(19)
(11)EP 3 818 047 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
27.07.2022 Bulletin 2022/30

(21)Application number: 19733494.9

(22)Date of filing:  27.06.2019
(51)International Patent Classification (IPC): 
C07D 231/12(2006.01)
C07D 403/04(2006.01)
A61K 31/4155(2006.01)
C07C 69/96(2006.01)
A61P 33/14(2006.01)
(52)Cooperative Patent Classification (CPC):
C07C 69/96; C07D 231/12; C07D 403/04; A61P 33/14
(86)International application number:
PCT/EP2019/067165
(87)International publication number:
WO 2020/007704 (09.01.2020 Gazette  2020/02)

(54)

NOVEL COMPOUNDS FOR CONTROLLING ARTHROPODS

NEUARTIGE VERBINDUNGEN ZUR BEKÄMPFUNG VON ARTHROPODEN

NOUVEAUX COMPOSÉS DE LUTTE CONTRE LES ARTHROPODES


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 05.07.2018 EP 18181950

(43)Date of publication of application:
12.05.2021 Bulletin 2021/19

(73)Proprietor: Bayer Animal Health GmbH
51373 Leverkusen (DE)

(72)Inventors:
  • TELSER, Joachim
    42115 Wuppertal (DE)
  • KRENZ, Ursula
    42799 Leichlingen (DE)
  • BÖRNGEN, Kirsten
    50859 Köln (DE)
  • TURBERG, Andreas
    42781 Haan (DE)
  • SOFIA, Klein
    50823 Köln (DE)
  • SCHMIDT, Franziska
    40627 Düsseldorf (DE)

(74)Representative: Cohausz & Florack 
Patent- & Rechtsanwälte Partnerschaftsgesellschaft mbB Bleichstraße 14
40211 Düsseldorf
40211 Düsseldorf (DE)


(56)References cited: : 
WO-A1-2016/020441
WO-A1-2016/174052
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    Introduction and Background of the Invention



    [0001] The present invention relates to novel halogen-substituted compounds, to processes for their preparation and to their use for controlling animal pests, in particular arthropods and especially insects and arachnids.

    State of the Art


    Ectoparasiticides



    [0002] Halogenated carboxamides with insecticidal and ectoparasiticidal activity are described in EP 1911751, WO 2012/069366, WO 2012/080376, WO 2012/107434, WO 2012/175474, WO2014/122083 and WO2015/067647. Combinations of halogenated carboxamides for the treatment of animal pests have been described in WO 2016/174052.

    [0003] Besides the aforementioned classes also other compounds with ectoparasiticidal activity are well-known in the art. Common to these molecules of a number of different molecular modes of action is that none of them exerts a broad arthropodicidal effect over a period of more than three months. Commercial use of prolonged broad arthropodicidal activity can only be found in constant release approaches as used in collars (e.g. deltamethrin in Scalibor® or flumethrin/imidacloprid in Seresto®). A convenient one-time parenteral application with broad arthropod control is not marketed or shown to work in practice to date. Reasons for failure in that area can be found in short halflife, low solubility, low bioavailability, insufficient stability, incomplete arthropod parasite spectrum, local and systemic side effects. A multitude of these parameters need to be improved to lead to a successful approach to fulfil the need of a systemic treatment of ectoparasites with an extended term of efficacy.

    Prodrugs



    [0004] In cases where the efficacy of a drug is limited by its physicochemical properties, a prodrug concept may be used. Prodrugs are defined as bioreversible derivatives of the corresponding parent drugs.This means that the prodrug carries a cleavable group, a so called pro-moiety. This group facilitates administration, absorption into the body and distribution in the treated animal or human.The pro-moiety is cleaved by biological or chemical transformations in the patient's body liberating the parent drug once the prodrug has been absorbed. A general overview of prodrug concepts can be found, for instance, in a review article by J. Rautio, H. Kumpulainen, T. Heimbach, R. Oliyai, D. Oh, T. Järvinen, J. Savolainen, Nature Reviews Drug Discovery 2008, 255-270. In many cases, the administration of a drug is limited by its poor aqueous solubility which can impact both oral and, even more so, parenteral administration. Prodrugs have been described for both oral and intravenous applications of drugs whereas little is known about prodrugs for subcutaneous use (see V.J. Stella, K.W. Nti-Addae, Advanced Drug Delivery Reviews 2007, 59, 677-694). Many prodrugs use an attachment group of the parent drug to link the pro-moiety via a linker group and optionally spacer groups. Attachment points are usually functional groups of the parent drug which allow the bioreversible chemical modification, for instance hydroxyl groups, carboxylic acid groups, amino groups, amides or other. A recent example of carbamate linkers attached to an amide group can be found in C. Liu, J. Lin, G. Everlof, C. Gesenberg, H. Zhang, P.H. Marathe, M. Malley, M.A. Gallella, M. McKinnon, J.H. Dodd, J.C. Barrish, G.L. Schieven, K. Leftheris, Bioorg. Med. Chem. Lett. 2013, 23, 3028-3033.

    [0005] Besides carbamates, also carbonate esters are occasionally described as linkers in the prodrug literature, e.g. for the modification of a pyridyl group (see E. Binderup, F. Björkling, P.V. Hjranaa, S. Latini, B. Balther, M. Carlsen, L. Binderup, Bioorg Med. Chem. Lett. 2005, 15, 2491-2494).

    [0006] It was thus an object of the present invention to provide novel compounds with high insecticidal and ectoparasiticidal systemic activity and enhanced solubility. A further object of the present invention was to provide novel compounds with high ectoparasiticidal, in particular insecticidal and/or acaricidal, systemic activity and improved bioavailability compared to known compounds. It was a further object of the present invention to provide novel compounds with high ectoparasiticidal, in particular insecticidal and/or acaricidal,systemic activity having sufficient stability in formulations for pharmaceutical administration. It was a further object of the present invention to provide novel compounds with high insecticidal and ectoparasiticidal systemic activity with optimum balance of stability in formulations for pharmaceutical administration and systemic release properties to release the active principle of the novel compounds under systemic conditions in the body. In a further object of the present invention the systemic release of the active principle of the novel compounds should occur at a suitable point of time or over a suitable time period to achieve improved systemic activity in the treatment. A further object of the present invention was to provide novel compounds with high insecticidal and ectoparasiticidal systemic activity and enhanced solubility in formulations for subcutaneous administration. The novel compounds should also not be toxic or release toxic groups upon administration.

    [0007] The inventors of the present invention now surprisingly found that with the new compounds of the present invention the disadvantages of the prior art can be avoided and the objects described above can be solved.

    [0008] Accordingly, the new compounds further exhibit and can therefore be employed particularly well in the animal health sector.

    Detailed Description of the Invention



    [0009] The present invention can be described in particular by the following embodiments:
    1. [1] In a first aspect the invention relates to compounds of formula (I)

      wherein
      Q
      is O or absent;
      L1
      is linear C2-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from halogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a moiety (CH2)n-X-(CH2)m wherein n and m are independently 0, 1 or 2 and X is C3-C7-cycloalkanediyl, which is optionally substituted with C1-C4 alkyl; or L1 is absent; with the proviso that in the case of L1 being absent, Q is also absent;
      L2
      is C=O or absent,
      L3
      is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2; or is C3-C7-cycloalkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4-alkyl and halogen;
      Y
      is selected from a group T1

      wherein
      R1, R2 and R3
      are each independently selected from hydrogen, halogen, cyano, nitro, linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, linear or branched halogen-substituted C1-C6-alkyl, halogen-substituted C1-C6-alkoxy, halogen substituted C3-C6-cycloalkyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, N-C1-C6-alkylamino, N,N-di-C1-C6-alkylamino, N-C1-C3-alkoxy-C1-C4-alkylamino and 1-pyrrolidinyl
      or a group T2

      wherein
      Z1 and Z2
      are each independently selected from hydrogen, halogen, cyano, nitro, linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halogen-substituted linear or branched C1-C6-alkyl, halogen-substituted C1-C6-alkoxy, halogen substituted C3-C6-cycloalkyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, N-C1-C6-alkylamino, N,N-di-C1-C6-alkylamino, N-C1-C3-alkoxy-C1-C4-alkylamino and 1-pyrrolidinyl; and
      Z3
      represents hydrogen or linear C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl or hetaryl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, amino, C1-C3-alkyl, C1-C3-alkoxy, hydroxycarbonyl, alkoxycarbonyl, alkylcarbamoyl, cycloalkylcarbamoyl and phenyl
      and to the salts thereof.
    2. [2] In a further aspect the invention relates to compounds of formula (I) as defined in [1] wherein
      Q
      is O;
      L2
      is C=O;
      L3
      is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2; and
      L1
      has the meaning as defined in [1];
      and the salts thereof.
    3. [3] In a further aspect the invention relates to compounds of formula (I) as defined in [1] or [2] wherein
      Q
      is O;
      L2
      is C=O;
      L3
      is a group (CH2)n-(CH=CH)-CH2)m, wherein n and m are 0; and
      L1
      has the meaning as defined in [1];
      and the salts thereof.
    4. [4] In a further aspect the invention relates to compounds of formula (I) as defined in [1] wherein
      Q
      is O
      L2
      is C=O
      L3
      is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and
      L1
      has the meaning as defined in [1];
      and the salts thereof.
    5. [5] In a further aspect the invention relates to compounds of formula (I) as defined in [1] wherein
      Q
      is O;
      L2
      is absent;
      L3
      is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and
      L1
      has the meaning as defined in [1];
      and the salts thereof.
    6. [6] In a further aspect the invention relates to compounds of formula (I) as defined in [1] wherein
      L1, L2 and Q
      are absent; and
      L3
      has the meaning as defined in [1];
      and the salts thereof.
    7. [7] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [6]
      wherein
      Q
      is O or absent;
      L1
      is linear C2-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl and C3-C6 cycloalkyl, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a moiety (CH2)n-X-(CH2)m wherein n and m are 0 and X is C5- or C6-cycloalkanediyl, which is optionally substituted with C1-C4 alkyl; or L1 is absent; with the proviso that in the case of L1 being absent, Q is also absent;
      L2
      is C=O or absent,
      L3
      is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are 0; or is C3-C7-cycloalkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4-alkyl and halogen;
      and the salts thereof.
    8. [8] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [7]
      wherein.
      Q
      is O or absent;
      L1
      is selected from 1,2-ethanediyl, 1,3-propanediyl, dimethyl-propanediyl, cyclopentanediyl, cyclohexanediyl; or
      L1
      is absent; with the proviso that in the case of L1 being absent, Q is also absent;
      L2
      is C=O or absent,
      L3
      has the meaning as defined in [1];
      and the salts thereof.
    9. [9] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [8]
      wherein
      Q
      is O or absent;
      L2
      is C=O or absent;
      L3
      is selected from methylene, 1,2-ethanediyl, 1,3-propanediyl, dimethyl-ethanediyl, , ethene-1,2-diyl, and cyclohexanediyl or a group

      , wherein n and m are independently 0, 1, 2;
      L1
      has the meaning as defined in [1];
      and the salts thereof.
    10. [10] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [9]
      wherein
      Q
      is O;
      and the salts thereof.
    11. [11] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [10]
      wherein
      L1
      is linear C2-C4 alkanediyl, which is optionally substituted with one or more C1-C4 alkyl groups, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded
      and the salts thereof.
    12. [12] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [11]
      wherein
      L2
      is C=O
      and the salts thereof.
    13. [13] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [12]
      wherein
      L3
      is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2, preferably n and m are 0;
      and the salts thereof.
    14. [14] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [13]
      wherein
      Y
      is selected from a group T1


      wherein
      R1, R2 and R3
      are each independently selected from hydrogen, halogen, linear or branched C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, linear or branched halogen-substituted C1-C3-alkyl, halogen-substituted C1-C3-alkoxy, halogen substituted C3-C6-cycloalkyl, and 1-pyrrolidinyl
      or a group T2

      wherein
      Z1
      represents linear or branched C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, which may independently of one another be substituted with 1 to 5 substituents selected from ^ hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy,
      Z2
      represents halogen, cyano, nitro, amino, or linear or branched C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy; and
      Z3
      represents hydrogen or linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl or hetaryl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy;
      and the salts thereof.
    15. [15] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [14]
      wherein
      Y
      is selected from a group T1


      wherein
      R1, R2 and R3
      are each independently selected from halogen, linear or branched halogen-substituted C1-C3-alkyl, and halogen-substituted C1-C3-alkoxy;
      or a group T2

      wherein
      Z1
      represents linear or branched C1-C3-alkyl or C3-C6-cycloalkyl, which may independently of one another be substituted with 1 to 5 halogen substituents,
      Z2
      represents linear or branched C1-C3-alkyl, which may be substituted with 1 to 5 halogen substituents, preferably with 1 to 3 halogen substituents, more preferably trifluoromethyl, or
      Z2
      represents nitro, methylsulphanyl, methylsulphinyl, methylsulphonyl, fluorine, chlorine, bromine, iodine; and
      Z3
      represents hydrogen or linear or branched C1-C6-alkyl which may be substituted with 1 to 5 substituents selected from hydroxy, halogen, C1-C3-alkyl, and C1-C3-alkoxy;
      and the salts thereof.
    16. [16] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [15]
      wherein
      Y
      is selected from a group T1


      wherein
      \R1
      is halogen;
      R2
      is linear or branched C1-C3-alkyl substituted with 1 to 7 halogen and
      R3
      is C1-C3-alkoxy substituted with 1 to 3 halogen;
      or a group T2

      wherein
      Z1
      represents linear or branched C1-C3-alkyl or C3-C6-cycloalkyl, substituted with 1 to 5 halogen substituents,
      Z2
      represents linear or branched C1-C3-alkyl substituted with 1 to 3 halogen substituents, or
      Z2
      represents nitro, methylsulphanyl, methylsulphinyl, methylsulphonyl, fluorine, chlorine, bromine, iodine; and
      Z3
      represents hydrogen or linear or branched C1-C6-alkyl;
      and the salts thereof.
    17. [17] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [16]
      wherein
      Y
      is selected from a group T1


      wherein
      R1
      is fluorine, bromine or chlorine, preferably chlorine;
      R2
      is linear or branched C1-C3-alkyl substituted with 1 to 7 fluorine and
      R3
      is C1-C3-alkoxy substituted with 1 to 3 fluorine;
      or a group T2

      wherein
      Z1
      represents trifluoromethyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl or pentafluoroethyl;
      Z2
      represents linear or branched C1-C3-alkyl substituted with 1 to 3 fluorine; and
      Z3
      represents linear or branched C1-C6-alkyl;
      and the salts thereof.
    18. [18] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [17]
      wherein
      Y
      is selected from a group T1


      wherein
      R1
      is chlorine;
      R2
      is CF3, C2F5 or C3F7 and
      R3
      is OCF3, OC2F5 or OC3F7;
      or a group T2

      wherein
      Z1
      represents trifluoromethyl or pentafluoroethyl;
      Z2
      represents trifluoromethyl; and
      Z3
      represents hydrogen, methyl, ethyl, or n-propyl;
      and the salts thereof.
    19. [19] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [18]
      wherein T1 is represented by the following group T1-1:

      and the salts thereof.
    20. [20] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [18]
      wherein T1 is represented by the following group T1-2:

      and the salts thereof.
    21. [21] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [18]
      wherein T1 is represented by the following group T2-1:

      and the salts thereof.
    22. [22] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects wherein Y is T1 as defined in any of the aspects [1] to [20];
      and the salts thereof.
    23. [23] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [22], which are in the form of salts, solvates, N-oxides and tautomeric forms thereof.
    24. [24] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [23], which are selected from

      (11E)-1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}phenyl)-2-(1 -cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridec-11-en-13-oic acid,

      (12E)-1-(2-Chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,11 -trioxo-4,6,10-trioxa-2-azatetradec-12-en-14-oic acid,

      1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid,

      (12E)-1-(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,10-trioxa-2-azatetradec-12-en-14-oic acid,

      1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,10-trioxa-2-azatetradecan-14-oic acid,

      (2E)-4-({(rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobut-2-enoic acid,

      4-({(rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobutanoic acid,

      1-(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oic acid,

      1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-12,12-dimethyl-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid,

      (2E)-4-({(1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)-oxy]cyclopentyl}oxy)-4-oxobut-2-enoic acid,

      4-({(1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)-oxy]cyclopentyl}oxy)-4-oxobutanoic acid,

      1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatetradecan-14-oic acid,

      1-[10-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-9-(1-cyanocyclopropyl)-6,10-dioxo-2,5,7-trioxa-9-azadecanan-1-oyl]cyclopropane-1-carboxylic acid,

      (2E)-4-({cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)-oxy]cyclohexyl}oxy)-4-oxobut-2-enoic acid,

      4-({cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl} oxy)-4-oxobutanoic acid,

      (2E)-4-({trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]-methoxy}carbonyl)oxy]cyclohexyl}oxy)-4-oxobut-2-enoic acid,

      cis-4-[({[(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]-methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid,

      trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] - methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid,

      [({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]acetic acid;

      and the salts solvates, N-oxides and tautomeric forms thereof.
    25. [25] In a further aspect the invention relates to compounds of formula (I) as defined in any one of the preceding aspects [1] to [24], which are for use as medicaments.
    26. [26] In a further aspect the invention relates to pharmaceutical compositions comprising at least one compound according to any of the preceding aspects [1] to [25].
    27. [27] In a further aspect the invention relates to pharmaceutical compositions according to aspect [26], comprising at least one further component selected from auxiliaries, excipients and/or solvents.
    28. [28] In a further aspect the invention relates to pharmaceutical compositions according to aspect [26] or [27], comprising at least one additional pharmaceutically active agent.
    29. [29] In a further aspect the invention relates to pharmaceutical compositions according to aspect [28], wherein the at least one additional pharmaceutically active agent is selected from the group of active agents with ectoparasiticidal activity, in particular with insecticidal and/or acaricidal activity, or from the group of antigens for vaccination purposes.
    30. [30] In a further aspect the invention relates to pharmaceutical compositions according to any of the preceding aspects [26] to [29], which are in the form of an injectable formulation.
    31. [31] In a further aspect the invention relates to pharmaceutical compositions according to any of the preceding aspects [26] to [29], which are in the form of a formulation for oral administration.
    32. [32] In a further aspect the invention relates to the compounds or the pharmaceutical compositions according to any of the preceding aspects for subcutaneous application.
    33. [33] In a further aspect the invention relates to the compounds or the pharmaceutical compositions according to any of the preceding aspects for oral application.
    34. [34] In a further aspect the invention relates to the compounds or the pharmaceutical compositions according to any of the preceding aspects for treating animals.
    35. [35] In a further aspect the invention relates to the compounds or the pharmaceutical compositions according to aspect [34], wherein the animals to be treated are selected from companion animals.
    36. [36] In a further aspect the invention relates to the compounds or the pharmaceutical compositions according to aspect [34] or [35], wherein the companion animals are selected from cats and dogs, preferably from dogs.
    37. [37] In a further aspect the invention relates to the use of the compounds or the pharmaceutical compositions according to any one of the preceding aspects for controlling insects and arachnids.
    38. [38] In a further aspect the invention relates to the use according to aspect [37], wherein the insects and arachnids are selected from the group of Chelicerata.
    39. [39] In a further aspect the invention relates to the use according to aspect [37] or [38], wherein the insects and arachnids are selected from the group consisting of ticks, lice, mosquitoes, flies, fleas, acari and mites.
    40. [40] In a further aspect the invention relates to the use of the compounds as defined in any one of the preceding aspects for preparing pharmaceutical compositions for controlling parasites on animals.
    41. [41] In a further aspect the invention relates to the use of the compounds or the pharmaceutical compositions according to any one of the preceding aspects with treatment intervals of 3 months to two years, preferably 4 months to one year.
    42. [42] In a further aspect the invention relates to the use of the compounds or the pharmaceutical compositions according to aspect [41], wherein the treatment intervals are 6 months to one year, preferably 9 months to one year.
    43. [43] In a further aspect the invention relates to the use of the compounds or the pharmaceutical compositions according to any of the preceding aspects, wherein the total amount of the compounds as defined in any one of the preceding aspects to be administered is in the range of from 0.01 to 200 mg/kg body weight per application, preferably in the range of from 0.1 to 100 mg/kg body weight per application, more preferably of from 0.5 to 75 mg/kg body weight per application, more preferably in the range of from 1.0 to 50 mg/kg body weight per application, most preferably in the range of from 2.0 to 20 mg/kg body weight per application.
    44. [44] In a further aspect the invention relates to a process for preparing the compounds according to any of the preceding aspects comprising the step of reacting a compound (A)

      (A)
      with a group (B)

      (B)
      wherein
      Y, Q, L1, L2 and L3 have the meaning as defined in any one of the preceding aspects and wherein PG1 represents a protecting group or hydrogen to form the compounds according to formula (I), and wherein in cases wherein PG1 is not hydrogen, deprotection is carried out to form the compounds (I).
    45. [45] In a further aspect the invention relates to the process according to aspect [44] further comprising the preliminary step of preparing the group (B) by
      1. i) reacting a compound (IIa) with a compound (IIIa) to form compound (Va), wherein PG2 is a protecting group or hydrogen, and wherein in cases wherein PG2 is not hydrogen (Va) is obtained by selectively cleaving PG2:

        wherein L1 and L3 have the meaning as defined in any one of the preceding aspects and wherein PG1 represents a protecting group or hydrogen;
        or
      2. ii) reacting a compound (VI) with compound (IIIb) to form compound (Vb) , wherein PG2 is a protecting group or hydrogen, and wherein in cases wherein PG2 is not hydrogen (Vb) is obtained by selectively cleaving PG2:

        wherein L1, L2 and L3 have the meaning as defined in any one of the preceding aspects and wherein PG1 represents a protecting group or hydrogen.
    46. [46] In a further aspect the invention relates to intermediate compounds according to formula (B),

      (B)
      wherein
      Q
      is O;
      L2
      is C=O;
      L1 and L3
      have the meaning as defined in any one of the preceding aspects and
      PG1
      represents a tert-butyl group.
    47. [47] In a further aspect the invention relates to intermediate compounds according to formula (C),

