4 substituents independently selected from F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; and/or two adjacent substituents out of the 0 to 4 substituents R4 form an anellated aryl or heteroaryl ring structure;
    R5 stands for H, C1-6 alkyl, halogen, —CN or CF3;
    R7 stands for H, C1-6 alkyl, C3-8 cycloalkyl, aryl, heteroaryl or for a C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group;
    s=0 or 1,
    t=0, 1, 2 or 3,
    R8 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group;
    R9a and R9b each independently denote H; F; Cl; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group;
    A stands for N or CH,
    
        with the proviso that if s=1 and t=0 then A stands for CH; and
        with the proviso that if s=0 then t=0 and A stands for N;
    
    
    R10 and R11 together with A represent a spirocyclic or cyclic group corresponding to formula II or III:






wherein

    c, d, e, f, u and v each independently denote 0, 1 or 2;
    R12, R13 and R27 each independently stand for 0 to 4 substituents, which are each independently selected from F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; and/or two of the 0 to 4 substituents R27 together represent a C1-3 alkylene bridge such that the cyclic compound represented in the general formula III assumes a bicyclically bridged form; and/or two adjacent substituents out of the 0 to 4 substituents R13 form an anellated aryl or heteroaryl; and/or two adjacent substituents out of the 0 to 4 substituents R27 form an anellated aryl or heteroaryl;
    X stands for CR14aR14b, NR15 of O;
    Y stands for CR16bR16b, NR17 or O;
    
        with the proviso that X does not denote NR15 if Y denotes NR17; and
        with the proviso that X and Y do not simultaneously denote O;

wherein

    
    
    R14a, R14b, R16a and R16b each independently denote H; F; Cl; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl and heteroaryl bound by a C1-6 alkylene group; and/or R14a and R14b can together stand for ═O and/or R16a and R16b can together stand for ═O;
    R15 and R17 each independently stand for H; C1-6 alkyl; C3-8 cycloalkyl, aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group;
    Z in formula II stands for CR18aR18b, NR19 or O; or
    Z in formula II, if X stands for O and f stands for 0, denotes —(C(R124)—C(R125))—,
    
        wherein
        R124 and R125 together with the carbon atoms linking them form a fused aryl or heteroaryl ring structure; or
    
    
    Z in the general formula II, if X stands for O and f stands for 0, denotes ═(N(CR126))—, wherein the N atom is singly bound to the O atom, and


R126 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group;

    Z in the general formula III stands for CR18aR18b, NR19, O, S, S(═O) or S(═O)2;

wherein



R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; or

    R18a stands for a group corresponding to formula IV:






wherein

    i and j each independently stand for 0 or 1;
    E stands for N or CH, with the proviso that if i stands for 1 and j stands for 0, then E stands for CH,
    R34 and R35 each independently denote H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkylene group; or
    R34 and R35 together with E form a 5- or 6-membered aryl or heteroaryl; or
    R34 and R35 together with E form a saturated heterocyclic structure corresponding to formula V:






wherein

    h and g each independently denote 0, 1 or 2;
    G stands for CR37aR37b, NR38, O, S, S═O or S(═O)2, with the proviso that if E stands for CH then G does not stand for CR37aR37b;
    R36 stands for 0 to 4 substituents which are each independently selected from H; F; Cl; Br; I; OH; SH; ═O; O—C1-6 alkyl; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; and/or two adjacent substituents R36 together represent an anellated aryl or heteroaryl ring structure;
    R37a and R37b each independently stand for H; F; Cl; Br; I; OH; SH; ═O; O—C1-6 alkyl;
    C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl and heteroaryl bound by a C1-6 alkylene group;
    R38 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkylene group;

wherein

    R18b stands for H; OH; C1-6 alkyl; C3-8 cycloalkyl; O—C1-6 alkyl; O—(C3-8 cycloalkyl); (C1-6 alkylene)-O—C1-6 alkyl; (C1-6 alkylene)-O—(C3-8 cycloalkyl); aryl or heteroaryl; O-aryl or O-heteroaryl; aryl, O-aryl, heteroaryl or O-heteroaryl bound by C1-6 alkylene; or
    R18b stands for a group corresponding to formula VI:






wherein

    k stands for 0 or 1;
    R39 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-3 alkylene group;
    R40 stands for C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; or
    R39 and R40 together with the N—C(═O) group linking them form a ring corresponding to formula VII:






wherein

    I stands for 0, 1 or 2; and
    R41 and R42 together with the carbon atoms linking them form an anellated aryl or heteroaryl;

wherein

    R19 stands for H; or (P)z—R22, and
    z stands for 0 or 1;
    P stands for (C═O), S(═O)2 or C(═O)—N(R24); wherein the N atom in the C(═O)—N(R24) group is linked to R22;
    R24 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkylene group;
    R22 stands for C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-6 alkylene group; or
    R22 stands for a group according to the general formula VIII,






wherein

    n stands for 0, 1 or 2;
    m stands for 0, 1 or 2;
    w stands for 0 or 1,
    M stands for CH or N;
    
        with the proviso that if P stands for C(═O)—NR24 and w stands for 0, then M stands for CH; and
        with the proviso that if z and w simultaneously stand for 0, then M stands for CH;
    
    
    L stands for CR44aR44b, NR45, O, S, S═O or S(═O)2;
    R43 stands for 0 to 4 substituents which are each independently selected from the group consisting of F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; and/or two adjacent substituents out of the 0 to 4 substituents R43 together represent an anellated aryl or heteroaryl ring structure;
    R44a and R44b each independently stand for H; F; Cl; Br; I; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; or
    R44a and R44b can together stand for ═O;
    R45 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; aryl, heteroaryl or C3-8 cycloalkyl bound by a C1-3 alkylene group;

or

wherein, if s and t in formula I simultaneously stand for O and A stands for N,

    R10 stands for H, C1-6 alkyl, C3-8 cycloalkyl or a C3-8 cycloalkyl bound by a C1-3 alkylene group;
    R11 stands for a phenyl group or a phenyl group bound by a C1-3 alkylene group, wherein the C1-3 alkylene group can be substituted with a —C(═O)R280 group and R280 stands for —N(C1-6 alkyl)2 or a 4- to 7-membered heterocyclyl, and wherein the phenyl group is substituted with an —(NR300R301) group or a 4- to 8, preferably 4 to 7-membered heterocyclyl, and the —(NR300R301) group and the 4- to 8, preferably 4 to 7, -membered heterocyclyl can be bound to the phenyl group by a C1-3 alkylene group and R300 and R301, each independently, stand for H or C1-6 alkyl;

wherein the aforementioned C1-6 alkyl, C1-3 alkylene, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-6 cycloalkyl, C3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl groups may each be unsubstituted or mono- or polysubstituted with identical or different substituents; and the aforementioned C1-6 alkyl, C1-3 alkylene, C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene groups may each be branched or unbranched;



in the form of an isolated enantiomer or an isolated diastereomer, the racemate, the enantiomers, the diastereomers, mixtures of the enantiomers and/or diastereomers, and each in the form of their bases and/or physiologically compatible salts.
In addition to the above described embodiments, the invention further comprises compounds in which in formula (V) two of the 0 to 4 substituents R36 together represent a C1-3-alkylene bridge, such that the cyclic compound represented by the formula (V) assumes a bicyclically bridged form;
In the foregoing formula (IV) the bonds shown between E and R34 and R35 should not be understood exclusively as single bonds; they can also be part of an aromatic system.
Within the meaning of the present invention the term “halogen” preferably stands for F, Cl, Br and I, in particular for F and Cl.
Within the meaning of this invention, the expression “C1-6 alkyl” includes acyclic saturated hydrocarbon groups having 1, 2, 3, 4, 5 or 6 C atoms, which can be branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents. The alkyl groups can preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. Particularly preferred alkyl groups can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
Within the meaning of this invention, the expression “C3-8 cycloalkyl” denotes cyclic saturated hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, which can be unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, at one or more ring members with identical or different substituents. C3-8 cycloalkyl can preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Within the meaning of this invention, the expression “aryl” denotes aromatic hydrocarbons, in particular phenyls and naphthyls. The aryl groups can also be fused to other saturated, (partially) unsaturated or aromatic ring systems. Each aryl group can be present in unsubstituted or mono- or polysubstituted form, for example di-, tri-, tetra- or pentasubstituted, wherein the aryl substituents can be identical or different and can be at any desired and possible position of the aryl. Aryl can advantageously be selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl, which can be unsubstituted or mono- or polysubstituted, for example with 2, 3, 4 or 5 substituents.
Within the meaning of the present invention, the expression “heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromatic group containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms can be identical or different and the heteroaryl can be unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents. The substituents can be bound to any desired and possible position of the heteroaryl. The heterocyclic compound can also be part of a bicyclic or polycyclic system, in particular a mono-, bi- or tricyclic system, which can then in total be more than 7-membered, preferably up to 14-membered. Preferred heteroatoms are selected from the group consisting of N, O and S. The heteroaryl group is preferably selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, benzooxazolyl, benzooxadiazolyl, imidazothiazolyl, dibenzofuranyl, dibenzothienyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazole, tetrazole, isoxazoyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl, in particular from the group consisting of thienyl (thiophenyl), pyridinyl (pyridyl), pyrimidinyl, thiazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, quinazolinyl, quinolinyl and isoquinolinyl, wherein the binding to the general structure (I) can be made via any desired and possible ring member of the heteroaryl group. The heteroaryl group can particularly preferably be selected from the group consisting of thienyl, imidazolyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl.
In the context of the present invention the expression “3- to 6-membered, 4 to 8 or 4- to 7-membered heterocyclyl”, unless specified further, includes both aromatic and saturated or partially unsaturated, 3-, 4-, 5- or 6-, 7 or 8-membered, mono or bicyclic hydrocarbon compounds in which one or more carbon ring members is each independently replaced by a heteroatom or a heteroatom group, in particular by N, O or S. For example, 1, 2 or 3 ring atoms in the heterocyclyl ring can be heteroatoms. Non-aromatic heterocyclyls can be unsubstituted, mono- or polysubstituted with identical or different substituents, wherein the substituents correspond to those described below in connection with the substitution of C3-8 cycloalkyls.
Aromatic heterocyclyls are synonymous with heteroaryls. The meaning of the term “heteroaryl” has already been described above and the possible substitution is likewise explained below.
Examples of 3-6-membered heterocyclyls are firstly the 5-6-membered heteroaryls already mentioned in connection with heteroaryls and secondly also pyrrolidinyl, piperidinyl, 2,6-dimethylpiperidine, 4,5-dihydro-1H-imidazo-2-yl or 1-methyl-4,5-dihydroimidazo-2-yl. In connection with the 4- to 7-membered heterocyclyl group in R11 this can be selected in particular from pyrrolidinyl, piperidinyl, 2,6-dimethylpiperidine, 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 4,5-dihydro-1H-imidazo-2-yl, 1-methyl-4,5-dihydroimidazo-2-yl or 4H-1,2,4-triazol-4-yl, each unsubstituted or optionally mono- or polysubstituted.
The expression “3- to 8-membered heterocycloalkyl” denotes saturated heterocyclic compounds which can exhibit 1, 2, 3, 4 or 5 each independently selected identical or different heteroatoms as ring members, preferably from the group N, O or S. If the heterocycloalkyl is bound to a heteroatom, for example N, the binding to the heterocycloalkyl is preferably made via one of the carbon ring members of the heterocycloalkyl. 3- to 8-membered heterocycloalkyls can in particular be 4-, 5- or 6-membered. Examples of 3- to 8-membered heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl and dioxolanyl, which optionally may be substituted as described below.
Within the meaning of the present invention, the expression “C1-3 alkylene group” or “C1-6 alkylene group” includes acyclic saturated hydrocarbon groups having respectively 1, 2 or 3 or 1, 2, 3, 4, 5 or 6 C atoms, which can be branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents and which link a corresponding radical to the higher-order general structure. The alkylene groups are preferably selected from the group consisting of —CH2—, —CH2—CH2—, —CH(CH3)—, —CH2—CH2—CH2—, —CH(CH3)—CH2—, —CH(CH2CH3)—, —CH2—(CH2)2—CH2—, —CH(CH3)—CH2—CH2—, —CH2—CH(CH3)—CH2—, —CH(CH3)—CH(CH3)—, —CH(CH2CH3)—CH2—, —C(CH3)2—CH2—, —CH(CH2CH2CH3)—, —C(CH3)(CH2CH3)—, —CH2—(CH2)3—CH2—, —CH(CH3)—CH2—CH2—CH2—, —CH2—CH(CH3)—CH2—CH2—, —CH(CH3)—CH2—CH(CH3)—, —CH(CH3)—CH(CH3)—CH2—, —C(CH3)2—CH2—CH2—, —CH2—C(CH3)2—CH2—, —CH(CH2CH3)—CH2—CH2—, —CH2—CH(CH2CH3)—CH2—, —C(CH3)2—CH(CH3)—, —CH(CH2CH3)—CH(CH3)—, —C(CH3)(CH2CH3)—CH2—, —CH(CH2CH2CH3)—CH2—, —C(CH2CH2CH3)—CH2—, —CH(CH2CH2CH2CH3)—, —C(CH3)(CH2CH2CH3)—, —C(CH2CH3)2— and —CH2—(CH2)4—CH2—. The alkylene groups are particularly preferably selected from the group consisting of —CH2—, —CH2—CH2— and —CH2—CH2—CH2—.
Within the meaning of the present invention the expression “—(O)0/1—C1-6 alkylene group” also includes in addition to the C1-6 alkylene groups described above such groups in which these groups are linked by an oxygen atom to the higher-order structure.
Within the meaning of the present invention, the expression “C2-6 alkenylene group” includes acyclic mono- or polyunsaturated, for example di-, tri- or tetraunsaturated, hydrocarbon groups having 2, 3, 4, 5 or 6 C atoms, which can be branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents and which link a corresponding radical to the higher-order general structure. The alkenylene groups include at least one C═C double bond. The alkenylene groups are preferably selected from the group consisting of —CH═CH—, —CH═CH—CH2—, —C(CH3)═CH2—, —CH═CH—CH2—CH2—, —CH2—CH═CH—CH2—, —CH═CH—CH═CH—, —C(CH3)═CH—CH2—, —CH═C(CH3)—CH2—, —C(CH3)═C(CH3)—, —C(CH2CH3)═CH—, —CH═CH—CH2—CH2—CH2—, —CH2—CH═CH2—CH2—CH2—, —CH═CH═CH—CH2—CH2— and —CH═CH2—CH—CH═CH2—.
Within the meaning of the invention, the expression “C2-6 alkynylene group” includes acyclic mono- or polyunsaturated, for example di-, tri- or tetraunsaturated, hydrocarbon groups having 2, 3, 4, 5 or 6 carbon atoms, which can be branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents and which link a corresponding radical to the higher-order general structure. The alkynylene groups include at least one C≡C triple bond. The alkynylene groups are preferably selected from the group consisting of —C≡C—, —C≡C—CH2—, —C≡C—CH2—CH2—, —C≡C—CH(CH3)—, —CH2—C≡C—CH2—, —C≡C—C≡C—, —C≡C—C(CH3)2—, —C≡C—CH2—CH2—CH2—, —CH2—C≡C—CH2—CH2—, —C≡C—C≡C—CH2— and —C≡C—CH2—C≡C—.
Within the meaning of the present invention the expression “aryl or heteroaryl bound by a C1-3 alkylene group, a C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group” means that the C1-3 alkylene groups, C1-6 alkylene groups, C2-6 alkenylene groups, C2-6 alkynylene groups and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl is bound to the higher-order general structure by a C1-3 alkylene group, C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group. Benzyl, phenethyl and phenylpropyl are cited by way of example.
Within the meaning of the present invention, the expression “C3-8 cycloalkyl, 3- to 6-membered or 4- to 7-membered heterocyclyl or 3- to 8-membered heterocycloalkyl bound by a C1-3 alkylene group, C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group” means that the C1-3 alkylene group, C1-6 alkylene group, C2-6 alkenylene group, C2-6 alkynylene group, C3-8 cycloalkyl and heterocycloalkyl have the meanings defined above and C3-8 cycloalkyl and heterocycloalkyl are bound to the higher-order general structure by a C1-3 alkylene group, C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group.
In connection with “alkyl”, “alkylene”, “alkenylene”, “alkynylene” and “cycloalkyl”, the term “substituted” within the meaning of this invention is understood to mean the replacement of a hydrogen with F, Cl, Br, I, CF3, OCF3, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, NO2, SH, S—C1-6 alkyl, C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkylene-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, CO2H, CO2—C1-6 alkyl, phenyl, phenoxy, benzyl, naphthyl, furyl, thienyl and pyridinyl, wherein polysubstituted groups are understood to mean groups which are substituted multiple times, for example twice or three times, at different or the same atoms, for example substituted three times at the same C atom, as in the case of CF3 or CH2CF3, or at different sites, as in the case of CH(Cl)—CH═CH—CHCl2. The polysubstitution can take place with identical or different substituents, as for example in the case of CH(OH)—CH═CH—CHCl2. It should be understood in particular to be the replacement of one or more hydrogens with F, Cl, NH2, OH, phenyl, O—CF3 or O—C1-6 alkyl, in particular methoxy.
In connection with “aryl” and “heteroaryl”, the term “substituted” within the meaning of this invention is understood to mean the mono- or polysubstitution, for example the di-, tri-, tetra- or pentasubstitution, of one or more hydrogen atoms of the corresponding ring system with F, Cl, Br, I, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, NH-aryl1, N(aryl1)2, N(C1-6 alkyl)aryl1, pyrrolinyl, piperazinyl, morpholinyl, azetidinyl, piperidinyl, thiazolinyl, azepanyl, diazepanyl, (C1-3 alkylene)-azetidinyl, (C1-3 alkylene)-pyrrolinyl, (C1-3 alkylene)-piperidinyl, (C1-3 alkylene)-morpholinyl, (C1-3 alkylene)-piperazinyl, (C1-3 alkylene)-thiazolinyl, (C1-3 alkylene)-azepanyl, (C1-3 alkylene)-diazepanyl, NO2, SH, S—C1-6 alkyl, OH, O—C1-6 alkyl, O—C1-6 alkyl-OH, C(═O)C1-6 alkyl, NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2—C1-6 alkyl, OCF3, CF3, —O—CH2—O—, —O—CH2—CH2—O—, —O—C(CH3)2—CH2—, unsubstituted C1-6 alkyl, pyrrolidinyl, imidazolyl, benzyloxy, phenoxy, phenyl, naphthyl, pyridinyl, —C1-3 alkylene-aryl1, benzyl, thienyl, furyl, wherein aryl1 stands for phenyl, thiazolyl, thienyl or pyridinyl, at one or different atoms, wherein the aforementioned substituents—unless otherwise specified—can themselves be substituted with the cited substituents. The polysubstitution of aryl and heteroaryl can be performed with identical or different substituents. Preferred substituents for aryl and heteroaryl can be selected from the group consisting of —O—C1-3 alkyl, unsubstituted C1-6 alkyl, F, Cl, Br, I, CN, CF3, OCF3, OH, SH, —CH2 azetidinyl, —CH2-pyrrolidinyl, —CH2-piperidinyl, —CH2-piperazinyl, —CH2-morpholinyl, phenyl, naphthyl, thiazolyl, thienyl and pyridinyl, in particular from the group consisting of F, Cl, CN, CF3, CH3; OCH3, OCF3 and —CH2-azetidinyl.
In connection with “anellated aryl” or “anellated heteroaryl”, “substituted” within the meaning of this invention is understood to mean, in addition to the possible substituents and substitution models defined above in connection with “aryl” and “heteroaryl”, 4- to 7-membered heterocyclyls as further possible substituents, which have the meaning defined above and can optionally be connected to the anellated aryl or heteroaryl by a C1-3 alkylene group. In particular the 4- to 7-membered heterocyclyls appearing as substituents can be selected from the group consisting of morpholinyl, azetidinyl, piperidinyl, thiazolinyl, azepanyl, diazepanyl, (C1-3 alkylene)-azetidinyl, (C1-3 alkylene)-pyrrolinyl, (C1-3 alkylene)-piperidinyl, (C1-3 alkylene)-morpholinyl, (C1-3 alkylene)-piperazinyl, (C1-3 alkylene)-thiazolinyl, (C1-3 alkylene)-azepanyl, (C1-3 alkylene)-diazepanyl, pyrrolidinyl, 2,6-dimethylpiperidine, (C1-3 alkylene)-2,6-dimethylpiperidine, 1H-pyrrol-1-yl, (C1-3 alkylene)-1H-pyrrol-1-yl, 1H-pyrrol-2-yl, (C1-3 alkylene)-1H-pyrrol-2-yl, 4,5-dihydro-1H-imidazo-2-yl, (C1-3 alkylene)-4,5-dihydro-1H-imidazo-2-yl, 1-methyl-4,5-dihydroimidazo-2-yl, (C1-3 alkylene)-1-methyl-4,5-dihydroimidazo-2-yl or 4H-1,2,4-triazol-4-yl-(C1-3 alkylene)-4H-1,2,4-triazol-4-yl, each unsubstituted or optionally mono- or polysubstituted, as defined above. In particular, the 4- to 7-membered heterocyclyls may be substituted with two adjacent substituents which together form an anellated aryl or heteroaryl, especially an anellated phenyl. Especially, piperidinyl may be substituted in such a manner that an 1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl is formed.
In connection with “3- to 8-membered heterocycloalkyl” the term “substituted” is understood to mean the replacement of a hydrogen at one or more ring members by F, Cl, Br, I, —CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, pyrrolinyl, piperazinyl, morpholinyl, NO2, SH, S—C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkylene-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, CO2H, CO2—C1-6 alkyl or benzyl. The polysubstitution can be performed with identical or different substituents. A hydrogen bound to an N ring member can be replaced with a C1-6 alkyl, C3-8 cycloalkyl, aryl, heteroaryl or a C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-3 alkylene group, wherein these alkyl, cycloalkyl, alkylene and aryl and heteroaryl groups can be unsubstituted or substituted as defined above. Examples of substituted 3- to 8-membered heterocycloalkyl groups include 1-methylpiperidin-4-yl, 1-phenylpiperidin-4-yl, 1-benzylpiperidin-4-yl, 1-methylpyrrolidin-3-yl, 1-phenylpyrrolidin-3-yl, 1-benzylpyrrolin-3-yl, 1-methylazetidin-3-yl, 1-phenyl-azetidin-3-yl or 1-benzylazetidin-3-yl.
In the chemical structural formulas which are used here to describe the compounds according to the invention, the symbol




is also used to describe one or more substitution models, wherein unlike the representation of a binding to a specific atom, this group is not bound to a specific atom within the chemical structural formula (Ra stands by way of example here for a substituent R having a number represented by the variable “a”). This can be explained by way of example by reference to the group





from the general formula (III) shown above: The definition for R27 indicates that R27 can stand for 0 to 4 substituents. Thus R27 can be absent, or 1, 2, 3 or 4 of the C- or N-bound hydrogen atoms within the substructure represented by the general formula (III) can be replaced by one of the substituents provided in the definition of R27, wherein each of the substituents can be selected each independently, in other words they can have different meanings, and C- and/or N-bound hydrogen atoms can be replaced at one or more C or N atoms. R27 can thus also replace a hydrogen atom bound to the ring and included in the group Z. As explained in the definition of R27, two of the substituents R27 can also together represent a C1-3 alkylene bridge or an anellated aryl or heteroaryl (also referred to as a fused aryl or heteroaryl or anellated/fused aryl or heteroaryl group), such that R27 in the general formula (III) also has the meanings shown below in schemes i) to iii) by way of example, in which R27 stands for two substituents at different C atoms or at one C and one N atom. Scheme ii) illustrates the scenario in which the variable u stands for 1. In the scenario illustrated in scheme iii) u and v stand for 1, an R27 replaces a hydrogen atom bound to the nitrogen and a further R27 a hydrogen atom bound to a carbon atom. Moreover, in the scenarios illustrated in schemes ii) and iii) the anellated aryl is substituted with a substituent selected the group defined above for these terms:









and





Persons skilled in the art understand from this representation that if two vicinal (adjacent) groups R27 form an anellated aryl or heteroaryl ring structure then the carbons borne by the anellated ring can no longer have a hydrogen.
The same applies to the substituents R4, R13, R36, R43 if they form an anellated aryl or heteroaryl ring structure and to R41, R42, R124 and R125. For example, in the scenario in which two adjacent substituents R4 form an unsubstituted, anellated aryl, the following scheme arises:




In the context of the present invention, the symbol




used in formulas represents a linking of a corresponding group to a higher-order general structure.

Persons skilled in the art understand that identical radicals used for the definition of different substituents are mutually independent.
Within the meaning of this invention the term “physiologically compatible salt” is understood to mean preferably salts of the compounds according to the invention with inorganic or organic acids, which are physiologically—particularly when used in humans and/or mammals—compatible. Examples of suitable 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-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. The salts of hydrochloric acid (hydrochlorides) and of citric acid (citrates) are particularly preferred.
Within the scope of the invention, the term “isolated” when used with reference to a stereoisomer (e.g., an enantiomer or diastereomer) means substantially separated from the opposite stereoisomer but not necessarily from other substances.
In preferred embodiments of the compounds according to the invention W1, W2 and W3 stand for CR5; or W1 and W2 stand for CR5 and W3 stands for N; or W1 stands for CR5 and W2 and W3 stand for N; or W3 stands for CR5 and W′ and W2 stand for N.
Other preferred embodiments of the compounds according to the invention are those in which B stands for O and R2a, R2b, R3a and R3b preferably stand for H; or B stands for C(R6a)(R6b) or a single bond and R2a, R2b, R3a, R3b, R6a and R6b each independently stand for H, F, CF3, OH, C1-6 alkyl or C1-6 alkoxy.
In the compounds according to the invention R1 preferably stands for phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl); benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl (dibenzothienyl), quinolinyl, isoquinolinyl, for a phenyl or naphthyl bound by a C1-3 alkylene group, or CH(phenyl)2, preferably for phenyl, naphthyl, benzothiophenyl, quinolinyl, isoquinolinyl or thienyl, particularly preferably for phenyl, naphthyl or benzothiophenyl (benzothienyl), each unsubstituted or mono- or polysubstituted, identically or differently, wherein the substituents are selected in particular from —O—C1-3 alkyl, C1-6 alkyl, F, Cl, Br, CF3, OCF3, OH, phenyl, naphthyl, thienyl, thiazolyl and pyridinyl, and wherein the alkylene groups cited above are each unsubstituted or mono- or polysubstituted, identically or differently, wherein the substituents are each independently selected from the group consisting of —O—C1-3 alkyl, F, Cl, Br, CF3, —OCF3, OH, phenyl, phenoxy, naphthyl, furyl, thienyl and pyridinyl.
R1 can stand in particular for phenyl or naphthyl, wherein the phenyl or naphthyl is unsubstituted or mono- or polysubstituted, for example di-, tri-, tetra- or pentasubstituted, with identical or different substituents selected from the group consisting of methyl, methoxy, CF3, OCF3, F and Cl.
In likewise preferred embodiments of the compounds according to the invention R1 is selected from 4-methylphenyl, 4-methoxy-2,3,6-trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 4-methoxy-2,3,5-trimethylphenyl, 2,4,6-trimethylphenyl, 1,3-dichloro-5-(trifluoromethyl)phenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 2-chloro-6-(trifluoromethyl)phenyl, 2,6-dichloro-4-methoxyphenyl, 2,6-dichloro-4-(trifluoromethyl)phenyl, 2-methyl-1-naphthyl, 2-chloro-1-naphthyl, 2-fluoro-1-naphthyl, 6-methoxy-2-naphthyl, 2-chloro-4-(trifluoromethoxy)phenyl, 4-chloro-2,5-dimethylphenyl, 2,6-dichloro-3-methylphenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-methylphenyl; 1-naphthyl and 2-naphthyl; in particular 4-methoxy-2,6-dimethylphenyl, 2-chloro-6-methylphenyl and 2-(trifluoromethyl)phenyl.
Likewise preferred embodiments of the compounds according to the invention are those in which in the general formula I the group Ac I




is selected from one of the following groups





preferably from





wherein

    R4 stands for 0 to 4 atoms or groups selected from H, F or C1-6 alkyl and/or two of the 0 to 4 substituents R4 together represent an anellated aryl or heteroaryl ring structure;
    R210 stands for 0 to 4 substituents independently selected from the group consisting of —O—C1-3 alkyl, C1-6 alkyl, F, Cl, Br, I, CF3, OCF3, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl, preferably from methyl, methoxy, O—CF3, CF3, F, Cl and Br.


In likewise preferred embodiments of the compounds according to the invention in formula (I) a stands for 1, b for 1, B for O and R2a, R2b, R3a and R3b for H; or a stands for 1 or 2, b for 0, B for a single bond and R2a and R2b for H.
Likewise preferred embodiments of the compounds according to the invention are those in which formula (II) assumes the following substructure (IIa):




Likewise preferred embodiments of the compounds according to the invention are those according to formula (I) in which a stands for 1, b for 1, B for O, R2a, R2b, R3a and R3b preferably stand for H and the substructure (B)




in formula (I) assumes the above described substructure (IIa)

wherein all other residues, variables and indices can have the above described meanings.

Likewise preferred embodiments of the compounds according to the invention are those in which the foregoing formula (III) assumes one of the following substructures (IIIa) or (IIIb):




Likewise preferred embodiments of the compounds according to the invention are those according to the above described general formula (I) in which a stands for 1 or 2, b for 0, B for a single bond and R2a and R2b preferably stand for H, and the substructure (B)




in formula (I) assumes one of the above shown substructures (IIIa) or (IIIb), wherein all other residues, variables and indices can have the above described meanings.

Likewise preferred embodiments of the compounds according to the invention are those in which the substructure according to the formula (IIa) shown above assumes the following substructure (IIb):




wherein in certain embodiments of these compounds according to the invention R8 stands for H or C1-6 alkyl, in each case unsubstituted or mono- or polysubstituted with identical or different substituents, and R9a and R9b each stand for H.

Likewise preferred embodiments of the compounds according to the invention are those compounds in which the substructures according to the formulas (IIIa) and (IIIb) shown above assume one of the following substructures (IIIc), (IIId) or (IIIe):




In certain embodiments of these compounds according to the invention s and t each stand for 0.
Likewise preferred embodiments of the compounds according to the invention are those in which the substructures according to the formulas (IIIa) and (IIIb) illustrated above can assume one of the substructures (IIIc) or (IIId) illustrated above and two of the substituents R27 together represent a C1-3 alkylene bridge, such that the cyclic compound represented in the substructure (IIIc) or (IIId) assumes a bicyclically bridged form. In certain embodiments of these compounds s and t are each 0.
Likewise preferred embodiments of the compounds according to the invention are those in which the substructures according to formulas (IIIa) and (IIIb) illustrated above assume one of the substructures (IIIc) or (IIIe) likewise illustrated above, s stands for 1 and t stands for 1, 2 or 3. In certain embodiments of these compounds according to the invention R8 stands for H, C1-6 alkyl or C3-6 cycloalkyl, each unsubstituted or mono- or polysubstituted.
Other preferred embodiments of the compounds according to the invention are those in which the substructure according to the formula (IIb) shown above assumes the following substructure (IIc):




wherein in certain embodiments of these compounds s and t each denote 0.

In other preferred embodiments of the compounds according to the invention the substructures illustrated above according to the formulas (IIIc) or (IIId) assume one of the following substructures (IIIf) or (IIIg),




wherein in certain embodiments of these compounds R27 stands for H and/or two of the substituents R27 form an anellated aryl or heteroaryl ring structure, in particular a benzo group.

Preferred embodiments of the compounds according to the invention are furthermore such compounds in which the substructures (IIIc) or (IIId) illustrated above represent one of the following groups A to H:




Persons skilled in the art will understand that the representation chosen for groups A to H includes all possible stereoisomers of these groups.

Other preferred embodiments of the compounds according to the invention are compounds in which the substructures (IIIc) or (IIIe) illustrated above represent a group corresponding to formula (IIIh) or formula (IIIi):




and R9a and R9b each stand for H. In certain embodiments of these compounds u and v each independently stand for 0 or 1. In particular u and v both stand for 1.

Other preferred embodiments of the compounds according to the invention are compounds in which in the substructure (IIc) illustrated above R16a and R16b each stand for H or together form ═O; R13 stands for H, aryl or heteroaryl and/or two of the substituents R13 together form ═O and/or two adjacent substituents R13 together form an anellated aryl or heteroaryl ring structure, in particular a benzo group, each unsubstituted or mono- or polysubstituted with identical or different substituents.
Other preferred embodiments of the compounds according to the invention are those compounds in which in the substructures illustrated above according to the formulas (IIIf) or (IIIg):

    R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, phenyl, pyridyl, thienyl, pyrimidyl, thiazolyl, imidazolyl or triazolyl, each unsubstituted or mono- or polysubstituted; phenyl, pyridyl, thienyl, pyrimidyl, thiazolyl, imidazolyl or triazolyl bound by an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted; or
    R18a stands for a structure corresponding to formula Iva:






    
    
        wherein
        i stands for 0 or 1;
        j stands for 0 or 1;
        h stands for 0 or 1;
        E stands for N or CH; with the proviso that if i stands for 1 and j stands for 0, then E stands for CH;
        G stands for CR37aR37b or NR38; wherein
        
            R37a and R37b each independently stand for H, F or C1-6 alkyl; and
            R38 stands for H; C1-6 alkyl, C3-6 cycloalkyl or pyridyl, in particular pyridin-4-yl;
        
        
    
    
    R18b stands for H; OH; C1-6 alkyl; phenyl, pyridyl, thienyl, thiazolyl, pyrimidyl, imidazolyl or triazolyl, each unsubstituted or mono- or polysubstituted; phenyl, pyridyl, thienyl, thiazolyl, pyrimidyl, imidazolyl or triazolyl, O-phenyl or O-pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents; or phenyl, pyridyl or thienyl bridged by C1-6 alkylene-NH(C═O), each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, or for C1-6 alkyl; phenyl, pyridyl, thienyl, thiazolyl, triazolyl, pyrimidinyl or imidazolyl bound by (C═O)0-1; each unsubstituted or mono- or polysubstituted with identical or different substituents; or phenyl, pyridyl, thienyl, thiazolyl, pyrimidinyl, triazolyl or imidazolyl bound by a C1-6 alkylene group; each unsubstituted or mono- or polysubstituted with identical or different substituents; or
    R19 stands for a structure corresponding to formula (VIIIa):






    
    
        wherein
        w stands for 0 or 1;
        n stands for 0 or 1;
        m stands for 0 or 1;
        M stands for CH or N, with the proviso that if w stands for 0, then M stands for CH;
        L stands for CR44aR44b or NR45; wherein
        
            R44a and R44b each independently stand for H, F or C1-6 alkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
            R45 stands for H; C1-6 alkyl, C3-6 alkyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents.
        
        
    
    


Further preferred embodiments of the compounds according to the invention are those compounds in which the substructures according to the formulas (IIIc) or (IIId) illustrated above represent one of the following groups A to H:




    R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for N(C1-6 alkyl)2, NH(C1-6 alkyl), azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl, phenyl, imidazolyl, triazolyl or pyridyl bound by an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R18b stands for H; OH; C1-6 alkyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl or pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl bound by a C1-6 alkylene group or a (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents.


Other preferred embodiments of the compounds according to the invention are those compounds in which in the substructures illustrated above according to the formulas (IIIh) or (IIIi):

    R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl), azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for N(C1-6 alkyl)2, NH(C1-6 alkyl), azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl, phenyl, imidazolyl, triazolyl or pyridyl bound by an —(O)0/1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R18b stands for H; OH; C1-6 alkyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl or pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; phenyl or pyridyl bound by a C1-6 alkylene group or (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents.


Other preferred embodiments of the compounds according to the invention are compounds in which the substructure corresponding to formula IIc assumes one of the following substructures SP:













wherein

    R13 stands for H or phenyl, unsubstituted or mono- or polysubstituted with identical or different substituents; and/or two groups R13 together form ═O; and/or two adjacent groups R13 together form an anellated aryl or heteroaryl ring structure, in particular a benzo group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R15 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl or pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R16a stands for H, C1-6 alkyl, phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl), azetidinyl; pyrrolidinyl, piperidinyl, alkyl)-piperazinyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for N(C1-6 alkyl)2, NH(C1-6 alkyl), azetidinyl, pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl, phenyl, imidazolyl, triazolyl or pyridyl bound by an —(O)0/1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R18b stands for H; OH; C1-6 alkyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl or pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl or pyridyl bound by a C1-6 alkylene group or (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R120 stands for H; F; Cl; OH; OCH3, O—CF3, C1-6 alkyl; CF3, or phenyl, unsubstituted or mono- or polysubstituted;
    R126 stands for H; C1-6 alkyl; C3-8 cycloalkyl; phenyl or pyridyl; or for C3-8 cycloalkyl, phenyl or pyridyl bound by a C1-3 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents.


Other preferred embodiments of the compounds according to the invention are compounds in which the following substructure (B) in formula I:




is selected from the group consisting of:




















    wherein
    h=0 or 1;
    g=0 or 1;
    m=0 or 1;
    n=0 or 1;
    o=0, 1, 2 or 3;
    r=1, 2 or 3, in particular 1 or 2;
    s=0 or 1;
    t=0, 1, 2 or 3, in particular 0, 1 or 2, with the proviso that if s stands for 0, then t likewise stands for 0;
    M1, M2 and M3 each stand for N or CH, wherein one variable out of M1, M2 and M3 stands for N and the other two stand for CH;
    R8 stands for H; C1-6 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; C3-6 cycloalkyl, in particular cyclopropyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R19 is selected from H; C1-6 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; C3-6 cycloalkyl, in particular cyclopropyl; each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R34 and R35 are preferably each independently methyl or ethyl or together with the N-atom linking them form an azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R38 stands for H, C1-6 alkyl, C3-6 cycloalkyl or pyridyl;
    R39 is selected from H; C1-6 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; C3-6 cycloalkyl, in particular cyclopropyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R45 stands for H, C1-6 alkyl, C3-6 cycloalkyl or pyridyl;
    R190 represents 0 to 4 substituents independently selected from F, Cl, O—CF3, CF3 and CN;
    R271 stands for H; and
    R272 stands for C1-4 alkyl, C3-6 cycloalkyl or a C3-6 cycloalkyl bound by a C1-3 alkylene group; or
    R271 and R272 together form a 4- to 7-membered heterocyclyl ring structure which may be substituted by 0 to 2 substituents selected from the group consisting of F, Cl, O—CF3, —CF3, or CN; or 2 adjacent substituents may together form an anellated aryl or heteroaryl ring structure, preferably an anellated benzo ring.


Other likewise preferred embodiments of the compound according to the invention are those in which in substructure (B) having the general formula I




    s stands for 1;
    t stands for 0, 1 or 2;
    R8 stands for H, C1-6 alkyl, C3-8 cycloalkyl or a C3-8 cycloalkyl bound by a C1-3 alkylene group;
    A stands for N or CH, with the proviso that if t stands for 0, then A stands for CH, and
    R10 and R11 together with A, to which they are bound, represent a 5- or 6-membered cycloalkyl or heterocycloalkyl group, to which a 5- or 6-membered aryl or heteroaryl ring structure is anellated, wherein the 5- or 6-membered, anellated aryl or heteroaryl ring structure is substituted with a (C1-6alkyl)amino, di(C1-6alkyl)amino group or a 4- to 7-membered N-containing heterocyclyl group, wherein the (C1-6 alkyl)amino and di(C1-6 alkyl)amino groups, the 4- to 7-membered heterocyclyl group and the C1-3 alkylene group to which these are bound can be unsubstituted, or mono- or polysubstituted with identical or different substituents selected from the same groups as defined above for the respective types of groups.


In likewise preferred embodiments of the compounds according to the invention the substructure B having the general formula I represents a group corresponding to formula B.50:




wherein

    R8 stands for H, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, cyclopropyl or a cyclopropyl bound by a C1-3 alkylene group, preferably H, methyl or cyclopropyl; wherein in all of these groups at least one C-bound H atom can be replaced by an F atom;
    u and v each independently stand for 0, 1 or 2, wherein u+v is greater than 0 and u+v is at most 3; and wherein u and v preferably simultaneously stand for 1;
    Λ A stands for CH2 or O, with the proviso that if A stands for 0 then u stands for 1;
    Π1 and Π2 each independently stand for CH or N, wherein Π1 and Π2 preferably both stand for CH or both stand for N;
    α stands for 0, 1, 2 or 3, preferably 1; and
    Rx and Ry, each independently stand for H, C1-6 alkyl, preferably methyl, F or CF3;


wherein Rx and Ry are preferably each H;

    T stands for N(R271)(R272), wherein
    
        R271 stands for H and
        R272 stands for C1-4 alkyl, C3-6 cycloalkyl or a C3-6 cycloalkyl bound by a C1-3 alkylene group; or
    
    
    T stands for a heterocyclyl ring selected from the group consisting of:






wherein

    R274 stands for 0 to 2 substituents independently selected from F, methyl, ethyl, CF3 and —CH2—CF3, and is preferably absent; or wherein two adjacent substituents R274 together form an anellated aryl or heteroaryl ring structure, preferably phenyl, or two substituents R274 together form a C1-3 alkylen bridge so that the heterocyclyl ring takes on a bicyclically bridged form;
    R275 represents a group selected from the group consisting of C1-4 alkyl,
    
        C3-6cycloalkyl or a C3-6 cycloalkyl bound by a C1-3 alkylene group, wherein R275 preferably stands for H or methyl; and
    
    
    R276 stands for F, Cl, methyl or CF3.


The group —(CRxRy)α-T is preferably bound to the position between Π1 and Π2.
In a preferred embodiment of the compounds according to the invention the substructure represented by formula B.50. is selected from:




wherein

    R8 stands for H, C1-6 alkyl, cyclopropyl or a cyclopropyl bound by a C1-3 alkylene, preferably for H or methyl, and all of these groups can be substituted in accordance with the definitions given above.


Other preferred embodiments of the compounds according to the invention are compounds in which the following substructure (B) from the formula I shown above




is selected from the group consisting of:





wherein all substituent groups and indices have the meanings given above in connection with the compounds according to the invention and the preferred embodiments thereof, and wherein compounds are preferred in which:

    c, d, e and f each independently stand for 0 or 1;
    u and v each independently stand for 0 or 1;
    t stands for 0, 1, 2 or 3, preferably for 0, 1 or 2;
    R8 stands for H; C1-6 alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; C3-6 cycloalkyl, in particular cyclopropyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R98 and R9b each independently stand for H; F; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; a C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; in particular for H, F, C3-6 cycloalkyl, phenyl or a C3-6 cycloalkyl or phenyl bound by a C1-3 alkylene group;
    R12, R13 and R27 each independently stand for 0 to 4 substituents independently selected from the group consisting of F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl; heteroaryl; C3-8 cycloalkyl, aryl or heteroaryl bound by a C1-6 alkylene group; preferably for F or C1-6 alkyl, or are absent;
    R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or N(C1-6 alkyl)2, NH(C1-6 alkyl), azetidinyl, pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl, phenyl, imidazolyl, triazolyl or pyridyl, in particular O-pyridyl, bound by an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
    R18b stands for H; OH; C1-6 alkyl; phenyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; phenyl or pyridyl bound by a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
    R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl bound by a C1-6 alkylene group or a (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents; or
    R19 stands for a structure corresponding to formula (VIIIa):






    
    
        wherein
        w stands for 0 or 1;
        n stands for 0 or 1;
        m stands for 0 or 1;
        M stands for CH or N, with the proviso that if w is 0, then M stands for CH;
        L stands for CR44aR44b, NR45 or O; wherein
        
            R44a and R44b each independently stand for H, F or C1-6 alkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
            R45 stands for H; C1-6 alkyl, C3-6 alkyl or pyridyl, each unsubstituted or mono- or polysubstituted with identical or different substituents.
        
        
    
    


In further preferred embodiments of the compounds according to the invention the substructure Ac II




In formula I is selected from the group consisting of:





wherein the various substituent groups, variables and indices have the meanings given above.

In likewise preferred embodiments of the compounds according to the invention the substructure Ac.II. is selected from the structures Ac.II.a-d, in particular Ac.II.c or Ac.II.d, and the substructure B is selected from the structures B.1 to B.49.
In further, likewise preferred embodiments of the compounds according to the invention the substructure Ac.II is selected from one of the structures Ac.II.e. and Ac.II.f., in particular Ac.II.e., and the substructure B is a structure according to the general formula B.50., in particular B.50.1 to B.50.3.
Further preferred embodiments of the compounds according to the invention are those according to one of the following formulas C.1. to C.16:










wherein the various substituent groups, variables and indices in formulas C.1. to C.16. have the meanings described above in connection with the compounds according to the invention and the preferred embodiments thereof.

In further preferred embodiments of the compounds according to the invention the compounds are represented by the formula C.9.




wherein

    R1 represents a group selected from 4-methoxy-2,6-dimethylphenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 2,6-dichloro-4-methylphenyl, 2-methyl-1-naphthyl, 2-chloro-1-naphthyl, 2-fluoro-1-naphthyl, and 2-(trifluoromethyl)-1-naphthyl;
    R4 is H; and

the moiety represented by the formula B1







represents





wherein

    c, d, e and f each independently represent 0 or 1 and preferably, the sum of c+d+e+f is equal or greater than 1, preferably equal or greater than 2;
    o represents 0 or 1;
    n and m are each independently selected from 0, 1 or 2;
    M1, M2 and M3 can each stand for N or CH, wherein one variable out of M1, M2 and M3 stands for N and the other two stand for CH; and wherein preferably M′ is N and M2 and M3 are CH;
    R8 represents H, Me, cyclopropyl, isopropyl or CH2CF3;
    R19 represents H; substituted or unsubstituted C1-6-alkyl, C3-6-cycloalkyl, aryl or heteroaryl; preferably pyridyl, especially 4-pyridyl, or phenyl, preferably substituted by 1 or 2 substituents each independently selected from F or Cl;
    R27 represents H or two substituents together forming a C1-3-alklylen bridge, such that the piperidinyl group to which the substituents R27 are bonded forms a bicyclic group;
    R34 and R35 are preferably each independently methyl or ethyl or together with the N-atom linking them form an azetidinyl; pyrrolidinyl, piperidinyl or 4-(C1-6 alkyl)-piperazinyl group, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
    R45 stands for H, C1-6 alkyl, C3-6 cycloalkyl or pyridyl, preferably 4-pyridyl.


In further preferred embodiments of the compounds according to the invention the compounds are represented by the formula D.1. or D.2.




wherein

    a represents 1,
    u represents 0 or 1, wherein u represents 1 if Λ is 0;
    v represents 0 or 1;
    α represents 1 or 2;
    Π represents CH2 or O;
    R1 is selected from 1-naphthyl, 2-naphthyl, 6-methoxy-2-naphthyl, 4-chloro-2,5-dimethylphenyl, 3-methylphenyl, 3-chlorophenyl, 3-(trifluoromethyl)phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluormethyl)phenyl or phenyl independently substituted in 2,3- or 3,4-positions by methyl, chloro or trifluoromethyl;
    R4 represents H;
    R8 stands for H, C1-6 alkyl, cyclopropyl or a cyclopropyl bound by a C1-3 alkylene, preferably for H or methyl; and
    R300 and R301 together with the N-atom to which they are bonded form a substituted or unsubstituted 4- to 7-membered heterocycle, preferably piperidine, or
    R300 and R301 each independently stand for H or substituted or unsubstituted C1-6 alkyl or C3-6-cycloalkyl; preferably, R300 and R301 are each independently selected from the group consisting of H, Me, Et, t-butyl, cyclopropyl, CH2CF3; or
    R300 and R301 together with the N-atom to which they are bonded form a substituted or unsubstituted heterocyclic group selected from the group consisting of piperidinyl, N—(C1-6-alkyl)piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl; and
    R303 is selected from H, F and CF3.


In further preferred embodiments of the invention, the compounds are selected from the group consisting of:

    1 2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone;
    2 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone;
    3 1-(7-Cyclopropyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)ethanone;
    4 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
    5 1-(4-(Pyridin-4-yloxy)piperidin-1-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone;
    6 2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1-yl)ethanone;
    7 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-N-methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)acetamide;
    8 2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
    9 2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide;
    10 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethanone;
    11 1-(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone;
    12 N-Methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetamide;
    13 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1-yl)ethanone;
    14 2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
    15 2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethanone;
    16 2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-N-methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)acetamide;
    17 N-(3,3-Dimethylpiperidin-4-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide;
    18 2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
    19 2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(piperidin-1-yl)ethanone;
    20 2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
    21 1-(2-(Pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-((2-(2-(trifluoromethypphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone
    22 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2,8-diazaspiro[4.5]decan-8-yl)ethanone
    23 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-((1R,3S,5S)-3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanone
    24 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)ethanon
    25 2-(2-(4-Chloro-2,5-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
    26 2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
    27 2-(2-(Phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
    28 2-(2-(2,3-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
    29 N-(6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide
    30 N-(6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-(3-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide
    31 N-(6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide
    32 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-[1-[5-(trifluoromethyl)-pyridin-2-yl]-piperidin-4-yl]-acetamide
    33 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-[1-[5-(trifluoromethyl)-pyridin-2-yl]-pyrrolidin-3-yl]-acetamide
    34 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-(4-pyridin-4-yl-piperidin-1-yl)-ethanone
    35 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[4-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone
    36 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-(1-pyridin-4-yl-piperidin-4-yl)-acetamide
    37 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[3-[(4-methyl-piperazin-1-yl)-methyl]-pyrrolidin-1-yl]-ethanone
    38 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-(3-pyridin-4-yloxy-pyrrolidin-1-yl)-ethanone
    39 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-methyl-N-(1-pyridin-4-yl-piperidin-4-yl)-acetamide
    40 2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[4-(3-methyl-3,6-diazabicyclo[2.2.1]heptan-6-yl)-piperidin-1-yl]-ethanone
    41 N-[2-[4-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    42 N-[(1R)-6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    43 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    44 N-[(1R)-6-[(4-Fluoro-piperidin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    45 2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[1R)-6-[(2,2,2-trifluoro-ethylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    46 N-[(1R)-1-[4-[(tert-Butylamino)-methyl]-phenyl]-ethyl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    47 2-(2-(3-Chlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
    48 2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(5-(piperidin-1-ylmethyl)-2,3-dihydro-1H-inden-2-yl)acetamide
    49 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    50 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    51 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    52 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    53 N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    54 N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    55 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    56 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    57 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    58 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    59 N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    60 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    61 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    62 N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    63 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    64 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    65 N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    66 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    67 N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    68 N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    69 N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    70 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    71 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    72 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    73 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    74 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    75 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    76 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    77 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    78 N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    79 2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    80 N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    81 N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    82 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    83 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    84 N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    85 2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    86 N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    87 N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    88 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    89 N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    90 N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    91 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    92 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    93 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    94 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    95 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    96 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    97 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    98 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    99 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    100 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    101 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    102 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    103 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    104 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    105 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    106 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    107 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    108 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    109 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    110 N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    111 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[2-(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    112 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    113 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    114 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    115 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    116 N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    117 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    118 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    119 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    120 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    121 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    122 N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    123 2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    124 N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    125 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    126 N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    127 N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    128 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    129 2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    130 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    131 N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    132 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    133 N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    134 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    135 N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    136 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide
    137 2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    138 2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide
    139 N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    140 N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    141 1-(4-Hydroxy-4-pyridin-3-yl-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    142 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-morpholin-4-yl-propyl)-acetamide
    143 N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    144 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    145 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone
    146 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone
    147 1-[4-[2-(2,5-Dimethyl-1H-pyrrol-1-yl)-ethyl]-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    148 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone
    149 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone
    150 2-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    151 N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    152 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone
    153 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-pyrrolidin-1-yl-ethyl)-acetamide
    154 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-morpholin-4-yl-propyl)-acetamide
    155 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide
    156 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    157 N-(1-Benzyl-pyrrolidin-3-yl)-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    158 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-(2-fluorophenyl)-piperazin-1-yl)-ethanone
    159 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-morpholin-4-yl-piperidin-1-yl)-ethanone
    160 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-piperidin-1-yl-piperidin-1-yl)-ethanone
    161 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-ethanone
    162 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone
    163 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone
    164 2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    165 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone
    166 N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    167 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-pyridin-3-yl-piperidin-1-yl)-ethanone
    168 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-pyrrolidin-1-yl-ethyl)-acetamide
    169 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide
    170 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    171 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(1-benzyl-pyrrolidin-3-yl)-acetamide
    172 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone
    173 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-ethyl-piperazin-1-yl)-ethanone
    174 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone
    175 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethanone
    176 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-morpholin-4-yl-piperidin-1-yl)-ethanone
    177 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-ethanone
    178 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[2-(2,5-dimethyl-1H-pyrrol-1-yl)-ethyl]piperazin-1-yl]-ethanone
    179 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone
    180 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone
    181 2-[4-[2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl][1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    182 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-pyrrolidin-3-yl)-methyl]-acetamide
    183 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone
    184 N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    185 N-[2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    186 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    187 1-(4-Ethyl-piperazin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    188 1-(4-Piperidin-1-yl-piperidin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    189 1-[4-(5-Methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    190 1-(4-Pyridin-2-yl-piperazin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    191 2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    192 N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    193 2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide
    194 2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    195 2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone
    196 2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]ethanone
    197 2-[4-[2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    198 N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    199 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide
    200 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    201 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone
    202 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone
    203 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone
    204 2-[4-[2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile
    205 N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[2-chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    206 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-pyrrolidin-1-yl]-ethanone
    207 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-piperidin-1-yl-propyl)-acetamide
    208 1-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    209 1-[4-(4-Chlorophenyl)-4-hydroxy-piperidin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    210 1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    211 1-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-piperidin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    212 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-piperidin-1-yl-ethyl)-acetamide
    213 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(piperidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone
    214 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3-methoxyphenyl)-piperazin-1-yl]-ethanone
    215 1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    216 1-(4-Isopropyl-piperazin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    217 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-pyrrolidin-1-yl]-ethanone
    218 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-piperidin-1-yl-propyl)-acetamide
    219 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethanone
    220 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-piperidin-1-yl]-ethanone
    221 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    222 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-piperidin-1-yl-ethyl)-acetamide
    223 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3-methoxyphenyl)-piperazin-1-yl]-ethanone
    224 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone
    225 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-isopropyl-piperazin-1-yl)-ethanone
    226 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-ethanone
    227 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-ethanone
    228 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethanone
    229 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methoxyphenyl)-piperazin-1-yl]-ethanone
    230 2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide
    231 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3,4-dichlorophenyl)-piperazin-1-yl]-ethanone
    232 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(p-tolyl-methyl)-piperazin-1-yl]-ethanone
    233 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-methoxyphenyl)-methyl]-piperazin-1-yl]-ethanone
    234 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2-fluorophenyl)-methyl]-piperazin-1-yl]-ethanone
    235 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-piperidin-3-yl)-methyl]-acetamide
    236 2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2,4,6-trimethyl-phenyl)-methyl]-piperazin-1-yl]-ethanone
    237 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methoxyphenyl)-piperazin-1-yl]-ethanone
    238 1-[4-(3,4-Dichlorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    239 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2,4,6-trimethyl-phenyl)-methyl]-piperazin-1-yl]-ethanone
    240 1-[4-[(4-Chlorophenyl)-methyl]-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    241 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(p-tolyl-methyl)-piperazin-1-yl]-ethanone
    242 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-methoxyphenyl)-methyl]-piperazin-1-yl]-ethanone
    243 1-[4-[(2-Fluorophenyl)-methyl]-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    244 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-piperidin-1-yl]-ethanone
    245 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone
    246 1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    247 3-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-propionitrile
    248 N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    249 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-chlorophenyl)-methyl]-piperazin-1-yl]-ethanone
    250 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-piperidin-1-yl]-ethanone
    251 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone
    252 1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    253 3-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-propionitrile
    254 N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[[2-chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide
    255 1-[2-(4-Dimethylaminophenyl)-azepan-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    256 2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-acetamide
    257 1-(4-Benzyl-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    258 1-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone
    259 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-acetamide
    260 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-(pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone
    261 2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-pyridine-3-carbonitrile
    262 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone
    263 2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone
    264 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-(pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone
    265 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone
    266 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(3,4-dichlorophenyl)-methyl]-piperazin-1-yl]-ethanone
    267 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-methyl-2-phenyl-piperazin-1-yl)-ethanone
    268 2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperidin-1-yl)-ethanone
    269 2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-pyridine-3-carbonitrile
    270 2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(4-dimethylaminophenyl)-pyrrolidin-1-yl]-ethanone

optionally in the form of an isolated enantiomer or an isolated diastereomer, the racemate, the enantiomers, the diastereomers, mixtures of enantiomers or diastereomers, each in the form of their bases and/or physiologically compatible salts, in particular hydrochloride salts.