      (C)
      wherein Y, Q, L1, L2 and L3 have the meaning as defined in any one of the preceding aspects and wherein PG1 represents a tert-butyl group.
    48. [48] In a further aspect the invention relates to intermediate compounds selected from tert-Butyl-2-{[(chloromethoxy)carbonyl]oxy}ethyl-(2E)-but-2-enedioate (Intermediate3A); tert-Butyl-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropane-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl-(2E)-but-2-enedioate (Intermediate 4A); tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl (2E)-but-2-enedioate (Intermediate 6A); tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]propyl (2E)-but-2-enedioate (Intermediate 7A); tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl butanedioate (Intermediate 9A); tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl butanedioate (Intermediate 10A); tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl (2E)-but-2-enedioate (Intermediate 12A); tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]-2,2-dimethylpropyl (2E)-but-2-enedioate (Intermediate 13A); tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl butanedioate (Intermediate 14A); tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]-2,2-dimethylpropyl butanedioate (Intermediate 15A); tert-Butyl (rel 1S,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (Intermediate 17A); tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate (Intermediate 18A); tert-Butyl (rel 1S,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate (Intermediate 19A); tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}benzoyl)(1 -cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl butanedioate (Intermediate 20A); tert-Butyl 3-[2-(benzyloxy)ethoxy]-2,2-dimethylpropanoate (Intermediate 21A); tert-Butyl 3-(2-hydroxyethoxy)-2,2-dimethylpropanoate (Intermediate 22A); tert-Butyl 3-(2-{[(chloromethoxy)carbonyl]oxy}ethoxy)-2,2-dimethylpropanoate (Intermediate 23A); tert-Butyl 1 -(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oate (Intermediate 24A); 1-tert-Butyl 4-(2-hydroxyethyl) 2,2-dimethylsuccinate (Intermediate 28A) 1-tert-Butyl 4-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) 2,2-dimethylbutanedioate (Intermediate 29A); 1-tert-Butyl 4-{2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl} 2,2-dimethylbutanedioate (Intermediate 30A); tert-Butyl (1S,2S)-2-hydroxycyclopentyl (2E)-but-2-enedioate (Intermediate 31A); tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (Intermediate 32A); tert-Butyl (1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate (Intermediate 33A); tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate (Intermediate 34A); tert-Butyl (1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}benzoyl)(1 -cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl butanedioate (Intermediate 35A); tert-Butyl 2-hydroxyethyl pentanedioate (Intermediate 36A); tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl pentanedioate (Intermediate 37A); tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl pentanedioate (Intermediate 38A); 1-tert-Butyl 1-(2-hydroxyethyl) cyclopropane-1,1-dicarboxylate (Intermediate 39A); 1-tert-Butyl 1-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) cyclopropane-1,1-dicarboxylate (Intermediate 40A); 1-tert-Butyl 1-{2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]ethyl} cyclopropane-1,1-dicarboxylate (Intermediate 41A); tert-Butyl-4-hydroxycyclohexyl (2E)-but-2-enedioate (Mixture of diastereomers) (Intermediate 42A); tert-Butyl cis-4-hydroxycyclohexyl (2E)-but-2-enedioate Intermediate 43A); tert-Butyl trans-4-hydroxycyclohexyl (2E)-but-2-enedioate (Intermediate 44A); tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (Intermediate 45A); tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (Intermediate 46A); tert-Butyl cis-4-hydroxycyclohexyl butanedioate (Intermediate 47A); tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl butanedioate (Intermediate 48A); tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexyl butanedioate (Intermediate 49A); tert-Butyl trans-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (Intermediate 50A); tert-butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (Intermediate 51A); tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (Intermediate 52A); tert-Butyl cis-4-[({[(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexane-1-carboxylate (Intermediate 53A); tert-Butyl trans-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (Intermediate 54A); tert-Butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexane-1-carboxylate (Intermediate 55A); tert-Butyl [({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]acetate (Intermediate 57A).

    Definitions



    [0010] "Arachnids" are a class (Arachnida) of joint-legged invertebrate animals (arthropods), in the subphylum Chelicerata. A preferred subclass of the arachnids are acari (or acarina) which comprise in particular mites and ticks.

    [0011] The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.

    [0012] The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

    [0013] As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2".

    [0014] As used herein, the position via which a respective subsituent is connected to the rest of the molecule may in a drawn structure be depicted by a star sign [] in said substituent.

    [0015] The term "comprising" when used in the specification includes "consisting of".

    [0016] If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.

    [0017] The terms as mentioned in the present text have the following meanings:
    The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, more particularly chlorine and/or fluorine.

    [0018] The term "C1-C4-alkanediyl" represents a divalent straight-chained (linear) or branched alkanediyl radical having from 1 to 4, preferably 1, 2 or 3, more preferably 2 or 3, carbon atoms. The term "C2-C4-alkanediyl" represents a divalent straight-chained (linear) or branched alkanediyl radical having from 2 to 4, preferably 2 or 3 carbon atoms. The following may be mentioned as preferred examples: methylene, 1,2-ethanediyl, ethane-1,1-diyl, 1,3-propylene (1,3-propanediyl), propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, 1,4-butylene (1,4-butanediyl), butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl. Preferred are methylene, 1,2-ethanediyl and 1,3-propylene (1,3-propanediyl), more preferred are 1,2-ethanediyl and 1,3-propylene (1,3-propanediyl).

    [0019] In the present invention a linear C1-C4-alkanediyl group or a C2-C4-alkanediyl group may be substituted with one or more groups independently selected from halogen (as defined above), C1-C4 alkyl and C3-C6 cycloalkyl. In the present invention a linear C1-C4-alkanediyl group or a C2-C4-alkanediyl group, which is substituted with one or more groups selected from C1-C4 alkyl comprises in particular a 1,2-dimethyl-ethanediyl group and a 2,2-dimethyl-1,3-propanediyl group.

    [0020] In the case of a C1-C4-alkanediyl group or a C2-C4-alkanediyl group which may be substituted with one or more C1-C4 alkyl substituents, it is also possible that two C1-C4-alkyl substituents form a ring together with the carbon atom to which they are bonded. Respective groups comprise in particular the following groups:



    [0021] Preferably a respective group is



    [0022] Therein n and m are independently 0, 1, 2 or 3. Preferably n and m are independently 0, 1 or 2. More preferably one of n and m is 0 and the other one is 1.

    [0023] The term "C1-C6-alkyl", comprises linear and branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C1-C4-alkyl" comprises linear and branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The term "C1-C3-alkyl" comprises linear and branched, saturated, monovalent hydrocarbon group having 1, 2 or 3 carbon atoms. Examples of the respective alkyl-groups are a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, a tert-butyl group etc., or an isomer thereof. Most preferred are methyl, ethyl, and n-propyl

    [0024] The term "C3-C7-cycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms. The term "C3-C6-cycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms. The term "C3-C5-cycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4 or 5 carbon atoms. Said C3-C7-cycloalkyl groups are for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. Particularly, said cycloalkyl group contains 3, 5 or 6 carbon atoms and is e.g. cyclopropyl, cyclopentyl or cyclohexyl.

    [0025] The term "C3-C7-cycloalkanediyl" represents a divalent monocyclic hydrocarbon radical having from 3 to 7, preferably from 3 to 6 ring carbon atoms. Examples are the following groups:



    and



    [0026] Therein, the following groups are preferred:



    [0027] Said C3-C7-cycloalkanediyl groups may be substituted with one or more groups independently selected from C1-C4-alkyl and halogen, each as defined above.

    [0028] In the present invention the subsituent L1 may be a moiety (CH2)n-X-(CH2)m wherein n and m are independently 0, 1 or 2 and wherein × is a C3-C7-cycloalkanediyl group as defined above. Therein, the groups (CH2)n and (CH2)m are bound to the C3-C7-cycloalkanediyl groups at the positions indicated with in the formulae supra. In the case of n and m both being 0 the respective moiety corresponds to a C3-C7-cycloalkanediyl group as defined above. Particular examples of said moiety comprise:

    with one of n or m being 1 and the other one being 0 and

    wherein in each case n and m are both 0.

    [0029] In the present invention the subsituent L3 may be a moiety (CH2)n-(CH=CH)-CH2)m wherein n and m are independently 0, 1 or 2. Examples comprise ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl, but-1-ene-1,3-diyl, but-2-ene-1,4-diyl, buta-1,3-diene-1,4-diyl, pent-2-ene-1,5-diyl, hex-3-ene-1,6-diyl and hexa-2,4-diene-1,6-diyl. Preferably n and m are both 0, i.e. an ethene-1,1-diyl group.

    [0030] Said (CH2)n-(CH=CH)-CH2)m groups may be substituted with one or more groups independently selected from C1-C4-alkyl, C3-C5-cycloalkyl and halogen, each as defined above.

    [0031] The term "C1-C6-alkoxy" represents a straight-chain or branched O-alkyl having 1 to 6 carbon atoms, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy and t-butoxy. Preference is also given to alkoxy groups having 1 to 4 carbon atoms. The inventive alkoxy groups may be substituted by one or more identical or different radicals.

    [0032] The term " C1-C6-alkylsulphanyl" represents straight-chain or branched S-alkyl having 1 to 6 carbon atoms, for example methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio and t-butylthio. Preference is also given to alkylsulphanyl groups having 1 to 4 carbon atoms. The inventive alkylsulphanyl groups may be substituted by one or more identical or different radicals.

    [0033] The term " C1-C6-alkylsulphinyl" represents straight-chain or branched alkylsulphinyl having 1 to 6 carbon atoms, for example methylsulphinyl, ethylsulphinyl, n-propylsulphinyl, isopropylsulphinyl, n-butylsulphinyl, isobutylsulphinyl, s-butylsulphinyl and t-butylsulphinyl. Preference is also given to alkylsulphinyl groups having 1 to 4 carbon atoms. The inventive alkylsulphinyl groups may be substituted by one or more identical or different radicals.

    [0034] The term "alkylsulphonyl" represents straight-chain or branched alkylsulphonyl having 1 to 6 carbon atoms, for example methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, isobutylsulphonyl, s-butylsulphonyl and t-butylsulphonyl. Preference is also given to alkylsulphonyl groups having 1 to 4 carbon atoms. The inventive alkylsulphonyl groups may be substituted by one or more identical or different radicals.

    [0035] The terms "halogen-substituted C1-C6-alkyl", "halogen-substituted C1-C6-alkoxy" and "halogen-substituted C3-C6-cycloalkyl" represent C1-C6-alkyl, C1-C6-alkoxy and C3-C6-cycloalkyl groups as defined above, which are mono- or polysubstituted by halogen up to the maximum possible number of substituents. Such groups are also referred to as halo groups (for example haloalkyl). In the case of polysubstitution by halogen, the halogen atoms may be the same or different, and may all be bonded to one carbon atom or may be bonded to a plurality of carbon atoms. Halogen is especially fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine and more preferably fluorine. More particularly, halogen-substituted groups are monohalocycloalkyl such as 1-fluorocyclopropyl, 2-fluorocyclopropyl or 1-fluorocyclobutyl, monohaloalkyl such as 2-chloroethyl, 2-fluoroethyl, 1-chloroethyl, 1-fluoroethyl, chloromethyl, or fluoromethyl; perhaloalkyl such as trichloromethyl or trifluoromethyl or CF2CF3, polyhaloalkyl such as difluoromethyl, 2-fluoro-2-chloroethyl, dichloromethyl, 1,1,2,2-tetrafluoroethyl or 2,2,2-trifluoroethyl. Further examples of haloalkyls are trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl and pentafluoro-t-butyl. Preference is given to haloalkyls having 1 to 4 carbon atoms and 1 to 9, preferably 1 to 5, identical or different halogen atoms selected from fluorine, chlorine and bromine, preferably from fluorine. Particular preference is given to haloalkyls having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms selected from fluorine and chlorine, such as, inter alia, difluoromethyl, trifluoromethyl or 2,2-difluoroethyl. Further examples of halogen-substituted compounds are haloalkoxy such as OCF3, OCHF2, OCH2F, OCF2CF3, OCH2CF3, OCH2CHF2 and OCH2CH2Cl, haloalkylsulphanyls such as difluoromethylthio, trifluoromethylthio, trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio or 2-chloro-1,1,2-trifluoroethylthio, haloalkylsulphinyls such as difluoromethylsulphinyl, trifluoromethylsulphinyl, trichloromethylsulphinyl, chlorodifluoromethylsulphinyl, 1-fluoroethylsulphinyl, 2-fluoroethylsulphinyl, 2,2-difluoroethylsulphinyl, 1,1,2,2-tetrafluoroethylsulphinyl, 2,2,2-trifluoroethylsulphinyl and 2-chloro-1,1,2-trifluoroethylsulphinyl, haloalkylsulphinyls such as difluoromethylsulphinyl, trifluoromethylsulphinyl, trichloromethylsulphinyl, chlorodifluoromethylsulphinyl, 1-fluoroethylsulphinyl, 2-fluoroethylsulphinyl, 2,2-difluoroethylsulphinyl, 1,1,2,2-tetrafluoroethylsulphinyl, 2,2,2-trifluoroethylsulphinyl and 2-chloro-1,1,2-trifluoroethylsulphinyl, haloalkylsulphonyl groups such as difluoromethylsulphonyl, trifluoromethylsulphonyl, trichloromethylsulphonyl, chlorodifluoromethylsulphonyl, 1-fluoroethylsulphonyl, 2-fluoroethylsulphonyl, 2,2-difluoroethylsulphonyl, 1,1,2,2-tetrafluoroethylsulphonyl, 2,2,2-trifluoroethylsulphonyl and 2-chloro-1,1,2-trifluoroethylsulphonyl. Most preferred fluorinated alkyl groups are CF3, C2F5 and C3F7 and most preferred fluorinated alkoxy groups are OCF3, OC2F5 and OC3F7.

    [0036] The terms "N-C1-C6-alkylamino", "N,N-di-C1-C6-alkylamino", and "N-C1-C3-alkoxy-C1-C4-alkylamino" represent an amino group substituted with one or two C1-C6-groups or an amino group substituted with one C1-C3-alkoxy group and one C1-C4-alkyl group, each as defined above.

    [0037] The term " C1-C6-alkylcarbonyl" represents straight-chain or branched alkyl-C(=O) having 2 to 7 carbon atoms such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, s-butylcarbonyl and t-butylcarbonyl. Preference is also given to alkylcarbonyls having 1 to 4 carbon atoms. The inventive alkylcarbonyls may be substituted by one or more identical or different radicals.

    [0038] The term "C2-C6-alkenyl" represents straight-chain or branched hydrocarbons preferably having 2 to 6 carbon atoms and at least one double bond, for example vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl. Preference is also given to alkenyls having 2 to 4 carbon atoms such as, inter alia, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl. The inventive alkenyls may be substituted by one or more identical or different radicals.

    [0039] The term " C2-C6- alkynyl" represents straight-chain or branched hydrocarbons preferably having 2 to 6 carbon atoms and at least one triple bond, for example 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and 2,5-hexadiynyl. Preference is also given to alkynyls having 2 to 4 carbon atoms such as, inter alia, ethynyl, 2-propynyl or 2-butynyl-2-propenyl. The inventive alkynyls may be substituted by one or more identical or different radicals.

    [0040] The term "aryl" represents a mono-, bi- or polycyclic aromatic system having preferably 6 to 14, especially 6 to 10, ring carbon atoms, for example phenyl, naphthyl, anthryl, phenanthrenyl, preferably phenyl. In addition, aryl also represents polycyclic systems such as tetrahydronaphthyl, indenyl, indanyl, fluorenyl, biphenyl, where the bonding site is on the aromatic system. The inventive aryl groups may be substituted by one or more identical or different radicals.

    [0041] The term "hetaryl" or "heteroaryl" represents heteroaromatic compounds, i.e. completely unsaturated aromatic heterocyclic compounds having at least one ring in which at least one carbon atom is replaced by a heteroatom, preferably by a heteroatom from the group consisting of N, O, S, P, B, Si, Se, and which may be unsubstituted or substituted, where the bonding site is on a ring atom. Unless defined differently, the heteroaryl ring contains preferably 3 to 9 ring atoms, especially 3 to 6 ring atoms, more preferably 5 to 7 ring atoms, and one or more, preferably 1 to 4, especially 1, 2 or 3, heteroatoms in the heteroaryl ring, preferably from the group consisting of N, O, and S, although no two oxygen atoms should be directly adjacent. The heteroaryl rings usually contain not more than 4 nitrogen atoms and/or not more than 2 oxygen atoms and/or not more than 2 sulphur atoms. Particular preference is given to 5-to 7-membered rings having 1 to 3, preferably 1 or 2, identical or different heteroatoms from the group above. Inventive heteroaryls are, for example, furyl, thienyl, pyrazolyl, imidazolyl, 1,2,3- and 1,2,4-triazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 1,2,5-oxadiazolyl, azepinyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl, oxepinyl, thiepinyl, 1,2,4-triazolonyl and 1,2,4-diazepinyl. The inventive heteroaryl groups may also be substituted by one or more identical or different radicals

    [0042] Preferred substituents of the aryl and heteroaryl groups are selected from hydroxy, halogen, cyano, nitro, amino, C1-C3-alkyl, C1-C3-alkoxy, hydroxycarbonyl, alkoxycarbonyl, alkylcarbamoyl, cycloalkylcarbamoyl and phenyl.

    [0043] Preferably the substituents Y, Q, L1, L2 and L3 have the meaning as defined above in the various aspects of the present invention.

    [0044] In a particularly preferred aspect of the invention the substituent Y in the compounds of formula (I) as defined anywhere herein is selected from a group T1 as defined herein, in particular a group T1-1 or T1-2, each as defined anywhere herein.

    [0045] Particularly preferred Examples of the present invention are listed in aspect [24] above and as shown in the Examples below. Preferred compounds according to formula (I) of the present invention are those of Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, and 16. More preferred compounds according to formula (I) of the present invention are those of Examples 1, 2, 4, 6, 10, 14, and 16.

    [0046] Salts of the inventive compounds that are suitable in accordance with the invention, for example salts with bases, are all customary non-toxic salts, preferably agriculturally and/or physiologically acceptable salts. Preference is given to salts with inorganic bases, for example alkali metal salts (e.g. sodium, potassium or caesium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts or salts with organic bases, in particular with organic amines, for example triethylammonium, dicyclohexylammonium, N,N'-dibenzylethylenediammonium, pyridinium, picolinium or ethanolammonium salts. Preferably salts of the compounds of the present invention are pharmaceutically acceptable salts.

    [0047] Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.

    [0048] The compounds of the present invention and their salts - to the extent applicable -can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain water or polar solvents (for example methanol or ethanol), respectively, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates of the compounds and their salts, to the extent applicable.

    [0049] Depending on the nature of the substituents, the compounds of the formula (I) may be in the form of geometric and/or optically active isomers or corresponding isomer mixtures in different compositions. These stereoisomers are, for example, enantiomers, diastereomers, atropisomers, tautomers or geometric isomers. Accordingly, the invention encompasses both pure stereoisomers and any mixtures of these isomers.

    [0050] The novel compounds according to the present invention are particularly suitable for the use as medicaments, in particular for the use as medicaments for the treatment of animals. The novel compounds according to the present invention are particularly suitable for the use as medicaments to act against animal parasites, especially ectoparasites, such as insects and arachnids or else. Ectoparasites are typically and preferably arthropods, especially insects such as flies (biting and licking), parasitic fly larvae, sucking lice, biting lice, fleas and the like; or acari such as ticks, for example hard ticks or soft ticks, or mites such as scab mites, bird mites and the like, and also aquatic ectoparasites such as copepods. The novel compounds of the present invention are particularly suitable to act against ticks, fleas, lice, flies and mites.

    [0051] The novel compounds of the formula (I) having favourable homeotherm toxicity are suitable for controlling parasites which occur in animal breeding and animal husbandry in livestock including aquaculture, breeding animals, zoo animals, laboratory animals, experimental animals and domestic animals. They are active against all or specific stages of development of the parasites.

    [0052] Agricultural livestock include, for example, mammals such as sheep, goats, horses, donkeys, camels, buffalo, rabbits, reindeer, fallow deer, and particularly cattle and pigs; poultry such as turkeys, ducks, geese, and particularly chickens; fish and crustaceans, for example in aquaculture, and also insects such as bees.

    [0053] Domestic animals (also indicated as companion animals) include, for example, mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, and particularly dogs, cats, cage birds, reptiles, amphibians and aquarium fish. Preferred companion animals are cats and dogs.

    [0054] In a preferred embodiment, the compounds of the formula (I) are administered to mammals.

    [0055] In a preferred embodiment the compounds of formula (I) are administered to cats.

    [0056] In a preferred embodiment the compounds of formula (I) are administered to dogs.

    [0057] Use of the compounds of the formula (I) for the control of animal parasites is intended to reduce or prevent illness, cases of deaths and reductions in performance (in the case of meat, milk, wool, hides, eggs, honey and the like), such that more economical and simpler animal keeping is enabled and better animal well-being is achievable.

    [0058] In relation to the animal health field, the term "control" or "controlling" means that the compounds of the formula (I) are effective in reducing the incidence of the particular parasite in an animal infected with such parasites to an innocuous degree. More specifically, "controlling" in the present context means that the compound of the formula (I) can kill the respective parasite, inhibit its growth, or inhibit its proliferation.

    [0059] These parasites include:

    From the order of the Anoplurida, for example, Haematopinus spp., Linognathus spp., Pediculus spp., Phthirus spp., Solenopotes spp.; specific examples are: Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asini macrocephalus, Haematopinus eurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloera vastatrix, Phthirus pubis, Solenopotes capillatus;

    From the order of the Mallophagida and the suborders Amblycerina and Ischnocerina, for example, Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp., Felicola spp.; specific examples are: Bovicola bovis, Bovicola ovis, Bovicola limbata, Damalina bovis, Trichodectes canis, Felicola subrostratus, Bovicola caprae, Lepikentron ovis, Werneckiella equi;

    From the order of the Diptera and the suborders Nematocerina and Brachycerina, for example, Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmia spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp., Melophagus spp., Rhinoestrus spp., Tipula spp.; specific examples are: Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora erythrocephala, Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Phlebotomus papatasi, Phlebotomus longipalpis, Odagmia ornata, Wilhelmia equina, Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea, Chrysops caecutiens, Chrysops relictus, Haematopota pluvialis, Haematopota italica, Musca autumnalis, Musca domestica, Haematobia irritans irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea albipuncta, Chrysomya chloropyga, Chrysomya bezziana, Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus, Lipoptena capreoli, Lipoptena cervi, Hippobosca variegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophilus inermis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca;

    From the order of the Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp.; specific examples are: Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsylla cheopis;

    From the order of the Heteropterida, for example, Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.