The numbering of the individual embodiments of the compounds according to the invention used above is retained in the following explanations of the present invention, particularly in the description of the examples.
According to one aspect of the present invention the compounds according to the invention preferably have an antagonistic action on the human B1R receptor or the B1R receptor of the rat. In a preferred embodiment of the invention the compounds according to the invention have an antagonistic action on both the human B1R receptor (hB1R) and on the B1R receptor of the rat (rB1R).
In a preferred embodiment of the present invention the compounds according to the invention 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 particularly preferred are compounds which exhibit at least 70%, in particular at least 80% and particularly preferably at least 90% inhibition on the human B1R receptor and on the B1R receptor of the rat at a concentration of 10 μM.
The agonistic or antagonistic action of substances on the bradykinin 1 receptor (B1R) of the human and rat species can be quantified 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 value 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 lead to 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 preferably act, for example, on the relevant B1R in connection with various diseases, such that they are suitable as a pharmaceutical active ingredient in pharmaceutical compositions. The invention therefore also provides pharmaceutical compositions containing at least one sulfonylated tetrahydroazolopyrazine according to the invention, optionally along with suitable additives and/or auxiliary substances and/or optionally further active ingredients.
The pharmaceutical compositions according to the invention are preferably suitable for combating pain, in particular pain selected from the group consisting of acute pain, neuropathic pain, visceral pain, chronic pain and inflammatory pain; or for the treatment of migraine; diabetes; diseases of the respiratory tract; inflammatory bowel diseases; neurological diseases; septic shock; reperfusion syndrome; obesity, and as an angiogenesis inhibitor.
The pharmaceutical compositions according to the invention optionally contain, in addition to at least one sulfonylated tetrahydroazolopyrazine according to the invention, suitable additives and/or auxiliary substances, including carrier materials, fillers, solvents, diluents, dyes and/or binders, and can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols. The choice of auxiliary substances, etc., and the amounts thereof to use depend on whether the medicinal product is to be administered by oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, nasal, buccal, rectal or topical means, for example on the skin, mucous membranes or in the eyes. Preparations in the form of tablets, pastilles, capsules, granules, drops, juices and syrups are suitable for oral administration. Solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration. Sulfonylated tetrahydroazolopyrazines according to the invention in a depot formulation, in dissolved form or in a plaster, optionally with addition of agents promoting skin penetration, are suitable preparations for percutaneous administration. Preparation forms suitable for oral or percutaneous administration can deliver the sulfonylated tetrahydroazolopyrazines according to the invention on a delayed release basis. The sulfonylated tetrahydroazolopyrazines according to the invention can also be used in parenteral long-term depot forms, such as implants or implanted pumps, for example. Other additional active ingredients known to persons skilled in the art can be added in principle to the pharmaceutical compositions according to the invention.
The amount of active ingredient to be administered to the patient varies according to the weight of the patient, the manner of administration, the indication and the severity of the illness. From 0.00005 to 50 mg/kg, preferably 0.01 to 5 mg/kg, of at least one sulfonylated tetrahydroazolopyrazine according to the invention are conventionally administered. A preferred form of the medicinal product contains a sulfonylated tetrahydroazolopyrazine according to the invention as an isolated diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of diastereomers and/or enantiomers.
B1R is involved in particular in the pain mechanism. The sulfonylated tetrahydroazolopyrazines according to the invention can accordingly be used for the preparation of a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
The invention therefore also provides for the use of a sulfonylated tetrahydroazolopyrazine according to the invention to prepare a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain. A particularly preferred embodiment of the present invention is the use of at least one of the sulfonylated tetrahydroazolopyrazines according to the invention to prepare a medicinal product for the treatment of inflammatory pain.
The invention also provides the use of a sulfonylated tetrahydroazolopyrazine according to the invention to prepare a medicinal product for the treatment of diabetes, diseases of the respiratory tract, for example bronchial asthma, allergies, COPD/chronic obstructive pulmonary disease or cystic fibrosis; inflammatory bowel diseases, for example ulcerative colitis or CD/Crohn's disease; neurological diseases, for example multiple sclerosis or neurodegeneration; inflammations of the skin, for example atopic dermatitis, psoriasis or bacterial infections; rheumatic diseases, for example rheumatoid arthritis or osteoarthritis; septic shock; reperfusion syndrome, for example following heart attack or stroke; obesity; and as an angiogenesis inhibitor.
In the above uses it may be preferred if the sulfonylated tetrahydroazolopyrazine that is used is in the form of an isolated diastereomer and/or enantiomer, a racemate or a non-equimolar or equimolar mixture of diastereomers or enantiomers.
The invention also provides a process for treating any of the aforementioned indications, in a non-human mammal or human requiring treatment, by administration of a therapeutically active dose of a sulfonylated tetrahydroazolopyrazine according to the invention or of a pharmaceutical composition according to the invention.
The present invention also provides a process for the preparation of the sulfonylated tetrahydroazolopyrazines according to the invention, in particular as described in the following description, examples and claims. The process according to the invention is represented in scheme 1.




Scheme 1

The free amines (A) and the carboxylic acids (S) are reacted in an amide formation in the presence of at least one dehydrating agent and optionally an organic base in an organic solvent to form the compounds (P) according to the invention. Sodium or magnesium sulfate, phosphorus oxide or reagents such as for example CDI, DCC (optionally polymer-bound), TBTU, EDCl, PyBOP or PFPTFA can be used as dehydrating agents, for example, also in the presence of HOAt or HOBt. Examples of suitable organic bases include triethylamine, DIPEA and pyridine, and examples of useful solvents include THF, dichloromethane, diethylether, dioxane, DMF and acetonitrile. The temperature in the amide formation step is preferably between 0 and 50° C.
The invention is described further hereinafter with reference to general synthesis methods and selected examples. These descriptions serve to further clarify the invention and should not be understood as having a limiting effect.
ABBREVIATIONS


    CDl 1,1′-carbonyldiimidazole
    d day(s)
    DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
    DCC N,N′-dicyclohexylcarbodiimide
    DCM dichloromethane
    DIPEA diisopropylethylamine
    DMAP 4-dimethylaminopyridine
    DMF dimethyl formamide
    DPPA phosphoric acid diphenyl ester azide
    EDCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide
    EtOH ethanol
    sat. saturated
    h hour(s)
    HBTU 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    HOAt 1-hydroxy-7-azabenzotriazole
    HOBt 1-hydroxybenzotriazole
    HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate
    LAH lithium aluminium hydride
    M molar
    MeOH methanol
    min minute(s)
    RT room temperature
    TBACl tetrabutylammonium chloride
    TEA triethylamine
    TFA trifluoroacetic acid
    THF tetrahydrofuran

General Synthesis of Acid Structural Units

Method A







Method A

The acylation with malonic acid monoester (1) can be performed using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM. Sodium methanolate, TEA, DIPEA or N-methylmorpholine, for example, can be used as bases. EDCl, HOBt, DCC, CDl, HBTU, DMAP or pentafluorophenyl diphenyl phosphinate, for example, are suitable as coupling reagents. The reaction time can vary between 1 hour and 3 days. The corresponding malonic acid monoester chloride can also be used in place of the corresponding malonic acid ester.
The subsequent cyclisation (2) to the cyclic imine is performed by reacting POCl3 in solvents such as for example benzene, toluene, ethanol or water or with polyphosphoric acid as solvent.
The reduction of the cyclic imine (3) can be performed using reducing agents such as for example NaBH4 in solvents such as for example ethanol, methanol or water, or by hydrogenolysis with catalysts such as for example Pd on BaSO4 in solvents such as for example ethanol.
The amines obtained are reacted by means of a sulfonylation (4) with sulfonyl chlorides, bromides or pentafluorophenolate R3SO2X (X═Cl, Br, OPFP) optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, DIPEA, TEA, pyridine, diethylamine or DBU, preferably in an organic solvent, for example acetonitrile, DCM or THF, to form the sulfonylated compounds.
The ester cleavage (5) is converted into the necessary acid structural units 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, DCM, THF, diethyl ether or these solvents as blends.
Method B




Method B: Route A and Route B

The acylation (AB1) with oxalic acid monoester can be performed using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM. Examples of suitable bases include sodium methanolate, TEA, DIPEA or N-methylmorpholine. EDCl, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyl diphenyl phosphinate are examples of suitable as coupling reagents. The reaction time can vary between 1 hour and 3 days. The corresponding oxalic acid monoester chloride can also be used in place of the corresponding oxalic acid ester.
The subsequent cyclisation (AB2) to the cyclic imine is performed by reacting POCl3 in solvents such as for example benzene, toluene, ethanol or water or with polyphosphoric acid as solvent.
Route A
The reduction (A1) of the cyclic imine can be performed using reducing agents such as for example lithium aluminium hydride in solvents such as for example diethyl ether or THF. Hydrogenolysis with heterogeneous catalysts such as Pd for example in solvents such as ethanol for example is also possible.
The resulting amino alcohols are reacted by means of a sulfonylation (A2) with sulfonyl chlorides, bromides or pentafluorophenolate R3SO2X (X═Cl, Br, OPFP) optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, DIPEA, TEA, pyridine, diethylamine or DBU, preferably in an organic solvent, for example acetonitrile, DCM or THF, to form the sulfonylated compounds.
The sulfonylated amino alcohols are converted into the esters in an acylation reaction (AB3) with halogenated ester derivatives using tetrabutylammonium chloride or bromide or tetrabutylammonium hydrogen sulfate, in a phase transfer reaction using an organic solvent such as for example toluene, benzene, DCM or xylene, also blends of these solvents, 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 being metal alcoholates such as sodium methanolate, sodium ethanolate, potassium tert-butylate, lithium or sodium bases such as lithium diisopropylamide, butyl lithium, tert-butyl lithium, sodium methylate or metal hydrides such as potassium hydride, lithium hydride, sodium hydride, conventional organic bases being DIPEA, TEA, in an organic solvent such as DCM, THF or diethyl ether. These esters obtained are converted in an ester cleavage (AB4) into the necessary acid structural units 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, DCM, THF, diethyl ether or these solvents as blends.
Route B
The reduction (B1) of the cyclic imine can be performed using reducing agents such as, for example, NaBH4 in solvents such as, for example, ethanol, methanol or water. Hydrogenolysis with catalysts such as Pd on BaSO4 for example in solvents such as ethanol for example is also possible.
The resulting amines are reacted by means of a sulfonylation (B2) with sulfonyl chlorides, bromides or pentafluorophenolate R3SO2X (X═Cl, Br, OPFP) optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, DIPEA, TEA, pyridine, diethylamine or DBU, preferably in an organic solvent, for example acetonitrile, DCM or THF, to form the sulfonylated compounds.
The reduction of the ester (B3) can be performed using reducing agents such as, for example, lithium aluminium hydride in solvents such as, for example, diethyl ether or THF.
The sulfonylated amino alcohols are converted to the necessary acid structural units in an acylation reaction (AB3) with subsequent ester cleavage (AB4) in an analogous manner to that described for Route A.
Synthesis of Sulfonyl Chlorides
4-Methoxy-2,6-dimethylbenzol-1-sulfonyl chloride




A solution of 3,5-dimethyl anisole (102.5 g, 753 mmol) in DCM (1000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml, 3763 mmol) in DCM (250 ml) was added dropwise to this solution. After a reaction time of 10 min the reaction solution was poured into an ice bath (1000 ml), the phases were separated and extracted once more with DCM (250 ml). The combined organic phases were washed with water (1000 ml) and saturated sodium chloride solution (1000 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (heptane/DCM 5:1). Yield: 63.5 g, 36%
6-Methoxynaphthalene-2-sulfonyl chloride




1. Sodium hydroxide (0.7 g) was added to a solution of sodium 6-hydroxynapthalene-2-sulfonate (9 mmol) in water (20 ml). Dimethyl sulfate (1.1 eq.) was added to this solution at 50-55° C. over 1 h, followed by sodium chloride (3.3 g). The solid that was formed was filtered off, washed with saturated NaCl solution and toluene and dried. Yield: 75%

2. Thionyl chloride (0.25 ml) was added to a cooled solution of 6-methoxynaphthalene-2-sulfonate (2 mmol) in dry DMF (1 ml) under N2. The reaction mixture was stirred for 3 h at 0° C. Iced water (20 ml) was added to the mixture, the solid was filtered off and washed with iced water. The solid was taken up in DCM (25 ml), the solution dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 75%

Synthesis of the Acid Structural Units Used in the Examples
The acid structural units listed in Table 1 were used for the synthesis of the example compounds.









TABLE 1





Acid
No.
Name











S1 
2-(2-(4-Methoxy-2,6- dimethylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 






S2 
2-(2-(6-methoxynaphthalen-2-ylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetic acid


 






S3 
2-((2-(4-Methoxy-2,6- dimethylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)acetic acid


 






S4 
2-((2-(2-(Trifluoromethyl)phenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)acetic acid


 






S5 
2-((2-(2-Chloro-6-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)acetic acid


 






S6 
2-(2-(2-Chloro-4- (trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 






S7 
2-(2-(4-Chloro-2,5- dimethylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-acetic acid


 






S8 
2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 






S9 
2-(2-(Phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 






S10
2-(2-(2,3-Dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 






S11
2-(2-Tosyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-1-yl)acetic acid


 






S12
2-(2-(3-Trifluoromethyl)phenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetic acid


 






S13
2-(2-(3-Chloro-4-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetic acid


 






S14
2-(2-(2-Chloro-6-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetic acid


 






S15
2-(2-(3-chlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid









Acid S1
2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid and
Acid S6
2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid




1. A mixture of 2,5-dimethoxytetrahydrofuran (126.7 ml, 0.98 mol) and N-acetylethylenediamine (100 g, 0.98 mol) in acetic acid (600 ml) was refluxed for 2 h. The reaction mixture was cooled to RT and concentrated to small volume. The residue was taken up in DCM and concentrated to small volume again. Purification was performed by column chromatography (silica gel, DCM/MeOH, 95:5).

2. A suspension of N-(2-aminoethyl)acetamide (79.79 g, 0.52 mol) in aqueous KOH (10%, 1200 ml) was refluxed. After cooling to RT the aqueous solution was extracted with DCM (2×800 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness.

3. 2-(1H-Pyrrol-1-yl)ethanamine (1.17 g, 10.6 mmol) was dissolved in DCM (30 ml) and mixed with malonic acid monoethyl ester (1.51 ml, 12.8 mmol), HOAt (1.45 g, 10.6 mmol) and EDCl (3.05 g, 15.9 mmol). The reaction solution was stirred overnight at RT and then concentrated to dryness. Purification was performed by column chromatography (silica gel, DCM/7M NH3 in MeOH, 99:1).

4. Polyphosphoric acid (15 ml) was added to the malonic acid amide (1.58 g, 7.1 mmol). The reaction batch was heated to 90° C. After a reaction time of 5 h the hot solution was poured into iced water and carefully made alkaline with solid NaHCO3. The aqueous phase was extracted twice with DCM (30 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness. Purification was performed by column chromatography (silica gel, DCM/MeOH, 99:1).

5. The imine (220 mg, 1.11 mmol) was dissolved in ethanol (4 ml). Pd/C (114 mg, 0.11 mmol) was added and the mixture was hydrogenated overnight at RT and under an H2 pressure of 2 bar. The catalyst was then separated off by filtering over celite and the filtrate was concentrated to dryness under reduced pressure. The product was used with no further purification.

6. The amine (231 mg, max. 1.11 mmol) was dissolved in DCM (5 ml). First TEA (0.31 ml, 2.22 mmol) and then the corresponding sulfonyl chloride (338 mg, 1.44 mmol), dissolved in DCM (2 ml), was then added dropwise. The reaction batch was stirred overnight at RT. The solvent was removed under reduced pressure. Purification was performed by column chromatography (silica gel, heptane/ethyl acetate, 3:1).

7. A mixture of sulfonamide (81 mg, 0.2 mmol), methanol (0.4 ml), THF (0.4 ml) and aqueous NaOH solution (4 M, 0.5 ml, 2.0 mmol) was stirred for 3 h at RT. The organic solvent was removed in a rotary evaporator. The suspension obtained was acidified at 0° C. with aqueous KHSO4 solution (0.5 M). DCM (15 ml) was added, the phases were separated and the solvent was removed in a rotary evaporator. The product was used with no further purification.















R1
Name


















S1




2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 


S6




2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid









Acid S2
2-(2-(6-Methoxynaphthalin-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)essigsäure, acid S7: 2-(2-(4-chloro-2,5-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid, acid S8: 2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid and acid S12: 2-(2-(3-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid




1. The amine (1.11 mmol) was dissolved in DCM (6 ml). First TEA (0.38 ml, 2.76 mmol) and then the sulfonyl chloride (1.11 mmol), dissolved in DCM (2 ml), was then added dropwise. The reaction batch was stirred overnight at RT. The solvent was removed under reduced pressure. Purification was performed by column chromatography (silica gel).

2. The ester cleavage was performed in the manner described for acid S1.















R1
Name


















S2 




2-(2-(6-Methoxynaphthalin-2-ylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)essigsäure


 


S7 




2-(2-(4-chloro-2,5-dimethylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid


 


S8 




2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)essigsäure


 


S9 




2-(2-(phenylsulfonyl)-1,2,3,4-tetrahydropyrrrolo[1,2- a]pyrazin-1-yl)acetic acid


 


S12




2-(2-(3-(trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrrolo[1,2-a]pyrazin-1-yl)acetic acid









Acid S3
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid




1. Method A: TEA (2 eq.) was added dropwise to a solution of 2-(1H-pyrrol-1-yl)ethanamine (16 g, 145 mmol) in DCM (400 ml) and ethyloxalyl chloride (1.11 eq.) was added at 0° C. The mixture was stirred for 5 h at RT, concentrated to small volume under vacuum and used in the following stage with no further purification.

Method B: To a solution of amine (9.0 g, 68.18 mmol, 1.0 eq.) in DCM (250 ml) was added HOAt (9.2 g, 68.18 mmol, 1.0 eq.), EDCl (19.5 g, 102.27 mmol, 1.5 eq.) and DIPEA (29 ml, 170 mmol, 2.5 eq.) followed by stirred for 30 min at RT. Monoethyl malonate (11.2 g, 102.27 mmol, 1.5 eq.) in DCM (50 ml) was added to the reaction mixture. The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with DCM (250 ml) and quenched with saturated NH4Cl solution (150 ml) and organic layer is separated. Organic layer is washed with saturated NaHCO3 solution (100 ml), brine (100 ml) and was dried in vacuo to afford solid residue which is purified by column chromatography (silica gel, 40% ethyl acetate/hexanes) to obtain the amide as light yellow oil. Yield: 51% (7.7 g, 34.4 mmol)

2. Method A:Ethyl 2-(2-(1H-pyrrol-1-yl)ethylamino)-2-oxoacetate was heated with polyphosphoric acid (7 eq.) for 4 h at 90° C. and then cooled to RT. Saturated NaHCO3 solution was added to the mixture and it was extracted with DCM. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (silica gel). Yield: 16%

Method B: Ethyl 2-(2-(1H-pyrrol-1-yl)ethylamino)-2-oxoacetate (7 g, 33.3 mmol, 1.0 eq.) was taken up in a round bottom flask and cooled with an ice-bath. Pre-cooled TFA (70 ml) was slowly added to the mixture and it was then stirred at RT for 18 h. TFA was evaporated under high-vacuum and the residue taken up in DCM. The resulting mixture was stirred with a saturated aqueous solution of sodium bicarbonate until the pH became neutral. The organic layer was separated and the aqueous layer extracted with DCM (3×150 ml). The combined organic portions were washed with water (2×80 ml), dried over sodium sulfate and concentrated under reduced pressure to yield the crude product. This was purified by column chromatography (silica gel, 25% ethyl acetate/hexanes) to yield the pure title compound as a brown oil. Yield: 62%

3. A suspension of LAH (2 eq.) in THF (4 ml) was added dropwise to a solution of ethyl 3,4-dihydropyrrolo[1,2-a]pyrazine-1-carboxylate (0.52 mmol, 1 eq.) in THF (1 ml) at 0° C. and the mixture was stirred for 1 h. Saturated Na2SO4 solution was added and the mixture was filtered. The solvent was removed and the reaction mixture was taken up in ethyl acetate, dried (Na2SO4) and concentrated to small volume. The crude product was used in the following step without further purification.

4. A solution of 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (1.1 eq.) in DCM (1 ml) was added slowly to a solution of (1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methanol (1 eq.) and TEA (2 eq.) in DCM at 0° C. and the mixture was stirred for 1 h. The reaction mixture was concentrated to small volume and purified by column chromatography (silica gel). Yield: 24%

5. Method A: t-Butyl bromoacetate (4.5 eq.) and 35% aqueous KOH solution were added to a solution of (2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methanol (1 eq.) and TBACl (1 eq.) in toluene (1.5 ml) and the mixture was stirred overnight at RT. The phases were separated and the organic phase was washed with water, dried (Na2SO4) and concentrated to small volume. The crude product was used in the following step without further purification.

Method B: To a cooled (0° C.) suspension of NaH (5.48 g, 22.84 mmol, 2.0 eq.) in THF (50 ml) was added dropwise a solution of (2-(4-methoxy-2,6-dimethylphenyl-sulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methanol (4 g, 11.42 mmol, 1.0 eq.) in THF (50 ml) and the reaction mixture was stirred at RT for 1 h. Then a solution of ethylbromoacetate (1.52 ml, 13.70 mmol, 1.2 eq.) in THF (50 ml) was added dropwise to the reaction mixture at 0° C. and it was stirred at RT for 2 h. The reaction mixture was quenched with ammonium chloride solution (50 ml) and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 15% ethyl acetate/hexanes) to yield the desired product as a white solid. Yield: 64% (3.2 g, 7.34 mmol)

6. Method A: KOH (2 eq.) was added to a solution of ethyl 2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetate (1 eq.) in MeOH at RT and the mixture was stirred for 3 h. The reaction mixture was concentrated to small volume and the residue taken up in water and washed with ethyl acetate. The aqueous phase was acidified to pH 3 to 4 and extracted with ethyl acetate. The organic phase was extracted with water and saturated sodium chloride solution, dried (Na2SO4), concentrated to small volume and used in the following step without further purification.

Method B: Ethyl-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetate (4.58 mmol, 1 eq.) was dissolved in ethanol (27 ml) and water (6 ml) and potassium hydroxide (1 M in water, 2 eq.) was added. The resulting mixture was stirred at RT for 16 h. Ethanol was removed in vacuo and the residue was taken up in water and diethylether (20 ml each). The aqueous phase was adjusted to pH 3 with 1 M HCl (aq) and extracted with ethyl acetate (3×30 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield the desired compound. Yield: 1.89 g (>99%)

Acid S4
2-((2-(2-(Trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid and acid
S5
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid




1. A mixture of methanol (45 ml) and water (5 ml) was cooled to 0° C. and added to the imine (2.35 g, 12.23 mmol). NaBH4 (555 mg, 14.67 mmol) was added in portions over 10 min. The reaction solution was stirred for 1 h at 0° C. The bulk of the organic solvent was removed under reduced pressure. NH3 solution (10%, 200 ml) and DCM (200 ml) followed by saturated NaCl solution (150 ml) were added to improve the phase separation. The phases were separated and the aqueous phase was extracted twice more with DCM (200 ml each). The combined organic phases were dried over Na2SO4 and concentrated to small volume. The crude product obtained was used in the next stage on the same day.

2. The reaction was performed under an N2 atmosphere. The amine (0.84 g, 4.32 mmol) was dissolved in DCM (10 ml). TEA (1.22 ml, 8.65 mmol) was added and the reaction batch was cooled to 0° C. Sulfonyl chloride (5.19 mmol) was added and the mixture was stirred for 1 h at 0° C. and then overnight at RT. The solvent was removed under reduced pressure. Purification was performed by column chromatography (silica gel, heptane/ethyl acetate, 3:1).

3. The reaction was performed under an N2 atmosphere. LiBH4 solution (2 M in THF, 2 ml, 4 mmol) was added to a solution of the ester (0.82 g, 2.038 mmol) in dry THF (50 ml) and the mixture was stirred overnight at RT. Na2SO4.10H2O was added until no further gas evolution was observed. The reaction mixture was stirred for 1 d at RT and then filtered over Na2SO4. The residue was washed with THF (approx. 50 ml). The combined organic phases were concentrated to small volume and the crude product used without further purification.

4. Aqueous NaOH solution (35%, 50 ml) followed by tent-butyl bromoacetate (1.62 ml, 11.11 mmol) were added to a solution of the alcohol (0.79 g, max. 2.01 mmol) and n-Bu4NCl (0.122 g, 0.439 mmol) in DCM (50 ml). The reaction mixture was stirred for 3 h at RT. It was then diluted with DCM (50 ml). The organic phase was washed first with water (3×50 ml) and then with saturated NaCl solution (50 ml). The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (silica gel, heptane/ethyl acetate, 4:1).

5. The tert-butyl ester (440 mg, 0.93 mmol) was dissolved in methanol (9 ml), THF (4 ml) and water (1 ml). NaOH (371 mg, 9.28 mmol) was added and then the mixture was stirred for 2 h at RT. The bulk of the organic solvent was then removed in a rotary evaporator. Ice (100 ml) and DCM (50 ml) were added and then aqueous KHSO4 solution (0.5 M, 50 ml) was added to the mixture. The phases were separated and the aqueous phase was extracted once more with DCM. The combined organic phases were dried over Na2SO4 and concentrated to small volume. The crude product obtained was used with no further purification.















R1
Name


















S4




2-((2-(2-(Trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid


 


S5




2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid









Acid S10
2-(2-(2,3-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid




1. The amine (2.4 mmol) was dissolved in THF (30 ml). NaHCO3 (6.0 mmol) was added followed by the addition of sulfonyl chloride (2.88 mmol) in THF (2 ml). The reaction was stirred at 25° C. for 16 h. Reaction mixture is evaporated to dryness under reduced pressure and crude product is purified by silica gel column chromatography (20% ethyl acetate in hexanes) to afford the sulfonamide.

2. A mixture of the sulfonamide (1.2 mmol), MeOH (2.7 ml), THF (5.5 ml) and aqueous LiOH solution (1.8 mmol in 2 ml water) was stirred at 25° C. for 3 h. Organic solvents were removed under reduced pressure. The resulting suspension was acidified with aqueous 1 M HCl while cooling at 0° C. DCM (20 ml) was added. Reaction mixture was extracted with DCM (3×20 ml) and evaporated to dryness under reduced pressure affording carboxylic acid (S10) which was used in the next step without further purification.















R1
Name


















S10




2-(2-(2,3-Dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid









Acid S11
2-(2-Tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid




1. The amine (3.36 mmol) was dissolved in THF (5 ml). TEA (5.05 mmol) was added followed by the addition of sulfonyl chloride (4.03 mmol). The reaction was stirred at 25° C. for 16 h. Solvent was evaporated to dryness under reduced pressure and the crude product was purified by silica gel column chromatography (50% ethyl acetate in hexane) to afford sulfonamide.

2. The ester cleavage was performed in the manner described for acid S1.















R1
Name


















S11




2-(2-Tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetic acid









Acid S13
2-(2-(3-Chloro-4-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid




1. TEA (8.4 ml, 0.06 mol) was added to a DCM (5 ml/mmol) solution of the amine (5 g, 0.0240 mol) at 0° C. under nitrogen followed by slow addition of the arylsulfonyl chloride (6.4 g, 0.029 mol). The reaction mixture was stirred at 25° C. for 18 h, diluted with DCM (20 ml), washed with saturated aq. NaHCO3 solution (20 ml), water (10 ml) and organic layer was dried over Na2SO4, evaporated to dryness under reduced pressure. The crude material was purified on silica gel (100-200 mesh) using 15-25% ethyl acetate in hexanes.

2. Arylsulfonamide (1 g, 0025 mol) was taken in a composite solution of THF/MeOH/H2O (5:3:1;  ̃4 ml/mmol) and cooled to 0° C. on an ice bath. Lithium hydroxide monohydrate (0.18 g, 0.0045) was added portion wise and reaction mixture was stirred for 3 to 7 h at 25° C. The solvents were evaporated and the residue was taken in water, washed with ethyl acetate (10 ml). The organic layer was kept aside and the aq. layer was made acidic with 2N aq. HCl solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude acid is purified on silica gel (100-200 mesh) using DCM in methanol to obtain pure compound.















R1
Name


















S13




2-(2-Tosyl-1,2,3,4-tetrahydrpyrrolo[1,2-a]pyrazin-1- yl)acetic acid


 


S15




2-(2-(3-Chlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid









Synthesis of Amine Structural Units
The amine structural units listed in Table 2 were used for the synthesis of the example compounds.










TABLE 2





Amine
No.
Name
Supplier











A1 
1-(1-Methylpiperidin-4- yl)piperazine
Fluka


 






A2 
2-Cyclopropyl-2,7- diazaspiro[4.4]nonane


 






A3 
2-(Pyridin-4-yl)-2,8- diazaspiro[4.5]decane


 






A4 
4-(Piperidin-4-yloxy)pyridine
Interchim


 






A5 
6-(Piperidin-1-ylmethyl)- 1,2,3,4- tetrahydronaphthalen-2- amine


 






A6 
6-(Piperidin-1-ylmethyl)- 1,2,3,4- tetrahydronaphthalen-1- amine


 






A7 
3-(Pyridin-4-yl)-3,9- diazaspiro[5.5]undecane


 






A8 
N-Methyl-2-(1-(pyridin-4- yl)piperidin-4-yl)ethanamine


 






A9 
Piperidine
Aldrich


 






A10
1,2,3,4- Tetrahydroisoquinoline
Aldrich


 






A11
1-Benzyl-3,3- dimethylpiperidin-4-amine


 






A12
2,2,2-Trifluoro-1-(2,8- diazaspiro[4.5]decan-2- yl)ethanone


 






A13
3-(Pyridin-4-yloxy)-8- azabicyclo[3.2.1]octane


 






A14
3-(4-(2-(Pyrrolidino-1- yl)ethoxy)piperidine-4- yl)pyridine


 






A15
6-((tert-Butylamino)methyl)- 1,2,3,4- tetrahydronaphthalen-2- amine


 






A16
N-[[5-(tert- Butoxycarbonylamino)- 5,6,7,8-tetrahydro- naphthalen-2-yl]-methyl]-N- methyl-carbamic acid 9H- fluoren-9-yl-methyl ester


 






A17
N-[6- (Dimethylaminomethyl)- 1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A18
N-[6-[(1-Methyl- propylamino)-methyl]- 1,2,3,4-tetrahydro- naphthalen-1-yl]carbamic acid tert-butyl ester


 






A19
N-[6-[(tert-Butylamino)- methyl]-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A20
N-[6-[(tert-Butyl-methyl- amino)-methyl]-1,2,3,4- tetrahydro-naphthalen-1-yl]- carbamic acid tert-butyl ester


 






A21
N-[6-(Pyrrolidin-1-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A22
N-[6-(Piperidin-1-yl-methyl)- 1,2,3,4-tetrahydro- naphthalen-1-yl]carbamic acid tert-butyl ester


 






A23
N-[6-(Morpholin-4-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A24
N-[6-[(4-Methyl-piperazin-1- yl)-methyl]-1,2,3,4- tetrahydro-naphthalen-1-yl]- carbamic acid tert-butyl ester


 






A25
N-[6-(8- Azabicyclo[3.2.1]octan-8-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A26
N-[6-[(Benzylamino)- methyl]-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A27
N-[6-(1,2,3,4-Tetrahydro- quinolin-1-yl-methyl)- 1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 






A28
N-[[6-(tert- Butoxycarbonylamino)- 5,6,7,8-tetrahydro- naphthalen-2-yl]-methyl]-N- methyl-carbamic acid 9H- fluoren-9-yl-methyl ester


 






A29
N-[6- (Dimethylaminomethyl)- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A30
N-[6-[(1-Methyl- propylamino)-methyl]- 1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A31
N-[6-[(tert-Butylamino)- methyl]-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A32
N-[6-[(tert-Butyl-methyl- amino)-methyl]-1,2,3,4- tetrahydro-naphthalen-2-yl]- carbamic acid tert-butyl ester


 






A33
N-[6-(Pyrrolidin-1-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A34
N-[6-(Piperidin-1-yl-methyl)- 1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A35
N-[6-(Morpholin-4-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A36
N-[6-[(4-Methyl-piperazin-1- yl)-methyl]-1,2,3,4- tetrahydro-naphthalen-2-yl]- carbamic acid tert-butyl ester


 






A37
N-[6-(8- Azabicyclo[3.2.1]octan-8-yl- methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A38
N-[6-[(Benzylamino)- methyl]-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 






A39
tert-Butyl 6-((3,4- dihydroquinolin-1(2H)- yl)methyl)-1,2,3,4- tetrahydronaphthalen-2- ylcarbamate


 






A40
1-(5- (Trifluoromethyl)pyridin-2- yl)piperidin-4-amine
Fluorochem


 






A41
1-(5- (Trifluoromethyl)pyridin-2- yl)pyrrolidin-3-amine
Chinglu Pharma- ceuticals


 






A42
4-(Piperidin-4-yl)pyridine
Interchim


 






A43
4-(piperidin-4- ylmethyl)pyridine
Interchim


 






A44
1-(pyridin-4-yl)piperidin-4- amine
ABCR


 






A45
1-methyl-4-(pyrrolidin-3- ylmethyl)piperazine
AKOS


 






A46
4-(pyrrolidin-3- yloxy)pyridine
Amatek Chem


 






A47
N-methyl-1-(pyridin-4- yl)piperidin-4-amine
Enamine


 






A48
2-methyl-5-(piperidin-4-yl)- 2,5- diazabicyclo[2.2.1]heptane


 






A49
2-(4-(4,5-Dihydro-1H- imidazol-2- yl)phenyl)ethanamine


 






A50
(R)-6-((tert- Butylamino)methyl)-1,2,3,4- tetrahydronaphthalen-1- amine


 






A51
N-Methyl-6-(piperidin-1- ylmethyl)-1,2,3,4- tetrahydronaphthalen-2- amine


 






A52
(R)-6-((4-Fluoropiperidin-1- yl)methyl)-1,2,3,4- tetrahydronaphthalen-1- amine


 






A53
(R)-6-((2,2,2- Trifluoroethylamino)methyl)- 1,2,3,4- tetrahydronaphthalen-1- amine


 






A54
(R)-N-(4-(1- Aminoethyl)benzyl)-2- methylpropan-2-amine


 






A56
5-(Piperidin-1-ylmethyl)-2,3- dihydro-1H-inden-2-amine


 






A57
2-([1,4]Diazepan-1-yl)- pyridine-3-carbonitrile
Maybridge


 






A58
3-(2,6-Dimethyl-piperidin-1- yl)-propyl-amine
Interchim


 






A59
[2-(4-Methyl-piperazin-1-yl)- 1-phenyl-ethyl]-amine
Interchim


 






A60
(1-Benzyl-pyrrolidin-3-yl)- methyl-amine
Akos


 






A61
(1-Benzyl-piperidin-3-yl)- methyl-amine
Maybridge


 






A62
5-Methyl-2-piperidin-4-yl- 1H-benzoimidazole
Interchim


 






A63
1-(2-Fluorophenyl)- piperazine
Aldrich


 






A64
1-Pyridin-2-yl-piperazine
Aldrich


 






A65
2-Pyrrolidin-1-yl-ethyl- amine
Aldrich


 






A66
3-Morpholin-4-yl-propyl- amine
Aldrich


 






A67
3-Piperazin-1-yl- propionitrile
Aldrich


 






A68
3-Piperidin-1-yl-propyl- amine
Aldrich


 






A69
Dimethyl-(4-pyrrolidin-2-yl- phenyl)-amine
ASDI


 






A70
1-(Pyrrolidin-2-yl-methyl)- piperidine
Interchim


 






A71
[4-(Azepan-2-yl)-phenyl]- dimethyl-amine
ASDI


 






A73
(1-Benzyl-pyrrolidin-3-yl)- amine
TCI


 






A75
Methyl-(2-morpholin-4-yl-1- phenyl-ethyl)-amine
Interchim


 






A76
1-(3-Methoxyphenyl)- piperazine
Aldrich


 






A77
1-(4-Fluorophenyl)- piperazine
Aldrich


 






A78
1-(4-Methoxyphenyl)- piperazine
Aldrich


 






A79
1-Ethyl-piperazine
Aldrich


 






A80
1-Phenyl-piperazine
Aldrich


 






A82
1-(1,3-Benzodioxol-5-yl- methyl)-piperazine
Aldrich


 






A83
2-Piperazine-1-yl-pyrimidine
Aldrich


 






A84
4-Pyrrolidin-1-yl-piperidine
Aldrich


 






A85
4-Benzyl-piperidine
Aldrich


 






A86
4-Piperidine-4-yl-morpholine
Aldrich


 






A87
1-Piperidin-4-yl-piperidine
Aldrich


 






A88
1-[[-Pyrrolidin-2-yl]-methyl]- pyrrolidine
Otava


 






A89
1-(5-Chloro-2-methyl- phenyl)-piperazine
Maybridge


 






A90
2-Piperazin-1-yl-pyridine-3- carbonitrile
Maybridge


 






A91
1-[5-(Trifluoromethyl)- pyridin-2-yl]-piperazine
Maybridge


 






A92
1-[3-Chloro-5- (trifluoromethyl)-pyridin-2- yl]-piperazine
Maybridge


 






A94
2-(Pyrrolidin-2-yl-methyl)- pyridine
Hansa


 






A95
2-(Piperidin-2-yl-methyl)- pyridine
Hansa


 






A96
4-(Piperidin-2-yl-methyl)- pyridine
Hansa


 






A97
4-(4-Chlorophenyl)- piperidin-4-ol
Aldrich


 






A98
4-Phenyl-piperidin-4-ol
Aldrich


 






A99
4-Benzyl-piperidin-4-ol
Alfa


 






A100
4-[3- (Trifluoromethyl)phenyl]- piperidin-4-ol
Alfa


 






A101
2-Piperazin-1-yl-ethanol
Aldrich


 






A102
1-(3,4-Dichlorophenyl)- piperazine
Aldrich


 






A103
1-[(3,4-Dichlorophenyl)- methyl]-piperazine
Aldrich


 






A105
1-[(4-Chlorophenyl)- methyl]-piperazine
Aldrich


 






A106
1-(p-Tolyl-methyl)- piperazine
Aldrich


 






A107
1-[(4-Methoxyphenyl)- methyl]-piperazine
Aldrich


 






A108
1-[(2-Fluorophenyl)-methyl]- piperazine
Aldrich


 






A109
1-Methyl-3-phenyl- piperazine
Aldrich


 






A110
4-Phenyl-piperidine
Aldrich


 






A111
4-Pyridin-3-yl-piperidin-4-ol
Interchim


 






A113
Methyl [2-(4-methyl- piperazin-1-yl)-1-phenyl- ethyl]-amine
Interchim


 






A114
1-Methyl-4-piperidin-4-yl- piperazine
Interchim


 






A115
Methyl-(2-piperidin-1-yl- ethyl)-amine
Chembridge


 






A116
1-(2-Piperidin-4-yl-ethyl)- piperidine
Interchim


 






A117
1-[2-(2,5-Dimethyl-1H- pyrrol-1-yl)-ethyl]-piperazine
Maybridge









Synthesis of 2-cyclopropyl-2,7-diazaspiro[4.4]nonane A2




1. NaCNBH3 (654 mg, 10.4 mmol) was added to a solution of 2-benzyl-2,7-diaza-spiro[4.4]nonane (450 mg, 2.08 mmol), acetic acid (1.19 ml, 20.8 mmol), molecular sieve (3 Å, beads) and (1-ethylcyclopropyloxy) trimethylsilane (2.09 ml, 10.4 mmol) in MeOH (45 ml) and the mixture was then refluxed. After 4 h the reaction batch was cooled to RT and filtered. The residue was washed with MeOH (50 ml) and the combined organic phases were concentrated to dryness. The residue was taken up in water (5 ml) and NaOH solution (2 M, 10 ml) and extracted with DCM (2×40 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was used with no further purification. Yield: 440 mg, 82%

2. A solution of benzylamine (440 mg, 1.72 mmol) in absolute EtOH (10 ml) was gassed for 10 min with N2. Then Pd (10% on carbon, 183 mg, 172 μmol) was added and the mixture was again gassed for 10 min with N2. The reaction batch was stirred overnight at RT under an H2 atmosphere (3 bar). On completion of the reaction the mixture was filtered over celite and rewashed with DCM (30 ml) and MeOH (30 ml). The combined filtrates were concentrated to dryness. The product was used without further purification.

Synthesis of 2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane A3




1. The reaction was performed under an N2 atmosphere. tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (869 mg, 3.62 mmol), 4-chloropyridine hydrochloride (1.08 g, 7.20 mmol) and TEA (2.5 ml, 18 mmol) were suspended in isopropanol (10 ml). The mixture was heated to 80° C. and stirred overnight at 80° C. Then the solvent was removed in a rotary evaporator. The residue was taken up in DCM and concentrated to small volume again. This process was repeated twice more. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2). The product obtained still contained impurities and was used in the next stage in that condition.

2. The reaction was performed under an N2 atmosphere. The carbamate (1.034 g, max. 3.26 mmol) was dissolved in MeOH (5 ml) and mixed with 4 M HCl in dioxane (5 ml). The reaction batch was stirred for 2 h at RT. Then the solvent was removed. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2→95:5→9:1). Yield: 455 mg, 58% over 2 stages.

Synthesis of 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine A5




1. Benzylamine (0.72 ml, 6.6 mmol) was added to a solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (1 g, 4.4 mmol) in DCM (88 ml), followed by a catalytic amount of acetic acid (0.74 ml). The reaction mixture was stirred for 30 min at 25° C., then Na(OAc)3BH (3.73 g, 17.6 mmol) was added and the mixture was stirred for 16 h. Then it was diluted with DCM (150 ml) and extracted with saturated bicarbonate solution and saturated sodium chloride solution. The organic phase was dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (100-200 mesh silica gel, 3% methanol in ethyl acetate). Yield: 95%

2. N-Benzyl-6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine was reacted with benzaldehyde under analogous reaction conditions to stage 1. Yield: 50%

3. A mixture of N,N-dibenzyl-6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (0.9 g, 2.21 mmol) and zinc cyanide (0.39 g, 3.32 mmol) in DMF (20 ml) was degassed with argon for 30 min and then mixed with xanthphos (0.256 g, 0.44 mmol) and tris(dibenzylidene acetone)dipalladium(0) (0.202 g, 0.22 mmol). The resulting reaction mixture was heated for 6 h at 100° C., then cooled, diluted with water and extracted with ethyl acetate (3×75 ml). The combined organic phases were washed with water (5×20 ml) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (100-200 mesh silica gel, 3% ethyl acetate in hexane). Yield: 50% 4.20% DIBAL in toluene (1.72 ml, 2.42 mmol) was added dropwise to a solution of 6-(dibenzylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.57 g, 1.61 mmol) in anhydrous toluene (20 ml) cooled to 0° C. The reaction mixture was slowly heated to 25° C. and stirred for 4 h. Then it was cooled again to 0° C. and 20 ml 10% hydrochloric acid were added dropwise. The reaction mixture was heated to 25° C. and stirred for 2 h. Then it was neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was extracted with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was used in the following stage with no further purification. Yield: 94%

5. 6-(Dibenzylamino)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde was reacted with piperidine under analogous reaction conditions to stage 1. Yield: 52%

6. Argon was added to a solution of N,N-dibenzyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (0.5 g, 1.17 mmol) in ethanol (80 ml) for 10 min and then 20% palladium hydroxide (120 mg) was added. The reaction mixture was stirred for 5 h under a hydrogen atmosphere and the progress was monitored hourly via LC-MS. The mixture was filtered over celite and washed with ethanol. The filtrate was concentrated to small volume under reduced pressure and the crude product used in the next stage with no further purification. Yield: quantitative

7. TEA (0.5 ml, 3.73 mmol) was added to a solution of 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (0.365 g, 1.49 mmol) in DCM (15 ml), followed by Boc anhydride (0.46 ml, 2.24 mmol) at 0° C. The reaction mixture was stirred for 2 h at 25° C., then iced water was added and the mixture was extracted with DCM (500 ml). The organic phase was extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (100-200 mesh silica gel, 2% methanol in DCM). Yield: 36%

8. TFA (2 ml/mmol) was added to a solution of tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.19 g, 0.55 mmol) in DCM (10 ml/mmol) at 0° C. and the mixture was stirred for 2 h at 25° C. The solvent was removed and the product was dried under vacuum. The crude product was used in the following stage with no further purification.

Method B
See Synthesis of amine A51 (Step 1-Step 4)
Synthesis of 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine A6




1. 5-Oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3 g) was refluxed for 16 h with 30 ml methanol, saturated with HCl gas. The reaction mixture was concentrated to small volume and the residue diluted with DCM. The organic phase was extracted with saturated NaHCO3 solution and saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume. Yield: quantitative

2. A (1M) solution of (R)-2-methyl-CBS-oxazaborolidine (0.12 ml, 0.12 mmol) was diluted with toluene (10 ml) and cooled to −10° C. BH3.SMe2 (0.3 ml, 2.94 mmol) was added slowly to this solution at −10° C., followed by the dropwise addition of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.5 g, 2.45 mmol) in THF (2 ml). The reaction mixture was stirred for 30 min and methanol (4 ml) was added at 0° C. Then the mixture was heated to 25° C. and stirred for 16 h. The reaction mixture was concentrated to small volume and the residue diluted with ethyl acetate. The organic phase was extracted with 0.1 N HCl (2×10 ml), 5% sodium bicarbonate solution (2×10 ml) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (20% ethyl acetate in hexane). Yield: 40%

3. DPPA (0.4 ml, 1.61 mmol) was added dropwise to a cold solution of (S)-methyl 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.22 g, 1.07 mmol) in toluene (5 ml), followed by DBU (0.24 ml, 1.61 mmol). The reaction mixture was slowly heated to 25° C. and stirred for 16 h. Then it was diluted with ethyl acetate (15 ml) and extracted with 0.1 N HCl, 5% sodium bicarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (20% ethyl acetate in hexane). Yield: 80%

4. A solution of (R)-methyl 5-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.39 mmol) in THF (2 ml) was added dropwise to a cold suspension of LAH (0.132 g, 3.46 mmol) in THF (2 ml). The reaction mixture was stirred for 30 min, then heated to 25° C. and stirred for a further 16 h. Then THF/H2O (9:1) was added, the mixture was filtered over celite and concentrated to small volume under reduced pressure. The crude product was used in the following stage without further purification. Yield: quantitative

5. TEA (4 ml, 28.25 mmol) and Boc anhydride (3.7 ml, 16.95 mmol) were added to a solution of (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (2 g, 11.3 mmol) in DCM (20 ml) cooled to 0° C. and the mixture was stirred for 16 h at RT. Then the mixture was diluted with DCM and extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (30% ethyl acetate in hexane). Yield: 51%

6. Manganese dioxide (2.78 g) was added to a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.8 g, 2.12 mmol) in anhydrous toluene (40 ml) and the mixture was refluxed for 16 h. The solid was filtered over celite, washed with ethyl acetate and the filtrate concentrated to small volume under reduced pressure. The crude product was purified by column chromatography (40% ethyl acetate in hexane). Yield: 44%

7. Sodium cyanoboron hydride (2.5 eq.) was added to a solution of (R)-tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.35 g, 1.27 mmol) and piperazine (1.5 eq.) in methanol (3 ml) at 25° C., followed by acetic acid (catalytic). The mixture was stirred for 16 h. The reaction progress was monitored by thin-layer chromatography. On completion of the reaction the mixture was concentrated under reduced pressure, the residue diluted with DCM and washed with saturated NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to small volume under reduced pressure. The crude product was purified by column chromatography (10% methanol in DCM). Yield: 36%

8. TFA (13 eq.) was added to a DCM solution (10 ml/mmol) of (R)-tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (1 eq.) at 0° C. and the mixture was stirred for 2 h at RT. The solvent was removed and the product was dried under vacuum. The crude product was used in the following stage without further purification.

Synthesis of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane A7




1. Sodium tert-butylate (4 mmol) was added to a solution of 4-bromopyridine hydrochloride (1.9 mmol) in dry toluene (10 ml) under argon, followed by 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.6 mmol) in toluene (5 ml). Argon was added to the mixture for 15 min, then (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.123 mmol) and tris(dibenzylidene acetone)dipalladium (0.041 mmol) were added. The mixture was heated at 90° C. for 4 h and the reaction progress was monitored by thin-layer chromatography. On completion of the reaction the mixture was diluted with ethyl acetate (100 ml) and extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (3% methanol in DCM). Yield: 45%

2. TFA (13 eq.) was added to a DCM solution (10 ml/mmol) of tert-butyl 9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 eq.) at 0° C. and the mixture was stirred for 2 h at RT. The solvent was removed and the product was dried under vacuum. The crude product was used in the following stage with no further purification. Yield: quantitative

Synthesis of N-methyl-2-(1-(pyridin-4-yl)piperidin-4-yl)ethanamine A8




1. (2.00 g, 8.76 mmol), 4-chloropyridine hydrochloride (1.31 g, 8.76 mmol) and TEA (2.44 ml, 17.55 mmol) were in i-PrOH (10 ml) and heated in the microwave for 2 h at 120° C. The solvent was removed under vacuum. The product was purified by column chromatography (silica gel, DCM/(7 M NH3 in MeOH, 99:1→98:2→95:5).

2. The reaction was performed under an argon atmosphere. The amine from stage 1 (1.87 g, 4.56 mmol) was dissolved in dry THF (75 ml) and cooled to 0° C. A solution of LAH (2.4 M in THF, 7.6 ml, 18.25 mmol) was added dropwise. On completion of the addition the mixture was heated to 60° C. After a reaction time of 4.5 h the mixture was cooled to RT and stirred overnight at RT. Na2SO4.10H2O was added to the reaction solution until no further H2 evolution could be detected. The viscous solution was dried by adding Na2SO4 and filtered after approximately 30 min. The residue was rewashed with THF. The combined filtrates were concentrated to dryness and the crude product obtained was purified by column chromatography.

Synthesis of 1-benzyl-3,3-dimethylpiperidin-4-amine A11




A solution of 1-benzyl-3,3-dimethylpiperidin-4-one (900 mg, 4.14 mmol) and acetic acid (474 μl, 8.28 mmol) in 7 M NH3 in MeOH (35.5 ml, 249 mmol) was first stirred for 30 min at RT. Then NaBH4 (1.57 g, 41.4 mmol) was added at RT. The reaction batch was stirred for 30 min at RT, concentrated and then diluted with DCM (100 ml). The organic phase was washed with saturated aqueous NaHCO3, dried and concentrated to dryness.
Synthesis of 2,2,2-Trifluoro-1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone A12




1. To a solution of 1-Boc-diamine hydrochloride (1.0 mmol) and TEA (2.5 mmol) in DCM (15 ml) was added Cbz-Cl (1.4 mmol) and then stirred at ° C. for 1 h. The reaction mixture was diluted with DCM (50 m). The organic layer was washed with water (10 ml), brine (10 ml), dried over anhydrous Na2SO4 and concentrated. The crude product is purified by column chromatography using 40% ethyl acetate in hexanes as eluent.

2. To a solution of step-1 product (1.2 mmol) in DCM (10 ml) was added TFA (2 ml) and stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure and crude mass was dissolved in DCM (10 ml) and then TEA (5 mmol) was added to the reaction mixture. To the solution was added trifluoroacetic anhydride (2.4 mmol) drop wise at 0° C. and stirred for 30 min at 25° C. The reaction mixture was diluted with DCM (50 ml). The organic layer is washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product is purified by column chromatography using 30% ethyl acetate in hexanes as eluent.

3. To a degassed solution of step-2 product (350 mg) in ethanol (30 ml) was added 10% Pd/C (70 mg) and hydrogenated under 2 Kg H2 pressure. The reaction mixture was filtered through celite and the filtrated was concentrated under reduced pressure to give the desired product which was used for amidation without further purification.

Synthesis of (1R,3S,5S)-3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane dihydrochloride [A13]
Stage (i)
(1R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate
Boc-nortropinone (2.5 g, 11.097 mmol) was dissolved in methanol (20 ml) and cooled with an ice bath. Sodium boron hydride (1.26 g, 33.291 mmol) was added slowly under protective gas. After stirring for 4 h at RT the mixture was hydrolysed with saturated sodium hydrogen carbonate solution (30 ml), the methanol was removed under vacuum and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were dried over magnesium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/dichloromethane/ammonia (25% eq.) (400:40:40:1). The isomers were separated in this process and they were assigned by NMR analysis. Yield: endo 53% [reacted further in stage (ii)], exo 25%
Stage (ii)
(1R,3S,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
(1R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq.) was dissolved in tetrahydrofuran (50 eq.) and 4-hydroxypyridine (1 eq.) and triphenylphosphine (1.25 eq.) were added. Diisopropylazodicarboxylate (1.25 eq.) was then added dropwise and the reaction mixture was heated to 55° C. After 15 h tetrahydrofuran was removed under vacuum, the residue was taken up in ethyl acetate (50 ml) and extracted with aqueous hydrogen chloride solution (2×40 ml, 1 mol/l). The aqueous phase was alkalized with sodium hydroxide solution (pH=8) and extracted with ethyl acetate (3×50 ml). These organic phases were combined, dried over Na2SO4 and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane (3:1). Yield: 65% [The other isomer can be obtained from the corresponding exo product from stage (i) in an analogous manner.]
Stage (iii)
(1R,3S,5S)-3-(Pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane dihydrochloride
(1R,3S,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq.) was added in hydrogen chloride in methanol (4 eq., 1.25 mol/l) and the reaction mixture was refluxed for 30 min. The solvent was removed under vacuum and the residue taken up in a little ethanol (5 ml) and then mixed with acetone (30 ml). The mixture was stirred for 30 min at RT and then diethyl ether (20 ml) was added. The precipitate was siphoned off, washed with diethyl ether and dried under vacuum. Yield: 90% [The other isomer can be obtained from the corresponding exo product of stage (i) in an analogous manner to stage (ii) and (iii).]
Synthesis of 3-(4-(2-(Pyrrolidino-1-yl)ethoxy)piperidine-4-yl)pyridine A14




1. 3-Bromo pyridine (22.47 mmol) in anhydrous diethyl ether (10 ml) was added dropwise (10 min) to a stirred solution of n-BuLi (24.7 mmol) in anhydrous diethyl ether (70 ml) under argon at −78° C. and stirred for 30 min. N-Boc-Piperidone (11.23 mol) in ether (10 ml) was then added to this mixture and stirred for additional 1 h at that temperature. The reaction mixture was allowed to warm to 25° C. and partitioned between ethyl acetate (150 ml) and water (80 ml). The aqueous phase was extracted with ethyl acetate (2×70 ml), combined organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to give a yellow liquid residue. The residue is then purified by flash chromatography (2% MeOH:DCM) to give the desired product.