    From the order of the Blattarida, for example, Blatta orientalis, Periplaneta americana, Blattela germanica and Supella spp. (e.g. Suppella longipalpa);

    From the subclass of the Acari (Acarina) and the orders of the Meta- and Mesostigmata, for example, Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp., Rhipicephalus (Boophilus) spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Dermanyssus spp., Rhipicephalus spp. (the original genus of multihost ticks), Ornithonyssus spp., Pneumonyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp., Acarapis spp.; specific examples are: Argas persicus, Argas reflexus, Ornithodorus moubata, Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens, Rhipicephalus evertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, Ixodes rubicundus, Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, Dermacentor variabilis, Hyalomma mauritanicum, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Rhipicephalus capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis, Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma cajennense, Dermanyssus gallinae, Ornithonyssus bursa, Ornithonyssus sylviarum, Varroajacobsoni;

    From the order of the Actinedida (Prostigmata) and Acaridida (Astigmata), for example, Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp and Laminosioptes spp.; specific examples are: Cheyletiella yasguri, Cheyletiella blakei, Demodex canis, Demodex bovis, Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Neotrombicula autumnalis, Neotrombicula desaleri, Neoschongastia xerothermobia, Trombicula akamushi, Otodectes cynotis, Notoedres cati, Sarcoptis canis, Sarcoptes bovis, Sarcoptes ovis, Sarcoptes rupicaprae (=S. caprae), Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psoergates ovis, Pneumonyssoidic mange, Pneumonyssoides caninum, Acarapis woodi.



    [0060] From the subclass of the copepods with the order of the Siphonostomatoida in particular the genera Lepeophtheirus and Caligus; the species Lepeophtheirus salmonis, Caligus elongatus and Caligus clemensi may be mentioned by way of example and with particular preference.

    [0061] According to a preferred embodiment the parasites are selected from the following group of ectoparsite species:

    Fleas: Ctenocephalides spp.;

    Ticks: Amblyomma spp., Dermacentor spp., Rhipicephalus spp., Ixodes spp., Haemaphysalis spp., Hyalomma spp.;

    Mites: Demodex spp., Otodectes spp., Sarcoptes spp.; and

    Lice: Linognathus spp.



    [0062] More particularly the parasites are selected from:

    Fleas: Ctenocephalides felis, Ctenocephalides canis;

    Ticks: Ixodes scapularis, Ixodes ricinus, Dermacentor variabilis, Amblyomma americanum, Rhipicephalus sanguineus, Dermacentor reticulatus, Ixodes holocyclus, Ixodes hexagonus, Haemaphysalis longicornis;

    Mites: Otodectes cynotis, Sarcoptes scabiei, Demodex canis; and

    Lice: Linognathus setosus.



    [0063] In general, the inventive active ingredients can be employed directly when they are used for the treatment of animals. They are preferably employed (administered) in the form of pharmaceutical compositions which may comprise pharmaceutically acceptable excipients, solvents and/or auxiliaries known in the prior art.

    [0064] The novel active compounds of the present invention may be administered in a known manner, by enteral administration in the form of, for example, tablets, capsules, potions, drenches, granules, pastes, boluses, the feed-through process and suppositories, by parenteral administration, for example by injection (intramuscular, subcutaneous, intravenous, intraperitoneal inter alia), implants, by nasal administration, by dermal administration in the form, for example, of dipping or bathing, spraying, pouring on and spotting on, washing and powdering, and also with the aid of moulded articles containing the active ingredient, such as collars, earmarks, tailmarks, limb bands, halters, marking devices, etc. Preferably the novel compounds of the present invention are administered by subcutaneous or oral administration, more preferably by subcutaneous administration (injection).

    [0065] The novel active compounds of the present invention can be formulated in any suitable administration form for oral and subcutaneous (injectable) administration known in the prior art.

    [0066] Based upon standard laboratory techniques known to evaluate compounds useful for controlling parasites on animals, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in animals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the subject treated, and the nature and extent of the condition treated.

    [0067] The content of the novel active compounds of the present invention in formulations for the use (unit dosage) according to the present invention may vary within wide limits. The active compound concentration of the application forms may be from 0.00000001 to 98% by weight of active compound, preferably from 0.00001 to 98 % by weight, more preferably from 0.001 to 98 % by weight. More preferably, the pharmaceutical compositions of the present invention may comprise the novel compounds of the invention in amounts from 0.01 to 98% by weight of active compound, preferably from 0.1 to 98 % by weight. , more preferably from 0.5 to 90 % by weight. The pharmaceutical compositions of the present invention may comprise the novel compounds of the invention in amounts from 0.001 to 95 % by weight of active compound, preferably from 0.01 to 95% by weight, preferably from 0.1 to 50 % by weight, more preferably from 5 to 30 % by weight.

    [0068] The total amount of the active ingredient to be administered will generally range from about 0.01 to 200 mg/kg body weight per application, preferably in the range of from 0.1 to 100 mg/kg body weight per application, more preferably of from 0.5 to 75 mg/kg body weight per application, more preferably in the range of from 1.0 to 50 mg/kg body weight and most preferably in the range of from 2.0 to 20 mg/kg body weight per application.

    [0069] In particular, the average dosage for administration by infusion techniques or by injection, including intravenous, intramuscular, and in particular subcutaneous injections will preferably be within the aforesaid ranges.

    [0070] The average dosage for oral administration will preferably be within the aforesaid ranges.

    [0071] Clinically useful dosing or administration intervals will range from one application per month to one application every two years, preferably the treatment interval is from one application every three months to one application every two years, more preferred treatment intervals are from one application every six months to one application every two years. Further preferred dosing or administration intervals will range from one application per month to one application every year, preferably one application every three months to one application every year, more preferably one application every four months to one application every year, in particular one application every six months to one application every year. According to a further embodiment the application interval may be from one application every nine months to one application per year.

    [0072] In addition, it is possible for "drug holidays", in which a subject is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability.

    [0073] Of course the specific initial and continuing dosage regimen, administered amount of active compound and the particular dosing interval will vary for each subject according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the subject, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

    [0074] In order to broaden the spectrum of activity, the novel active compounds of the present invention can be used in combination with suitable synergists, repellents or other active ingredients, for example acaricides, insecticides, anthelmintics, anti-protozoal agents.

    [0075] For example the compounds of the present invention can be used in combination with chloride channel activators or modulators from the class of the macrocylic lactones, in particular avermectins/milbemycins, e.g. abamectin, doramectin, emamectin benzoate, eprinomectin, ivermectin, latidectin, lepimectin, milbemycin oxime, milbemectin, moxidectin and selamectin, particular preference is given here, for applications against ectoparasites, to doramectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin or selamectin.

    [0076] Further, the the compounds of the present invention can be used in combination with antigens for vaccination purposes. Examples for vaccines which may be combined with the compounds of the present invention are against leptospirosis, infectious tracheobronchitis, leishmaniasis or lyme borreliosis (lyme disease).

    Process for Preparing the Novel Compounds of Formula (I)



    [0077] The novel compounds (I) according to the present invention can be synthesised according to general Schemes 1 to 3 as shown below. Generally, the synthesis can be divided into two stages.

    [0078] In the first stage, a protected pro-moiety is built up with a terminal alcohol function that will become part of the carbonate ester linker in the novel compounds of the invention.

    [0079] In the second stage, the terminal alcohol group of the pro-moiety is converted into a chloromethyl carbonate ester that is then coupled to a halogenated amide group of an active compound moiety and eventually deprotected to give a free carboxylic acid.

    [0080] The first stage of the synthesis differs depending on the meaning of the substituents L1, L2 and Q in the compounds of formula (I) whereas the second stage is common for all compounds of the present invention.

    First Stage of the Process - building up the pro-moiety


    Synthesis route (a) for Compounds (I) wherein L2 is C=O and Q is O



    [0081] The following Scheme 1 describes the synthesis of the protected pro-moiety of the above mentioned first stage of the process of the present invention for preparing compounds (I) wherein L1 and L3 have the meaning as defined anywhere above and wherein L2 is selected to be C=O and Q is selected to be O.



    [0082] Therein, PG1 is a protecting group. Protecting groups suitable for the protection of carboxylic acids together with methods for deprotection are described in P.G. Wuts, Greene's Protective Groups in Organic Synthesis, Wiley 2014. In a preferred case of the present invention, PG1 is a tert-butyl group. PG2 is a protecting group suitable for the protection of alcohols or PG2 is hydrogen. In the case of PG2 being hydrogen, the step (IVa) in the above shown Scheme 1 is obsolete as then the compound (IIIa) is directly reacted to form compound (Va).

    [0083] In a preferred case of the present invention, PG2 is hydrogen and no deprotection step (IVa → Va) is necessary.

    [0084] In the above shown Scheme 1 for preparing the protected pro-moiety in the first stage of the process of the present invention, a compound of formula (IIa) is reacted with an acid of formula (IIIa). To this end, the acid (IIIa) is first activated by converting it into an acid chloride or into an activated ester using a coupling agent such as HATU, TBTU. Suitable coupling methods are known e.g. from C.A.G.N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827-10852. In a second step, the activated acid is reacted with compound (IIa) in the presence of a base.

    [0085] In a preferred case, acid (IIIa) is activated by converting it into the acid chloride using oxalic chloride in the presence of a catalytic amount of DMF in dichloromethane and is then reacted with (IIa) in the presence of an amine base, e.g. DIPEA, TEA in a polar aprotic solvent, e.g. DMF, THF, acetonitrile. Optionally, a catalytic amount of DMAP may be used to facilitate this reaction.

    [0086] In cases where PG2 is not hydrogen, compound (Va) is obtained by selectively cleaving PG2 from the compound (IVa) in the presence of PG1.

    Synthesis route (b) for Compounds (I) wherein L2 is absent and Q is O



    [0087] The following Scheme 2 describes the synthesis of the protected pro-moiety of the above mentioned first stage of the process of the present invention for preparing compounds (I) wherein L1 and L3 have the meaning as defined anywhere above and wherein L2 is absent and Q is selected to be O.



    [0088] Therein, × is a leaving group and may be Cl, Br, I, or a sulfonate ester such as triflate, mesylate or paratoluenesulfonate ester. × may also be OH. In a preferred case, × is a halogen selected from Cl, Br or I.

    [0089] PG2 is a protecting group suitable for the protection of alcohols or PG2 is hydrogen. In the case of PG2 being hydrogen, the step (IVb) in the above shown Scheme 2 is obsolete as then the compound (IIIb) is directly reacted to form compound (Vb).

    [0090] In a preferred case of the present invention, PG2 is a benzyl ether group or a substituted benzyl ether group.

    [0091] In the above shown Scheme 2 for preparing the protected pro-moiety in the first stage of the process of the present invention, in a first step, compound (VI) is reacted with compound (IIIb) under the conditions of a Williamson ether synthesis.This requires to treat a solution of (IIIb) with a base, then add compound (VI) and let the reaction proceed at room temperature or above. Strong bases can be used, for instance hydride bases, bis(trimethyldisilyl)amide (HMDS) bases, amidine bases or phosphazene bases.

    [0092] In a preferred case, sodium hydride or sodium bis(trimethyldisilyl)amide is used. Preferred solvents are polar aprotic solvents, e.g. THF or DMF.

    [0093] The ether products (IVb) are converted into alcohols (Vb) by removal of the protecting group PG2.

    [0094] In a preferred case, PG2 is a benzyl group and removal is accomplished by hydrogenation in the presence of palladium on charcoal in a protic solvent such as methanol, ethanol, acetic acid or mixtures of these solvents.

    Synthesis route (c) for Compounds (I) wherein Q is absent



    [0095] The following Scheme 3 describes the synthesis of the protected pro-moiety of the above mentioned first stage of the process of the present invention for preparing compounds (I) wherein L1, L2 and L3 have the meaning as defined anywhere above and wherein Q is absent and thus, no bond between L1-Q or L2-Q or L3-Q needs to be formed.

    PG1 is a protecting group suitable for the protection of carboxylic acids. By preference, PG1 is a tert-butyl group. Compounds of formula (Vc) can be obtained commercially or synthesized according to methods described in the well-known literature.

    Second Stage of the Process - preparation of Compounds (I)



    [0096] The second stage of the process of the present invention is shown in Scheme 4.



    [0097] Therein, L1, L2, L3, Q, R and PG1 are defined as described above.

    [0098] This second stage of the synthesis of the invention may be carried out starting from any intermediate (Va), (Vb) and (Vc), resulting from the first stage of the process as described above. Said starting intermediates are herein generally designated as intermediate (V).

    [0099] In a first step of the second stage of the process, intermediate compounds (V) are treated with chloromethyl carbonochloridate leading to chloromethyl esters (VII). The reaction is carried out in a solvent in the presence of a base. Dipolar aprotic solvents such as DMF, THF, acetonitrile, or pyridine can be used. The base may be an amine base like e..g. DIPEA, TEA, DMAP. In a preferred case, pyridine serves both as the solvent and the base.

    [0100] In the next step of the second stage of the process, an amide of formula (VIII) is treated with a base and then reacted with a chlorocarbonate ester of formula (VII). Strong bases can be used, for instance tert-butylates, hydride bases, amide bases, bis(trimethyldisilyl)amide (HMDS) bases, amidine bases or phosphazene bases. In a preferred case, sodium hydride or NaHMDS is used. The reaction is generally carried out in a solvent, usually in a polar aprotic solvent such as THF, diethyl ether, DMF or a mixture of a polar aprotic solvent and other solvents.

    [0101] The protecting group PG1 can be cleaved to provide the compound (I) of the present invention. In a preferred case, PG1 is a tert-butyl group and is removed by treating compound (IX) with a solution of hydrochloric acid in 1,4 dioxane or with a solution of TFA in dichloromethane.

    Examples


    List of Abbreviations



    [0102] 
    AA
    Amblyomma americanus (parasitology)
    abs.
    Absolute
    Ac
    Acetyl
    aq.
    Aqueous, aqueous solution
    AUC
    Area under the curve (in Pharmacokinetics)
    cat.
    Catalytic
    CF
    Ctenocephalides felis (parasitology)
    CI
    Chemical ionisation (mass spectroscopy)
    conc
    Concentrated
    d
    Doublet (NMR)
    d
    Day(s)
    dd
    Doublet of doublet (NMR)
    DCM
    Dichloromethane
    DIPEA
    N,N,-diisopropylethylamine (Hünig's base)
    DMAP
    4-Dimethylaminopyridine
    DMF
    N,N-dimethylformamide
    DMSO
    Dimethylsulfoxide
    dt
    Doublet of triplet (NMR)
    DV
    Dermacentor variabilis (parasitology)
    ent
    Enantiomeric
    eq.
    Equivalent(s)
    ESI
    Electrospray-ionisation (mass spectroscopy)
    F
    Bioavailability (in Pharmacokinetics)
    GC
    Gas chromatography
    GC/MS
    Gas chromatography coupled to mass spectroscopy
    h
    Hour(s)
    HATU
    O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate
    HMDS
    Bis(trimethyldisilyl)amide formerly also referred to as hexamethyldisilazide, counterion in strongly basic salts such as LiHMDS, NaHMDS, KHMDS
    HPLC
    High pressure liquid chromatography
    iPr
    Isopropyl
    IR
    Ixodes rhicinus (parasitology)
    iv
    Intravenous (PK)
    KHMDS
    Potassium bis(trimethyldisilyl)amide
    LC
    Liquid chromatography
    LC-MS
    Liquid chromatography coupled to mass spectroscopy
    LiHMDS
    Lithium bis(trimethyldisilyl)amide
    Lit.
    Literature
    m
    Multiplet (NMR)
    Me
    Methyl
    min
    Minute(s)
    MS
    Mass spectroscopy
    MTBE
    tert-Butyl methyl ether
    NaHMDS
    Sodium bis(trimethyldisilyl)amide
    NMP
    N-Methyl-2-pyrrolidone
    NMR
    Nuclear magnetic resonance spectroscopy
    PBS
    Phosphate buffered saline
    PEG
    Polyethylene glycol
    PK
    Pharmacokinetics
    Pr
    Propyl
    q (or quart)
    Quartet (NMR)
    qd
    Quartet of doublet (NMR)
    quant
    quantitative (referring to chemical yield)
    quint
    Quintet (NMR)
    rac
    racemic
    RP
    reverse phase (for liquid chromatography)
    RS
    Rhipicephalus sanguineus (parasitology)
    Rt
    Retention time (chromatography)
    s
    Singulet (NMR)
    Sc
    Subcutaneous (PK and pharmacology)
    SD
    Study day
    sept
    Septet (NMR)
    t
    Triplet (NMR)
    t
    Time point (during an experiment)
    to
    Time point at beginning of an experiment
    TBTU
    O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetra-fluoroborate
    tBu
    tert-Butyl
    td
    Triplett of doublett (NMR)
    TEA
    triethylamine
    TFA
    Trifluoro acetic acid
    THF
    Tetrahydrofuran
    UV
    Ultraviolett-spectroscopy

    Analytical Methods


    Method 1 (HPLC-MS)



    [0103] Instrument: Agilent MS Quad 6150;HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 × 2.1 mm; Eluent A: 1 1 water + 0.25 ml 99%ige Formic acid , Eluent B: 1 1 Acetonitrile + 0.25 ml 99%ige Formic acid; Gradient: 0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0 min 5% A Column temperature: 50°C; Flow: 1,20 ml/min; UV-Detektion: 205 - 305 nm.

    Method 2 (HPLC-MS)



    [0104] Instrument: Waters ACQUTTY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 × 1 mm; eluent A: 1 1 water + 0.25 ml 99%ige formic acid , eluent B: 1 L acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A column temperature: 50°C; flow: 0.40 ml/min; UV-detection: 210 nm.

    Method 3 (HPLC-MS)



    [0105] Instrument MS: Thermo Scientific FT-MS; instrument UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 × 75 mm, C18 1.8 µm; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; column temperature: 50°C; flow: 0.90 ml/min; UV-detection: 210 nm/ Optimum Integration Path 210-300 nm

    Method 4 (HPLC-MS)



    [0106] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 1 mm; eluent A: 1 L water + 0.25 ml 99% formic acid , eluent B: 1 L acetonitrile+ 0.25 ml 99% formic acid; gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A column temperature: 50°C; flow: 0.35 ml/min; UV-Detection: 210 nm.

    Method 5 (HPLC-MS)



    [0107] The column used was a Shim-pack XR-ODS, 2.2 µm, 3.0 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in acetonitrile) over 4.70 min with a total run time of 5.00 min. The column temperature was at 45 °C with the flow rate of 1.20 mL/min.

    Method 6 (HPLC-MS)



    [0108] The column used was a Shim-pack XR-ODS, 2.2 µm, 3.0 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in acetonitrile) over 1.70 min with a total run time of 2.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.

    Method 7 (HPLC-MS)



    [0109] The column used was a Kinetex EVO C18 100A, 2.6 µm, 3.0 × 50 mm. A linear gradient was applied, starting at 90% A (A: 0.03% NH3H2O in water) and ending at 95% B (B: acetonitrile) over 1.70 min with a total run time of 2.00 min. The column temperature was at 40 °C with the flow rate of 1.20 mL/min.

    Method 8 (HPLC)



    [0110] Instrument: HP 1260 Infinity HPLC System with G4212B diode array detector; column: Kromasil 100 C18ec 5 µm 250 × 4 mm; eluent A: 1 L water + 1.0 mL TFA, eluent B: 1 L acetonitrile+ 1.0 mL TFA; gradient: 0.0 min 98% A → 1.0 min 98% A → 8.0 min 30% A → 16.0 min 30% A → 19.0 min 2% A → 20.0 min 2% A → 23.0 min 98% A → 25.0 min 30% A, column temperature: 37°C; flow: 1.5 mL/min; UV-Detection: 214 nm, injection volume 10 µL.

    Method 9 (HPLC-MS)



    [0111] Instrument: HP 1200 Infinity HPLC System with G1315B diode array detector; Waters MS QuattroMicro (ESI+/ESI-) column: Kromasil 100 C18ec 5 µm 250 × 4 mm; eluent A: 1 L water + 0.5 mL 50% HCOOH, eluent B: 1 L acetonitrile+ 0.5 mL 50% HCOOH; gradient: 0.0 min 98% A → 1.0 min 98% A → 8.0 min 30% A → 16.0 min 30% A → 19.0 min 2% A → 20.0 min 2% A → 23.0 min 98% A → 25.0 min 30% A, column temperature: 37°C; flow: 1.5 mL/min; UV-Detection: 214 nm, injection volume 10 µL

    Synthesis of Starting Materials



    [0112] 2-Chlor-5-{1-[2-chlor-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (CAS-RN 1771742-44-9) was synthesised as described in WO 2015/067646 A1.

    [0113] (2E)-4-tert-Butoxy-4-oxobut-2-enic acid (CAS RN 135355-96-3) was synthesised according to the method published by P.A. Clarke, R.L. Davie S Peace, Tetrahedron Lett 2002, 43, 2753-2756. tert-Butyl 3-hydroxy-2,2-dimethylpropanoate (CAS RN 25307-76-0) was prepared as decribed in WO2007/116922 (page 51)

    [0114] tert-Butyl cis-4-hydroxycyclohexanecarboxylate (CAS-RN 931110-79-1) was prepared according to a procedure described in WO 2009/081195.

    [0115] tert-Butyl trans-4-hydroxycyclohexanecarboxylate (CAS-RN 869193-57-7) was prepared according to a procedure described in 2010126030.

    [0116] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (CAS-RN 1621436-41-6) was prepared according to procedures described in WO 2014/122083 A1, WO 2015/078846 A1 and WO 2015/181139 A1.

    Synthesis of Intermediates


    Intermediate 1A


    tert-Butyl-(2E)-4-chloro-4-oxobut-2-enoate



    [0117] 



    [0118] (2E)-4-tert-Butoxy-4-oxobut-2-enic acid (172 mg, 1.00 mmol) and DMF (5 µL) were dissolved in DCM (2.0 mL) and cooled to 0 °C. Oxalic chloride (1.0 ml, 2.0 M, 2.0 mmol) was added dropwise under stirring. Stirring was continued until the evolution of gas ceased. Then, the solvent was distilled and the residue was used without purification in the next step. Yield: 191 mg (quant.).

    Intermediate 2A


    tert-Butyl-2-hydroxyethyl-(2E)-but-2-enedioate



    [0119] 



    [0120] Ethylene glycol (1.1 ml, 20 mmol) and DIPEA (520 µl, 3.0 mmol) were dissolved in DCM (2.0 ml) and a solution of tert-Butyl-(2E)-4-chloro-4-oxobut-2-enoate (Intermediate 1A, 191 mg, 1.00 mmol) in DCM (3.0 mL) was slowly added. The mixture was stirred at ambient temperature for 16 h. Then, water was added, the mixture was extracted with 3 portions of DCM and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The solution was purified by chromatography on silica gel (cyclohexane / ethyl acetate 1:1). The title compound (166 mg, 77 % of theory) was obtained LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m/z = 217 [M+H]+

    [0121] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.467 (16.00), 3.607 (0.69), 3.618 (0.75), 4.144 (0.83), 4.157 (0.96), 4.169 (0.75), 4.875 (0.72), 6.690 (1.30), 6.698 (1.32).

    Intermediate 3A


    tert-Butyl-2-{[(chloromethoxy)carbonyl]oxy}ethyl-(2E)-but-2-enedioate



    [0122] 



    [0123] tert-Butyl-2-hydroxyethyl-(2E)-but-2-enedioate (intermediate 2A, 164 mg, 758 µmol) was dissolved in pyridine (3.0 mL) and the solution was cooled to 0°C. Chloromethyl carbonochloridate (100 µl, 1.2 mmol) was added at once and the mixture was stirred at room temperature for 45 min. The solvent was evaporated. The residue was redissolved in ethyl acetate (100 mL ) washed with water (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 3:1) to give 174 mg (74 % of theory) of the title compound.

    [0124] LC-MS (method 2): Rt = 0.98 min; MS (ESIpos): m/z = 143 [M+H-C6H12ClO7]+

    [0125] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.461 (16.00), 4.402 (0.63), 4.411 (0.64), 4.416 (0.79), 4.452 (0.80), 4.456 (0.64), 4.466 (0.64), 5.906 (3.88), 6.674 (3.58).

    Intermediate 4A


    tert-Butyl-2-[([[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropane-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl-(2E)-but-2-enedioate



    [0126] 



    [0127] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (8.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µl, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (19 mg, 125 µmol) and a solution of tert-butyl-2-{[(chlormethoxy)carbonyl]oxy}ethyl-(2E)-but-2-enedioate (intermediate 3A, 116 mg, 375 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 60 min. The reaction mixture was poured into water (30 mL) and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 210 mg (91 % of theory) of the title compound were obtained.

    [0128] LC-MS (method 3): Rt = 2.70 min; MS (ESIpos): m/z = 943 [M+Na] +

    [0129] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.76), 0.008 (0.80), 1.356 (0.69), 1.443 (16.00), 4.308 (0.69), 6.647 (3.15), 7.801 (0.59), 7.927 (0.68), 8.201 (0.73), 8.436 (0.70), 8.765 (0.47).

    Intermediate 5A


    tert-Butyl 3-hydroxypropyl (2E)-but-2-enedioate



    [0130] 



    [0131] Propane-1,3-diol (7.2 ml, 100 mmol) and DIPEA (2.6 mL, 15.0 mmol) were dissolved in DCM (25 ml) and a solution of tert-Butyl-(2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 953 mg, 5.0 mmol) in DCM (15 mL) was slowly added. The mixture was stirred for a few minutes and then quenched with water. The mixture was extracted with 3 portions of DCM and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 1:1) to give title compound (800 mg, 69 % of theory).

    [0132] LC-MS (method 3): Rt = 1.51 min; MS (ESIpos): m/z = 175 [M+H-C4H8]+

    [0133] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.464 (16.00), 1.755 (0.65), 1.768 (1.00), 1.781 (0.66), 3.476 (0.80), 3.486 (0.81), 4.197 (0.69), 4.210 (1.44), 4.223 (0.66), 4.529 (0.43), 4.539 (0.89), 4.550 (0.40), 6.658 (2.00), 6.665 (1.99).

    Intermediate 6A


    tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl (2E)-but-2-enedioate



    [0134] 



    [0135] tert-Butyl 3-hydroxypropyl (2E)-but-2-enedioate (intermediate 5A, 800 mg, 3.47 mmol) was dissolved in pyridine (13 mL) and the solution was cooled to 0°C. Chloromethyl carbonochloridate (460 µl, 5.2 mmol) was added at once and the mixture was stirred at room temperature for 45 min. The solvent was evaporated. The residue was redissolved in ethyl acetate (250 mL ) washed with water (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (cyclohexane -> cyclohexane / ethyl acetate 85:15) to give 1.13 g (quant.) of the title compound.

    [0136] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.465 (16.00), 1.761 (1.01), 2.007 (0.54), 2.020 (0.80), 2.032 (0.55), 3.602 (0.83), 4.213 (0.61), 4.225 (1.23), 4.238 (0.58), 4.283 (0.64), 4.296 (1.34), 4.308 (0.61), 5.889 (4.18), 6.673 (4.59).

    Intermediate 7A


    tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propyl (2E)-but-2-enedioate



    [0137] 



    [0138] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (195 mg, 300 µmol) was dissolved in dry THF (9.6 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (960 µl, 0.50 M solution in toluene, 480 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (23 mg, 150 µmol) and a solution of tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl (2E)-but-2-enedioate (intermediate 6A, 145 mg, 450 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 60 min. The reaction mixture was poured into water (30 mL) and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 195 mg (69 % yield) of the title compound were obtained.

    [0139] LC-MS (method 2): Rt = 1.51 min; MS (ESIpos): m/z = 935 [M+H]+

    [0140] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.99), 0.006 (0.67), 1.356 (0.48), 1.446 (16.00), 6.643 (1.46), 7.925 (0.48), 8.200 (0.54), 8.203 (0.52).

    Intermediate 8A


    tert-Butyl 2-hydroxyethyl butanedioate



    [0141] 



    [0142] tert-Butyl 2-hydroxyethyl (2E)-but-2-enedioate (intermediate 2A, 345 mg, 1.60 mmol) was dissolved in ethanol (35 mL) under an argon atmosphere. 10% Palladium on charcoal (84.9 mg, 79.8 µmol) was added and the mixture was hydrogenated for 30 min at ambient pressure at room temperature. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was distilled. 347 mg (quant.) of the title compound were obtained.

    [0143] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.385 (16.00), 2.450 (0.68), 2.455 (0.60), 2.465 (0.86), 2.467 (0.93), 3.532 (0.41), 3.545 (0.87), 3.558 (0.98), 3.571 (0.47), 4.003 (0.86), 4.016 (1.07), 4.029 (0.77), 4.778 (0.68).

    Intermediate 9A


    tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl butanedioate



    [0144] 



    [0145] tert-Butyl 2-hydroxyethyl butanedioate (intermediate 8A, 170 mg, 779 µmol) was dissolved in pyridine (5.0 mL) and the solution was cooled to 0 °C. Chloromethyl carbonochloridate (100 µl, 1.2 mmol) was added at once and the mixture was stirred at room temperature for 45 min. The solvent was evaporated. The residue was redissolved in ethyl acetate (100 mL ) washed with water (30 mL) and brine (30 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (gradient cyclohexane - cyclohexane / ethyl acetate 7:3) to give 189 mg (78 % of theory) of the title compound.

    [0146] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.381 (16.00), 2.449 (0.71), 2.455 (0.58), 2.465 (0.79), 2.467 (0.83), 2.516 (0.86), 4.252 (0.57), 4.263 (0.73), 4.269 (0.55), 4.275 (0.87), 4.373 (0.90), 4.378 (0.56), 4.385 (0.74), 4.388 (0.54), 4.395 (0.59), 5.905 (3.70).

    Intermediate 10A


    tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl butanedioate



    [0147] 



    [0148] 2-Chlor-5- {1-[2-chlor-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (258 mg, 397 µmol) was dissolved in dry THF (13 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.3 mL, 0.50 M solution in toluene, 640 µmol) was added dropwise and the mixture was stirred for 30 min. at - 45 °C. Then, sodium iodide (30 mg, 198 µmol) and a solution of tert-butyl 2-{[(chloromethoxy)carbonyl]oxy} ethyl butanedioate (intermediate 9A, 185 mg, 595 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (30 mL) and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 272 mg (100 % purity, 74 % yield) of the title compound were obtained.

    [0149] LC-MS (method 3): Rt = 2.67 min; MS (ESIpos): m/z = 923 [M+H]+

    [0150] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.00), 0.008 (0.86), 1.353 (16.00), 1.758 (0.64), 2.073 (0.70), 2.414 (0.92), 2.430 (1.07), 2.459 (0.86), 2.475 (0.91), 2.524 (0.56), 4.184 (0.90), 7.612 (0.44), 7.798 (0.77), 7.826 (0.46), 7.935 (1.11), 8.208 (1.25), 8.444 (1.01), 8.770 (0.84).

    Intermediate 11A


    tert-Butyl 3-hydroxy-2,2-dimethylpropyl (2E)-but-2-enedioate



    [0151] 



    [0152] 2,2-dimethylpropane-1,3-diol (3.12 g, 30.0 mmol)and N,N-diisopropylethylamine (3.1 mL, 18 mmol) were dissolved in DCM (30 mL) and a solution of tert-butyl (2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 1.14 g, 6.00 mmol) in DCM (15 mL) was slowly added. The mixture was stirred at ambient temperature for 30 min. Then, water was added, the mixture was extracted with 3 portions of DCM and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The solution was purified by chromatography on silica gel (gradient cyclohexane - cyclohexane / ethyl acetate 3:1). 1.35 g (98 % purity, 85 % yield) of the title compound was obtained.

    [0153] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (9.22), 1.469 (16.00), 3.189 (1.31), 3.202 (1.33), 3.929 (2.93), 4.641 (0.79), 6.663 (1.97), 6.676 (1.95).

    Intermediate 12A


    tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl (2E)-but-2-enedioate



    [0154] 



    [0155] tert-Butyl 3-hydroxy-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 11A, 675 mg, 2.61 mmol) was dissolved in pyridine (30 mL) and the solution was cooled to 0 °C. Chloromethyl carbonochloridate (350 µl, 3.9 mmol) was added at once and the mixture was stirred at room temperature for 60 min. The solvent was evaporated. The residue was redissolved in ethyl acetate (250 mL ) washed with water (20 mL) and brine (20 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (gradient cyclohexane - cyclohexane / ethyl acetate 8:2). 782 mg (98 % purity, 84 % yield) of the title compound were isolated.

    [0156] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.962 (8.32), 1.470 (16.00), 3.979 (2.70), 4.073 (2.62), 5.891 (3.77), 6.692 (3.31).

    Intermediate 13A


    tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy] -2,2-dimethylpropyl (2E)-but-2-enedioate



    [0157] 



    [0158] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (301 mg, 463 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.2 mL, 0.50 M solution in toluene, 600 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, sodium iodide (35 mg, 232 µmol) and a solution of tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 12A, 195 mg, 556 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (30 mL) and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 303 mg (68 % yield) of the title compound were obtained.

    [0159] LC-MS (method 4): Rt = 5.54 min; MS (ESIpos): m/z = 963 [M+H]+

    [0160] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.883 (2.25), 1.448 (16.00), 1.464 (0.51), 2.524 (0.93), 3.911 (1.10), 6.656 (1.25), 7.800 (0.60), 7.929 (0.60), 8.203 (0.70), 8.436 (0.53), 8.753 (0.43).

    Intermediate 14A


    tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl butanedioate



    [0161] 



    [0162] tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 12A, 390 mg, 1.11 mmol) was dissolved in THF (20 mL) under an argon atmosphere. 10% Palladium on charcoal (87.9 mg, 111 µmol) was added and the mixture was hydrogenated for 40 min at ambient pressure at room temperature. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was distilled. 385 mg (93 % purity, 92 % yield) of the title compound were obtained.

    [0163] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.924 (8.41), 1.355 (0.62), 1.378 (16.00), 2.459 (0.44), 2.463 (0.69), 2.470 (0.79), 2.478 (1.07), 2.480 (1.14), 2.515 (0.83), 2.523 (0.76), 3.848 (2.59), 4.021 (2.73), 5.896 (3.77).

    Intermediate 15A


    tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy] -2,2-dimethylpropyl butanedioate



    [0164] 



    [0165] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (301 mg, 463 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.2 mL, 0.50 M solution in toluene, 600 µmol) was added dropwise and the mixture was stirred 30 min. at - 45 °C. Then, a solution of sodium iodide (35 mg, 232 µmol) and tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl butanedioate (intermediate 14A, 196 mg, 556 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 90 min. The reaction mixture was poured into water (30 mL) and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 303 mg (68 % yield) of the title compound were obtained.

    [0166] LC-MS (method 4): Rt = 5.41 min; MS (ESIpos): m/z = 965 [M+H]+

    [0167] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.62), 0.849 (3.68), 1.352 (16.00), 1.753 (0.56), 2.327 (0.54), 2.442 (0.99), 2.670 (0.56), 3.784 (1.09), 3.866 (0.68), 7.803 (1.05), 7.936 (0.96), 8.213 (1.17), 8.442 (0.88), 8.758 (0.80).

    Intermediate 16A


    tert-Butyl (rel 1S,2R)-2-hydroxycyclopentyl (2E)-but-2-enedioate



    [0168] 



    [0169] cis-Cyclopentane-1,2-diol (2.68 g, 26.2 mmol) and N,N-diisopropylethylamine (2.7 mL, 16 mmol) were dissolved in DCM (25mL). Then, a solution of tert-butyl (2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 1.00 g, 5.25 mmol) in DCM (5 mL) was added dropwise at room temperature. The mixture was stirred for 16 h. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with 3 portions of MTBE. Water was stripped off by filtration over a Chromabond PTS device and the solvent was distilled.The residue was purified by flash chromatography on silica gel (gradient cyclohexane / ethyl acetate 9:1 - 1:1) 1.09 g (81 % yield) of the title compound was isolated.

    [0170] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.469 (16.00), 4.746 (0.91), 4.760 (0.88), 6.680 (1.91), 6.694 (1.92).

    Intermediate 17A


    tert-Butyl (rel 1S,2R)-2-1[(chloromethoxy)carbonyl]oxylcyclopentyl (2E)-but-2-enedioate



    [0171] 



    [0172] tert-Butyl (rel 1S,2R)-2-hydroxycyclopentyl (2E)-but-2-enedioate (intermediate 16A, 700 mg, 2.73 mmol) was dissolved in pyridine (30 mL) and the solution was cooled to 0 °C. Chloromethyl carbonochloridate (364 µl, 4.1 mmol) was added at once and the mixture was stirred at room temperature for 90 min. Then, the mixture was poured into water, the pH was adjusted to 4 by addition of 1M hydrochloric acid and the mixture was extracted with 3 portions of DCM. The combined organic layers were washed with 1M hydrochloric acid, water and brine. Residual water was stripped by filtration over a Chromabond PTS device, the solvent was distilled. The title compound (900 mg, 94 % yield) was used without further purification.

    [0173] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.453 (16.00), 1.465 (0.48), 1.820 (0.42), 5.220 (0.43), 5.833 (0.76), 5.849 (1.28), 5.893 (1.30), 5.910 (0.77), 6.626 (3.81).

    Intermediate 18A


    tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate



    [0174] 



    [0175] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (475 mg, 732 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (2.3 mL, 0.50 M solution in toluene, 1.2 mmol) was added dropwise and the mixture was stirred 30 min. at - 45 °C. Then, a solution of sodium iodide (55 mg, 366 µmol) and tert-butyl (rel 1S,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (intermediate 17A, 383 mg, 1.10 mmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into concentrated aqueous ammonium chloride solution and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried passing them over a Chromabond PTS device and evaporated. The crude product was purified by flash chromatography (silica gel, gradient DCM - DCM / ethyl acetate 1:1) and subsequently by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 460 mg (100 % purity, 65 % yield) of the title compound were obtained.

    [0176] LC-MS (method 3): Rt = 2.79 min; MS (ESIneg): m/z = 1005 [M-H+CHOOH]-

    [0177] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.66), 0.008 (0.58), 1.437 (16.00), 1.553 (0.48), 1.740 (1.41), 1.958 (0.49), 5.117 (0.49), 6.608 (2.79), 7.590 (0.53), 7.788 (1.06), 7.818 (0.61), 7.935 (1.45), 8.210 (1.58), 8.427 (1.74), 8.739 (0.99).

    Intermediate 19A


    tert-Butyl (rel 1S,2R)-2-1[(chloromethoxy)carbonyl]oxylcyclopentyl butanedioate



    [0178] 



    [0179] tert-Butyl (rel 1S,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (intermediate 17A, 450 mg, 1.29 mmol) was dissolved in THF (20 mL) under an argon atmosphere. 10% Palladium on charcoal (28 mg, 26 µmol) was added and the mixture was hydrogenated for 16 h at ambient pressure at room temperature. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was distilled. 430 mg (95 % yield) of the title compound were isolated.

    [0180] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.381 (16.00), 2.474 (0.49), 5.071 (0.45), 5.883 (1.66), 5.891 (1.67).

    Intermediate 20A


    tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl butanedioate



    [0181] 



    [0182] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (531 mg, 817 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45 °C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (2.6 mL, 0.50 M solution in toluene, 1.3 mmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (61 mg, 409 µmol) and tert-butyl (rel 1S,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate (intermediate 19A, 430 mg, 1.23 mmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into concentrated aqueous ammonium chloride solution and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried passing them over a Chromabond PTS device and evaporated. The crude product was purified by flash chromatography (silica gel, gradient DCM - DCM / ethyl acetate 1:1) and subsequently by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 520 mg (98 % purity, 64 % yield) of the title compound were obtained.

    [0183] LC-MS (method 3): Rt = 2.76 min; MS (ESIpos): m/z = 963 [M+H]+

    [0184] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.333 (16.00), 1.356 (4.31), 1.507 (0.70), 1.757 (1.39), 1.898 (0.71), 2.184 (0.44), 2.367 (2.00), 4.885 (0.53), 4.998 (0.61), 7.587 (0.66), 7.608 (0.79), 7.805 (2.03), 7.824 (1.01), 7.937 (2.06), 8.212 (2.29), 8.445 (1.64), 8.756 (1.57).

    Intermediate 21A


    tert-Butyl 3-[2-(benzyloxy)ethoxy]-2,2-dimethylpropanoate



    [0185] 



    [0186] tert-Butyl 3-hydroxy-2,2-dimethylpropanoate (CAS RN 25307-76-0, 871 mg, 5.00 mmol) was dissolved in THF (25 mL) and cooled to -20 °C. Sodium bis(trimethylsilyl)amide (3.0 mL, 2.0 M in THF, 6.0 mmol) was added in small portions and the mixture was stirred at -20 °C for 30 min. Then, [(2-iodoethoxy)methyl]benzene (3.93 g, 15.0 mmol) was added and the mixture was first stirred at room temperature over night and was then heated to reflux for 16 h. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled and the residue was purified by chromatography on silica gel (gradient DCM - DCM / ethyl acetate 9:1). 305 mg (20 % yield) of the title compound were obtained.

    [0187] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.054 (9.88), 1.361 (16.00), 3.378 (3.21), 3.541 (3.94), 4.490 (2.46), 7.316 (1.28), 7.321 (1.60), 7.337 (0.52), 7.339 (0.59).

    Intermediate 22A


    tert-Butyl 3-(2-hydroxyethoxy)-2,2-dimethylpropanoate



    [0188] 



    [0189] tert-Butyl 3-[2-(benzyloxy)ethoxy]-2,2-dimethylpropanoate (intermediate 21A, 303 mg, 982 µmol) was dissolved in glacial acetic acid (15 mL), 10% palladium on charcoal (105 mg, 98.2 µmol) was added and the mixture was hydrogenated at ambient pressure and room temperature for 3 h. Another portion of 10% palladium on charcoal (105 mg, 98.2 µmol) was added and hydrogenation was continued for another 3 h.. The catalyst was filtered off and the solvent was distilled. The crude product was dissolved in DCM, washed with concentrated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated again. 198 mg (92 % yield) of the title compound were obtained.

    [0190] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.047 (9.81), 1.380 (16.00), 3.362 (3.22), 3.379 (0.40), 3.392 (1.07), 3.405 (0.94), 3.449 (0.48), 3.461 (0.95), 3.475 (0.70), 4.483 (0.45), 4.496 (0.90), 4.509 (0.41).

    Intermediate 23A


    tert-Butyl 3-(2-{[(chloromethoxy)carbonyl]oxy}ethoxy)-2,2-dimethylpropanoate



    [0191] 



    [0192] tert-Butyl 3-(2-hydroxyethoxy)-2,2-dimethylpropanoate (intermediate 22A, 95 mg, 435 µmol) was dissolved in pyridine (5.0 mL) under an argon atmosphere and cooled to 0 °C. Chloromethyl carbonochloridate (58 µl, 650 µmol) was added at once and the mixture was stirred at room temperature for 45 min. The solvent was distilled, the residue was taken up into ethyl acetate (50 mL), washed consecutively with water, and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (gradient cyclohexane - cyclohexane ethyl acetate 82.5:17.5) to yield 103 mg (76 % of theory) of the title compound.