2. Anhydrous potassium hydroxide (11.25 mmol) was added to a mixture of the alcohol (2.25 mmol) and the bromide (3.375 mmol) in degassed toluene (25 ml), followed by 18-Crown-6 (catalytic amount). The reaction mixture was then heated at reflux for 12 h after which toluene was evaporated and water was added to the residue. The aqueous layer was then extracted with DCM (3×60 ml). The organic washings were combined, washed with brine and dried over anhydrous sodium sulfate. Finally, the organic layer was dried in vacuo to yield a solid residue which is purified on silica gel (100-200 mesh) eluting with 4% methanol in DCM to get the product

3. To a cooled (0° C.) solution Boc-compound (0.33 mmol) in DCM (3.5 ml) was added TFA (0.7 ml) and the reaction mixture was stirred at 25° C. for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to get crude product which is directly used in the next step.

Synthesis of 6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-amine A15




1. NH4OAc (10.19 g, 0.13 mol, 10 eq.) was added to a solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (3 g, 0.13 mol, 1 eq.) in MeOH (100 ml) and the mixture was stirred for 2 h at RT. NaBH3CN (990 mg, 0.015 mol, 1.2 eq.) was added to the reaction mixture and it was stirred for another 16 h at RT. The reaction mixture was concentrated under reduced pressure, diluted with water (100 ml) and acidified with 1 N HCl solution. The mixture was extracted with DCM (2×100 ml) and the aqueous part basified with 1 N NaOH solution. Then the aqueous part was extracted with DCM (4×200 ml). The organic part was washed with brine (100 ml), dried over Na2SO4 and concentrated under reduced pressure. The reddish crude liquid thus obtained was used for the next step without further purification. Yield: 2.6 g

2. To a mixture of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (5.5 g, 24.3 mmol, 1 eq.) in DCM (120 ml) and TEA (10.24 ml, 72 mmol, 3 eq.) was added dropwise boc-anhydride (6 ml, 26 mmol, 1.1 eq.) at 0° C. and the mixture was then stirred at RT for 16 h. After completion of the reaction (monitored by TLC) the mixture was diluted with DCM (100 ml), the organic layer washed with water (100 ml) and brine (100 ml), and dried over anhydrous Na2SO4. The solvent was then evaporated to yield the desired compound as an off-white solid which was used in the next step without further purification. Yield: 7 g

3. BuLi (1.5 M, 15 ml, 22.5 mmol, 2 eq.) was added dropwise to a stirred solution of tert-butyl 6-bromo-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (3.5 g, 10.73 mmol, 1 eq.) in THF (100 ml) at −78° C. and the reaction mixture was stirred for 45 min at the same temperature. Then DMF (3 ml, 32.1 mmol, 3 eq.) was added to the reaction mixture very slowly at −78° C. and it was stirred for 1 h. After completion of the reaction (monitored by TLC) the mixture was quenched with saturated NH4Cl solution (20 ml) and diluted with ethyl acetate (100 ml). The organic part was separated, washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. It was concentrated under reduced pressure to yield the crude product which was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give the desired compound as a yellowish liquid. Yield: 75% (2.2 g, 8 mmol)

4. A solution of t-BuNH2 (0.8 ml, 7.6 mmol, 1 eq.) in DCM (3 ml) was added to a solution of tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (2.1 g, 7.6 mmol, 1 eq.) in dry DCM (100 ml) at 0° C. and resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 0° C., then NaBH3CN (4.45 g, 20.9 mmol, 3.0 eq.) was added portionwise and the mixture was then stirred at 25° C. for 16 h. The mixture was diluted with DCM (200 ml), washed with water (2×50 ml) and brine (2×50 ml) and the organics were dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (silica gel; 5% EtOAc/hexanes) to yield the desired product as a white solid. Yield: 72% (1.8 g, 5.4 mmol)

5. TFA (14 ml, 0.192 mol, 40 eq.) was added to a solution of tert-butyl 6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.6 g, 4.8 mmol, 1.0 eq.) in DCM (100 ml) at 0° C. and resulting reaction mixture was stirred at 25° C. for 30 min. The solvent was evaporated under reduced pressure and the residue obtained was diluted with EtOH (50 ml). The mixture was basified with Amberlyst (A-21,  ̃6 g) to pH 9-10 and then stirred for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a yellowish solid which was used for the next step without further purification. Yield: quantitative

Synthesis of N-[[5-(tert-Butoxycarbonylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-methyl]-N-methyl-carbamic acid 9H-fluoren-9-yl-methyl ester A16




1. To a stirred solution of 6-hydroxy-1-tetralone (3 g, 0.0184 mol) and 2,6-Lutidine (9.6 ml, 0.082 mol, 4.5 eq.) in DCM (48 ml) at 0° C. was added slowly Triflic anhydride (4.5 ml, 0.0274 mol, 1.5 eq.) and the reaction mixture was stirred for 1 h at 0° C. Water (48 ml) was added to quench the reaction. After stirring for 15 min at RT the mixture was diluted with DCM (96 ml) and the layer were separated. The organic layer was washed with 10% aqueous NaHCO3 solution (100 ml), water (100 ml) and then brine (50 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200). The product is eluted in 2% ethyl acetate/hexane.

2. To a stirred solution of step 1 product (2 g, 0.0068 mol) and NH4OAc (5.23 g, 0.0068 mol, 1.0 eq.) in MeOH (30 ml) was added slowly NaBH3CN (0.512 g, 0.0082 mol, 1.2 eq.) at RT and the reaction mixture was stirred for 20 h. The reaction mixture was concentrated under reduced pressure, diluted with water (10 ml), acidified 0.1 M HCl to pH ̃2 and extracted with DCM (20 ml). The aqueous layer was basified with 0.1 N NaOH and extracted with DCM (3×20 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield the title compound.

3. To the stirred solution of step-3 product (0.8 g, 0.003 mol) in DCM (10 ml) was added TEA (2 ml, 0.009 mol, 3.0 eq.) at 0° C. Boc anhydride (0.7 ml, 0.0036 mol, 1.2 eq.) was added and the reaction mixture is stirred overnight at RT. The reaction mixture was diluted with DCM (20 ml) and washed with water, then brine. The DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (100-200 mesh). The pure product is eluted in 2% Ethyl acetate/Hexane.

4. To a stirred solution of step 3 product (0.395 g, 0.001 mol) in methanol (10 ml) was added Pd (OAc)2 (3.0 mol %) and dppf (6 mol %) and the reaction mixture was purged with carbon monoxide for 30 min. The reaction was stirred at 70° C. for 14 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (silica gel 100-200). The pure product was eluted with 10% Ethyl acetate in hexane.

5. To the stirred suspension of LAH (1.08 g. 0.23 mol, 1.2 eq.) in THF (50 ml) was added a solution of step 4 compound (7.0 g, 0.023 mol) in THF (50 ml) at 0° C. and the reaction mixture was stirred for 30 min at 0° C. After completion of the reaction the reaction mixture was quenched with Na2SO4.10H2O (20 g) and the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to afford the colorless solid compound.

6. To the stirred solution of oxalyl chloride (0.149 g, 0.001 mol, 2 eq.) in DCM (2 ml) was added DMSO (0.168 g, 0.002 mol, 4 eq.) in DCM (2 ml) at −78° C. and stirred for 10 min. Then a solution of step-5 compound (0.15 g, 0.0005 mol) in DCM (2 ml) was added to the reaction mixture. The reaction mixture is stirred at −78° C. for 30 min. TEA (0.5 ml, 0.002 mol, 5.0 eq.) was added and the reaction mixture was stirred for additional 30 min. The reaction mixture was warmed to RT, added water and extracted with DCM (2×10 ml). The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield the solid compound.

7. To a stirring solution of step-6 compound (1.0 g, 0.003636 mol, 1 eq) in DCM (20 ml) was added methylamine hydrochloride (0.3558 g, 0.004363 mol, 1.2 eq.) at RT and then the reaction mixture was stirred for 2 h at RT. Na(OAc)3BH (2.3125 g, 0.0109 mol, 3 eq.) was then added to the reaction mixture at RT. The final reaction mixture then stirring over 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and organic part washed by water (2×20 ml) and by brine (20 ml). The organic layer then dried over Na2SO4, evaporated in reduced pressure to get the crude material, which was purified by column chromatography (silica gel 100-200; 5% methanol/DCM) to desired product.

8. To a solution of step-4 product (0.45 g, 0.0015 mol) in water (9 ml), NaHCO3 (0.26 g, 0.003 mol, 2 eq.) was added. A solution of Fmoc-Cl (0.6 g, 0.00225 mol, 1.5 eq.) in dioxane (9 ml) was added at 5° C. and then the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The concentrated mass was diluted with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified using column chromatography (silica gel 100-200; 15% ethyl acetate/hexane) to give the desired product.

Synthesis of Amines A17-A27




1. To a stirring solution of the aldehyde (1.0 g, 0.003636 mol, 1 eq.) in DCM (20 ml) was added the according amine (for A17 and A25 the amine hydrochloride) (1.2 eq.) at RT. The reaction mixture was stirred for 2 h at RT. Na(OAc)3BH (2.3125 g, 0.0109 mol, 3 eq.) was then added to the reaction mixture at RT. The final reaction mixture then was stirring over 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and organic part washed by water (2×20 ml) and by brine (20 ml). The organic layer then dried over Na2SO4, evaporated under reduced pressure to get the crude material, which was purified by column chromatography (silica gel 100-200; 5% methanol/DCM)













No.
NR1R2
Name







A17




N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A18




N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A19




N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A20




N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4- tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A21




N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A22




N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A23




N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A24




N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4- tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A25




N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4- tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A26




N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-1-yl]-carbamic acid tert-butyl ester


 


A27




N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-1,2,3,4- tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester









Synthesis of N-[[6-(tert-Butoxycarbonylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-methyl]-N-methyl-carbamic acid 9H-fluoren-9-yl-methyl ester A28




1. To a stirring solution of 6-bromo-2-tetralone (1.0 g, 0.00444 mol, 1 eq.) in methanol (139 ml) was added ammonium acetate (3.4218 g, 0.04444 mol, 10 eq.). The reaction mixture then stirred over 1 h at RT. Sodium cyanoborohydride (0.335 g, 0.00533 mol, 12 eq.) was then added to the reaction mixture at RT and then stirred for 20 h. The solvent of the reaction mixture was evaporated under reduced pressure. The residue then dissolved in water (50 ml) and acidified by 1(N)HCl solution up to PH ̃2. The aqueous part was extracted with DCM (2×50 ml). The aqueous part was then basified with 1(N) NaOH solution up to PH ̃10. The aqueous part was extracted with DCM (2×100 ml). The combined organic part was washed with brine (30 ml), dried over Na2SO4, and evaporated under reduced pressure to get the product 6-bromo-1,2,3,4-tetrahydro-2-napthyl amine.

2. To a stirring solution of 6-bromo-1,2,3,4-tetrahydro-2-napthyl amine (0.5 g, 0.00221 mol, 1 eq.) in DCM (15 ml), triethyl amine (0.9 ml, 0.00663 mol, 3 eq.) was added at RT. The reaction mixture was then stirred at RT for 20 min. The reaction mixture was cooled to 0° C. and boc-anhydride (0.578 g, 0.002654 mol, 1.2 eq.) was added slowly. The reaction mixture was stirred for 1 h at RT. The reaction mixture was diluted with DCM (70 ml) and washed by water (2×30 ml) and by brine (20 ml). The organic layer then was dried over Na2SO4, evaporated in reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 5% ethyl acetate/hexane).

3. A stirring solution of step-2 compound (0.7 gm, 0.002147 mol, 1 eq) in dry THF (28 ml) was cooled to −78° C. n-Buli (2M) solution (2.147 ml, 0.004294 mol, 2 eq) was added to the reaction mixture drop wise under argon atmosphere. The reaction mixture was then stirred over 45 min at −78° C. DMF (0.6636 ml, 0.008588 mol, 4 eq) was added to the reaction mixture at −78° C. The reaction mixture was slowly warmed to RT over 1 h. The reaction mixture was quenched by saturated ammonium chloride solution (10 ml). The aqueous part was extracted with ethyl acetate (2×30 ml). The combined organic part was washed with brine (20 ml). The organic layer then was dried over Na2SO4, evaporated in reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 10% ethyl acetate/hexane).

4. To a stirring solution of step-3 compound (1.0 g, 0.003636 mol, 1 eq.) in DCM (20 ml) was added methylamine hydrochloride (0.3558 g, 0.004363 mol, 1.2 eq) at RT and then the reaction mixture was stirred for 2 h at RT. Na(OAc)3BH (2.31 g, 0.0109 mol, 3 eq) was then added to the reaction mixture at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and organic part washed with water (2×20 ml) and brine (20 ml). The organic layer then was dried over Na2SO4, evaporated under reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 5% methanol/DCM) to desired product.

5. To a solution of step-4 product (0.45 g, 0.0015 mol) in water (9 ml), NaHCO3 (0.26 g, 0.003 mol, 2 eq.) was added. A solution of Fmoc-Cl (0.6 g, 0.00225 mol, 1.5 eq.) in dioxane (9 ml) was added at 5° C. and then the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The concentrated mass was diluted with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified using column chromatography (silica gel 100-200; 15% ethyl acetate/hexane) to give the desired product.

Synthesis of Amines A29-A39




1. To a stirring solution of the aldehyde (1.0 g, 0.003636 mol, 1 eq.) in DCM (20 ml) was added the according amine (for A29 and A37 the amine hydrochloride) (0.3558 g, 0.004363 mol, 1.2 eq) at RT and then the reaction mixture was stirred for 2 h at RT. Na(OAc)3BH (2.31 g, 0.0109 mol, 3 eq) was then added to the reaction mixture at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and the organic part was washed with water (2×20 ml) and brine (20 ml). The organic layer was dried with Na2SO4, evaporated in reduced pressure to get the crude material, which was purified by column chromatography (silica gel 100-200; 5% methanol/DCM).













No.
NR1R2
Name







A29




N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A30




N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A31




N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A32




N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4- tetrahydro-naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A33




N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A34




N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A35




N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A36




N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4- tetrahydro-naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A37




N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4- tetrahydro-naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A38




N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro- naphthalen-2-yl]-carbamic acid tert-butyl ester


 


A39




tert-butyl 6-((3,4-dihydroquinolin-1(2H)-yl)methyl)- 1,2,3,4-tetrahydronaphthalen-2-ylcarbamate









Synthesis of 2-Methyl-5-(piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride A48




1. tert-Butyl 4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxylate 2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (1.715 mmol, 1 eq.), tert-butyl 4-oxopiperidine-1-carboxylate (2.401 mmol, 1.4 eq.) and triethylamine (4.288 mmol, 2.5 eq.) were dissolved in dichloromethane (120 mmol, 70 eq.) and the resulting mixture was stirred for 5 min at RT under nitrogen. Subsequently sodium triacetoxy borohydride (2.401 mmol, 1.4 eq.) was added and the mixture stirred for 16 h at RT. Ethyl acetate (30 ml) and sat. aq. sodium hydrogen carbonate solution (30 ml) were added to the reaction mixture and it was stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol/DCM, 10:10:5+25% aq ammonia) to yield the title compound. Yield: 0.35 g (69%)

2. 2-Methyl-5-(piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride Tert-butyl 4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1-carboxylate (1.158 mmol, 1 eq.) was dissolved in Ethanol (7 ml) and acetyl chloride (5.76 mmol, 5 eq.) was added at 0° C. The mixture was stirred at RT for 16 h, at which time a light solid had precipitated. The suspension was diluted with diethyl ether (30 ml) and the solid was collected by filtration and washed with diethyl ether (50 ml). The title compound thus obtained was dried under high vacuum. Yield: 0.34 g (>99%)

Synthesis of 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine A49




1. Boc2O (818 mg, 3.75 mmol, 1.5 eq.) was added to a stirred solution of 2-(4-bromophenyl)ethanamine (500 mg, 2.5 mmol, 1.0 eq.) and TEA (1.5 ml, 7.5 mmol, 3.0 eq.) in DCM (25 ml) at 0° C. and resulting reaction mixture is stirred at 25° C. for 6 h. The reaction mixture was diluted with DCM (75 ml), washed with water (2×50 ml) and brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue triturated with hexanes to yield the desired product as an off white solid. Yield: 100% (750 mg, 2.5 mmol)

2. A mixture of tert-butyl 4-bromophenethylcarbamate (750 mg, 2.5 mmol, 1.0 eq.) and Zn(CN)2 (439 mg, 3.75 mmol, 1.5 eq.) in dry DMF (15 ml) was degassed with argon for 15 min. Xanthphos (290 mg, 0.5 mmol, 0.2 eq.) and Pd2(dba)3 (229 mg, 0.25 mmol, 0.1 eq.) were added to the reaction mixture and it was heated to 100° C. for 18 h. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (neutral alumina, 10% ethyl acetate in hexanes) to yield the desired product as a reddish solid. Yield: 73% (450 mg, 1.83 mmol)

3. P2S5 (48 mg) was added to a mixture of tert-butyl 4-cyanophenethylcarbamate (450 mg, 1.83 mmol, 1.0 eq.) and freshly distilled ethylenediamine (2.4 ml, 33.85 mmol, 18.5 eq.) and the resulting reaction mixture was heated to 120° C. for 4 h. The reaction mixture was cooled to 25° C. and poured into ice-cold water (20 ml). It was then extracted with DCM (40 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure to yield the desired product. Yield: 94% (500 mg, 1.73 mmol)

4. TFA (1 ml) was added to a solution of tert-butyl 4-(4,5-dihydro-1H-imidazol-2-yl)phenethylcarbamate (214 mg, 0.74 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was directly used in the next step.

Synthesis of amine (R)-6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine A50




1. A solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (5.0 g, 26.3 mmol, 1.0 eq.) in MeOH (50 ml) was saturated with HCl gas and then heated at reflux for 16 h. The reaction mixture was concentrated and the residue was diluted with DCM (250 ml). The organic layer was washed with saturated NaHCO3 solution (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to yield the desired product. Yield: 95% (5.1 g, 25.0 mmol)

2. A 1 M solution of (R)-2-methyl-CBS-oxazaborolidine (1.25 ml, 1.25 mmol, 0.05 eq.) in toluene was diluted with toluene (100 ml) and cooled to −10° C. BH3.DMS (2.9 ml, 30 mmol, 1.2 eq.) was added dropwise, followed by a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (5.1 g, 25 mmol) in THF (20 ml), which was also added dropwise. The bath temperature was kept at −10° C. throughout the addition. The reaction mixture was stirred for 1 h, at which point methanol (40 ml) was added at the same temperature. The reaction mixture was slowly brought to RT and stirred for 16 h. The mixture was then concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate (200 ml). The organic layer was washed with 0.1 N HCl (100 ml), 5% NaHCO3 solution (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the title compound as a light yellow semi-solid. Yield: 57% (2.95 g, 14.3 mmol)

3. DPPA (4.61 ml, 21.4 mmol, 1.5 eq.) and DBU (3.2 ml, 21.4 mmol, 1.5 eq.) were added dropwise to a solution of (S)-methyl 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.95 g, 14.3 mmol, 1.0 eq.) in toluene (70 ml) at 0° C. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (70 ml) and washed with 0.1 N HCl (70 ml), 5% NaHCO3 (70 ml) and brine (70 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to yield the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the title compound as a yellow semi solid. Yield: 97% (3.22 g, 13.9 mmol)

4. A solution of (R)-methyl 5-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.22 g, 13.9 mmol, 1.0 eq.) in THF (50 ml) was added dropwise to a suspension of LAH (1.06, 3.46 mmol, 2.0 eq.) in THF (50 ml) at 0° C. and the reaction mixture was stirred at same temperature for 30 min. and then for 16 h at RT. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with THF—H2O (9:1, 10 ml) and filtered through celite. The filtrate was concentrated under reduced pressure to give the desired compound as a yellow semi-solid which was used in the next step without further purification. Yield: 99.5% (2.45 g, 13.84 mmol)

5. Boc-anhydride (10.2 ml, 46.68 mmol, 1.5 eq.) was added to a solution of (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (6.9 g, 38.9 mmol, 1.0 eq.) in DCM (150 ml) at 0° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then diluted with DCM (150 ml) and washed with water (150 ml) and brine (150 ml). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (silica gel; 30% ethyl acetate/hexanes) to get the desired compound as a white solid. Yield: 65% (7.0 g, 25.27 mmol)

6. Methanesulfonyl chloride (1.7 ml, 21.66 mmol, 2.0 eq.) was added dropwise to a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (3.0 g, 10.83 mmol, 1.0 eq.) and TEA (5.27 ml, 37.9 mmol, 3.5 eq.) in DCM (100 ml) at 0° C. and the resulting reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with DCM (100 ml) and washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to get the crude product which was used in the next step without further purification. Yield: 73% (2.8 g, 7.89 mmol, crude)

7. A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (2.8 g, 7.89 mmol, 1.0 eq.), tert-butyl amine (8.4 ml, 78.9 mmol, 10.0 eq.) and K2CO3 (2.72 g, 19.72 mmol, 2.5 eq.) in THF (80 ml) was heated at reflux for 16 h. After completion of the reaction (monitored by TLC) the solvent was evaporated under reduced pressure and the residue was diluted with water (80 ml), extracted with DCM (100 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the title compound as light yellow semi-solid. Yield: 26% (700 mg, 2.11 mmol)

8. TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (300 mg, 0.898 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 4 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to get the desired product which is used in the next step.

Synthesis N-Methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine A51




1. 1N NaOH solution (40 ml) was added to a suspension of 6-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (15.0 g, 79.0 mmol, 1.0 eq.) in dioxane-water (4:1, 100 ml) and then (Boc)2O (25.83 ml, 118.5 mmol, 1.5 eq.) was added dropwise to the reaction mixture at 0° C. and it was stirred at RT for 4 h. Dioxane was evaporated under reduced pressure and the residual aqueous layer was diluted with water (200 ml) and acidified with KHSO4 solution. The solid product was collected by filtration and dried to yield the desired compound as a white solid. Yield: 96% (22.0 g, 75.6 mmol)

2. To a suspension of 6-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (18.0 g, 61.86 mmol, 1.0 eq.) in THF (200 ml) was added HATU (23.5 g, 61.86 mmol, 1.0 eq.) and DIPEA (30.62 ml, 185.6 mmol, 3.0 eq.) at 0° C. and the reaction mixture was allowed to stir for 15 min. Piperidine (18.3 ml, 185.6 mmol, 3.0 eq.) was added dropwise to the reaction mixture at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (300 ml), washed with sat. NaHCO3 solution (200 ml), sat. NH4Cl solution (200 ml), water (200 ml) and brine (200 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; 1-3% MeOH/DCM) to yield the desired product as a brownish sticky solid. Yield: 90% (19.93 g, 55.67 mmol)

3. TFA (25 ml) was added to a cooled (0° C.) solution of tert-butyl 6-(piperidine-1-carbonyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (8.33 g, 23.26 mmol, 1.0 eq.) in DCM (25 ml) and the reaction mixture was stirred at RT for 4 h. After completion of the reaction (monitored by TLC) the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH (225 ml), basified with Amberlyst (A-21) ion exchange resin up to pH≈9-10 and filtered. The filtrate was concentrated to dryness to obtain the desired product as a light yellow solid which was employed in the next step.

4. (6-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)(piperidin-1-yl)methanone (23.26 mmol, 1.0 eq.) was added portionwise to a stirred suspension of LAH (4.42 g, 116.3 mmol, 5.0 eq.) in dry THF (60 ml) under a N2 atmosphere at 0° C. and the resulting reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a THF-water mixture (9:1, 60 ml) and the diluted with THF (300 ml). 10% NaOH solution (12 ml) was added to the mixture at −10° C. and it was stirred at RT for 2 h. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness to yield the desired product as a light brown sticky oil. Yield: 90% (5.10 g, 20.9 mmol)

5. (Boc)2O (6.54 ml, 30.0 mmol, 1.5 eq.) was added dropwise to a mixture of 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (4.88 g, 20.0 mmol, 1.0 eq.) and TEA (5.55 ml, 40.0 mmol, 2.0 eq.) in DCM (50 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with DCM (50 ml), washed with sat. NH4Cl solution (2×50 ml) and brine (50 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to yield the crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to obtain the desired product as an off white solid. Yield: 80% (5.5 g, 15.98 mmol)

6. A solution of tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (500 mg, 1.45 mmol, 1.0 eq.) in THF (5 ml) was added dropwise to a stirred suspension of LAH (552 mg, 14.5 mmol, 10.0 eq.) in THF (10 ml) at 0° C. After complete addition, the reaction mixture was warmed to RT and stirred for 10 min. Then the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to RT and quenched with THF-water (9:1, 4.5 ml) and then 20% NaOH solution was added at 0° C. The reaction mixture was diluted with THF (50 ml) and stirred at RT for 1 h. The mixture was then filtered through celite and the filtrate was concentrated to dryness to yield desired product which was employed in the next step without further purification. Yield: 85% (320 mg, 1.24 mmol)

Synthesis (R)-6-((4-Fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine A52




1. A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (2.0 g, 5.633 mmol, 1.0 eq.), 4-fluoropiperidine.HCl (0.78 g, 5.633 mmol, 1.0 eq.) and K2CO3 (2.33 g, 16.9 mmol, 3.0 eq.) in THF (25 ml) was heated at reflux for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml), washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 40% ethyl acetate/hexanes) to yield the title compound as a light yellow solid. Yield: 60% (1.22 g, 3.37 mmol)

2. TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (325 mg, 0.898 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 4 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was employed in the next step.

Synthesis (R)-6-((2,2,2-Trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine A53




1. A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (400 mg, 1.13 mmol, 1.0 eq.), 2,2,2-trifluoroethanamine (360 μl, 4.52 mmol, 4.0 eq.) and K2CO3 (470 mg, 3.39 mmol, 3.0 eq.) in THF (10 ml) was heated at 100° C. in sealed tube for 16 h. After completion of the reaction (monitored by TLC), the mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (20 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid. Yield: 37% (150 mg, 0.412 mmol)

2. (R)-6-((2,2,2-Trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((2,2,2-trifluoroethylamino)-methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (230 mg, 0.64 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was used in the next step.

Synthesis of (R)—N-(4-(1-Aminoethyl)benzyl)-2-methylpropan-2-amine A54




1. Boc-anhydride (2.2 ml, 11.1 mmol, 1.2 eq.) was added to a solution of (R)-methyl 4-(1-aminoethyl)benzoate hydrochloride (2.0 g, 9.2 mmol, 1.0 eq.) and TEA (2.4 ml, 18.4 mmol, 2.0 eq.) in DCM (50 ml) at 0° C. and the reaction mixture was stirred at RT for 16 h. The mixture was diluted with DCM (75 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the desired compound as a white solid. Yield: 64% (2.0 g, 7.16 mmol)

2. A solution of (R)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate (2.0 g, 7.16 mmol, 1.0 eq.) in THF (50 ml) was added dropwise to a suspension of LAH (326 mg, 8.6 mmol, 1.2 eq.) in THF (50 ml) at 0° C. and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by LCMS) the reaction mixture was quenched with THF—H2O (9:1, 20 ml) and filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 30% ethyl acetate/hexanes) to yield the title compound as a yellow semi solid. Yield: 83% (1.5 g, 5.97 mmol)

3. Methanesulfonyl chloride (360 μl, 4.78 mmol, 1.2 eq.) was added to a solution of (R)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate (1.0 g, 3.98 mmol, 1.0 eq.) and TEA (1 ml, 7.96 mmol, 2.0 eq.) in DCM (30 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM (50 ml) and washed with water (20 ml) and brine (20 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to yield the crude product which was used in the next step without further purification.