    [0193] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.040 (9.89), 1.374 (16.00), 3.377 (3.16), 3.607 (0.73), 3.615 (0.58), 3.619 (0.81), 3.623 (0.61), 3.630 (0.79), 4.273 (0.79), 4.279 (0.60), 4.284 (0.81), 4.288 (0.62), 4.295 (0.75), 5.893 (4.01).

    Intermediate 24A


    tert-Butyl 1-(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oate



    [0194] 



    [0195] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl-N-(1(1-cyanocyclopropyl)benzamide (179 mg, 276 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (720 µL, 0.50 M solution in toluene, 331 µmol) was added dropwise and the mixture was stirred 30 min. at - 45 °C. Then, a solution of sodium iodide (21 mg, 138 µmol) and tert-butyl 3-(2-{[(chloromethoxy)carbonyl]oxy}ethoxy)-2,2-dimethylpropanoate (intermediate 23A, 103 mg, 331 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 90 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (silica gel, gradient DCM - DCM / ethyl acetate 1:1) and subsequently by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 200 mg (78 % yield) of the title compound were obtained.

    [0196] LC-MS (method 4): Rt = 5.47 min; MS (ESIpos): m/z = 923 [M+H]+

    [0197] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.22), 0.008 (1.08), 0.997 (11.12), 1.235 (0.47), 1.331 (16.00), 1.754 (1.15), 2.328 (0.74), 2.332 (0.55), 2.366 (0.48), 2.523 (1.67), 2.670 (0.78), 2.710 (0.50), 3.326 (2.99), 3.535 (1.49), 4.113 (0.84), 7.590 (0.68), 7.612 (0.81), 7.780 (1.11), 7.804 (0.91), 7.825 (0.81), 7.936 (1.99), 8.210 (2.27), 8.440 (1.72), 8.763 (1.49).

    Intermediate 25A


    4-Ethoxy-2,2-dimethyl-4-oxobutanoic acid



    [0198] 



    [0199] A solution of 3,3-dimethyl-dihydrofuran-2,5-dione, 70.0 g (0.55 mol) in ethanol (400 mL) was stirred at 50 °C over night. After cooling down to room temperature, the solvent was removed under vacuum and the residue was triturated with hexane at -50 °C. The precipitated solid was collected to afford the title compound (60.0 g, 63% of theory) as a white solid.

    [0200] LC-MS (method 6): Rt = 0.89 min, MS (ESIpos): m/z = 175 [M+H]+.

    Intermediate 26A


    1-tert-Butyl 4-ethyl 2,2-dimethylsuccinate



    [0201] 



    [0202] 4-Ethoxy-2,2-dimethyl-4-oxobutanoic acid (intermediate 25A,110 g, 0.63 mol), magnesium sulfate (304 g, 2.53 mol), and tert-butanol (330 mL), was dissolved in DCM (2.6 L) Sulfuric acid (93.0 g (0.95 mol), was added dropwise slowly at 0 °C. The resulting mixture was stirred at room temperature over night. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution. DCM was added to extract the desired product, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford 70.0 g (37%) of the product as colorless oil.

    [0203] LC-MS (method 7): Rt = 1.26 min, MS (ESIpos): m/z = 253 [M+Na]-.

    Intermediate 27A


    4-tert-Butox-3,3-dimethl-4-oxobutanoic acid;



    [0204] 



    [0205] To a solution of 1-tert-butyl 4-ethyl 2,2-dimethylsuccinate, (intermediate 26A, 70.0 g, 0.3 mol) in ethanol (1.4 L) and water (700 mL), potassium hydroxide (85.3 g, 1.52 mol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to 3-4 by adding 1M hydrochloric acid. The resulting solution was extracted with ether 3 times, and the combined ether phases were dried over sodium sulfate and concentrated to afford the title compound (37.0 g, 68% of theory) as a yellow solid.

    [0206] LC-MS (method 7): Rt =0.36 min, MS (ESIpos): m/z = 201 [M-H]

    Intermediate 28A


    1-tert-Butyl 4-(2-hydroxyethyl) 2,2-dimethylsuccinate;



    [0207] 



    [0208] A mixture of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid, (intermediate 27A, 35.0 g 173.1 mmol) and potassium carbonate, 120 g (0,.87 mol) in DMF (1.0 L) was stirred at room temperature for 1 hour. 2-bromoethanol, 42.90 g (346.1 mmol), was added and the resulting mixture was stirred over night. The solvent was removed under vacuum. The residue was purified with silica gel column chromatograph (hexane/tert-butyl methyl ether 1:1) to give the title compound (22.6 g, 52% of theory) as yellow oil.

    [0209] LC-MS (method 5): Rt = 1.39 min, MS (ESIpos): m/z = 269 [M+Na]-.

    [0210] 1H-NMR (400 MHz, CD3OD): δ [ppm] = 1.21 (s, 6H), 1.43 (s, 9H), 2.59 (s, 2H), 3.73 (t, 2H), 4.11 (t, 2H).

    Intermediate 29A


    1-tert-Butyl 4-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) 2,2-dimethylbutanedioate



    [0211] 



    [0212] 1-tert-Butyl 4-(2-hydroxyethyl) 2,2-dimethylbutanedioate (intermediate 28A, 246 mg, 1.00 mmol) was dissolved in pyridine (5.0 mL) under an argon atmosphere and cooled to 0 °C. Chloromethyl carbonochloridate (130 µl, 1.5 mmol) was added at once and the mixture was stirred at room temperature for 45 min. The solvent was distilled, the residue was taken up into ethyl acetate (50 mL), washed consecutively with water, and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (gradient cyclohexane - cyclohexane ethyl acetate 3:1) to yield 228 mg (66 % yield) of the title compound.

    Intermediate 30A


    1-tert-Butyl 4-{2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxylcarbonyl)oxy]-ethyl} 2,2-dimethylbutanedioate



    [0213] 



    [0214] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (285 mg, 439 µmol) was dissolved in dry THF (10 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.4 mL, 0.50 M solution in toluene, 700 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, a solution of sodium iodide (33 mg, 220 µmol) and 1-tert-butyl 4-(2-{[(chloromethoxy)carbonyl]oxy} ethyl) 2,2-dimethylbutanedioate (intermediate 29A, 227 mg, 98 % purity, 659 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 90 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 318 mg (100 % purity, 76 % yield) of the title compound were obtained.

    [0215] LC-MS (method 3): Rt = 2.74 min; MS (ESIpos): m/z = 951 [M+H]+

    [0216] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.48), 0.008 (0.44), 1.098 (10.35), 1.326 (16.00), 1.356 (3.74), 1.756 (0.99), 2.073 (0.53), 2.183 (0.41), 4.168 (1.32), 4.197 (0.89), 7.592 (0.58), 7.611 (0.67), 7.788 (1.00), 7.806 (0.85), 7.827 (0.69), 7.935 (1.73), 8.208 (1.98), 8.438 (1.58), 8.767 (1.29).

    Intermediate 31A


    tert-Butyl (1S,2S)-2-hydroxycyclopentyl (2E)-but-2-enedioate



    [0217] 



    [0218] (1S,2S)-Cyclopentane-1,2-diol (2.68 g, 26.2 mmol) and N,N-diisopropylethylamine (2.7 ml, 16 mmol) were dissolved in DCM (25mL). Then, a solution of tert-butyl (2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 1.00 g, 5.25 mmol) in DCM (5 mL) was added dropwise at room temperature. The mixture was left stirring for 16 h. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with 3 portions of MTBE. Water was stripped off by filtration over a Chromabond PTS device and the solvent was distilled.The residue was purified by flash chromatography on silica gel (gradient cyclohexane / ethyl acetate 9:1 - 1:1) 270 mg (20 % yield) of the title compound was isolated.

    [0219] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.460 (16.00), 4.957 (0.94), 4.967 (0.91), 6.638 (4.27).

    Intermediate 32A


    tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate



    [0220] 



    [0221] tert-Butyl (1S,2S)-2-hydroxycyclopentyl (2E)-but-2-enedioate (intermediate 31A, 275 mg, 1.07 mmol) was dissolved in pyridine (10 mL) and the solution was cooled to 0°C. Chloromethyl carbonochloridate (190 µl, 2.1 mmol) was added dropwise and the mixture was stirred at room temperature over night. Then, the mixture was poured into water, the pH was adjusted to 4 by addition of 1M hydrochloric acid and the mixture was extracted with 3 portions of DCM. The combined organic layers were washed with 1M hydrochloric acid, water and brine. Residual water was stripped by filtration over a Chromabond PTS device, the solvent was distilled. The title compound (244 mg, 65 % yield) was used without further purification.

    [0222] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.464 (16.00), 1.734 (0.55), 1.744 (0.63), 1.753 (0.41), 5.890 (3.40), 6.666 (1.88), 6.677 (1.86).

    Intermediate 33A


    tert-Butyl (1S,2S)-2-[([[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(tri-fluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)-oxy]cyclopentyl (2E)-but-2-enedioate



    [0223] 



    [0224] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (199 mg, 308 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (23 mg, 154 µmol) and tert-butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (intermediate 32A, 118 mg, 338 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into concentrated aqueous ammonium chloride solution and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried passing them over a Chromabond PTS device and evaporated. The crude product was purified by flash chromatography (silica gel, gradient DCM - DCM / ethyl acetate 1:1) and subsequently by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 120 mg (41% yield) of the title compound were obtained.

    [0225] LC-MS (method 3): Rt = 2.83 min; MS (ESIpos): m/z = 961 [M+H]+

    [0226] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.66), 1.443 (16.00), 1.681 (0.41), 1.751 (0.43), 2.521 (0.65), 6.621 (1.79), 6.631 (1.85), 7.798 (0.73), 7.929 (0.62), 8.203 (0.66), 8.436 (0.70), 8.761 (0.47).

    Intermediate 34A


    tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate



    [0227] 



    [0228] tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (intermediate 32A, 130 mg, 373 µmol) was dissolved in THF (5 mL) and 10% palladium on charcoal (39.7 mg, 10 % purity, 37.3 µmol) was added. The mixture was hydrogenated at room temperature at ambient pressure over night. Then, the catalyst was filtered off and the filtrate was evaporated. The title compound (124 mg (95 % yield) was used without further purification.

    [0229] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.356 (0.45), 1.383 (16.00), 1.700 (0.43), 1.714 (0.69), 1.721 (0.41), 1.727 (0.58), 2.452 (0.51), 2.456 (0.55), 2.463 (0.86), 2.468 (0.72), 2.483 (0.92), 5.886 (3.56).

    Intermediate 35A


    tert-Butyl (1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(tri-fluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)-oxy]cyclopentyl butanedioate



    [0230] 



    [0231] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (203 mg, 313 µmol) was dissolved in dry THF (8 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (813 µL, 0.50 M solution in toluene, 407 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (23 mg, 154 µmol) and tert-butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate (intermediate 34A, 120 mg, 344 µmol) in THF (4.0 mL) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into concentrated aqueous ammonium chloride solution and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried passing them over a Chromabond PTS device and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 100 mg (33% yield) of the title compound were obtained.

    [0232] LC-MS (method 3): Rt = 2.78 min; MS (ESIpos): m/z = 963 [M+H]+

    [0233] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.022 (0.79), 1.235 (1.58), 1.354 (16.00), 1.650 (0.71), 1.753 (0.79), 1.963 (0.39), 2.424 (1.58), 2.435 (1.50), 4.955 (0.47), 7.586 (0.47), 7.603 (0.55), 7.799 (1.10), 7.819 (0.55), 7.934 (1.34), 8.208 (1.50), 8.211 (1.50), 8.442 (1.10), 8.760 (0.95).

    Intermediate 36A


    tert-Butyl 2-hydroxyethyl pentanedioate



    [0234] 



    [0235] Ethane-1,2-diol (5.3 mL, 96 mmol) was dissolved in DCM (10mL). and N,N-diisopropylethylamine (5.0 ml, 29 mmol) was added. Then, a solution of tert-butyl 5-chloro-5-oxopentanoate (CAS RN 2011712-15-3, 1.98 g, 9.58 mmol) in DCM (5 mL) was added under cooling with an ice bath. The reaction was left stirring over night, then poured into water and the pH was adjusted to 5-6 with 1M hydrochloric acid. The mixture was extracted with 2 portions of DCM, the combined organic extracts were briefly washed with concentrated aqueous sodium hydrogen carbonate, dried by passing through a Chromabond PTS device and evaporated. The residue was purified by chromatography over silica gel (gradient cyclohexane / ethyl acetate 80:20 - 50:50 giving 670 mg (30 % yield) of the title compound.

    [0236] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.395 (16.00), 1.706 (0.61), 1.725 (0.92), 1.743 (0.66), 2.215 (0.78), 2.234 (1.37), 2.252 (0.67), 2.308 (0.75), 2.327 (1.33), 2.345 (0.67), 3.546 (0.79), 3.559 (0.90), 3.572 (0.46), 4.008 (0.83), 4.021 (0.97), 4.034 (0.75), 4.772 (0.78).

    Intermediate 37A


    tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl pentanedioate



    [0237] 



    [0238] tert-Butyl 2-hydroxyethyl pentanedioate (intermediate 36A, 640 mg, 2.76 mmol) was dissolved in pyridine (10 mL), chloromethyl carbonochloridate (490 µl, 5.5 mmol) was added dropwise and the mixture was stirred at room temperature over night. Then, the mixture was poured into 1M hydrochloric acid and the mixture was extracted with 3 portions of DCM. The combined organic layers were washed with 1M hydrochloric acid, water and concentrated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. The title compound (648 mg, 72 % yield) was used without further purification.

    [0239] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (16.00), 1.701 (0.62), 1.720 (1.00), 1.738 (0.77), 2.210 (0.76), 2.229 (1.45), 2.247 (0.80), 2.322 (0.72), 2.340 (1.29), 2.358 (0.66), 4.256 (0.53), 4.267 (0.76), 4.272 (0.57), 4.278 (0.86), 4.383 (0.78), 4.389 (0.50), 4.394 (0.67), 4.405 (0.52), 5.901 (3.42).

    Intermediate 38A


    tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-ethyl pentanedioate



    [0240] 



    [0241] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (300 mg, 462 µmol) was dissolved in dry THF (5 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.2 mL, 0.50 M solution in toluene, 600 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (35 mg, 231 µmol) and tert-butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl pentanedioate (intermediate 37A, 180 mg, 554 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into concentrated aqueous ammonium chloride solution and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried passing them over a Chromabond PTS device and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 155 mg (36 % yield) were obtained.

    [0242] LC-MS (method 3): Rt = 2.69 min; MS (ESIpos): m/z =937 [M+H]+

    [0243] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.356 (0.65), 1.369 (16.00), 1.669 (0.42), 1.687 (0.60), 1.705 (0.46), 2.178 (0.46), 2.196 (0.83), 2.215 (0.41), 2.296 (0.54), 4.180 (0.46), 7.934 (0.61), 8.207 (0.68), 8.440 (0.54), 8.767 (0.43).

    Intermediate 39A


    1-tert-Butyl 1-(2-hydroxyethyl) cyclopropane-1,1-dicarboxylate



    [0244] 



    [0245] 1-(tert-Butoxycarbonyl)cyclopropane-1-carboxylic acid (600 mg, 3.22 mmol) was dissolved in DCM (6.0 mL) and one drop of DMF was added. The solution was cooled to 0°C and oxalic dichloride (560 µl, 6.4 mmol) was added dropwise. The cooling bath was removed and the reaction was left stirring at room temperature until the evolution of gas ceased. Volatiles were removed at room temperature under reduced pressure. The resulting acid chloride was dissolved in DCM (5 mL) and added to a solution of ethane-1,2-diol (1.8 mL, 32 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.7 mmol) in DCM. The mixture was left stirring over night at room temperature and was then poured into water and pH was adjusted to 6-6 by addition of 1M hydrochloric acid. This mixture was extracted with 2 portions of DCM, the combined organic extracts were washed with concentrated aqueous solution of sodium hydrogen carbonate, passed over a Chromabond PTS device and evaporated. The crude product was purified by chromatography on silica gel (gradient cyclohexane / ethyl acetate 80:20 - 50:50) to give 450 mg (61 % yield) of the title compound.

    [0246] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.252 (0.80), 1.260 (1.68), 1.266 (0.91), 1.281 (0.95), 1.286 (1.65), 1.295 (0.71), 1.408 (16.00), 3.554 (0.44), 3.567 (0.95), 3.580 (1.02), 3.594 (0.46), 4.053 (0.94), 4.066 (1.13), 4.079 (0.81), 4.768 (0.43), 4.781 (0.85).

    Intermediate 40A


    1-tert-Butyl 1-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) cyclopropane-1,1-dicarboxylate



    [0247] 



    [0248] 1-tert-Butyl 1-(2-hydroxyethyl) cyclopropane-1,1-dicarboxylate (intermediate 39A, 445 mg, 1.93 mmol) was dissolved in pyridine (5.0 mL), chloromethyl carbonochloridate (340 µl, 3.9 mmol) was added dropwise and the mixture was stirred at room temperature over night. Then, the mixture was poured into 1M hydrochloric acid and the resulting mixture was extracted with 3 portions of DCM. The combined organic layers were washed with 1M hydrochloric acid, water and concentrated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. The title compound (648 mg, 72 % yield) was used without further purification.

    [0249] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.284 (3.08), 1.288 (2.98), 1.297 (0.63), 1.397 (16.00), 1.420 (1.60), 4.312 (0.60), 4.319 (0.70), 4.322 (0.77), 4.333 (0.97), 4.394 (0.94), 4.398 (0.71), 4.405 (0.74), 4.415 (0.53), 5.911 (3.59).

    Intermediate 41A


    1-tert-Butyl 1-{2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-ethyl} cyclopropane-1,1-dicarboxylate



    [0250] 



    [0251] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (630 mg, 971 µmol) was dissolved in dry THF (20 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (2.5 mL, 0.50 M solution in toluene, 1.3 mmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (73 mg, 485 µmol) and 1-tert-butyl 1-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) cyclopropane-1,1-dicarboxylate (intermediate 40A, 470 mg, 1.46 mmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 570 mg (63 % yield) of the title compound were obtained.

    [0252] LC-MS (method 3): Rt = 2.70 min; MS (ESIpos): m/z = 935 [M+H]+

    [0253] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.245 (5.40), 1.324 (0.81), 1.356 (16.00), 1.758 (1.11), 4.235 (2.81), 7.592 (0.58), 7.612 (0.73), 7.791 (1.07), 7.807 (0.95), 7.829 (0.76), 7.935 (1.90), 8.209 (2.10), 8.213 (2.09), 8.443 (1.47), 8.766 (1.30).

    Intermediate 42A


    tert-Butyl-4-hydroxycyclohexyl (2E)-but-2-enedioate (Mixture of diastereomers)



    [0254] 



    [0255] Cyclohexane-1,4-diol (mixture of cis and trans diastereomers, 23.23 g, 200 mmol) and N,N-diisopropylethylamine (5.23 mL, 30 mmol) were suspended in THF (100 mL). A solution of tert-butyl (2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 1.91 g, 10.0 mmol) in THF (20 mL) was slowly added. Eventually, the reaction was quenched by addition of water and extracted with 3 portions of DCM. The combined organic extracts were dried over sodium sulfate, evaporated and purified by flash chromatography over silica gel (gradient cyclohexane - cyclohexane / ethyl acetate 3:2). The resulting product (1.60 g, 59% of theory) was obtained as a mixture of isomers.

    [0256] LC-MS (method 2): Rt = 0.89 min (58 area%) and 0.91 min (42 area%); MS (ESIpos): m/z = 288 [M+NH4]+

    Intermediate 43A


    tert-Butyl cis-4-hydroxycyclohexyl (2E)-but-2-enedioate



    [0257] 



    [0258] The product mixture of intermediate 42A (1.60 g, 5.92 mmol) was submitted to preparative SFC in order to separate the diasteremers. SFC conditions: column Chirapak AD-H (SFC) 5 µm, 250x30 mm; eluent: carbon dioxide / ethanol 7:3; pressure: 135 bar; eluent temperature: 38 °C, cyclone temperature 40 °C; flow: 125 mL/min; UV detection at 210 nm.

    [0259] The first peak (Rt = 1.02 min) was collected and evaporated. This material was dissolved in DCM, filtered over a layer of diatomaceous earth and was eventually evaporated. Yield: 845 mg of the title compound. The stereochemistry was assigned by comparison to authentic (1r,4r)-isomer prepared from pure trans-cyclohexane-1,4-diol (intermediate 44A).

    [0260] LC-MS (method 4): Rt = 2.68 min; MS (ESIpos): m/z = 288 [M+NH4]+

    [0261] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.467 (16.00), 1.549 (0.57), 1.559 (0.73), 1.580 (0.45), 1.590 (0.58), 4.513 (0.84), 4.523 (0.83), 6.650 (2.12), 6.655 (2.11).

    Intermediate 44A


    tert-Butyl trans-4-hydroxycyclohexyl (2E)-but-2-enedioate



    [0262] 



    [0263] From the preparative SFC separation described in intermediate 43A, the second peak (Rt = 2.09 min) was collected. This material was dissolved in DCM, filtered over a layer of diatomaceous earth and was eventually evaporated. Yield: 365 mg of the title compound.

    [0264] The stereochemistry was assigned by comparison with material prepared independently using commercialy available trans-1,4-cyclohexanediol (CAS RN 6995-79-5):
    trans-Cyclohexane-1,4-diol (CAS RN 6995-79-5, 1.00 g, 8.61 mmol) and N,N-diisopropylethylamine (900 µl, 5.2 mmol) were dissolved in THF (20 mL) and a solution of tert-butyl (2E)-4-chloro-4-oxobut-2-enoate (intermediate 1A, 328 mg, 1.72 mmol) in THF (5 mL) was slowly added. Eventually, the reaction was quenched by addition of water and extracted with 3 portions of DCM. The combined organic extracts were dried over sodium sulfate, evaporated and purified by flash chromatography over silica gel (gradient cyclohexane - cyclohexane / ethyl acetate 1:1). 214 mg (46 % yield) were isolated.

    [0265] LC-MS (method 4): Rt = 2.63 min; MS (ESIpos): m/z = 288 [M+NH4]+

    [0266] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.280 (0.56), 1.303 (0.62), 1.417 (0.73), 1.458 (16.00), 1.788 (0.54), 1.795 (0.57), 1.814 (0.49), 1.821 (0.46), 1.879 (0.57), 1.886 (0.55), 1.904 (0.50), 4.567 (1.04), 4.575 (0.91), 4.732 (0.42), 5.750 (0.62), 6.633 (2.89).

    Intermediate 45A


    tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate



    [0267] 



    [0268] tert-Butyl cis-4-hydroxycyclohexyl (2E)-but-2-enedioate (intermediate 43A, 210 mg, 777 µmol) was dissolved in pyridine (5.0 mL), chloromethyl carbonochloridate (100 µL, 1.2 mmol) was added and the mixture was stirred at room temperature for 45 min. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (100 mL) and subsequently washed with, water and 3 portions of brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 198 mg (100 % purity, 70 % yield) of the title compound were isolated.

    [0269] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.466 (16.00), 1.736 (0.43), 1.749 (0.66), 1.758 (0.83), 1.767 (0.71), 1.785 (0.78), 1.796 (0.93), 1.811 (0.60), 5.901 (3.59), 6.675 (4.24).

    Intermediate 46A


    tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-cyclohexyl (2E)-but-2-enedioate



    [0270] 



    [0271] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl-N-(1-cyanocyclopropyl)benzamide (275 mg, 424 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.4 mL, 0.50 M solution in toluene, 680 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (32 mg, 212 µmol) and tert-butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (intermediate 45A, 231 mg, 636 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 325 mg (100 % purity, 79 % yield) of the title compound were obtained.

    [0272] LC-MS (method 2): Rt = 1.55 min; MS (ESIpos): m/z = 975 [M+H]+

    [0273] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.452 (16.00), 1.691 (0.98), 1.762 (0.44), 3.518 (0.87), 6.653 (2.33), 7.802 (0.68), 7.923 (0.57), 8.196 (0.66), 8.453 (0.46), 8.776 (0.42).

    Intermediate 47A


    tert-Butyl cis-4-hydroxycyclohexyl butanedioate



    [0274] 



    [0275] tert-Butyl cis-4-hydroxycyclohexyl (2E)-but-2-enedioate (intermediate 43A, 210 mg, 777 µmol) was dissolved in ethanol (10 mL) and hydrogenated at ambient pressure and room temperature in the presence of 10% palladium on activated charcoal (41 mg, 39 µmol) for 90 min. The mixture was filtered over a pad of diatomaceous earth and evaporated. The title compound (167 mg, 79 % yield) was used without further purification.

    [0276] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.384 (16.00), 1.504 (0.69), 1.522 (1.45), 2.444 (0.40), 4.477 (0.80), 4.487 (0.80).

    Intermediate 48A


    tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl butanedioate



    [0277] 



    [0278] tert-Butyl cis-4-hydroxycyclohexyl butanedioate (intermediate 47A, 165 mg, 606 µmol) was dissolved in pyridine (7.0 mL), chloromethyl carbonochloridate (58 µl, 0.9 mmol) was added and the mixture was stirred at room temperature for 45 min. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (100 mL) and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 3:1). 180 mg (100 % purity, 81 % yield) of the title compound were isolated.

    [0279] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.382 (16.00), 1.664 (0.50), 1.679 (0.78), 1.691 (0.67), 1.702 (0.47), 1.743 (0.47), 1.760 (0.73), 1.772 (0.70), 2.454 (0.42), 2.457 (0.40), 2.461 (0.65), 2.469 (1.10), 2.479 (1.14), 5.894 (3.54).

    Intermediate 49A


    tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-cyclohexyl butanedioate



    [0280] 



    [0281] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (267 mg, 411 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.1 ml, 0.50 M solution in toluene, 530 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (31 mg, 206 µmol) and tert-butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (intermediate 48A, 180 mg, 493 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 45 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 277 mg (100 % purity, 69 % yield) of the title compound were obtained.

    [0282] LC-MS (method 4): Rt = 5.30 min; MS (ESIpos): m/z = 977 [M+H]+

    [0283] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.356 (1.04), 1.369 (16.00), 1.633 (0.73), 1.662 (0.71), 1.761 (0.41), 2.442 (0.57), 2.449 (0.90), 2.462 (0.95), 2.470 (0.60), 2.476 (0.50), 7.800 (0.68), 7.934 (0.56), 8.208 (0.62), 8.212 (0.61), 8.448 (0.44), 8.772 (0.42).

    Intermediate 50A


    tert-Butyl trans-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate



    [0284] 



    [0285] tert-butyl trans-4-hydroxycyclohexyl (2E)-but-2-enedioate (intermediate 44A, 210 mg, 777 µmol) was dissolved in pyridine (3.0 mL), chloromethyl carbonochloridate (120 µl, 1.2 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (50 mL) and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 237 mg (84 % yield) of the title compound were isolated.

    [0286] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.463 (16.00), 1.599 (0.86), 1.615 (0.87), 1.981 (0.42), 5.896 (3.73), 6.663 (4.43).

    Intermediate 51A


    tert-butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-cyclohexyl (2E)-but-2-enedioate



    [0287] 



    [0288] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (19 mg, 125 µmol) and tert-butyl trans-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (intermediate 50A, 136 mg, 375 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 197 mg (81 % of theory) of the title compound were obtained.

    [0289] LC-MS (method 4): Rt = 5.49 min; MS (ESIpos): m/z = 975 [M+H]+

    [0290] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.459 (16.00), 1.502 (0.48), 3.392 (0.44), 5.757 (0.95), 6.641 (1.72), 7.804 (0.56), 7.929 (0.58), 8.206 (0.69), 8.461 (0.55), 8.779 (0.53).

    Intermediate 52A


    tert-Butyl cis-4-{[(chloromethoxy)carbonyl]oxylcyclohexane-1-carboxylate



    [0291] 



    [0292] tert-Butyl cis-4-hydroxycyclohexane-1-carboxylate (CAS-RN 931110-79-1, 401 mg, 2.00 mmol) was dissolved in pyridine (6.5 mL), chloromethyl carbonochloridate (300 µl, 3.0 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (50 mL) and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 478 mg (82 % yield) of the title compound were isolated.

    [0293] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.397 (16.00), 1.639 (0.63), 1.646 (0.61), 1.654 (0.51), 5.887 (3.63).

    Intermediate 53A


    tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-cyclohexane-1-carboxylate



    [0294] 



    [0295] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (19 mg, 125 µmol) and tert-butyl cis-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (intermediate 52A, 110 mg, 375 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 196 mg (87 of theory) of the title compound were obtained.

    [0296] LC-MS (method 4): Rt = 5.41 min; MS (ESIpos): m/z = 905 [M+H]+

    [0297] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.234 (0.49), 1.358 (0.50), 1.375 (16.00), 1.395 (0.47), 1.400 (0.55), 1.591 (0.91), 1.605 (0.84), 1.660 (0.56), 1.762 (0.59), 7.813 (0.87), 7.932 (1.04), 8.209 (1.16), 8.452 (0.78), 8.777 (0.76).

    Intermediate 54A


    tert-Butyl trans-4-1[(chloromethoxy)carbonyl]oxylcyclohexane-1-carboxylate



    [0298] 



    [0299] tert-Butyl trans-4-hydroxycyclohexane-1-carboxylate (CAS RN 869193-57-7, 401 mg, 2.00 mmol) was dissolved in pyridine (6.5 mL), chloromethyl carbonochloridate (300 µl, 3.0 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (50 mL) and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 500 mg (85 % yield) of the title compound were isolated.

    [0300] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.389 (16.00), 1.413 (0.58), 1.429 (1.06), 1.446 (0.66), 1.984 (0.44), 5.881 (3.82).

    Intermediate 55A


    tert-Butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoro-methoxy)phenyl]-1-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-cyclohexane-1-carboxylate



    [0301] 



    [0302] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (19 mg, 125 µmol) and tert-butyl trans-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (intermediate 54A, 110 mg, 375 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). 191 mg (98 % purity, 82 % of theory) of the title compound were obtained.

    [0303] LC-MS (method 4): Rt = 5.44 min; MS (ESIpos): m/z = 905 [M+H]+

    [0304] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.129 (0.53), 1.257 (0.72), 1.391 (13.61), 1.407 (2.06), 1.780 (0.74), 1.847 (0.61), 2.564 (16.00), 7.620 (0.48), 7.634 (0.53), 7.806 (0.79), 7.827 (0.56), 7.842 (0.50), 7.957 (1.20), 8.234 (1.26), 8.478 (0.93), 8.801 (0.92).

    Intermediate 56A


    tert-Butyl {[(chloromethoxy)carbonyl]oxy}acetate



    [0305] 



    [0306] tert-Butyl hydroxyacetate (CAS-RN 50595-15-8, 264 mg, 2.00 mmol) was dissolved in pyridine (6.5 mL), chloromethyl carbonochloridate (300 µl, 3.0 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, the solvent was distilled, the residue was dissolved in ethyl acetate (50 mL) and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 430 mg (89 % purity, 85 % yield) of the title compound were isolated.

    [0307] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.426 (2.11), 1.431 (16.00), 4.688 (3.87), 5.946 (4.12).

    Intermediate 57A


    tert-Butyl [({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluorometh-oxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy] acetate



    [0308] 



    [0309] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (19 mg, 125 µmol) and tert-butyl {[(chloromethoxy)carbonyl]oxy}acetate (intermediate 56A, 84.2 mg, 375 µmol) in THF (3 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10µm, water-acetonitrile gradient with 0,01% TFA in both eluents, 90:10->5:95). of the title compound were obtained. 120 mg (57 % yield) were isolated.

    [0310] LC-MS (method 4): Rt = 4.99 min; MS (ESIpos): m/z = 837 [M+H]+

    [0311] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.77), 1.235 (1.70), 1.357 (10.57), 1.364 (16.00), 1.417 (1.30), 1.504 (0.42), 1.767 (1.65), 2.184 (0.68), 4.491 (3.15), 6.872 (0.44), 7.604 (0.89), 7.618 (0.98), 7.782 (1.45), 7.813 (1.01), 7.826 (0.95), 7.939 (2.92), 8.214 (3.08), 8.440 (5.00), 8.760 (1.98).

    Intermediate 58A


    tert-Butyl 4-{[(chloromethoxy)carbonyl]oxy}butanoate



    [0312] 



    [0313] tert-butyl 4-hydroxybutanoate (CAS RN 59854-12-5, 250 mg, 1.56 mmol) was dissolved in pyridine (5.1 mL).This solution was cooled to 0°C, chloromethyl carbonochloridate (240 µL, 2.4 mmol) was added and the mixture was stirred at room temperature over night. Then, the solvent was distilled, the residue was dissolved in ethyl acetate and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 263 mg (67 % yield) of the title compound were isolated. 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.400 (16.00), 1.836 (0.69), 1.847 (1.06), 1.859 (0.73), 2.271 (0.87), 2.283 (1.65), 2.295 (0.78), 4.185 (0.85), 4.196 (1.73), 4.207 (0.83), 5.890 (3.93).

    Intermediate 59A


    tert-butyl 4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] butanoate



    [0314] 



    [0315] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (292 mg, 528 µmol) was dissolved in dry THF (16 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.6 mL, 0.50 M solution in toluene, 840 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (39.5 mg, 264 µmol) and tert-Butyl 4-{[(chloromethoxy)carbonyl]oxy}butanoate (intermediate 58A, 160 mg, 633 µmol) in THF (5.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 231 mg (100 % purity, 57 % yield)of the title compound were obtained.

    [0316] LC-MS (Method 4): Rt = 4.80 min; MS (ESIpos): m/z = 769 [M+H]+

    [0317] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.367 (16.00), 1.754 (1.69), 1.764 (1.54), 2.074 (1.78), 2.204 (0.77), 2.216 (1.32), 2.228 (0.72), 3.824 (7.66), 4.021 (0.65), 7.616 (0.65), 7.629 (0.72), 7.825 (1.06), 7.849 (0.68), 7.863 (0.64), 8.566 (1.34), 8.842 (1.30).

    Intermediate 60A


    tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropanoate



    [0318] 



    [0319] tert-butyl 3-hydroxy-2,2-dimethylpropanoate (CAS RN 25307-76-0, 348 mg, 2.00 mmol) was dissolved in pyridine (7.0 mL).This solution was cooled to 0°C, chloromethyl carbonochloridate (240 µL, 3.0 mmol) was added and the mixture was stirred at room temperature over night. Then, the solvent was distilled, the residue was dissolved in ethyl acetate and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate). 258 mg (48 % yield) of the title compound were isolated.

    [0320] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.118 (9.71), 1.371 (0.81), 1.378 (16.00), 4.194

    Intermediate 61A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoate



    [0321] 



    [0322] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide(262 mg, 475 µmol) was dissolved in dry THF (15 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.5 mL, 0.50 M solution in toluene, 760 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (35.6 mg, 237 µmol) and tert-butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropanoate (intermediate 60A, 190 mg, 712 µmol)) in THF (5.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over the weekend. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 166 mg (91 % purity, 41 % yield) of the title compound were obtained.

    [0323] LC-MS (Method 4): Rt = 5.02 min; MS (ESIpos): m/z = 727 [M+H]+

    [0324] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.59), -0.008 (3.30), 0.008 (3.41), 1.044 (9.00), 1.095 (2.59), 1.109 (0.96), 1.235 (0.98), 1.306 (1.20), 1.329 (16.00), 1.370 (5.59), 1.379 (2.07), 1.484 (0.42), 1.758 (1.21), 2.524 (1.26), 3.824 (11.37), 4.024 (1.01), 4.069 (0.85), 7.613 (0.75), 7.633 (0.91), 7.826 (1.30), 7.846 (1.05), 7.868 (0.89), 8.560 (1.75), 8.815 (1.78).

    Intermediate 62A


    tert-Butyl trans-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate



    [0325] 



    [0326] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (203 mg, 368 µmol) was dissolved in dry THF (9 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.1 mL, 0.50 M solution in toluene, 590 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (27.5 mg, 184 µmol) and tert-butyl (1r,4r)-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (intermediate 50A, 200 mg, 551 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 206 mg (100 % purity, 64 % yield) of the title compound were obtained.

    [0327] LC-MS (Method 4): Rt = 5.12 min; MS (ESIpos): m/z = 879 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.60), 0.008 (0.70), 1.157 (0.55), 1.175 (1.11), 1.193 (0.57), 1.234 (0.40), 1.458 (16.00), 1.504 (0.55), 1.767 (0.41), 1.856 (0.44), 1.988 (2.03), 3.823 (3.34), 4.021 (0.47), 4.039 (0.47), 6.638 (1.73), 7.840 (0.56), 8.579 (0.55), 8.844 (0.53).

    Intermediate 63A


    tert-Butyl trans-4-[(1[12-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylate



    [0328] 



    [0329] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (315 mg, 569 µmol) was dissolved in dry THF (16 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.8 mL, 0.50 M solution in toluene, 910 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (42.7mg, 285 µmol) and tert-butyl (1s,4s)-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (intermediate 52A,250 mg, 854 µmol)in THF (5.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 311 mg (98 % purity, 66 % yield) of the title compound were obtained.

    [0330] LC-MS (Method 4): Rt = 5.08 min; MS (ESIpos): m/z = 809 [M+H]+

    [0331] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.357 (1.18), 1.379 (16.00), 1.590 (0.86), 1.767 (0.56), 2.075 (1.06), 3.826 (5.33), 7.612 (0.43), 7.627 (0.48), 7.851 (1.16), 7.861 (0.58), 8.574 (0.95), 8.848 (0.92).

    Intermediate 64A


    tert-Butyl trans-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(l-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylate



    [0332] 



    [0333] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (189 mg, 342 µmol) was dissolved in dry THF (11 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.1 mL, 0.50 M solution in toluene, 550 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (25.6 mg, 171 µmol) and tert-Butyl (1r,4r)-4-{[(chloromethoxy)carbonyl]oxy}cyclohexane-1-carboxylate (intermediate 54A,150 mg, 512 µmol) in THF (3.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 201 mg (100 % purity, 73 % yield) of the title compound were obtained.

    [0334] LC-MS (Method 4): Rt = 5.07 min; MS (ESIpos): m/z = 809 [M+H]+

    [0335] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.234 (0.53), 1.335 (0.85), 1.358 (1.57), 1.370 (16.00), 1.765 (0.75), 1.824 (0.66), 2.075 (6.04), 3.370 (0.40), 3.828 (6.58), 7.623 (0.61), 7.637 (0.71), 7.827 (0.96), 7.850 (0.62), 7.865 (0.59), 8.579 (1.25), 8.847 (1.22).

    Intermediate 65A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propyl(2E)-but-2-enedioate



    [0336] 



    [0337] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (228 mg, 413 µmol) was dissolved in dry THF (16 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.3 mL, 0.50 M solution in toluene, 660 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (31.0 mg, 207 µmol) and tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl (2E)-but-2-enedioate (intermediate 6A, 200 mg, 620 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature at 2h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 202 mg (100 % purity, 58 % yield) of the title compound were obtained.

    [0338] LC-MS (Method 4): Rt = 4.85 min; MS (ESIpos): m/z = 783 [M+H]+

    [0339] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.450 (16.00), 1.760 (0.45), 1.926 (0.42), 2.073 (0.68), 3.820 (3.80), 4.138 (0.56), 4.154 (0.67), 6.643 (1.46), 7.830 (0.49), 7.842 (0.41), 8.559 (0.63), 8.835 (0.60).

    Intermediate 66A


    tert-Butyl 3-hydroxypropyl butanedioate



    [0340] 



    [0341] tert-Butyl 3-hydroxypropyl (2E)-but-2-enedioate (intermediate 5A, 450 mg, 1.95 mmol) was dissolved in ethanol (10 mL) under an argon atmosphere. 10% Palladium on charcoal (41.6 mg, 39.1 µmol) was added and the mixture was hydrogenated over night at ambient pressure at room temperature. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was distilled. 430 mg (95 % yield) of the title compound were obtained.

    [0342] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.384 (16.00), 1.685 (0.76), 1.701 (1.19), 1.717 (0.80), 2.438 (0.52), 2.440 (0.48), 2.445 (0.66), 2.453 (0.95), 2.454 (1.08), 2.467 (1.04), 2.477 (0.61), 2.484 (0.54), 3.427 (0.41), 3.443 (0.93), 3.456 (0.92), 4.049 (0.78), 4.065 (1.59), 4.082 (0.75), 4.484 (0.42), 4.496 (0.85).

    Intermediate 67A


    tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl butanedioate



    [0343] 



    [0344] tert-Butyl 3-hydroxypropyl butanedioate (intermediate 66A,120mg, 517 µmol) was dissolved in pyridine (4.0 mL). This solution was cooled to 0°C, chloromethyl carbonochloridate (69 µl, 770 µmol) was added and the mixture was stirred at room temperature for 2h. Then, the solvent was distilled, the residue was dissolved in ethyl acetate and subsequently washed with water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 144 mg (100 % purity, 86 % yield) of the title compound were isolated.

    [0345] LC-MS (Method 4): Rt = 3.09 min; MS (ESIpos): m/z =151 [M+H]+

    [0346] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.381 (16.00), 1.931 (0.71), 1.947 (1.08), 1.963 (0.73), 2.450 (0.62), 2.456 (0.65), 2.466 (1.08), 2.482 (1.11), 4.073 (0.74), 4.089 (1.51), 4.105 (0.72), 4.235 (0.76), 4.251 (1.58), 4.267 (0.75), 5.894 (3.71).

    Intermediate 68A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] propyl butanedioate



    [0347] 



    [0348] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (159 mg, 287 µmol) was dissolved in dry THF (9 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (900 µL, 0.50 M solution in toluene, 460 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (21.5 mg, 144 µmol) and tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propyl butanedioate (intermediate 67A,140 mg, 431 µmol)in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 3h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 196 mg (100 % purity, 81 % yield) of the title compound were obtained.

    [0349] LC-MS (Method 4): Rt = 4.71 min; MS (ESIpos): m/z = 841 [M+H]+

    [0350] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (6.03), 1.045 (6.10), 1.360 (16.00), 1.761 (0.67), 1.842 (0.45), 1.857 (0.64), 1.872 (0.48), 2.086 (2.40), 2.437 (1.36), 2.451 (1.24), 3.757 (0.42), 3.772 (0.56), 3.788 (0.43), 3.821 (5.60), 4.011 (0.50), 4.026 (0.88), 4.042 (0.56), 4.086 (0.65), 7.635 (0.47), 7.832 (0.72), 7.843 (0.60), 7.865 (0.43), 8.563 (0.91), 8.837 (0.91).

    Intermediate 69A


    1-tert-Butyl 1-{2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl} cyclopropane-1,1-dicarboxylate



    [0351] 



    [0352] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (171 mg, 310 µmol) was dissolved in dry THF (8 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (910 µL, 0.50 M solution in toluene, 500 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (27.9 mg, 186 µmol) and 1-tert-Butyl 1-(2-{[(chloromethoxy)carbonyl]oxy} ethyl) cyclopropane-1,1-dicarboxylate (intermediate 40A,150 mg, 465 µmol) in THF (3.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 3h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 180 mg (86 % purity, 60 % yield) of the title compound were obtained.

    [0353] LC-MS (Method 4): Rt = 4.77 min; MS (ESIpos): m/z = 783 [M+H]+

    [0354] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.80), 1.175 (1.60), 1.193 (0.88), 1.249 (6.35), 1.358 (16.00), 1.760 (1.22), 1.988 (2.93), 2.073 (1.87), 3.820 (11.25), 4.021 (0.72), 4.038 (0.73), 4.236 (3.37), 7.614 (0.71), 7.636 (0.88), 7.831 (1.26), 7.849 (0.99), 7.871 (0.84), 8.561 (1.70), 8.834 (1.60).

    Intermediate 70A


    tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethylpentanedioate



    [0355] 



    [0356] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (238 mg, 431 µmol) was dissolved in dry THF (12mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.4 mL, 0.50 M solution in toluene, 690 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (32.3 mg, 216 µmol)and tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl pentanedioate (intermediate 37A, 210 mg, 647 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 201 mg (66 % purity, 37 % yield) of the title compound were obtained.