4. A mixture of (R)-4-(1-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate (1.0 g, 3.03 mmol, 1.0 eq.), tert-butyl amine (1.6 ml, 15.15 mmol, 5.0 eq.) and K2CO3 (1.04 g, 7.59 mmol, 2.5 eq.) in THF (30 ml) was heated at reflux for 20 h. After completion of the reaction (monitored by TLC) the solvent was evaporated under reduced pressure and the residue was diluted with water (50 ml), extracted with DCM (100 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (neutral alumina; 0.5% MeOH/DCM) to yield the title compound as a light yellow sticky solid. Yield: 32% (300 mg, 0.98 mmol)

5. TFA (1 ml) was added to a solution of (R)-tert-butyl 1-(4-((tert-butylamino)methyl)-phenyl)ethylcarbamate (370 mg, 1.2 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was used in the next step.

Synthesis of 5-(piperidin-1-ylmethyl)-2,3-dihydro-1H-inden-2-amine A56




1. Boc-anhydride (1.8 ml, 8.23 mmol, 1.2 eq.) was added drop wise to a mixture the amine (2.0 g, 6.85 mmol, 1.0 eq.) and DIPEA (3.3 ml, 17.12 mmol, 2.5 eq.) in DCM (20 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with DCM (100 ml) and washed with water (60 ml), brine (60 ml), dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to get the Boc-protected compound, which was used in the next step without further purification. Yield: 94% (2.0 g, 6.41 mmol).

2. BuLi (1.5 M, 10.7 ml, 16.05 mmol, 2.5 eq.) was added drop wise to a stirred solution of the Boc-protected compound (2.0 g, 6.41 mmol, 1.0 eq.) in THF (80 ml) at −78° C. and the reaction mixture was stirred for 30 min at same temperature. Then DMF (2.5 ml, 32.1 mmol, 5.0 eq.) was added to the reaction mixture at −78° C. The reaction mixture was slowly warmed to RT and stirred for 15 min. After completion of reaction (monitored by TLC), the mixture was quenched with saturated NH4Cl (50 ml) and diluted with ethyl acetate (100 ml). Organic layer is separated and dried over Na2SO4. the solvent was evaporated under reduced pressure to get crude product which was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to get pure aldehyde as a white solid. Yield: 60% (1.0 g, 3.83 mmol).

3. A mixture of the aldehyde (1.0 g, 3.83 mmol, 1.0 eq.) and piperidine (0.52 ml, 5.36 mmol, 1.4 eq.) in dry DCM (100 ml) was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and then Na(OAc)3BH (1.21 g, 5.74 mmol, 1.5 eq.) was added portion-wise and stirred at RT for 14 h. The reaction mixture was diluted with DCM (150 ml) and washed with water (2×70 ml), brine (2×70 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and residue was purified by column chromatography (silica gel; 2% MeOH/DCM) to get desired product as alight yellow sticky solid. Yield: 35% (450 mg, 1.36 mmol).

4. TFA (1 ml) was added to a solution of the diamine (248 mg, 0.75 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 1 h. The solvent was evaporated under reduced pressure and residue was azeotroped twice with toluene to get desired amine which was used for the next step without further purification.



SYNTHESIS OF EXAMPLES 1-48
Example 1
2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone




Acid S1 (85 mg, 0.2 mmol) was dissolved in DCM (5 ml) and cooled to 0° C. 1-(1-Methylpiperidin-4-yl)piperazine A1 (45 mg, 0.25 mmol), DIPEA (0.043 ml, 0.25 mmol), EDCl (47 mg, 0.25 mmol) and HOAt (3 mg, 0.02 mmol) were added and the reaction batch was stirred overnight at RT. Then the solvent was removed in a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, heptane/ethyl acetate, 4:1→DCM/7 M NH3 in MeOH, 95:5).
m/z 544.7 [MH]+.
Example 2
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone




The reaction was performed under an N2 atmosphere. A solution of acid S3 (0.42 mmol), 1-(1-methylpiperidin-4-yl)piperazine A1 (92 mg, 0.5 mmol) and HOAt (5.7 mg, 0.042 mmol) in DCM (5 ml) was cooled to 0° C. EDCl (89 mg, 0.46 mmol) was added and the reaction batch was stirred for 1 h at 0° C. and overnight at RT. Then further 1-(1-methylpiperidin-4-yl)piperazine A1 (38 mg, 0.21 mmol), EDCl (40 mg, 0.21 mmol) and HOAt (5.7 mg, 0.042 mmol) were added and the mixture was stirred for 3 days at RT. Then the solvent was removed in a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, DCM/7 M NH3 in MeOH, 98:2→95:5). m/z=574.8 [MH]+
Example 3
1-(7-Cyclopropyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)ethanone




Acid S1 (70 mg, 0.185 mmol) was dissolved in DCM (5 ml) and cooled to 0° C. Amine A2 (36.9 mg, 0.218 mmol), DIPEA (0.061 ml, 0.37 mmol), EDCl (53 mg, 0.277 mmol) and HOAt (2.5 mg, 0.018 mmol) were added and the reaction batch was stirred for 3 h at RT. The reaction batch was washed with HCl (0.5 M, 20 ml) and saturated NaCl solution. The organic phase was dried over Na2SO4 and concentrated to small volume. The crude product obtained was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 99:1→98:2) and then by preparative HPLC. m/z=527.7 [MH]+
Example 4
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone




The reaction was performed under an N2 atmosphere. A solution of acid S3 (90 mg, 0.22 mmol) and amine A3 (58 mg, 0.264 mmol) in DCM (10 ml) was cooled to 0° C. HOAt (3 mg, 0.022 mmol) and EDCl (51 mg, 0.26 mmol) were added and the reaction batch was stirred for 1 h at 0° C. and then for 1 h at RT. DIPEA (0.058 ml, 0.331 mmol) was added and the mixture was stirred overnight at RT. Then the solvent was removed in a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, DCM/7 M NH3 in methanol, 98:2→97:3). m/z=608.8 [MH]+
Example 5
1-(4-(Pyridin-4-yloxy)piperidin-1-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone




The reaction was performed under an N2 atmosphere. A solution of acid S4 (0.27 g, 0.645 mmol), 4-(piperidin-4-yloxy)pyridine dihydrochloride A4 (243 mg, 0.968 mmol) and DIPEA (0.338 ml, 1.935 mmol) in DCM (10 ml) was cooled to 0° C. HOAt (9 mg, 0.066 mmol) and EDCl (186 mg, 0.97 mmol) were added and the reaction batch was stirred overnight at RT. Then the solvent was removed in a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, DCM/7 M NH3 in MeOH, 99:1). m/z=579.6 [MH]+
Example 8
2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide




DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid S2 (0.2325 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine A5 (0.2325 mmol, 1.0 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 58%; m/z=627.4 [MH]+
Example 9
2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N—((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide




DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-acetic acid S2 (0.195 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-amine A6 (0.234 mmol, 1.2 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated NaCl solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 55%; m/z=627.4 [MH]+
Example 10
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethanone




DIPEA (9 eq.), HOBt (3 eq.) and EDCl (3 eq.) were added to a solution of acid S3 (1 eq.) in DCM (5 ml) at 0° C. and the mixture was stirred for 10 min. Then 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane A7 (1.2 eq.) was added and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with DCM and extracted with aqueous NH4Cl and aqueous NaHCO3 solution. The crude product was concentrated to small volume and purified by column chromatography (alox). Yield: 30%; m/z=622.4 [MH]+
Example 11
1-(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone




A solution of acid S4 (160 mg, 0.382 mmol), amine A7 (128 mg, 0.421 mmol), DIPEA (0.2 ml, 1.147 mmol) and EDCl (88 mg, 0.459 mmol) in DCM (5 ml) was cooled to 0° C. and mixed with HOAt (5.21 mg, 0.038 mmol). The reaction batch was heated to RT and stirred at this temperature for 16 h. The solvent was removed in a rotary evaporator and the crude product was purified twice by column chromatography (silica gel, DCM/(7 M NH3 in MeOH, 99:1→98:2→95:5). m/z=632.7 [MH]+
Example 14
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone




A solution of acid S5 (200 mg, 0.501 mmol), amine A3 (175 mg, 0.602 mmol), DIPEA (0.219 ml, 1.254 mmol) and EDCl (106 mg, 0.552 mmol) in dry DMF (5 ml) was stirred at 0° C. and mixed with HOAt (6.83 mg, 0.050 mmol). The reaction batch was heated to RT and stirred at this temperature for 16 h. The solvent was removed in a rotary evaporator and the crude product was purified by column chromatography (silica gel, DCM/(7 M NH3 in MeOH, 99:1→98:2→95:5). m/z=599.2 [MH]+
Example 17
N-(3,3-Dimethylpiperidin-4-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide




1. Amine A11 (159 mg, 633 μmol), HOAt (14.39 mg, 106 μmol) and EDCl (152 mg, 793 μmol) were added to a solution of acid S1 (200 mg, 528 μmol) in DCM (5 ml). After 3 h further amine A11 (108 mg, 430 μmol) was added and the mixture was stirred overnight at RT. The solvent was then siphoned off completely and the crude product obtained was purified by column chromatography (silica gel, DCM/(7 M NH3 in MeOH), 99:1).

2. A solution of the product from stage 1 (213 mg, 368 μmol) in dry THF was first rinsed with N2 for 10 min, then Pd/C (39.2 mg, 37 μmol) was added and the solution was rinsed again with N2 for 10 min. The reaction batch was stirred overnight at RT under an H2 atmosphere (9 bar) and then filtered over diatomaceous earth. The diatomaceous earth was washed repeatedly with DCM. The combined organic phases were concentrated to small volume and the product was purified by preparative HPLC. The solvent was removed by freeze drying. m/z=489.7 [MH]+

Example 18
2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)-ethanone




Amine A3 (107 mg, 0.49 mmol) and HOAt (12.2 mg, 0.09 mmol) were added to a solution of acid S1 (170 mg, 0.45 mmol) in DCM (5 ml), followed by EDCl (129 mg, 0.67 mmol). The reaction mixture was stirred for 3 h at RT and then concentrated to dryness. The product was purified by preparative HPLC. The solvent was removed by freeze drying. m/z=578.7 [MH]+
Example 19
2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(piperidin-1-yl)ethanone




Carboxylic acid S6 (400 mg, 0.947 mmol) was suspended in THF (10 ml) and TEA (0.15 ml, 1.136 mmol), EDCl (181.5 mg, 0.947 mmol) and HOBt (150 mg, 0.947 mmol) were added in succession. The reaction batch was stirred for 1 h at RT and then piperidine A9 (0.947 mmol) was added. The reaction mixture was stirred for a further hour and then diluted with ethyl acetate (40 ml). The organic phase was washed successively with water and saturated NaCl solution, dried over Na2SO4 and concentrated to small volume. The crude product was processed by column chromatography. m/z=490.9 [MH]+
Example 22
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2,8-diazaspiro[4.5]decan-8-yl)ethanone




1. To an ice-cold solution of acid S3 (0.612 mmol) and DIPEA (1.3 mmol) in THF (2.5 ml) was added HATU (0.612 mmol) and the reaction mixture was stirred for 15 min. Then a solution of amine A12 (0.735 mmol) in THF (1 ml) was added slowly and allowed to stir at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography using 1-5% MeOH in DCM as eluent. Yield: 50%

2. To a solution of step-1 product (180 mg) in MeOH (5 ml) was added 1N NaOH solution (5 ml) at 0° C. Then the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography on neutral alumina using 1-10% MeOH in DCM as eluent. m/z=530.7 [MH]+

Example 23
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-((1R,3S,5S)-3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanone




DIPEA (3.96 mmol) and HATU (1.49 mmol) were added to a cooled (0° C.) solution of S3 (0.99 mmol) in THF (10 ml) and reaction mixture was stirred for 15 min. A solution of amine A13 (0.99 mmol) in THF (5 ml) was added drop wise and the reaction mixture was stirred at 25° C. for 14 h. the solvent was evaporated under reduced pressure and the residue was dissolved in DCM (50 ml), washed with saturated NH4Cl solution (20 ml), saturated NaHCO3 solution (20 ml), brine (20 ml). the organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography to yield the desired compound. m/z=594.7 [MH]+
Example 24
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)ethanone




To a solution of acid S3 (0.74 mmol) in THF (15 ml) was added DIPEA (2.96 mmol) at 0° C. followed by the addition of HATU (1.1 mmol). The resultant solution was allowed to stir at RT for 15 min. It was again cool to 0° C. and a solution of amine A14 (0.88 mmol) in THF (5 ml) was added. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, saturated sodium bicarbonate and finally with brine. The organic layer was dried over Na2SO4 and evaporated to dryness under reduced pressure to get the crude product which was purified by neutral alumina column chromatography to obtain desired product.
Example 25
2-(2-(4-chloro-2,5-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide




The carboxylic acid S7 (0.486 mmol) was dissolved in DCM (5 ml) and cooled to 0° C. followed by the addition of DIPEA (1.215 mmol), EDCl (0.729 mmol) and HOAt (0.486 mmol) and then reaction mixture was stirred at 25° C. for 15 min. The reaction mixture was again cooled down to 0° C. and a solution of amine A5 (0.486 mmol) in DCM (5 ml) was added. Reaction mixture was stirred at 25° C. for 16 h and then diluted with DCM. Reaction mixture was successively washed with sodium bicarbonate (10 ml), ammonium chloride solution (10 ml), water (10 ml) and brine (10 ml). Organic layer is dried over Na2SO4 and concentrated to dryness to afford crude product which is purified by silica gel column chromatography (3% methanol-DCM) to afford the product as white solid. m/z=609.4 [MH+]
Example 31
N-(6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazin-1-yl)acetamide




To a cooled (0° C.) suspension of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S2) (310 mg, 0.77 mmol, 1.0 eq.) in DCM (20 ml) was added HATU (600 mg, 1.54 mmol, 2 eq.) and DIPEA (0.4 ml, 2.31 mmol, 3 eq.) and the reaction mixture was allowed to stir for 30 min. Finally, 6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A15) (180 mg, 0.77 mmol, 1.0 eq.) was added and the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (100 ml) and successively washed with ammonium chloride solution (50 ml), sodium bicarbonate solution (50 ml), water (10 ml) and brine (10 ml). The organics were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 6% MeOH/DCM) to yield the pure title compound as a white solid. Yield: 34% (160 mg, 0.26 mmol); MS, Rt=3.6 min; m/z=615.1 [MH]+
The synthesis of further example compounds took place by the methods already described. The following Table 3 shows the method used to prepare each of these further compounds.



















As per



Example



example
m/z


no.
Acid
Amine
Product
no.
MH+




















6
S5 
A4 * 2 HCl



 2-((2-(2-Chloro-6-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1- yl)ethanone
5
560.1


 


7
S3 
A8



 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)-N-methyl-N-(2-(1-pyridin-4- yl)piperidin-4-yl)ethyl)acetamide
4 (silica gel, DCM/7 M NH3 in methanol, 98:2)
610.8


 


12
S4 
A8



 N-Methyl-N-(2-(1-(pyridin-4-yl)piperidin-4- yl)ethyl)-2-((2-(2- (trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)acetamide
4 (silica gel, DCM/7 M NH3 in methanol, 99:1 → 98:2 → 95:5).
620.7


 


13
S3 
A4 * 2 HCl



 2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1- yl)ethanone
5
569.7


 


15
S5 
A7



 2-((2-(2-Chloro-6-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)-1-(9-(pyridin-4-yl)-3,9- diazaspiro[5.5]undecan-3-yl)ethanone
14
613.2


 


16
S5 
A8



 2-((2-(2-Chloro-6-methylphenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)-N-methyl-N-(2-(1-(pyridin-4- yl)piperidin-4-yl)ethyl)acetamide
4 (silica gel, DCM/7 M NH3 in methanol, 99:1 → 98:2 → 95:5).
601.2


 


20
S6 
A10



 2-(2-(2-Chloro-4- (trifluoromethyl)phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(3,4- dihydroisoquinolin-2(1H)-yl)ethanone
19
539.0


 


21
S4 
A3 * 2 HCl



 1-(2-(Pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8- yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1- yl)methoxy)ethanone
11
617.7


 


26
S8 
A5



 2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6- (piperidin-1-ylmethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)acetamide
25
615.3


 


27
S9 
A5



 2-(2-(phenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6- (piperidin-1-ylmethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)acetamide
25
547.4


 


28
S10
A5



 2-(2-(2,3-dichlorophenylsulfonyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6- (piperidin-1-ylmethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)acetamide
25
615.3


 


29
S11
A5



 N-(6-(piperidin-1-ylmethyl)-1,2,3,4- tetrahydronaphthalen-2-yl)-2-(2-tosyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-1- yl)acetamide
25
561.4


 


30
S12
A5



 N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro- naphthalen-2-yl)-2-(2-(3-(trifluoromethyl)- phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a]pyrazin-1-yl)acetamide
25
615.4









Synthesis of Examples 32-40




To a solution of 2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetic acid (S-3) (0.367 mmol, 1 eq.) and N-ethyl-diisopropylamine (0.734 mmol, 2 eq.) in DCM (7 ml) were added N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (0.44 mmol, 1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.073 mmol, 0.2 eq.) at 0° C. and the resulting mixture was stirred for 15 min at RT. The solution was cooled to 0° C. and the Amine (1 eq., see table) was added. The mixture was stirred at RT for 16 h. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate and extracted with 10% aq. ammonium chloride solution (1×), sat. aq. sodium hydrogen carbonate solution (1×) and sat. aq. NaCl-solution (1×). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/ethanol/25% aq ammonia (1000:100:5), ethyl acetate/methanol/25% aq ammonia (100:100:1) or ethyl acetate/cyclohexane (100:400).

    (i) In the case of amine hydrochloride salts the amount of N-ethyl-diisopropylamine employed was adjusted according to the stoichiometry of the hydrochloride salts.

















Example


Amine

Analysis


Nr.
Structure
Name
Structure
Yield
(LC/MS)[




















32




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-N-[1- [5-(trifluoromethyl)-pyridin-2-yl]- piperidin-4-yl]-acetamide




60% (0.14 g)
Rt = 4.8 min; m/z = 636.31 [MH]+


 


33




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-N-[1- [5-(trifluoromethyl)-pyridin-2-yl]- pyrrolidin-3-yl]-acetamide




35% (0.08 g)
Rt = 4.1 min; m/z = 622.0 [MH]+


 


34




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-1-(4- pyridin-4-yl-piperidin-1-yl)- ethanone




69% (0.14 g)
Rt = 3.0 min; m/z = 553.1 [MH]+


 


35




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-1-[4- (pyridin-4-yl-methyl)-piperidin- 1-yl]-ethanone




72% (0.15 g)
Rt = 3.1 min; m/z = 567.1 [MH]+


 


36




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-N-(1- pyridin-4-yl-piperidin-4-yl)- acetamide




77% (0.16 g)
Rt = 3.3 min; m/z = 568.1 [MH]+


 


37




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-1-[3- [(4-methyl-piperazin-1-yl)- methyl]-pyrrolidin-1-yl]- ethanone




52% (0.11 g)
Rt = 2.7 min; m/z = 574.1 [MH]+


 


38




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-1-(3- pyridin-4-yloxy-pyrrolidin-1-yl)- ethanone




74% 0.15 g)
Rt = 2.9 min; m/z = 555.1 [MH]+


 


39




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-N- methyl-N-(1-pyridin-4-yl- piperidin-4-yl)-acetamide




75% (0.16 g)
Rt = 3.2 min; m/z = 582.1 [MH]+


 


40




2-[[2-[(4-Methoxy-2,6-dimethyl- phenyl)sulfonyl]-1,2,3,4- tetrahydro-pyrrolo[1,2- a]pyrazin-1-yl]-methoxy]-1-[4- (3-methyl-3,6- diazabicyclo[2.2.1]heptan-6-yl)- piperidin-1-yl]-ethanone




23% (0.05 g)
Rt 2.4 min; m/z 586.1 [MH]+









Example 41
N-[2-[4-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide




HATU (563 mg, 1.48 mmol, 2.0 eq.) was added to a mixture of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S-2) (297 mg, 0.74 mmol, 1.0 eq.), 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine (A49) (140 mg, 0.74 mmol, 1.0 eq.), and DIPEA (0.39 ml, 2.22 mmol, 3.0 eq.) in THF (10 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM (30 ml) and washed with saturated ammonium chloride solution (15 ml), saturated sodium bicarbonate solution (15 ml), water (15 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product which was purified by column chromatography (neutral alumina; 1% MeOH/DCM) to afford the desired product as an off-white solid. Yield: 35% (140 mg, 0.245 mmol); MS, Rt=3.3 min; m/z=572.5 [MH]+
Example 42
N-[(1R)-6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide




To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (0.47 ml, 2.694 mmol, 3.0 eq.) and HATU (410 mg, 1.08 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A50) (0.898 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 1.5% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 19% (94 mg, 0.171 mmol); MS, Rt=3.2 min; m/z=549.1 [MH]+
Example 43
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide




To a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazin-1-yl)acetic acid (S2) (200 mg, 0.5 mmol, 1.0 eq.) in THF (6 ml) were added DIPEA (300 μl, 2.0 mmol, 4.0 eq.) and HATU (190 mg, 0.5 mmol, 1.0 eq.) at 0° C. and the resulting mixture was stirred for 15 min at same temperature. A solution of N-methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A51) (0.6 mmol, 1.2 eq.) in THF (4 ml) was added to the reaction mixture and it was allowed to stir at RT for 16 h. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 2-4% MeOH/DCM) to yield the desired product as a white solid. Yield: 47% (150 mg, 0.234 mmol); MS, Rt=3.7 min; m/z=641.1 [MH]+
Example 44
N-[(1R)-6-[(4-Fluoro-piperidin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide




DIPEA (630 μl, 3.592 mmol, 4.0 eq.) was added to a stirred solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in DCM (15 ml), followed by EDCl (260 mg, 1.347 mmol, 1.5 eq.) and HOBT (183 mg, 1.347 mmol, 1.5 eq.) which were added at 0° C. The reaction mixture was allowed to stir for 30 min. A solution of R)-6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A52) (0.898 mmol, 1.0 eq.) in DCM (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (50 ml), sat. NaHCO3 solution (50 ml), water (50 ml) and brine (50 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the desired compound as an off white solid. Yield: 38% (197 mg, 0.34 mmol); MS, Rt=3.2 min; m/z=579.1 [M H]+
Example 45
2-(2-Tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N—((R)-6-((2,2,2-trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide




To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (214 mg, 0.64 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (340 μl, 1.92 mmol, 3.0 eq.) and HATU (292 mg, 0.77 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((2,2,2-trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A53) (0.64 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 0.7% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 22% (80 mg, 0.14 mmol); MS, Rt=3.2 min; m/z=575.0 [MH]+
Example 46
N-[(1R)-1-[4-[(tert-Butylamino)-methyl]-phenyl]-ethyl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide




To a suspension of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (405 mg, 1.2 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (1.0 ml, 6.0 mmol, 5.0 eq.) and HATU (547 mg, 1.4 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)—N-(4-(1-aminoethyl)-benzyl)-2-methylpropan-2-amine (A54) (1.2 mmol, 1.0 eq.) in THF (3 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (70 ml) and washed with sat. NH4Cl solution (25 ml), sat. NaHCO3 solution (25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 3% MeOH/DCM) to yield the desired product as a light brown solid. Yield: 29% (180 mg, 0.334 mmol); MS, Rt=2.9 min; m/z=523.1 [M H]+
Example 47
2-(2-(3-chlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide




To a solution of acid S15 (300 mg, 0.847 mmol, 1.0 eq.) in THF (8 ml) were added DIPEA (0.5 ml, 2.542 mmol, 3.0 eq.) and HATU (642 mg, 1.695 mmol, 2.0 eq.) at 0° C. and stirred for 15 min at same temperature. A solution of amine A5 (1.27 mmol, 1.2 eq.) in THF (5 ml) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with sat. NH4Cl solution (10 ml), sat. NaHCO3 solution (10 ml), water (10 ml), brine (10 ml). Organic layer is dried over Na2SO4 and concentrated under reduced pressure to get crude product which is purified by column chromatography (silica gel; 2-4% MeOH/DCM) to yield desired product as white solid. Yield: 30% (150 mg, 0.258 mmol); MS, Rt=3.2 min; m/z=581.0 [MH]+
Example 48
2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazin-1-yl)-N-(5-(piperidin-1-ylmethyl)-2,3-dihydro-1H-inden-2-yl)-acetamide




To a suspension of acid S2 (250 mg, 0.625 mmol, 1.0 eq.) in DCM (5 ml) were added DIPEA (250 μl, 1.25 mmol, 2.0 eq.) and HATU (332 mg, 0.875 mmol, 1.4 eq.) at 0° C. and stirred for 15 min at same temperature. A solution of amine A56 (0.75 mmol, 1.2 eq.) in DCM (3 ml) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was diluted with DCM (75 ml) and washed with sat. NH4Cl solution (30 ml), sat. NaHCO3 solution (30 ml), water (30 ml), brine (30 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude product which was purified by column chromatography (neutral alumina; 0.5% MeOH/DCM) to yield desired product as off white solid. Yield: 31% (120 mg, 0.196 mmol); MS, Rt=3.4 min; m/z=613.0 [MH]+

Synthesis of the examples 49-132 (Method A)




1. The Boc-protected amine (A17-A27 or A29-A39) (0.00019 mol) was treated with TFA (2 ml) in DCM (8 ml) at 0° C. and the resulting reaction mixture was allowed to stir at 25° C. for 4 h (monitored by TLC). The solvent was completely evaporated, dried properly to remove traces of TFA and the residue was directly used in library synthesis.

2. To a solution of acid Building Block (0.00023 mol, 1.2 eq.) in DCM (4 ml) was added EDCl.HCl (0.00046 mol, 2 eqv), HOBt (0.00023 mol) at 0° C. and reaction mixture was stirred at the same temperature for another 15 mins. In another round-bottom flask, the Boc-deprotected amine BB (0.00019 mol, 1 eqv) in DCM (2 ml) was cooled in ice bath, treated with DIPEA (0.00069 mol, 3 eqv) and was added to the reaction mixture at 0° C. Reaction mixture was stirred at RT for 16 h and diluted with DCM. The organic layer was successively washed with aqueous ammonium chloride, sodium bicarbonate and brine and finally dried over Na2SO4. Evaporation of organic layer under reduced pressure gave the crude product which was purified by prep.HPLC using aqueous ammonia method

Synthesis of the examples 133-140 (Method B)







1. The Boc-protected amine A16 or A28 (0.00019 mol) was treated with TFA (2 ml) in DCM (8 ml) at 0° C. and the resulting reaction mixture was allowed to stir at 25° C. for 4 h (monitored by TLC). The solvent was completely evaporated, dried properly to remove traces of TFA and the residue was directly used in library synthesis.

2. To a solution of acid (0.00023 mol, 1.2 eq.) in DCM (4 ml) was added EDCl.HCl (0.00046 mol, 2 eqv), HOBt (0.00023 mol) at 0° C. and reaction mixture was stirred at the same temperature for another 15 mins. In another round-bottom flask, the Boc-deprotected amine BB (0.00019 mol, 1 eqv) in DCM (2 ml) was cooled in ice bath, treated with DIPEA (0.00069 mol, 3 eqv) and was added to the reaction mixture at 0° C. The reaction mixture was stirred at RT for 16 h and diluted with DCM. The organic layer was successively washed with aqueous ammonium chloride, sodium bicarbonate and brine and finally dried over Na2SO4. Evaporation of the organic layer under reduced pressure gave the crude product which is purified by column chromatography to give the pure desired product.