    [0357] LC-MS (Method 4): Rt = 4.75 min; MS (ESIpos): m/z = 785 [M+H]+

    [0358] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.373 (16.00), 1.668 (0.43), 1.687 (0.62), 1.705 (0.49), 1.761 (0.42), 2.180 (0.44), 2.198 (0.82), 2.216 (0.44), 2.295 (0.59), 3.821 (3.64), 4.177 (0.53), 7.834 (0.44), 8.559 (0.60), 8.836 (0.55).

    Intermediate 71A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropyl butanedioate



    [0359] 



    [0360] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (261 mg, 472 µmol) was dissolved in dry THF (12mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.4 mL, 0.50 M solution in toluene, 760 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (35.4 mg, 236 µmol) and tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl butanedioate (intermediate 14A,250 mg, 709 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 1h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 349 mg (100 % purity, 85 % yield) of the title compound were obtained.

    [0361] LC-MS (Method 4): Rt = 4.98 min; MS (ESIpos): m/z = 868 [M+H]+

    [0362] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (1.90), 1.175 (0.72), 1.355 (7.00), 1.988 (1.27), 2.444 (0.47), 2.466 (0.44), 2.523 (0.41), 3.318 (16.00), 3.321 (15.00), 3.785 (0.54), 3.822 (2.61), 7.842 (0.55).

    Intermediate 72A


    tert-Butyl [({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] acetate



    [0363] 



    [0364] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (246 mg, 445 µmol) was dissolved in dry THF (13mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.8 mL, 0.50 M solution in toluene, 710 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (33.4 mg, 223 µmol) and tert-Butyl {[(chloromethoxy)carbonyl]oxy}acetate (intermediate 56A,150 mg, 668 µmol) in THF (4.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 230 mg (100 % purity, 70 % yield) of the title compound were obtained.

    [0365] LC-MS (Method 4): Rt = 4.65 min; MS (ESIpos): m/z = 685 [M+H]+

    [0366] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.365 (16.00), 1.430 (1.20), 1.772 (1.41), 2.075 (0.41), 3.295 (0.63), 3.823 (13.60), 4.502 (3.21), 7.628 (0.89), 7.642 (0.99), 7.825 (1.45), 7.855 (0.91), 7.868 (0.87), 8.558 (3.53), 8.829 (2.26).

    Intermediate 73A


    1-tert-Butyl 1-methyl cyclopropane-1,1-dicarboxylate



    [0367] 



    [0368] To a solution of tert-Butyl methyl malonate (CAS-RN: 42726-73-8, 35.00 g, 200.92 mmol) in N,N-dimethylformamide (350 mL), 1-bromo-2-chloroethane(40 ml, 401.84 mmol), potassium carbonate (69.42 g, 502.30 mmol) and 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate(11.15 g, 50.32 mmol) was added with stirring at room temperature. After stirring for 48 h, the reaction mixture was diluted with water (800 mL) and extracted with diethyl ether (800 mL three times). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 40 g (60% purity, 60 % yield) of the title compound as a colourless oil.

    [0369] 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.175 (0.54), 1.260 (0.47), 1.271 (2.24), 1.278 (2.26), 1.289 (0.47), 1.369 (0.41), 1.379 (0.40), 1.398 (16.00), 1.408 (13.59), 1.989 (1.01), 2.891 (0.41), 3.387 (2.76), 3.639 (4.45), 3.652 (5.98).

    Intermediate 74A


    1-(tert-Butoxycarbonyl)cyclopropane-1-carboxylic acid



    [0370] 



    [0371] To a solution of 1-tert-Butyl 1-methyl cyclopropane-1,1-dicarboxylate (intermediate 73A, 40.00 g, 119.86 mmol) in a mixture of tetrahydrofuran (200 mL), methanol (100 mL) and water (100 mL), lithium hydroxide monohydrate (10.06 g, 239.72 mmol) was added. The mixture was stirred at room temperature for 2 h, then most of the solvents was removed by evaporation under vacuum, the residue was diluted with water (200 mL) and extracted with diethyl ether (200 mL three times). The aqueous layer was acidified to pH 2-3 with ice-cold 6 M hydrochloric acid and extracted with dichloromethane (2.0 L three times), dried over anhydrous sodium sulfate and filtered. The residue was concentrated under reduced pressure to give 12.00 g (95% purity, 51% yield) of the title compound as a colourless oil. 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.202 (0.43), 1.213 (1.95), 1.223 (2.00), 1.233 (0.52), 1.397 (16.00).

    Intermediate 75A


    tert-Butyl 1-(hydroxymethyl)cyclopropane-1-carboxylate



    [0372] 



    [0373] To a solution of 1-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid (Intermediate 74A, 12.80 g, 68.74 mmol), and triethylamine (13.91 g, 137.48 mmol) in tetrahydrofuran (160 mL), isobutyl chloroformate (11.74 g, 85.93 mmol) was added dropwise whith stirring at 0 °C. Stirring was maintained for 1 h, then the mixture was filtered and washed with tetrahydrofuran (20 mL) .The filtrate was cooled to 0 °C and then a solution of sodium borohydride (5.20 g, 137.48 mmol) in 1-methyl-2-pyrrolidinone (20 ml) was added. The reaction mixture was stirred at room temperature for 2 h then diluted with ether (100 mL), washed with saturated sodium bicarbonate aqueous solution(200 ml), water (200 mL) and brine (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (120 g, eluent: petroleum ether-ethyl acetate 20:1) to give 6.50 g (95% purity, 52% yield) of the title compound as colourless oil.

    [0374] 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 0.785 (0.92), 0.794 (1.35), 0.805 (0.61), 0.911 (0.57), 0.922 (1.34), 0.931 (0.88), 0.945 (0.40), 1.375 (16.00), 1.398 (0.50), 3.502 (1.55), 3.521 (1.64), 4.499 (0.48), 4.518 (1.00), 4.538 (0.48), 5.760 (0.80).

    Intermediate 76A


    tert-Butyl 2-({[(chloromethoxy)carbonyl]oxy}methyl)-2-methylbutanoate



    [0375] 



    [0376] tert-Butyl 2-(hydroxymethyl)-2-methylbutanoate (intermediate 75A, 377 mg, 2.00 mmol) was dissolved in pyridine (6.5 mL) and the solution was cooled to 0 °C. Chloromethyl carbonochloridate (300 µL, 3.0 mmol) was added at once and the mixture was stirred at room temperature for 2 h. The solvent was evaporated. The residue was redissolved in ethyl acetate (50 mL) washed with water (20 mL) and brine (20 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 4:1) to give 440 mg (100 % purity, 78 % yield) of the title compound.

    [0377] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.985 (0.51), 0.992 (1.36), 0.997 (1.36), 1.004 (0.54), 1.129 (0.63), 1.135 (1.42), 1.140 (1.22), 1.147 (0.40), 1.374 (16.00), 4.290 (3.28), 5.905 (3.83)

    Intermediate 77A


    tert-Butyl 1-{[({[{2-chloro-5-12'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl}cyclopropane-1-carboxylate



    [0378] 



    [0379] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (278 mg, 504 µmol) was dissolved in dry THF (16 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.6 mL, 0.50 M solution in toluene, 810 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (37.7 mg, 236 µmol) and tert-Butyl 2-({[(chloromethoxy)carbonyl]oxy}methyl)-2-methylbutanoate (intermediate 76A, 200 mg, 756 µmol) in THF (5.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 213 mg (100 % purity, 54 % yield) of the title compound were obtained.

    [0380] LC-MS (Method 4): Rt = 4.87 min; MS (ESIpos): m/z = 781 [M+H]+

    [0381] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.913 (1.97), 1.085 (2.09), 1.235 (0.58), 1.318 (16.00), 1.368 (1.19), 1.761 (1.15), 2.075 (1.55), 3.374 (1.26), 3.824 (11.32), 4.118 (0.50), 4.154 (0.54), 7.619 (0.89), 7.633 (1.03), 7.844 (1.57), 7.852 (1.19), 7.866 (0.95), 8.568 (1.94), 8.838 (1.81).

    Intermediate 78A


    tert-Butyl trans-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate



    [0382] 



    [0383] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (120 mg, 217 µmol) was dissolved in dry THF (7 mL). This solution was cooled to -45 °C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 350 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide(19.5 mg, 130 µmol) and tert-Butyl (1S,4S)-4-{[(chloromethoxy)carbonyl]oxy}cyclohexyl (2E)-but-2-enedioate (intermediate 45A,118 mg, 326 µmol)) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 120 mg (100 % purity, 63 % yield) of the title compound were obtained.

    [0384] LC-MS (Method 4): Rt = 5.07 min; MS (ESIpos): m/z = 879 [M+H]+

    [0385] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.60), -0.008 (1.01), 0.008 (1.09), 1.234 (1.46), 1.356 (0.79), 1.457 (16.00), 1.685 (1.04), 1.767 (0.57), 2.073 (4.31), 2.086 (0.45), 3.816 (3.69), 6.652 (1.84), 7.843 (0.62), 8.572 (0.58), 8.847 (0.56).

    Intermediate 79A


    tert-Butyl 2-[([{[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl butanedioate



    [0386] 



    [0387] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (111 mg, 200 µmol) was dissolved in dry THF (6 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (640 µL, 0.50 M solution in toluene, 320 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide (18 mg, 120 µmol) and tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy}ethyl butanedioate(intermediate 9A, 93 mg, 300 µmol)) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 45 min.. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 132 mg (100 % purity, 80 % yield) of the title compound were obtained.

    [0388] LC-MS (Method 4): Rt = 4.75 min; MS (ESIpos): m/z = 827 [M+H]+

    [0389] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.44), 0.008 (0.50), 1.235 (0.40), 1.356 (16.00), 1.385 (0.59), 1.763 (0.67), 2.416 (0.87), 2.431 (1.09), 2.459 (0.91), 2.474 (0.91), 3.441 (1.82), 4.184 (0.96), 4.212 (0.65), 7.615 (0.40), 7.636 (0.50), 7.838 (0.79), 7.868 (0.47), 8.562 (1.02), 8.837 (0.97).

    Intermediate 80A


    tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl (2E)-but-2-enedioate



    [0390] 



    [0391] 2-Chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (75.0 mg, 136 µmol) was dissolved in dry THF (4 mL). This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (400 µL, 0.50 M solution in toluene, 220 µmol) was added dropwise and the mixture was stirred for 30 min. at -45 °C. Then, a solution of sodium iodide(10.2 mg, 67.8 µmol)and tert-Butyl 2-{[(chloromethoxy)carbonyl]oxy} ethyl (2E)-but-2-enedioate (intermediate 3A,62.8 mg, 204 µmol)in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 1h. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm, water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 75.7 mg (100 % purity, 68 % yield) of the title compound were obtained.

    [0392] LC-MS (Method 4): Rt = 4.85 min; MS (ESIpos): m/z = 825 [M+H]+

    Intermediate 81A


    tert-Butyl 1-{[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl}cyclopropane-1-carboxylate



    [0393] 



    [0394] 2-Chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (6.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (18.7 mg, 125 µmol) and a solution of tert-Butyl 2-({[(chloromethoxy)carbonyl]oxy}methyl)-2-methylbutanoate (intermediate 76A, 105 mg, 375 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 205 mg (100 % purity, 93 % yield) of the title compound were obtained.

    [0395] LC-MS (Method 4): Rt = 5.25 min; MS (ESIneg): m/z = 920 [M-H]-

    [0396] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.913 (1.92), 1.078 (2.08), 1.162 (1.60), 1.176 (3.19), 1.190 (1.66), 1.234 (0.56), 1.313 (16.00), 1.357 (4.37), 1.757 (1.28), 1.990 (5.95), 2.185 (0.49), 4.009 (0.50), 4.023 (1.43), 4.038 (1.42), 4.052 (0.51), 4.120 (0.57), 4.150 (0.59), 7.596 (0.82), 7.612 (0.98), 7.809 (2.54), 7.826 (0.98), 7.943 (2.24), 8.220 (2.52), 8.454 (2.00), 8.772 (1.80).

    Intermediate 82A


    tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propanoate



    [0397] 



    [0398] tert-Butyl 3-hydroxypropanoate (CAS-RN: 59854-11-4, 590 µl, 4.0 mmol) was dissolved in pyridine (13.0 mL) and the solution was cooled to 0 °C. Chloromethyl carbonochloridate (610 µL, 6.0 mmol) was added at once and the mixture was stirred at room temperature for 2 h. The solvent was evaporated. The residue was redissolved in ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL) dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 4:1) to give 768 mg (80 % of theory) of the title compound.

    [0399] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.402 (16.00), 2.619 (0.78), 2.631 (1.48), 2.643 (0.80), 4.337 (0.80), 4.349 (1.48), 4.361 (0.77), 5.897 (3.97).

    Intermediate 83A


    tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl} benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propanoate



    [0400] 



    [0401] 2-Chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (6.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (18.7 mg, 125 µmol) and a solution of tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propanoate (intermediate 82A, 89.5 mg, 375 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 60 min. The reaction mixture evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 198 mg (100 % purity, 93 % yield) of the title compound were obtained.

    [0402] LC-MS (Method 4): Rt = 5.10 min; MS (ESIneg): m/z = 849 [M-H]-

    [0403] 1H-NMR (500 MHz, DMSO-d6)δ[ppm]: 1.234 (0.54), 1.360 (16.00), 1.757 (1.05), 2.077 (0.83), 2.184 (0.45), 2.524 (0.86), 4.181 (0.62), 7.596 (0.68), 7.613 (0.79), 7.785 (1.08), 7.813 (0.76), 7.830 (0.70), 7.942 (1.84), 8.217 (2.09), 8.220 (2.05), 8.451 (1.54), 8.771 (1.42).

    Intermediate 84A


    tert-Butyl 4-[({[(2-chloro-5-11-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]butanoate



    [0404] 



    [0405] 2-Chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (162 mg, 250 µmol) was dissolved in dry THF (6.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (800 µL, 0.50 M solution in toluene, 400 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (18.7 mg, 125 µmol) and a solution of tert-Butyl 4-{[(chloromethoxy)carbonyl]oxy}butanoate (intermediate 58A, 94.8 mg, 375 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 196 mg (100 % purity, 91 % yield) of the title compound were obtained.

    [0406] LC-MS (Method 4): Rt = 5.19 min; MS (ESTpos): m/z = 865 [M+H]+

    [0407] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.234 (0.53), 1.365 (16.00), 1.756 (1.66), 2.202 (0.65), 2.216 (1.11), 2.231 (0.61), 4.023 (0.62), 7.592 (0.54), 7.609 (0.63), 7.789 (0.91), 7.807 (0.65), 7.823 (0.56), 7.941 (1.34), 8.216 (1.50), 8.451 (1.18), 8.779 (1.11).

    Intermediate 85A


    tert-Butyl (1R,2R)-2-[({[[2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl butanedioate



    [0408] 



    [0409] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (105 mg, 190 µmol) was dissolved in dry THF (6.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (600 µL, 0.50 M solution in toluene, 300 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (14.2 mg, 95 µmol) and a solution of tert-Butyl (1R,2R)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl butanedioate (intermediate 34A, 100 mg, 285 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature for a night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 87.1 mg (95 % purity, 50 % yield) of the title compound were obtained.

    [0410] LC-MS (Method 4): Rt = 5.05 min; MS (ESIpos): m/z = 867 [M+H]+

    [0411] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.236 (0.45), 1.357 (16.00), 1.382 (0.41), 1.655 (0.49), 1.757 (0.55), 2.085 (4.91), 2.183 (0.77), 2.423 (1.20), 2.438 (0.96), 2.500 (11.24), 3.821 (5.47), 5.746 (3.10), 6.871 (0.49), 7.832 (0.60), 7.843 (0.47), 8.556 (0.70), 8.826 (0.67).

    Intermediate 86A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropyl (2E)-but-2-enedioate



    [0412] 



    [0413] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (210 mg, 380 µmol) was dissolved in dry THF (10 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (900 µL, 0.50 M solution in toluene, 600 µmol) was added dropwise and the mixture was stirred 30 min. at -45 °C. Then, sodium iodide (28.5 mg, 190 µmol) and a solution of tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 12A,200 mg, 570 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 295 mg (100 % purity, 89 % yield) of the title compound were obtained.

    [0414] LC-MS (Method 4): Rt = 5.12 min; MS (ESIpos): m/z = 811 [M+H]+

    [0415] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.93), 0.008 (1.01), 0.887 (2.51), 1.356 (1.22), 1.453 (16.00), 2.073 (5.27), 3.438 (1.10), 3.821 (3.53), 3.911 (1.18), 6.654 (1.00), 7.840 (0.73), 8.556 (0.55), 8.828 (0.50).

    Intermediate 87A


    1-tert-Butyl 4-{2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl} 2,2-dimethylbutanedioate



    [0416] 



    [0417] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (97.9 mg, 177 µmol) was dissolved in dry THF (5.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (560 µL, 0.50 M solution in toluene, 280 µmol) was added dropwise and was added 30 min. at -45 °C. Then, sodium iodide (13.3 mg, 88.6 µmol) and a solution of 1-tert-Butyl 4-(2-{[(chloromethoxy)carbonyl]oxy} ethyl) 2,2-dimethylbutanedioate (intermediate 29A,90.0 mg, 266 µmol) in THF (2.0 mL) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. 1-tert-Butyl 4-(2-{[(chloromethoxy)carbonyl]oxy}ethyl) 2,2-dimethylbutanedioate (intermediate 29A, 30.0 mg, 88.7 µmol) was added and was added. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 56.2 mg (100 % purity, 37 % yield) of the title compound were obtained.

    [0418] LC-MS (Method 4): Rt = 4.93 min; MS (ESIpos): m/z = 855 [M+H]+

    [0419] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.143 (2.13), 1.228 (2.13), 1.239 (3.20), 1.912 (4.27), 2.392 (3.20), 2.430 (5.33), 2.619 (3.20), 2.660 (5.33), 3.338 (4.27), 3.353 (5.33), 3.362 (3.20), 3.388 (16.00), 3.494 (14.93), 3.512 (6.40), 7.023 (2.13), 7.108 (2.13), 7.193 (2.13).

    Intermediate 88A


    Benzyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropanoate



    [0420] 



    [0421] Benzyl 3-hydroxy-2,2-dimethylpropanoate (CAS-RN: 17701-61-0,417 mg, 2.00 mmol) was dissolved in pyridine (7.5 mL) and the solution was cooled to 0°C.Chloromethyl carbonochloridate (270 µL, 3.0 mmol) was added at once and the mixture was stirred at room temperature for 16h. The solvent was evaporated. The residue was redissolved in ethyl acetate (50 mL ) washed with water (20 mL) and brine (20 mL) dried over anhydrous sodium sulfate and evaporated.The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 5:1) to give 230 mg (100 % purity, 38 % yield) of the title compound.

    [0422] LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 301 [M+H]+

    [0423] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.53), 0.008 (0.63), 1.195 (16.00), 4.263 (5.41), 5.122 (4.61), 5.875 (6.25), 7.322 (1.17), 7.340 (2.99), 7.360 (1.79), 7.375 (1.15).

    Intermediate 89A


    Benzyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoate



    [0424] 



    [0425] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (331 mg, 510 µmol) was dissolved in dry THF (15 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.6 mL, 0.50 M solution in toluene, 820 µmol) was added dropwise and was added 30 min. at -45 °C. Then, sodium iodide (38.2 mg, 255 µmol) and a solution of benzyl 3-{[(chloromethoxy)carbonyl]oxy}-2,2-dimethylpropanoate (intermediate 88A,230 mg, 765 µmol)in THF (2 ml) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 90 min. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 435 mg (99 % purity, 92 % yield)of the title compound were obtained.

    [0426] LC-MS (Method 3): Rt = 2.72 min; MS (ESIpos): m/z = 913 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.58), 0.008 (2.47), 1.122 (16.00), 1.157 (2.02), 1.175 (2.57), 1.193 (1.74), 1.235 (1.44), 1.356 (3.95), 1.490 (0.69), 1.644 (0.62), 1.754 (2.39), 1.988 (2.13), 2.184 (0.50), 2.328 (0.69), 2.524 (2.36), 2.670 (0.76), 4.021 (0.56), 4.039 (0.62), 4.098 (2.12), 5.070 (6.65), 5.240 (0.53), 5.374 (0.55), 7.301 (7.10), 7.313 (5.22), 7.328 (3.15), 7.579 (1.35), 7.600 (1.58), 7.772 (2.32), 7.800 (1.93), 7.820 (1.60), 7.934 (3.98), 8.206 (4.50), 8.422 (4.34), 8.704 (4.44).

    Intermediate 90A


    tert-Butyl (1S,2S)-2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate



    [0427] 



    [0428] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (87.1 mg, 157 µmol) was dissolved in dry THF (6.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (600 µL, 0.50 M solution in toluene, 250 µmol) was added dropwise and was added 30 min. at -45 °C. Then, sodium iodide (11.8 mg, 78.7 µmol) and a solution of tert-Butyl (1S,2S)-2-{[(chloromethoxy)carbonyl]oxy}cyclopentyl (2E)-but-2-enedioate (intermediate 32A,82.4 mg, 236 µmol) THF (2.0 ml) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95).57.6 mg (42 % yield)of the title compound were obtained.

    [0429] LC-MS (Method 4): Rt = 5.19 min; MS (ESIpos): m/z = 809 [M+H]+

    [0430] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.41), 0.008 (0.46), 1.235 (0.76), 1.356 (3.04), 1.447 (16.00), 1.462 (1.49), 1.675 (0.48), 1.759 (0.52), 2.183 (0.41), 3.820 (4.01), 5.754 (4.57), 6.622 (0.82), 6.632 (0.97), 7.839 (0.85), 8.557 (0.59), 8.831 (0.57).