3. The step-2 product (0.0001 mol) was stirred at RT with 20% piperidine in acetonitrile (6 ml) for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude is purified by prep.HPLC purification using aqueous ammonia method.

Synthesis of the Examples 141-270 (Method C)
To a solution of CDI (0.105 M in DCM, 1 ml) a solution of the acid (0.05 M in DCM, 2 ml) was added. The reaction mixture was stirred for 1 h at RT. A solution of the amine (0.1 M in DCM, 1 ml) was added and the reaction mixture was stirred for additional 16 h. After that time water (3 ml) was added, the mixture was shaken for 15 min. and the organic layer was separated. Brine was added and after separation of the organic layer the products were evaporated and purified by HPLC.
The following compounds were synthesized:

















Acid
Amine
Method
M+






















49
S13
A33
A
581.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


50
S13
A34
A
595.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


51
S13
A38
A
617.2
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


52
S13
A39
A
643.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-







tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


53
S12
A23
A
617.2
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


54
S11
A23
A
563.1
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


55
S13
A24
A
610.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-







methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


56
S13
A22
A
595.1
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


57
S13
A23
A
597.3
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


58
S11
A29
A
521.3
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


59
S12
A24
A
630.3
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


60
S13
A31
A
583.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


61
S13
A36
A
610.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-







methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


62
S11
A30
A
549.3
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


63
S13
A30
A
583.4
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-







methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


64
S12
A31
A
603.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


65
S12
A30
A
603.4
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


66
S13
A35
A
597.4
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


67
S12
A35
A
617.3
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


68
S12
A36
A
630.5
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


69
S12
A39
A
663.5
N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-







1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


70
S13
A19
A
583.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


71
S13
A37
A
621.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


72
S11
A19
A
549.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


73
S11
A32
A
563.3
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


74
S11
A20
A
563.4
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


75
S13
A32
A
597.3
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


76
S13
A20
A
597.3
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


77
S11
A37
A
587.5
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


78
S11
A24
A
576.2
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


79
S11
A39
A
609.2
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-







methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-







acetamide


80
S11
A22
A
561.4
N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


81
S11
A36
A
576.2
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


82
S12
A19
A
603.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


83
S12
A38
A
637.4
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


84
S12
A33
A
601.4
N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


85
S11
A21
A
547.2
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-1-yl]-acetamide


86
S12
A21
A
601.2
N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


87
S11
A35
A
563.2
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


88
S12
A37
A
641.2
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


89
S12
A22
A
615.4
N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


90
S12
A27
A
663.4
N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-







1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


91
S13
A21
A
581.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


92
S12
A29
A
575.2
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


93
S11
A38
A
583.4
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


94
S2
A33
A
613.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


95
S2
A25
A
653.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-







naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


96
S2
A29
A
587.5
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-







yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-







1-yl]-acetamide


97
S2
A32
A
629.5
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-







naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


98
S2
A21
A
613.3
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


99
S2
A36
A
642.5
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-







methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


100
S2
A26
A
649.3
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-







yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-







1-yl]-acetamide


101
S2
A38
A
649.3
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-







yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-







1-yl]-acetamide


102
S13
A17
A
555.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


103
S2
A37
A
653.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-







naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


104
S2
A20
A
629.4
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-







naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


105
S2
A39
A
675.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-







tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


106
S2
A17
A
587.4
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-







yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-







1-yl]-acetamide


107
S11
A17
A
521.4
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


108
S11
A25
A
587.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


109
S12
A25
A
641.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


110
S13
A25
A
621.4
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


111
S13
A26
A
617.4
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


112
S12
A26
A
637.5
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


113
S12
A20
A
617.3
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


114
S2
A19
A
615.4
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-







yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-







1-yl]-acetamide


115
S13
A29
A
555.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


116
S12
A32
A
617.4
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


117
S2
A24
A
642.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-







methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


118
S2
A35
A
629.5
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


119
S13
A27
A
643.3
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-







tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


120
S2
A23
A
629.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


121
S2
A30
A
615.3
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-







methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


122
S11
A31
A
549.3
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


123
S11
A33
A
547.5
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-







tetrahydro-naphthalen-2-yl]-acetamide


124
S12
A17
A
575.2
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


125
S2
A18
A
615.3
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-







methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


126
S11
A18
A
549.4
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







acetamide


127
S11
A26
A
583.4
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


128
S2
A22
A
627.3
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


129
S11
A27
A
609.2
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-







methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-







acetamide


130
S2
A27
A
675.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-







tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


131
S12
A18
A
603.3
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-







tetrahydro-naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


132
S13
A18
A
583.2
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-







methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


133
S11
A16
B
507.4
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


134
S2
A16
B
573.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


135
S12
A16
B
561.2
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


136
S13
A16
B
541.4
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-1-yl]-acetamide


137
S2
A28
B
573.4
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


138
S13
A28
B
541.4
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-







(methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-acetamide


139
S12
A28
B
561.2
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


140
S11
A28
B
507.4
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-







naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


141
S1
A111
C
538.7
1-(4-Hydroxy-4-pyridin-3-yl-piperidin-1-yl)-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]ethanone


142
S1
A66
C
504.6
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-







morpholin-4-yl-propyl)-acetamide


143
S1
A58
C
530.7
N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


144
S1
A63
C
540.7
1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


145
S1
A81
C
522.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-







phenyl-piperazin-1-yl)-ethanone


146
S1
A116
C
556.8
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone


147
S1
A117
C
567.8
1-[4-[2-(2,5-Dimethyl-1H-pyrrol-1-yl)-ethyl]-







piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-ethanone


148
S1
A62
C
575.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-







ethanone


149
S1
A64
C
523.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-







pyridin-2-yl-piperazin-1-yl)-ethanone


150
S1
A57
C
562.7
2-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







[1,4]diazepan-1-yl]-pyridine-3-carbonitrile


151
S1
A60
C
550.7
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


152
S1
A91
C
591.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-







(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-







ethanone


153
S14
A65
C
465.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-







pyrrolidin-1-yl-ethyl)-acetamide


154
S14
A66
C
495.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-







morpholin-4-yl-propyl)-acetamide


155
S14
A58
C
521.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-







dimethyl-piperidin-1-yl)-propyl]-acetamide


156
S14
A59
C
570.2
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-







methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide


157
S14
A73
C
527.1
N-(1-Benzyl-pyrrolidin-3-yl)-2-[2-[(2-chloro-6-methyl-







phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetamide


158
S14
A63
C
531.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-







fluorophenyl)-piperazin-1-yl]-ethanone


159
S14
A86
C
521.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-







morpholin-4-yl-piperidin-1-yl)-ethanone


160
S14
A87
C
519.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-piperidin-







1-yl-piperidin-1-yl)-ethanone


161
S14
A114
C
534.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-







piperazin-1-yl)-piperidin-1-yl]-ethanone


162
S14
A83
C
515.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-







2-yl-piperazin-1-yl)-ethanone


163
S14
A62
C
566.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-







1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone


164
S14
A57
C
553.1
2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







[1,4]diazepan-1-yl]-pyridine-3-carbonitrile


165
S14
A116
C
547.2
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-







piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone


166
S14
A60
C
541.1
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(2-chloro-







6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


167
S9
A111
C
480.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-pyridin-3-







yl-piperidin-1-yl)-ethanone


168
S9
A65
C
416.5
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-pyrrolidin-1-yl-ethyl)-







acetamide


169
S9
A58
C
472.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-







piperidin-1-yl)-propyl]-acetamide


170
S9
A59
C
521.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-







1-yl)-1-phenyl-ethyl]-acetamide


171
S9
A74
C
478.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-(1-benzyl-pyrrolidin-3-







yl)-acetamide


172
S9
A63
C
482.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-







piperazin-1-yl]-ethanone


173
S9
A79
C
416.5
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-ethyl-piperazin-1-yl)-







ethanone


174
S9
A81
C
464.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperazin-1-







yl)-ethanone


175
S9
A84
C
456.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrrolidin-1-yl-







piperidin-1-yl)-ethanone


176
S9
A86
C
472.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-morpholin-4-yl-







piperidin-1-yl)-ethanone


177
S9
A114
C
485.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-piperazin-







1-yl)-piperidin-1-yl]-ethanone


178
S9
A117
C
509.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[2-(2,5-dimethyl-1H-







pyrrol-1-yl)-ethyl]-piperazin-1-yl]-ethanone


179
S9
A83
C
466.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-2-yl-







piperazin-1-yl)-ethanone


180
S9
A62
C
517.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-







benzoimidazol-2-yl)-piperidin-1-yl]-ethanone


181
S9
A57
C
504.6
2-[4-[2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-







yl]-pyridine-3-carbonitrile


182
S9
A60
C
492.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-pyrrolidin-3-







yl)-methyl]-acetamide


183
S9
A91
C
533.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-(trifluoromethyl)-







pyridin-2-yl]-piperazin-1-yl]-ethanone


184
S12
A58
C
540.6
N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


185
S12
A59
C
589.7
N-[2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethyl]-2-[2-







[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


186
S12
A63
C
550.6
1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


187
S12
A79
C
484.5
1-(4-Ethyl-piperazin-1-yl)-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


188
S12
A87
C
538.6
1-(4-Piperidin-1-yl-piperidin-1-yl)-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


189
S12
A62
C
585.6
1-[4-(5-Methyl-1H-benzoimidazol-2-yl)-piperidin-1-







yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


190
S12
A64
C
533.6
1-(4-Pyridin-2-yl-piperazin-1-yl)-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


191
S12
A57
C
572.6
2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







[1,4]diazepan-1-yl]-pyridine-3-carbonitrile


192
S12
A60
C
560.6
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[3-







(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


193
S7
A58
C
535.2
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-







(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide


194
S7
A59
C
584.2
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-







(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide


195
S7
A63
C
545.1
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(2-fluorophenyl)-piperazin-1-yl]-ethanone


196
S7
A62
C
580.2
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-







ethanone


197
S7
A57
C
567.1
2-[4-[2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







[1,4]diazepan-1-yl]-pyridine-3-carbonitrile


198
S7
A60
C
555.1
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-chloro-







2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


199
S6
A58
C
575.1
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-







(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide


200
S6
A59
C
624.1
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-







(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide


201
S6
A63
C
585.0
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(2-fluorophenyl)-piperazin-1-yl]-ethanone


202
S6
A62
C
620.1
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-







ethanone


203
S6
A64
C
568.0
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-







pyridin-2-yl-piperazin-1-yl)-ethanone


204
S6
A57
C
607.1
2-[4-[2-[2-[[2-Chloro-4-(trifluoromethyl)-







phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-







a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-







carbonitrile


205
S6
A60
C
595.1
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[2-chloro-







4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


206
S1
A94
C
522.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-







(pyridin-2-yl-methyl)-pyrrolidin-1-yl]-ethanone


207
S1
A68
C
502.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-







piperidin-1-yl-propyl)-acetamide


208
S1
A89
C
571.1
1-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-2-[2-







[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


209
S1
A97
C
572.1
1-[4-(4-Chlorophenyl)-4-hydroxy-piperidin-1-yl]-2-[2-







[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


210
S1
A99
C
551.7
1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


211
S1
A100
C
605.7
1-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-piperidin-







1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







ethanone


212
S1
A115
C
502.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-







methyl-N-(2-piperidin-1-yl-ethyl)-acetamide


213
S1
A70
C
528.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-







(piperidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone


214
S1
A76
C
552.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(3-methoxyphenyl)-piperazin-1-yl]-ethanone


215
S1
A77
C
540.7
1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


216
S1
A80
C
488.7
1-(4-Isopropyl-piperazin-1-yl)-2-[2-[(4-methoxy-2,6-







dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


217
S14
A94
C
513.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-







yl-methyl)-pyrrolidin-1-yl]-ethanone


218
S14
A68
C
493.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-piperidin-







1-yl-propyl)-acetamide


219
S14
A98
C
528.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-







4-phenyl-piperidin-1-yl)-ethanone


220
S14
A100
C
596.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-hydroxy-







4-[3-(trifluoromethyl)phenyl]-piperidin-1-yl]-ethanone


221
S14
A113
C
584.2
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[2-







(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide


222
S14
A115
C
493.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-







piperidin-1-yl-ethyl)-acetamide


223
S14
A76
C
543.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3-







methoxyphenyl)-piperazin-1-yl]-ethanone


224
S14
A77
C
531.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-







fluorophenyl)-piperazin-1-yl]-ethanone


225
S14
A80
C
479.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-isopropyl-







piperazin-1-yl)-ethanone


226
S9
A89
C
513.1
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-chloro-2-methyl-







phenyl)-piperazin-1-yl]-ethanone


227
S9
A97
C
514.0
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-chlorophenyl)-4-







hydroxy-piperidin-1-yl]-ethanone


228
S9
A98
C
479.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-phenyl-







piperidin-1-yl)-ethanone


229
S9
A78
C
494.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methoxyphenyl)-







piperazin-1-yl]-ethanone


230
S7
A113
C
598.2
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-







methyl-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-







ethyl]-acetamide


231
S9
A102
C
533.5
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3,4-dichlorophenyl)-







piperazin-1-yl]-ethanone


232
S9
A106
C
492.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(p-tolyl-methyl)-







piperazin-1-yl]-ethanone


233
S9
A107
C
508.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-methoxyphenyl)-







methyl]-piperazin-1-yl]-ethanone


234
S9
A108
C
496.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2-fluorophenyl)-







methyl]-piperazin-1-yl]-ethanone


235
S9
A61
C
506.7
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-piperidin-3-







yl)-methyl]-acetamide


236
S12
A104
C
588.7
2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2,4,6-







trimethyl-phenyl)-methyl]-piperazin-1-yl]-ethanone


237
S6
A78
C
597.1
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(4-methoxyphenyl)-piperazin-1-yl]-ethanone


238
S1
A102
C
591.6
1-[4-(3,4-Dichlorophenyl)-piperazin-1-yl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


239
S1
A104
C
578.8
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







[(2,4,6-trimethyl-phenyl)-methyl]-piperazin-1-yl]-







ethanone


240
S1
A105
C
571.1
1-[4-[(4-Chlorophenyl)-methyl]-piperazin-1-yl]-2-[2-







[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


241
S1
A106
C
550.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







(p-tolyl-methyl)-piperazin-1-yl]-ethanone


242
S1
A107
C
566.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-







[(4-methoxyphenyl)-methyl]-piperazin-1-yl]-







ethanone


243
S1
A108
C
554.7
1-[4-[(2-Fluorophenyl)-methyl]-piperazin-1-yl]-2-[2-







[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


244
S1
A95
C
536.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-







(pyridin-2-yl-methyl)-piperidin-1-yl]-ethanone


245
S1
A96
C
536.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-







(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone


246
S1
A82
C
580.7
1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-







[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-







ethanone


247
S1
A67
C
499.6
3-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







piperazin-1-yl]-propionitrile


248
S1
A61
C
564.7
N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


249
S14
A105
C
561.5
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-







chlorophenyl)-methyl]-piperazin-1-yl]-ethanone


250
S14
A95
C
527.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-







yl-methyl)-piperidin-1-yl]-ethanone


251
S14
A96
C
527.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-4-







yl-methyl)-piperidin-1-yl]-ethanone


252
S14
A82
C
571.1
1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-







[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


253
S14
A67
C
490.0
3-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







piperazin-1-yl]-propionitrile


254
S6
A61
C
609.1
N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[[2-chloro-







4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide


255
S1
A71
C
578.8
1-[2-(4-Dimethylaminophenyl)-azepan-1-yl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


256
S1
A75
C
580.7
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-







methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-







acetamide


257
S1
A85
C
535.7
1-(4-Benzyl-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-







dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


258
S1
A101
C
490.6
1-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-2-[2-[(4-







methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone


259
S14
A75
C
571.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-







morpholin-4-yl-1-phenyl-ethyl)-acetamide


260
S14
A88
C
505.1
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-







(pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone


261
S14
A90
C
539.1
2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







piperazin-1-yl]-pyridine-3-carbonitrile


262
S14
A92
C
616.5
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-







5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-







ethanone


263
S14
A101
C
481.0
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-







tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-







hydroxy-ethyl)-piperazin-1-yl]-ethanone


264
S9
A88
C
456.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-(pyrrolidin-1-yl-







methyl)-pyrrolidin-1-yl]-ethanone


265
S9
A92
C
568.0
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-5-







(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-







ethanone


266
S9
A103
C
547.5
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(3,4-







dichlorophenyl)-methyl]-piperazin-1-yl]-ethanone


267
S9
A109
C
478.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-methyl-2-phenyl-







piperazin-1-yl)-ethanone


268
S9
A110
C
463.6
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-







pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperidin-1-







yl)-ethanone


269
S12
A90
C
558.6
2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-







piperazin-1-yl]-pyridine-3-carbonitrile


270
S6
A69
C
595.1
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-







1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-







(4-dimethylaminophenyl)-pyrrolidin-1-yl]-ethanone









1. Functional Investigation on the Bradykinin 1 Receptor (B1R)

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

2. Method:

Chinese hamster ovary cells (CHO K1 cells) which are stably transfected with the human B1R gene (hB1R cells) or the B1R gene of the rat (rB1R cells) are used. For functional investigations these cells are plated-out onto black 96-well plates with a clear base (BD Biosciences, Heidelberg, Germany or Greiner, Frickenhausen, Germany) in a density of 20,000-35,000 cells/well. Overnight the cells are incubated at 37° C. and 5% CO2 in culture medium (hB1R cells: Ham's Nutrient Mixture F12, Gibco Invitrogen GmbH, Karlsruhe, Germany or DMEM, Sigma-Aldrich, Taufkirchen, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen, Karlsruhe, Germany) with 10 vol. % FBS (foetal bovine serum, Gibco Invitrogen GmbH, Karlsruhe, Germany or PAN Biotech GmbH, Aidenbach, Germany).

On the following day the cells are loaded 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 mM probenecid (Sigma-Aldrich, Taufkirchen, Germany) and 10 mM HEPES (Sigma-Aldrich, Taufkirchen, Germany) for 60 min at 37° C. The plates are subsequently washed twice with HBSS buffer, and HBSS buffer which additionally contains 0.1% BSA (bovine serum albumin; Sigma-Aldrich, Taufkirchen, Germany), 5.6 mM glucose and 0.05% gelatine (Merck KGaA, Darmstadt, Germany) is added. After a further incubation of 20 minutes at RT, the plates are inserted into the FLIPR for Ca2+ measurement. Alternatively they are washed with buffer A (15 mM HEPES, 80 mM NaCl, 5 mM KCl, 1.2 mM CaCl2, 0.7 mM MgSO4, 2 g/l glucose, 2.5 mM probenecid) and loaded with buffer A with added 2.5 μM Fluo-4 and 0.025% Pluronic F127 (Sigma-Aldrich, Taufkirchen, Germany). The cells are then washed twice with buffer A and incubated for 30 minutes with buffer A, which additionally contains 0.05% BSA and 0.05% gelatine, at RT and then used for Ca2+ measurement in the FLIPR. The Ca2+-dependent fluorescence is measured here before and after addition of substances (λex=488 nm, λem=540 nm). The quantification is performed by measuring the highest fluorescence intensity (FC, fluorescence counts) over time.
3. FLIPR Assay:
The FLIPR protocol comprises two additions of substance. Test substances (10 μM) are first pipetted onto the cells and the Ca2+ inflow is compared with the control (hB1R: Lys-Des-Arg9 bradykinin >=50 nM; rB1R: Des-Arg9 bradykinin 10 μM). The value in % activation based on the Ca2+ signal after addition of Lys-Des-Arg9 bradykinin (>=50 nM) or Des-Arg9 bradykinin (10 μM) is obtained therefrom. After incubation for 10-20 minutes, Lys-Des-Arg9 bradykinin (hB1R) or Des-Arg9 bradykinin (rB1R) is applied in the EC80 concentration and the inflow of Ca2+ is likewise determined.
Antagonists lead to a suppression of the Ca2+ inflow. The % inhibition in comparison with the maximum achievable inhibition is calculated.
The substances are added in varying concentrations in order to determine the IC50 value. Double or triple determinations (n=2 or n=3) are performed and these are repeated in at least one further independent experiment (N>=2).
The compounds preferably exhibit a B1R antagonistic action on the human receptor and/or on the rat receptor. The following data is provided in Table 8 below by way of example: (“% Inh. (rat B1R) 10 μM” stands for “% inhibition rat B1R at 10 μM” and “% Inh. (hum. B1R) 10 μM” stands for “% inhibition human B1R at 10 μM”).













B1R antagonism.
B1R antagonism.



human [10 μM]
rat [10 μM]


Example
% inhibition
% inhibition

















1
94.8
100.34


2
99.93
98.91


3
69.58
58.81


4
99.76
103.71


5
99.81
101.52


6
99.61
100.12


7
99.93
102.03


8
99.93
103.7


9
99.49
102.71


10
99.78
103.32


11
99.87
98.12


12
99.51
99.28


13
100.11
100.21


14

108.86


15
99.91
98.26


16
99.89
98.54


17
97.44
99.21


18
99.88
94.79


19

−7.98


20

30.705


21
99.95
113.24


22
99.59
113.09


23
100.18
107.92


24
99.94
113.51


25
95.99
103.03


26
98.94
101.67


27
99.96
101.83


28
99.55
100.48


29
99.84
101.89


30
99.82
102.38


31
100.19
103.50


32
8.84
65.45


33
15.73
58.08


34
99.21
103.42


35
97.66
101.49


36
97.50
103.44


37
97.84
104.35


38
98.11
104.44


39
99.56
105.20


40
99.6
94.9


41
100.08
103.30


42
99.86
107.37


43
99.48
103.42


44
99.28
103.51


45
50.62
64.04


46
55.80
29.01


47
99.86
106.11


48
99.59
104.69


49
99.86
99.99


50
99.72
99.51


51
99.53
103.05


52
96.04
102.55


53
99.01
102.22


54
99.02
100.20


55
99.78
99.42


56
99.73
97.97


57
98.55
101.21


58
99.96
103.23


59
99.75
76.24


60
99.77
99.49


61
99.70
100.00


62
99.21
98.41


63
99.72
91.12


64
99.87
101.98


65
99.08
98.74


66
99.89
100.32


67
99.73
101.07


68
99.72
98.87


69
62.82
90.72


70
99.87
101.58


71
99.85
101.63


72
99.90
101.12


73
99.85
103.21


74
99.73
91.19


75
99.87
101.55


76
99.81
100.94


77
99.25
103.44


78
99.84
86.20


79
57.86
99.32


80
99.78
100.74


81
99.14
102.32


82
99.92
100.55


83
99.35
101.37


84
99.77
100.50


85
99.88
101.43


86
99.81
97.46


87
99.42
101.97


88
99.89
96.48


89
100.02
99.10


90
54.58
51.42


91
99.91
99.05


92
99.87
102.08


93
99.87
96.83


94
99.88
100.99


95
99.69
99.78


96
99.93
102.36


97
99.84
102.50


98
99.86
99.70


99
99.76
100.79


100
99.85
102.95


101
99.93
102.87


102
99.86
100.64


103
99.98
102.01


104
99.90
103.08


105
99.80
102.66


106
99.96
100.99


107
99.33
98.43


108
99.91
101.09


109
99.83
99.85


110
99.90
98.83


111
99.95
102.77


112
99.79
102.31


113
99.81
97.08


114
100.01
99.57


115
99.84
101.81


116
99.75
101.87


117
99.96
98.80


118
99.99
101.75


119
23.42
62.23


120
97.85
101.68


121
99.90
99.49


122
99.57
100.67


123
99.99
101.26


124
99.67
97.31


125
99.63
99.14


126
99.94
101.86


127
97.40
101.17


128
99.77
103.12


129
46.07
74.72


130
73.58
98.78


131
99.83
100.99


132
99.81
101.63


133
99.44
103.88


134
99.81
103.33


135
99.58
104.28


136
99.70
−29.23


137
99.72
103.80


138
99.76
102.59


139
99.14
102.59


140
96.09
101.77


141

37.775


142

37.915


143

37.35


144

70.29


145

57.67


146

73.45


147

86.49


148

70.445


149

68.93


150

50.33


151

104.35


152

50.925


153

15.82


154

41.85


155

61.5


156

95.1


157

69.5


158

32.045


159

3.48


160

42.775


161

10.5


162

25.205


163

39.715


164

44.065


165

55.765


166

99.115


167

0.145


168

40.095


169

7.565


170

68.405


171

24.36


172

14.07


173

9.74


174

27.99


175

9.54


176

26.725


177

−1.9


178

17.245


179

20.77


180

32.945


181

33.865


182

37.455


183

56.08


184

19.43


185

76.44


186

24.425


187

18.32


188

−2.25


189

−1.61


190

20.44


191


192


193


194


195


196


197


198


199


200


201


202


203


204


205


206


207


208


209


210


211


212


213


214


215


216


217


218


219


220


221


222


223


224


225


226


227


228


229


230

5.28


231

−0.67


232

2.94


233

20.63


234

17.34


235

−14.02


236

9.23


237

9.45


238

17.61


239

−8.74


240

55.88


241

46.81


242

8.40


243

29.36


244

−37.61


245

−21.48


246

6.85


247

−27.36


248

84.04


249

−12.55


250

−38.00


251

−37.07


252

−10.50


253

−39.06


254

8.85


255

−7.23


256

5.54


257

75.53


258

9.05


259

4.54


260

−11.39


261

29.81


262

−12.50


263

2.37


264

1.78


265

17.92


266

−3.52


267

−4.75


268

27.96


269

1.05


270

3.10









The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

## Claims

1. A compound corresponding to the formula (I):



wherein
a stands for 1 or 2;
b stands for 0, 1 or 2;
B stands for C(R6a(R6b), NR7, O or a single bond, with the proviso that if b is 0, then B does not stand for NR7;
W1, W2 and W3 each stand for CR5;
R1 stands for aryl, heteroaryl, CH(aryl)2 or an aryl or heteroaryl group bound via a C1-3 alkylene group;
R2a, R2b, R3a, R3b, R6a and R6b each independently stand for H, F, Cl, Br, I, —CF3, OH, SH, O—C1-6 alkyl, C1-6 alkyl, C3-8 cycloalkyl, aryl or heteroaryl; or for a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group or C2-6 alkenylene group; or
R2a and R2b and/or R3a and R3b can together denote ═O;
R4 stands for 0 to 4 substituents each independently selected from the group consisting of F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl and heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group;
R5 stands for H, C1-6 alkyl, halogen, —CN or CF3;
R7 stands for H, C1-6 alkyl, C3-8 cycloalkyl, aryl, heteroaryl or for a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group, C2-6 alkenylene group or C2-6 alkynylene group;
s is 0 or 1,
t is 0, 1, 2 or 3,
R8 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group;
R9a and R9b each independently denote H; F; Cl; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group;
A stands for N or CH, with the proviso that if s is 1 and t is 0, then A stands for CH; and with the proviso that if s is 0, then t is 0, and A stands for N;
R10 and R11 together with A represent a spirocyclic or cyclic group corresponding to formula (II) or formula (III):




wherein
c, d, e, f, u and v each independently denote 0, 1 or 2;
R12, R13 and R27 each independently stand for 0 to 4 substituents each independently selected from the group consisting of F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl; heteroaryl; and C3-8 cycloalkyl, aryl or heteroaryl bound via a C1-6 alkylene group; or
two substituents R27 together represent a C1-3 alkylene bridge such that the cyclic group of formula (III) assumes a bicyclically bridged form; or
two adjacent substituents R13 form an anellated aryl or heteroaryl ring; or
two adjacent substituents R27 form an anellated aryl or heteroaryl ring which optionally may be substituted by a 4- to 7-membered heterocyclyl group, which in turn can optionally be connected to the anellated aryl or heteroaryl ring by a C1-3 alkylene group;
X stands for CR14aR14b, NR15 or O;
Y stands for CR16aR16b, NR17 or O;
with the proviso that X does not denote NR15 if Y denotes NR17; and
with the proviso that X and Y do not simultaneously denote O;
wherein
R14a, R14b, R16a and R16b each independently denote H; F; Cl; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group; or
R14a and R14b can together stand for ═O; or
R16a and R16b can together stand for ═O;
R15 and R17 each independently stand for H; C1-6 alkyl; C3-8 cycloalkyl, aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group;

Z in formula (II) stands for CR18aR18b, NR19 or O; or
if X stands for O and f is 0, then Z in formula (II) may denote —(C(R124)—C(R125))—,
wherein R124 and R125 together with the carbon atoms linking them form a fused aryl or heteroaryl ring; or
if X stands for O, and f is for 0, then Z in formula (II) may denote ═(N(CR126))—, wherein the N atom is singly bound to the O atom, and R126 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group;
Z in formula (III) stands for CR18aR18b, NR19, O, S, S(═O) or S(═O)2; wherein
R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group; or
R18a stands for a structure corresponding to formula (IV),





wherein
i and j each independently stand for 0 or 1;
E stands for N or CH, with the proviso that if i is 1 and j is 0, then E stands for CH,
R34 and R35 each independently denote H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or an aryl, heteroaryl or C3-8 cycloalkyl group bound via a C1-3 alkylene group; or
R34 and R35 together with E form a 5- or 6-membered aryl or heteroaryl ring; or
R34 and R35 together with E form a saturated heterocyclic structure corresponding to formula (V),




wherein
h and g each independently denote 0, 1 or 2;
G stands for CR37aR37b, NR38, O, S, S═O or S(═O)2, with the proviso that if E stands for CH, then G does not stand for CR37aR37b;
R36 stands for 0 to 4 substituents each independently selected from the group consisting of H; F; Cl; Br; I; OH; SH; ═O; O—C1-6 alkyl; C1-6 alkyl; C3-8 cycloalkyl; aryl and heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound by a C1-6 alkylene group; or
two adjacent substituents R36 together represent an anellated aryl or heteroaryl ring; or
two substituents R36 together represent a C1-3-alkylene bridge such that the cyclic structure represented by formula (V) assumes a bicyclically bridged form;
R37a and R37b each independently denote H; F; Cl; Br; I; OH; SH; ═O; O—C1-6 alkyl; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl and heteroaryl group bound via a C1-6 alkylene group;
R38 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or an aryl, heteroaryl or C3-8 cycloalkyl group bound via a C1-3 alkylene group;
R18b stands for H; OH; C1-6 alkyl; C3-8 cycloalkyl; O—C1-6 alkyl; O—(C3-8 cycloalkyl); (C1-6 alkylene)-O—C1-6 alkyl; (C1-6 alkylene)-O—(C3-8 cycloalkyl); aryl; heteroaryl; O-aryl or O-heteroaryl; or an aryl, O-aryl, heteroaryl or O-heteroaryl group bound via a C1-6 alkylene group; or
R18b stands for a structure corresponding to formula (VI),




wherein
k is 0 or 1;
R39 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-3 alkylene group;
R40 stands for C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group; or
R39 and R40 together with the N—C(═O) group linking them form a ring corresponding to formula (VII),




wherein
I stands for 0, 1 or 2; and
R41 and R42 together with the carbon atoms linking them form an anellated aryl or heteroaryl ring;

R19 stands for H; or (P)z—R22, wherein
z is 0 or 1;
P stands for (C═O), S(═O)2 or C(═O)—N(R24); wherein the N atom in the C(═O)—N(R24) group is linked to R22;
R24 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl, heteroaryl or a C3-8 cycloalkyl group bound via a C1-3 alkylene group;
R22 stands for C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or an aryl, heteroaryl or C3-8 cycloalkyl group bound via a C1-6 alkylene group; or
R22 stands for a group corresponding to formula (VIII),




wherein
n is 0, 1 or 2;
m is 0, 1 or 2;
w is 0 or 1,
M stands for CH or N; with the proviso that if P stands for C(═O)—NR24 and w is 0, then M stands for CH; and with the proviso that if z and w are each 0, then M stands for CH;
L stands for CR44aR44b, NR45, O, S, S═O or S(═O)2;
R43 stands for 0 to 4 substituents each independently selected from the group consisting of F; Cl; OH; ═O; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl and heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group; or
two adjacent substituents R43 together represent an anellated aryl or heteroaryl ring;
R44a and R44b each independently stand for H; F; Cl; Br; I; OH; C1-6 alkyl; O—C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or a C3-8 cycloalkyl, aryl or heteroaryl group bound via a C1-6 alkylene group; or
R44a and R44b can together stand for ═O;
R45 stands for H; C1-6 alkyl; C3-8 cycloalkyl; aryl or heteroaryl; or an aryl, heteroaryl or C3-8 cycloalkyl group bound via a C1-3 alkylene group;
or wherein, if s and t in formula (I) each are 0 and A stands for N,
R10 stands for H, C1-6 alkyl or —C(═O)—R280, wherein
R280 stands for —N(C1-6 alkyl)2 or a 4- to 7-membered heterocyclyl group; and

R11 stands for a phenyl group or a phenyl group bound via a C1-3 alkylene group, wherein the C1-3 alkylene group optionally may be substituted with a —C(═O)R280 group and R280 stands for —N(C1-6 alkyl)2 or a 4- to 7-membered heterocyclyl group; or
wherein the phenyl group optionally may be substituted with an —(NR300R301) group or a 4- to 8-membered heterocyclyl group, and the —(NR300R301) group or the 4- to 8-membered heterocyclyl group optionally may be bound to the phenyl group by a C1-3 alkylene group and
R300 and R301 each independently stand for H or C1-6 alkyl;
wherein the aforementioned C1-6 alkyl, C1-3 alkylene, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8-cycloalkyl groups can each be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, NO2, SH, S—C1-6 alkyl, C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkylene-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, CO2H, CO2—C1-6 alkyl, phenyl, phenoxy, benzyl, naphthyl, furyl, thienyl and pyridinyl;
wherein the aforementioned aryl and heteroaryl groups can each be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of F, Cl, Br, I, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, NH-aryl1, N(aryl1)2, N(C1-6 alkyl)aryl1, pyrrolinyl, piperazinyl, morpholinyl, azetidinyl, piperidinyl, thiazolinyl, azepanyl, diazepanyl, (C1-3 alkylene)-azetidinyl, (C1-3 alkylene)-pyrrolinyl, (C1-3 alkylene)-piperidinyl, (C1-3 alkylene)-morpholinyl, (C1-3 alkylene)-piperazinyl, (C1-3 alkylene)-thiazolinyl, (C1-3 alkylene)-azepanyl, (C1-3 alkylene)-diazepanyl, NO2, SH, S—C1-6 alkyl, OH, O—C1-6 alkyl, O—C1-6 alkyl-OH, C(═O)C1-6 alkyl, NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2—C1-6 alkyl, OCF3, CF3, —O—CH2—O—, —O—CH2—CH2—O—, —O—C(CH3)2—CH2—, unsubstituted C1-6 alkyl, pyrrolidinyl, imidazolyl, benzyloxy, phenoxy, phenyl, naphthyl, pyridinyl, —C1-3 alkylene-aryl1, benzyl, thienyl, and furyl, wherein aryl1 stands for phenyl, thiazolyl, thienyl or pyridinyl;
wherein the aforementioned heterocyclyl group can be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of F, Cl, Br, I, —CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkylene-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkylene-OH)2, pyrrolinyl, piperazinyl, morpholinyl, NO2, SH, S—C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkylene-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, CO2H, CO2—C1-6 alkyl or benzyl, and
wherein the aforementioned C1-6 alkyl, C1-3 alkylene, C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene groups may each be branched or unbranched;
or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1, wherein
(a1) formula (II) assumes the following substructure (IIa):





or
(a2) formula (III) assumes one of the following substructures (IIIa) or (IIIb):

3. A compound as claimed in claim 2, wherein
(a1) the substructure (IIa) assumes the following substructure (IIb):




or
(a2) the substructures (IIIa) and (IIIb) assume one of the following substructures (IIIc), (IIId) or (IIIe):

4. A compound as claimed in claim 3, wherein:
(a1) the substructure (IIa) assumes the substructure (IIb),
R8 stands for H; C1-6 alkyl, or C3-6 cycloalkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents, and
R9a and R9b each stand for H; or

(a2) the substructures (IIIa) and (IIIb) assume one of the substructures (IIIc) or (IIId), and
s and t each stand for 0; or

(a3) the substructures (IIIa) and (IIIb) assume one of the substructures (IIIc) or (IIId), and
two of the substituents R27 together represent a C1-3 alkylene bridge such that the cyclic structure represented in substructure (IIIc) or (IIId) assumes a bicyclically bridged form, and
s and t are each o; or

(a4) the substructures (IIIa) and (IIIb) assume one of the substructures (IIIc) or (IIIe),
s stands for 1 and t for 1, 2 or 3; and
R8 stands for H, C1-6 alkyl or C3-6 cycloalkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents.

5. A compound as claimed in claim 4, wherein
(a1) substructure (IIb) assumes the following substructure (IIc):




and wherein s and t each denote 0;
or

(a2) the substructures (IIIc) or (IIId) assume one of the following substructures (IIIf) or (IIIg),




wherein
R27 stands for H or methyl; or
two adjacent substituents R27 form an anellated aryl or heteroaryl ring;
or

(a3) the substructures (IIIc) or (IIId) represent one of the following groups (A) to (H):




or
(a4) the substructures (IIIc) or (IIIe) represent a group corresponding to one of formulas (IIIh) or (IIIi),




and R9a and R9b each stand for H.

6. A compound as claimed in claim 5, wherein
(a1) in the substructure (IIc),
R16a and R16b each stand for H or together form ═O;
R13 stands for aryl or heteroaryl; or
two substituents R13 together form ═O; or
two adjacent substituents R13 form an anellated aryl or heteroaryl ring;
or

(a2) in the substructures (IIIf) or (IIIg)
R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, phenyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, triazolyl or thienyl, each unsubstituted or mono- or polysubstituted; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl or thienyl bound via an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted;
or

R18a stands for a structure corresponding to formula (VIIa)




wherein
i is 0 or 1;
j is 0 or 1;
h is 0 or 1;
E stands for N or CH; with the proviso that if i is 1 and j is 0, then E stands for CH;
G stands for CR37aR37b or NR38; wherein
R37a and R37b each independently stand for H; F or C1-6 alkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
R38 stands for H; C1-6 alkyl, C3-6 cycloalkyl or pyridyl;

R18b stands for H; OH; C1-6 alkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thienyl or thiazolyl; each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, O-phenyl, O-pyridyl, imidazolyl, triazolyl, thienyl or thiazolyl bound via a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bridged by C1-6 alkylene-NH(C═O), each unsubstituted or mono- or polysubstituted with identical or different substituents,
R19 stands for H; C1-6 alkyl; or C3-8 cycloalkyl, or for C1-6 alkyl; phenyl, pyridyl, thienyl, thiazolyl, triazolyl, pyrimidinyl or imidazolyl bound by (C═O)0-1; each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, thienyl, thiazolyl, pyrimidinyl, triazolyl or imidazolyl bound by a C1-6 alkylene group; each unsubstituted or mono- or polysubstituted with identical or different substituents; or
R19 stands for a structure corresponding to formula (VIIIa)




wherein
w is 0 or 1;
n is 0 or 1;
m is 0 or 1;
M stands for CH or N, with the proviso that if w is 0, then M stands for CH;
L stands for CR44aR44b or NR45; wherein
R44a and R44b each independently stand for H; F or C1-6 alkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
R45 stands for H; C1-6 alkyl, C3-6 cycloalkyl or pyridyl;
or

(a3) the substructures (IIIc) or (IIId) represent one of the following groups (A) to (H),




wherein
R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for —N(C1-6 alkyl)2; —NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, imidazolyl, triazolyl, thienyl, thiazolyl, pyrimidinyl or pyridyl bound by an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R18b stands for H; OH; C1-6 alkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bound via a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl bound via a C1-6 alkylene group or a (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
or

(a4) in the substructures (IIIh) or (IIIi)
R18a stands for H; C1-6 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for —N(C1-6 alkyl)2; —NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl bound via an —O)0/1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R18b stands for H; OH; C1-6 alkyl; phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl bound via a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents; and
R19 stands for H; C1-6 alkyl; C3-8 cycloalkyl, phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, thienyl, imidazolyl, thiazolyl or triazolyl bound by a C1-6 alkylene group or a (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents.

7. A compound as claimed in claim 1, wherein in the substructure (B) in formula (I)



stands for 1;
t stands for 0, 1 or 2;
R8 stands for H, C1-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkyl bound via a C1-3 alkylene group;
A stands for N or CH, with the proviso that if t is 0, then A stands for CH, and
R10 and R11 together with A form a 5- or 6-membered cycloalkyl or heterocycloalkyl group to which a 5- or 6-membered aryl or heteroaryl ring is anellated,
wherein the anellated, 5- or 6-membered aryl or heteroaryl ring is substituted with a (C1-6 alkyl)amino, di(C1-6 alkyl)amino or 4- to 7-membered N-containing heterocyclyl group, and
wherein the (C1-6 alkyl)amino, di(C1-6 alkyl)amino or 4- to 7-membered N-containing heterocyclyl group optionally may be bound to the anellated aryl or heteroaryl ring via a C1-3 alkylene group, and the C1-3 alkylene group can be unsubstituted or mono- or polysubstituted with identical or different substituents.

8. A compound as claimed in claim 7, wherein the substructure B in formula (I) represents a group corresponding to formula (B.50):



wherein
R8 stands for H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, cyclopropyl or a cyclopropyl group bound via a C1-3 alkylene group, wherein in any of these groups at least one C-bound H atom optionally may be replaced by an F atom;
u and v each independently stand for 0, 1 or 2, with the proviso that u+v is greater than 0, and u+v is at most 3;
Λ stands for CH2 or O, with the proviso that if Λ is 0, then u stands for 1;
Π1 and Π2 each independently stand for CH or N;
α stands for 0, 1, 2 or 3; and
each occurrence of Rx and Ry independently stands for H, C1-6 alkyl, F or CF3;
T stands for N(R271)(R272), wherein
R271 stands for H, and
R272 stands for C1-4 alkyl, C3-6 cycloalkyl or a C3-6 cycloalkyl group bound via a C1-3 alkylene group; or

T stands for a heterocyclyl group selected from the group consisting of:





wherein
R274 stands for 0 to 2 substituents, each independently selected from the group consisting of F, methyl, ethyl, CF3 and —CH2—CF3; or
two adjacent substituents R274 together form an anellated aryl or heteroaryl ring; or
two substituents R274 together form a C1-3 alkylene bridge so that the heterocyclyl group assumes a bicyclically bridged form;
R275 represents H or a group selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl and a C3-6 cycloalkyl group bound via a C1-3 alkylene group; and
R276 stands for F, Cl, methyl or CF3.

9. A compound as claimed in claim 8, wherein
R8 stands for H, methyl or cyclopropyl;
u and v each stand for 1;
Π1 and Π2 both stand for CH or both stand for N;
α stands for 1;
each occurrence of Rx and Ry stands for H or methyl;
R274 is absent; or two adjacent substituents R274 together form a phenyl ring; and
R275 stands for H or methyl.

10. A compound as claimed in claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

11. A compound as claimed in claim 10, wherein said mixture is a racemic mixture.

12. A compound as claimed in claim 1, wherein said compound is in the form of an isolated stereoisomer.

13. A compound as claimed in claim 1, wherein
B stands for O, and R2a, R2b, R3a and R3b each stand for H; or
B stands for C(R6a)(R6b) or a single bond, and R2a, R2b, R3a, R3b, R6a and R6b each independently stand for H, F, CF3, OH, C1-6 alkyl or O—C1-6alkyl.

14. A compound as claimed in claim 1, wherein R1 stands for phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl; benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl; or CH(phenyl)2; each unsubstituted or monosubstituted or identically or differently polysubstituted with substituents independently selected from the group consisting of —O—C1-3 alkyl, C1-6 alkyl, F, Cl, Br, I, CF3, OCF3, OH, SH, phenyl, naphthyl, furyl, thiazolyl, thienyl and pyridinyl.

15. A compound as claimed in claim 1, wherein in formula (I) the group (Ac I)




is



wherein
R4 stands for 0 to 4 substituents selected from the group consisting of H, F and C1-6 alkyl.

16. A compound as claimed in claim 1, wherein
a is 1, b is 1, B stands for O, and R2a, R2b, R3a and R3b each stand for H; or
a is 1 or 2; b is 0; B stands for a single bond, and R2a and R2b each stand for H.

17. A compound as claimed in claim 1, wherein
(a1) the substructure (IIc) can assume one of the following substructures (SP1) to (SP34):













wherein
R13 stands for H or phenyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or
two substituents R13 together form ═O; or
two adjacent substituents R13 form an anellated aryl or heteroaryl ring:
R15 stands for H; C3-8 cycloalkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bound via a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R16a stands for H, C1-6 alkyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R18a stands for H; C1-8 alkyl; C3-8 cycloalkyl, N(C1-6 alkyl)2; NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for —N(C1-6 alkyl)2; —NH(C1-6 alkyl); azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bound via an —(O)0-1—C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R18b stands for H; OH; C1-6 alkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bound via a C1-6 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R19 stands for H; C3-8 cycloalkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted with identical or different substituents; or for phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl bound via a C1-6 alkylene group or (C═O) group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R120 stands for H; F; Cl; OH; OCH3, C1-6 alkyl; phenyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R126 stands for H; C3-6 alkyl; C3-6 cycloalkyl; phenyl, pyridyl, pyrimidinyl, imidazolyl, triazolyl, thiazolyl or thienyl; or for C3-6 cycloalkyl, phenyl or pyridyl bound via a C1-3 alkylene group, each unsubstituted or mono- or polysubstituted with identical or different substituents.

18. A compound as claimed in claim 1, wherein in formula (I) the substructure (B)




is selected from the group consisting of:


















wherein
h is 0 or 1;
g is 0 or 1;
m is 0 or 1;
n is 0 or 1;
o is 0, 1, 2 or 3;
r is 1, 2 or 3;
s is 0 or 1;
t is 0, 1, 2 or 3, with the proviso that ifs is 0, then t is 0;
M1, M2 and M3 can each stand for N or CH, wherein one of M1, M2 and M3 stands for N and the other two stand for CH;
R8 stands for H; C1-6 alkyl, or C3-6 cycloalkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R19 is selected from H; C1-6 alkyl; or C3-6 cycloalkyl; each unsubstituted or mono- or polysubstituted with identical or different substituents;
R34 and R35 are each independently methyl or ethyl or together with the N-atom linking them form an azetidinyl; pyrrolidinyl, piperidinyl, 4-(C1-6 alkyl)-piperazinyl group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R38 stands for H, C1-6 alkyl, C3-6 cycloalkyl or pyridyl;
R39 is selected from H; C1-6 alkyl; or C3-6 cycloalkyl, each unsubstituted or mono- or polysubstituted with identical or different substituents;
R45 stands for H, C1-6 alkyl, C3-6 cycloalkyl or pyridyl;
R190 represents 0 to 4 substituents each independently selected from the group consisting of F, Cl, O—CF3, CF3 and CN,
R271 stands for H; and
R272 stands for C1-4 alkyl, C3-6 cycloalkyl or a C3-6 cycloalkyl group bound via a C1-3 alkylene group; or
R271 and R272 together form a 4- to 7-membered heterocyclyl group, which may be substituted by 0 to 2 substituents selected from the group consisting of F, Cl, O—CF3, —CF3, and CN; or
two adjacent substituents may together form an anellated aryl or heteroary ring.

19. A compound as claimed in claim 1, selected from the group consisting of:
2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)ethanone;
1-(7-Cyclopropyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
1-(4-(Pyridin-4-yloxy)piperidin-1-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone;
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1-yl)ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-N-methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)acetamide;
2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
2-(2-(6-Methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethanone;
1-(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone;
N-Methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)acetamide;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-4-yloxy)piperidin-1-yl)ethanone;
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethanone;
2-((2-(2-Chloro-6-methylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-N-methyl-N-(2-(1-(pyridin-4-yl)piperidin-4-yl)ethyl)acetamide;
N-(3,3-Dimethylpiperidin-4-yl)-2-(2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide;
2-(2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(2-(pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethanone;
2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(piperidin-1-yl)ethanone;
2-(2-(2-Chloro-4-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
1-(2-(Pyridin-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-((2-(2-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(2,8-diazaspiro[4.5]decan-8-yl]ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-((1R,3S,5S)-3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanone;
2-((2-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)methoxy)-1-(4-(pyridin-3-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)ethanone;
2-(2-(4-Chloro-2,5-dimethylphenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
2-(2-(Phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
2-(2-(2,3-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
N-(6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide;
N-(6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-(3-(trifluoromethyl)phenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide;
N-(6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetamide;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-[1-[5-(trifluoromethyl)-pyridin-2-yl]-piperidin-4-yl]-acetamide;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-[1-[5-(trifluoromethyl)-pyridin-2-yl]-pyrrolidin-3-yl]-acetamide;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-(4-pyridin-4-yl-piperidin-1-yl)-ethanone;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[4-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-(1-pyridin-4-yl-piperidin-4-yl)-acetamide;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[3-[(4-methyl-piperazin-1-yl)-methyl]-pyrrolidin-1-yl]-ethanone;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-(3-pyridin-4-yloxy-pyrrolidin-1-yl)-ethanone;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-N-methyl-N-(1-pyridin-4-yl-piperidin-4-yl)-acetamide;
2-[[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-methoxy]-1-[4-(3-methyl-3,6-diazabicyclo[2.2.1]heptan-6-yl)-piperidin-1-yl]-ethanone;
N-[2-[4-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-ethyl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[(1R)-6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[(1R)-6-[(4-Fluoro-piperidin-1-yl)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1R)-6-[(2,2,2-trifluoro-ethylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[(1R)-1-[4-[(tert-Butylamino)-methyl]-phenyl]-ethyl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-(2-(3-chlorophenylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide;
2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-N-(5-(piperidin-1-ylmethyl)-2,3-dihydro-1H-inden-2-yl)acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1, 2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(1-Methyl-propylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(1, 2,3,4-Tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1, 2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(4-Methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(Pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(1,2,3,4-Tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2a]pyrazin-1-yl]-acetamide;
N-[6-(8-Azabicyclo[3.2.1]octan-8-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(3-chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[(6-methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(tert-Butyl-methyl-amino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(4-methyl-piperazin-1-yl)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1,2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(morpholin-4-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-[(tert-Butylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(pyrrolidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Dimethylaminomethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-[(1-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-[(Benzylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(piperidin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-(p-Tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1, 2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(1, 2,3,4-tetrahydro-quinolin-1-yl-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-[(1-Methyl-propylamino)-methyl]-1, 2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-[(1-methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetamide;
2-[2-[(6-Methoxy-naphthalen-2-yl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
2-[2-[(3-Chloro-4-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[6-(methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetamide;
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[6-(Methylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-[2-(p-tolylsulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
1-(4-Hydroxy-4-pyridin-3-yl-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-morpholin-4-yl-propyl)-acetamide;
N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone;
1-[4-[2-(2,5-Dimethyl-1H-pyrrol-1-yl)-ethyl]-piperazin-1-yl]-2-[2-[(4-methoxy 2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone;
2-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-morpholin-4-yl-propyl)-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
N-(1-Benzyl-pyrrolidin-3-yl)-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-morpholin-4-yl-piperidin-1-yl)-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-piperidin-1-yl-piperidin-1-yl)-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone;
2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-ethanone;
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-pyridin-3-yl-piperidin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(1-benzyl-pyrrolidin-3-yl)-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-ethyl-piperazin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-morpholin-4-yl-piperidin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[2-(2,5-dimethyl-1H-pyrrol-1-yl)-ethyl]-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone;
2-[4-[2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-pyrrolidin-3-yl)-methyl]-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone;
N-[3-(2,6-Dimethyl-piperidin-1-yl)-propyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
N-[2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
1-[4-(2-Fluorophenyl)-piperazin-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-(4-Ethyl-piperazin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-(4-Piperidin-1-yl-piperidin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-[4-(5-Methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-(4-Pyridin-2-yl-piperazin-1-yl)-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide;
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone;
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone;
2-[4-[2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[(4-chloro-2,5-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[3-(2,6-dimethyl-piperidin-1-yl)-propyl]-acetamide;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-methyl-1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethanone;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone;
2-[4-[2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-[1,4]diazepan-1-yl]-pyridine-3-carbonitrile;
N-[(1-Benzyl-pyrrolidin-3-yl)-methyl]-2-[2-[[2-chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-pyrrolidin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-piperidin-1-yl-propyl)-acetamide;
1-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-[4-(4-Chlorophenyl)-4-hydroxy-piperidin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-piperidin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-piperidin-1-yl-ethyl)-acetamide;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(piperidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3-methoxyphenyl)-piperazin-1-yl]-ethanone;
1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-(4-Isopropyl-piperazin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-pyrrolidin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-(3-piperidin-1-yl-propyl)-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-piperidin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-piperidin-1-yl-ethyl)-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3-methoxyphenyl)-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-n-1-yl]-1-(4-isopropyl-piperazin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methoxyphenyl)-piperazin-1-yl]-ethanone;
2-[2-[(4-Chloro-2,5-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-1-phenyl-ethyl]-acetamide;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(3,4-dichlorophenyl)-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(p-tolyl-methyl)-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-methoxyphenyl)-methyl]-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2-fluorophenyl)-methyl]-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-[(1-benzyl-piperidin-3-yl)-methyl]-acetamide;
2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2,4,6-trimethyl-phenyl)-methyl]-piperazin-1-yl]-ethanone;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(4-methoxyphenyl)-piperazin-1-yl]-ethanone;
1-[4(3,4-Dichlorophenyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(2,4,6-trimethyl-phenyl)-methyl]-piperazin-1-yl]-ethanone;
1-[4-[(4-Chlorophenyl)-methyl]-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(p-tolyl-methyl)-piperazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-methoxyphenyl)-methyl]-piperazin-1-yl]-ethanone;
1-[4-[(2-Fluorophenyl)-methyl]-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-piperidin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone;
1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
3-[4-[2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-propionitrile;
N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(4-chlorophenyl)-methyl]-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-2-yl-methyl)-piperidin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(pyridin-4-yl-methyl)-piperidin-1-yl]-ethanone;
1-[4-(1,3-Benzodioxol-5-yl-methyl)-piperazin-1-yl]-2-[2-[(2-chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
3-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-propionitrile;
N-[(1-Benzyl-piperidin-3-yl)-methyl]-2-[2-[[2-chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetamide;
1-[2-(4-Dimethylaminophenyl)-azepan-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(4-Methoxy-2,6-dimethyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-acetamide;
1-(4-Benzyl-piperidin-1-yl)-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
1-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-2-[2-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1, 2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-N-methyl-N-(2-morpholin-4-yl-1-phenyl-ethyl)-acetamide;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-(pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone;
2-[4-[2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-pyridine-3-carbonitrile;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone;
2-[2-[(2-Chloro-6-methyl-phenyl)sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[(2S)-2-(pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[3-chloro-5-(trifluoromethyl)-pyridin-2-yl]-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[4-[(3,4-dichlorophenyl)-methyl]-piperazin-1-yl]-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-methyl-2-phenyl-piperazin-1-yl)-ethanone;
2-[2-(Benzenesulfonyl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-(4-phenyl-piperidin-1-yl)-ethanone;
2-[4-[2-[2-[[3-(Trifluoromethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-acetyl]-piperazin-1-yl]-pyridine-3-carbonitrile;
2-[2-[[2-Chloro-4-(trifluoromethyl)-phenyl]sulfonyl]-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-1-yl]-1-[2-(4-dimethylaminophenyl)-pyrrolidin-1-yl]-ethanone;

or a physiologically compatible salt thereof.

20. A pharmaceutical composition comprising a compound as claimed in claim 1 and at least one pharmaceutically acceptable carrier or auxiliary substance.