    Intermediate 91A


    tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] propanoate



    [0431] 



    [0432] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (276 mg, 500 µmol) was dissolved in dry THF (12.0 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (1.6 mL, 0.50 M solution in toluene, 800 µmol) was added dropwise and was added 30 min. at -45 °C. Then, sodium iodide (37.5 mg, 250 µmol) and a solution of tert-Butyl 3-{[(chloromethoxy)carbonyl]oxy}propanoate (intermediate 82A,179 mg, 750 µmol) THF (4 ml) was added, the dry ice bath was removed and the mixture was stirred at room temperature over night. The reaction mixture was poured into water and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 254 mg (100 % purity, 67 % yield) of the title compound were obtained.

    [0433] LC-MS (Method 4): Rt = 4.70 min; MS (ESIpos): m/z = 699 [M+H]+

    [0434] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.365 (16.00), 1.758 (1.31), 2.071 (4.24), 3.822 (11.81), 4.183 (0.88), 7.616 (0.74), 7.630 (0.85), 7.818 (1.23), 7.854 (0.94), 7.868 (0.93), 8.556 (1.65), 8.827 (1.62).

    Intermediate 92A


    tert-Butyl 1-{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oate



    [0435] 



    [0436] 2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (138 mg, 250 µmol) was dissolved in dry THF (5.5 mL) This solution was cooled to -45°C on an acetone - dry ice bath. Potassium bis(trimethylsilyl)amide (650 µL, 0.50 M solution in toluene, 330 µmol) was added dropwise and was added 30 min. at -45 °C. Then, sodium iodide (18.7 mg, 125 µmol) and a solution of tert-Butyl 3-(2-{[(chloromethoxy)carbonyl]oxy}ethoxy)-2,2-dimethylpropanoate (intermediate 23A,93.2 mg, 300 µmol)THF (2.0 ml) was added, the dry ice bath was removed and the mixture was stirred at room temperature for 30min. The reaction mixture evaporated. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 110 mg (100 % purity, 53 % yield) of the title compound were obtained.

    [0437] LC-MS (Method 4): Rt = 5.15 min; MS (ESIpos): m/z = 771 [M+H-C4H8]++

    [0438] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.68), 1.001 (10.40), 1.041 (2.96), 1.043 (3.10), 1.236 (0.57), 1.335 (16.00), 1.357 (6.04), 1.374 (4.82), 1.376 (3.88), 1.755 (1.20), 2.183 (0.59), 2.515 (0.76), 2.518 (0.74), 2.521 (0.68), 3.267 (0.76), 3.271 (0.48), 3.329 (3.16), 3.359 (0.65), 3.369 (0.78), 3.376 (0.59), 3.537 (1.72), 3.819 (14.82), 4.113 (0.87), 5.247 (0.59), 7.614 (0.74), 7.628 (0.87), 7.815 (1.24), 7.850 (0.87), 7.863 (0.83), 8.552 (1.72), 8.826 (1.63).

    Synthesis of Example Compounds according to the Present Invention


    Example Compound 1


    (11E)-1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridec-11-en-13-oic acid



    [0439] 



    [0440] tert-Butyl 2-[({[(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phcnyl]-1H-pyrazol-4-yl}bcnzoyl)(1-cyanocyclopropyl)amino]mcthoxy} carbonyl)oxy]ethyl (2E)-but-2-enedioate (intermediate 4A, 105 mg, 114 µmol) was dissolved in 30% TFA in DCM (11 mL) and stirred at ambient temperature for 45 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acctonitrilc-watcr gradient with 0,01%TFA in both eluents, 10:90->95:5) and eventually by flash chromatography over silica gel eluted consecutively with cyclohexane, cyclohexane / ethyl acetate 4:1, ethyl acetate and finally ethyl acetate / methanol 10:1.The title compound was isolated in a yield of 56 mg (57% of theory).

    [0441] LC-MS (method 2): Rt = 1.26 min; MS (ESIpos): m/z = 865 [M+H]+

    [0442] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.74), -0.008 (16.00), 0.008 (11.78), 0.146 (1.48), 0.853 (0.63), 1.183 (0.78), 1.235 (3.59), 1.259 (1.56), 1.298 (0.78), 1.337 (0.81), 1.352 (0.85), 1.504 (1.96), 1.643 (1.89), 1.756 (6.78), 2.328 (1.41), 2.367 (1.07), 2.670 (1.44), 2.710 (0.96), 4.311 (11.48), 5.273 (1.44), 5.409 (1.48), 6.621 (1.48), 6.661 (10.11), 6.675 (13.67), 6.715 (2.04), 7.583 (3.30), 7.603 (4.07), 7.799 (9.78), 7.823 (4.70), 7.928 (11.37), 8.204 (11.96), 8.441 (10.78), 8.764 (7.52), 11.201 (0.52), 13.223 (1.63).

    Example Compound 2


    (12E)-1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,11-trioxo-4,6,10-trioxa-2-azatetradec-12-en-14-oic acid



    [0443] 



    [0444] tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]propyl (2E)-but-2-enedioate (intermediate 7A, 60.0 mg, 64.1 µmol) was dissolved in 30% TFA in DCM (3.0 mL) and stirred at ambient temperature for 15 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 38.0 mg (64 % yield) of the title compound were obtained.

    [0445] LC-MS (method 4): Rt = 4.34 min; MS (ESIpos): m/z = 879 [M+H]+

    [0446] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.56), 1.235 (1.78), 1.490 (2.29), 1.655 (1.95), 1.756 (8.08), 1.930 (7.19), 2.363 (1.39), 2.637 (1.28), 4.123 (6.58), 4.159 (10.37), 5.254 (1.56), 5.405 (1.67), 6.638 (1.90), 6.670 (15.33), 6.679 (16.00), 6.710 (2.01), 7.589 (4.40), 7.605 (5.24), 7.790 (8.59), 7.803 (6.63), 7.820 (5.30), 7.927 (13.60), 8.201 (15.00), 8.443 (10.98), 8.766 (9.59), 13.209 (0.78).

    Example Compound 3


    1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid



    [0447] 



    [0448] tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]

    [0449] methoxy}carbonyl)oxy]ethyl butanedioate (intermediate 10A, 100 mg, 108 µmol) was dissolved in 30% TFA in DCM (5.0 mL) and stirred at ambient temperature for 15 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 78.0 mg (95 % purity, 79 % yield) of the title compound were obtained.

    [0450] LC-MS (method 4): Rt = 4.20 min; MS (ESIpos): m/z = 867 [M+H]+

    [0451] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.42), -0.022 (0.86), -0.008 (3.63), 0.008 (2.88), 1.235 (1.93), 1.513 (2.33), 1.647 (2.07), 1.761 (8.31), 2.323 (0.89), 2.328 (1.12), 2.367 (1.10), 2.441 (11.63), 2.454 (15.22), 2.473 (12.55), 2.670 (1.10), 2.710 (0.99), 3.540 (1.05), 3.552 (0.99), 3.566 (0.78), 4.018 (0.47), 4.030 (0.44), 4.183 (11.61), 4.363 (0.89), 5.279 (1.65), 5.403 (1.75), 7.556 (0.44), 7.592 (4.26), 7.612 (5.25), 7.758 (0.84), 7.801 (11.92), 7.824 (5.73), 7.936 (14.56), 8.209 (16.00), 8.213 (15.61), 8.446 (12.94), 8.770 (10.75), 12.198 (0.81).

    Example Compound 4


    (12E)-1-(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,10-trioxa-2-azatetradec-12-en-14-oic acid



    [0452] 



    [0453] tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 13A, 298 mg, 309 µmol) was dissolved in 30% TFA in DCM (15 mL) and stirred at ambient temperature for 25 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 204 mg (100 % purity, 73 % yield) of the title compound were obtained.

    [0454] LC-MS (method 4): Rt = 4.60 min; MS (ESIpos): m/z = 907 [M+H]+

    [0455] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.25), 0.888 (16.00), 1.235 (0.89), 1.751 (2.55), 2.073 (13.35), 2.328 (1.35), 2.367 (0.82), 2.670 (1.53), 2.710 (0.97), 3.915 (7.86), 5.399 (0.64), 6.688 (12.63), 7.577 (1.40), 7.599 (1.79), 7.800 (3.96), 7.930 (4.29), 8.203 (5.10), 8.439 (4.13), 8.753 (3.27), 13.206 (1.89).

    Example Compound 5


    1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,10-trioxa-2-azatetradecan-14-oic acid



    [0456] 



    [0457] tert-Butyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]-2,2-dimethylpropyl butanedioate (intermediate 15A, 325 mg, 337 µmol) was dissolved in 30% TFA in DCM (16 mL) and stirred at ambient temperature for 10 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 237 mg (77 % yield) of the title compound were obtained.

    [0458] LC-MS (method 4): Rt = 4.54 min; MS (ESIpos): m/z = 909 [M+H]+

    [0459] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.76), 0.008 (1.95), 0.848 (16.00), 1.234 (0.49), 1.501 (0.70), 1.757 (2.59), 2.073 (8.11), 2.328 (1.65), 2.366 (1.08), 2.463 (4.81), 2.670 (1.68), 2.710 (1.05), 3.784 (4.59), 3.867 (2.84), 5.404 (0.59), 7.585 (1.35), 7.606 (1.62), 7.803 (4.27), 7.938 (4.38), 8.210 (5.05), 8.443 (3.68), 8.760 (3.19), 12.197 (2.14).

    Example Compound 6


    (2E)-4-({(rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobut-2-enoic acid



    [0460] 



    [0461] tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate (intermediate 18A, 455 mg, 473 µmol) was dissolved in in DCM (10 mL) and TFA (1.8 mL) was added. The mixture was stirred at ambient temperature for 1 h. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 135 mg (100 % purity, 32 % yield) of the title compound were obtained.

    [0462] LC-MS (method 2): Rt = 1.34 min; MS (ESIpos): m/z = 905 [M+H]+

    [0463] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.57), -0.008 (4.30), 0.008 (3.38), 0.146 (0.39), 1.029 (0.75), 1.235 (1.80), 1.459 (3.38), 1.547 (4.12), 1.742 (13.68), 1.958 (4.30), 2.073 (1.10), 2.328 (1.36), 2.367 (1.71), 2.524 (4.08), 2.671 (1.36), 2.711 (1.58), 4.944 (3.59), 5.110 (4.82), 5.244 (1.75), 6.632 (10.43), 7.568 (4.34), 7.587 (5.35), 7.790 (15.30), 7.810 (6.44), 7.934 (14.73), 8.209 (16.00), 8.432 (15.39), 8.741 (9.60), 13.189 (2.81).

    Example Compound 7


    4-({(rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobutanoic acid



    [0464] 



    [0465] tert-Butyl (rel 1R,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl butanedioate (intermediate 20A, 515 mg, 534 µmol) was dissolved in DCM (10 mL) and TFA (2.1 mL) was added. The mixture was stirred at ambient temperature for 20 min. The volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 300 mg (98 % purity, 61 % yield) of the title compound were obtained.

    [0466] LC-MS (method 3): Rt = 2.41 min; MS (ESIpos): m/z = 907 [M+H]+

    [0467] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.23), 0.008 (1.36), 1.218 (1.44), 1.235 (0.94), 1.283 (3.94), 1.509 (4.09), 1.628 (4.47), 1.693 (5.07), 1.758 (8.98), 1.908 (4.09), 2.074 (2.64), 2.671 (0.76), 2.711 (0.65), 4.874 (2.93), 4.996 (3.70), 5.277 (1.31), 7.588 (4.05), 7.609 (5.11), 7.802 (12.66), 7.820 (6.24), 7.936 (13.33), 8.211 (14.70), 8.405 (0.96), 8.444 (11.48), 8.759 (9.61), 12.165 (16.00).

    Example Compound 8


    1-(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oic acid



    [0468] 



    [0469] tert-Butyl 1-(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl] -1H-pyrazol-4-yl} phenyl)-2-(1-cyanocyclopropyl)-11,11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oate (intermediate 24A, 195 mg, 211 µmol) was dissolved in 30% TFA in DCM (10 mL) and stirred for 5 min at room temperature. Volatiles were evaporated under vacuum at ambient temperature. The residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 152 mg (83 % yield) of the title compound were isolated.

    [0470] LC-MS (method 4): Rt = 4.57 min; MS (ESIpos): m/z = 867 [M+H]+

    [0471] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.027 (5.86), 1.758 (0.71), 3.340 (16.00), 3.360 (2.50), 3.546 (0.85), 4.115 (0.46), 7.611 (0.45), 7.794 (0.72), 7.802 (0.70), 7.824 (0.46), 7.937 (1.16), 8.213 (1.28), 8.444 (1.07), 8.768 (0.88).

    Example Compound 9


    1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-12,12-dimethyl-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid



    [0472] 



    [0473] 1-tert-Butyl 4-{2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl} 2,2-dimethylbutanedioate (intermediate 30A, 310 mg, 100 % purity, 326 µmol) was dissolved in 30% TFA in DCM (16 mL) and stirred for 10 min at room temperature. Volatiles were evaporated and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 207 mg (71 % yield) of the title compound were obtained.

    [0474] LC-MS (method 4): Rt = 4.43 min; MS (ESIpos): m/z = 895 [M+H]+

    [0475] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.63), -0.007 (7.27), 0.006 (4.39), 0.116 (0.58), 1.127 (16.00), 1.168 (1.12), 1.512 (0.48), 1.660 (0.43), 1.760 (1.88), 2.362 (0.42), 2.636 (0.45), 3.541 (1.40), 4.157 (2.46), 4.200 (1.25), 7.593 (1.01), 7.609 (1.16), 7.793 (1.88), 7.805 (1.58), 7.822 (1.24), 7.935 (3.31), 8.208 (3.72), 8.441 (2.73), 8.769 (2.32).

    Example Compound 10


    (2E)-4-({(1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobut-2-enoic acid



    [0476] 



    [0477] tert-Butyl (1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate (intermediate 33A, 120 mg, 125 µmol) was dissolved in DCM (5.0 mL) and TFA (480 µL) was added. The mixture was stirred at room temperature for 1 h. Then, another 480 µL of TFA were added and stirring was continued for 45 min.The solvent was distilled at room temperature under vacuum and the residue was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 58.0 mg (51 % yield) of the title compound were obtained.

    [0478] LC-MS (method 3): Rt = 2.46 min; MS (ESIpos): m/z = 905 [M+H]+

    [0479] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.27), -0.008 (9.64), 0.008 (10.30), 0.146 (1.15), 1.141 (1.33), 1.235 (2.85), 1.465 (2.61), 1.501 (2.30), 1.673 (8.42), 1.754 (9.70), 2.025 (4.55), 2.328 (1.70), 2.367 (2.36), 2.670 (1.64), 2.710 (2.36), 4.883 (3.33), 5.067 (4.30), 5.277 (1.45), 5.384 (1.39), 6.583 (5.09), 6.622 (13.39), 6.669 (16.00), 6.709 (6.00), 7.583 (4.00), 7.603 (4.97), 7.799 (14.30), 7.820 (5.82), 7.931 (12.73), 8.204 (13.94), 8.442 (13.33), 8.762 (9.27), 13.231 (1.45).

    Example Compound 11


    4-({(1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobutanoic acid



    [0480] 



    [0481] tert-Butyl (1S,2S)-2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclopentyl butanedioate (intermediate 35A, 100 mg, 104 µmol) was dissolved in DCM (5.0 mL) and TFA (1.0 mL) was added. The mixture was stirred at room temperature for 30 min, then volatiles were evaporated at room temperature under vacuum. The crude product was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 66 mg (70 % yield) of the title compound were obtained.

    [0482] LC-MS (method 3): Rt = 2.41 min; MS (ESIpos): m/z = 907 [M+H]+

    [0483] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.67), 0.008 (3.56), 1.235 (0.89), 1.567 (2.67), 1.646 (4.44), 1.755 (4.44), 1.953 (2.67), 2.330 (1.78), 2.368 (2.67), 2.445 (16.00), 2.672 (1.78), 2.712 (1.78), 3.071 (0.89), 3.105 (0.89), 3.229 (1.78), 3.489 (0.89), 3.643 (0.89), 3.664 (0.89), 4.279 (0.89), 4.791 (1.78), 4.955 (2.67), 5.389 (0.89), 7.585 (2.67), 7.606 (2.67), 7.799 (6.22), 7.823 (2.67), 7.936 (7.11), 8.209 (8.00), 8.442 (6.22), 8.759 (5.33).

    Example Compound 12


    1-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatetradecan-14-oic acid



    [0484] 



    [0485] tert-Butyl 2-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl pentanedioate (intermediate 38A, 150 mg, 160 µmol) was dissolved in DCM (5.0 mL) and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 10 min, then volatiles were evaporated at room temperature under vacuum. The crude product was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 79 mg (56 % yield) of the title compound were obtained.

    [0486] LC-MS (method 3): Rt = 2.34 min; MS (ESIpos): m/z = 881 [M+H]+

    [0487] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.83), 0.008 (6.71), 0.146 (0.91), 1.044 (0.61), 1.235 (1.59), 1.508 (2.69), 1.681 (9.25), 1.699 (12.06), 1.718 (9.78), 1.756 (7.51), 2.073 (4.51), 2.203 (8.87), 2.221 (16.00), 2.240 (7.85), 2.293 (6.10), 2.311 (10.65), 2.328 (7.70), 2.366 (1.97), 2.670 (1.97), 2.709 (1.67), 3.409 (8.80), 4.177 (9.52), 4.216 (6.26), 4.590 (0.76), 5.175 (1.21), 5.272 (1.52), 5.404 (1.71), 7.557 (1.25), 7.588 (4.09), 7.608 (5.04), 7.757 (2.35), 7.794 (8.95), 7.823 (5.12), 7.935 (13.95), 8.209 (15.32), 8.442 (11.79), 8.767 (9.21), 12.058 (1.97).

    Example Compound 13


    1-[10-(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}phenyl)-9-(1-cyanocyclopropyl)-6,10-dioxo-2,5,7-trioxa-9-azadecanan-1-oyl]cyclopropane-1-carboxylic acid



    [0488] 



    [0489] 1-tert-Butyl 1-{2-[({[(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]ethyl} cyclopropane-1,1-dicarboxylate (intermediate 41 A, 570 mg, 609 µmol) was dissolved in DCM (10 mL) and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 10 min, then volatiles were evaporated at room temperature under vacuum. The crude product was purified by preparative HPLC (RP C-18 10µm acetonitrile-water gradient with 0,01%TFA in both eluents, 10:90->95:5). 365 mg (66 % yield) of the title compound were obtained.

    [0490] LC-MS (method 3): Rt = 2.39 min; MS (ESIpos): m/z = 879 [M+H]+

    [0491] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.280 (16.00), 1.505 (0.86), 1.648 (0.73), 1.762 (2.91), 2.073 (0.50), 2.328 (0.52), 2.670 (0.53), 4.226 (6.88), 5.277 (0.61), 5.395 (0.64), 7.591 (1.44), 7.611 (1.82), 7.802 (3.23), 7.826 (1.95), 7.936 (5.09), 8.212 (5.51), 8.446 (4.38), 8.767 (3.48), 12.780 (0.99).

    Example Compound 14


    (2E)-4-({cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl}oxy)-4-oxobut-2-enoic acid



    [0492] 



    [0493] tert-Butyl cis-4-[({[(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (intermediate 46A, 320 mg, 328 µmol) was dissolved in 30% TFA in DCM (16 mL) and the mixture was stirred at ambient temperature for 25 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 215 mg (71 % yield) of the title compound.

    [0494] LC-MS (method 4): Rt = 4.57 min; MS (ESIpos): m/z = 919 [M+H]+

    [0495] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.46), 0.008 (3.26), 1.234 (0.64), 1.697 (11.46), 1.764 (4.98), 2.073 (1.23), 2.328 (2.39), 2.366 (1.39), 2.670 (2.23), 2.710 (1.35), 3.472 (14.21), 4.595 (1.71), 4.850 (2.19), 5.261 (0.84), 6.643 (0.88), 6.683 (16.00), 6.688 (15.20), 6.727 (0.84), 7.593 (2.11), 7.614 (2.43), 7.802 (7.68), 7.821 (3.18), 7.924 (6.29), 8.196 (7.44), 8.452 (5.13), 8.775 (4.74), 13.181 (0.64).

    Example Compound 15


    4-({cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl}oxy)-4-oxobutanoic acid



    [0496] 



    [0497] tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino] methoxy}carbonyl)oxy]cyclohexyl butanedioate (intermediate 49A, 273 mg, 279 µmol) was dissolved in 30% TFA in DCM (14 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 255 mg (99 % yield) of the title compound.

    [0498] LC-MS (method 4): Rt = 4.50 min; MS (ESIpos): m/z = 921 [M+H]+

    [0499] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), -0.008 (5.28), 0.008 (4.78), 0.146 (0.62), 1.234 (0.45), 1.505 (1.28), 1.663 (9.81), 1.762 (5.48), 2.073 (2.23), 2.323 (2.10), 2.327 (2.89), 2.332 (2.23), 2.366 (1.20), 2.443 (2.27), 2.467 (15.05), 2.473 (16.00), 2.523 (8.99), 2.665 (2.47), 2.670 (3.34), 2.674 (2.52), 2.710 (1.40), 4.566 (2.02), 4.725 (2.72), 5.262 (0.91), 5.410 (0.95), 7.592 (2.27), 7.614 (2.76), 7.801 (8.74), 7.820 (3.59), 7.937 (7.55), 8.210 (8.29), 8.214 (8.29), 8.451 (6.06), 8.773 (5.65), 12.184 (1.36).

    Example Compound 16


    (2E)-4-({trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl}oxy)-4-oxobut-2-enoic acid



    [0500] 



    [0501] tert-Butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (intermediate 51A, 192 mg, 197 µmol) was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 30 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 133 mg (73 % of theory) of the title compound.

    [0502] LC-MS method 4): Rt = 4.56 min; MS (ESIpos): m/z = 919 [M+H]+

    [0503] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (3.06), 0.006 (2.21), 1.234 (0.72), 1.511 (9.00), 1.654 (2.19), 1.766 (7.12), 1.860 (7.44), 2.365 (0.55), 2.639 (0.54), 4.561 (3.25), 4.806 (3.40), 5.262 (1.65), 5.408 (1.74), 6.636 (2.45), 6.668 (15.70), 6.679 (16.00), 6.710 (2.42), 7.601 (5.00), 7.617 (5.79), 7.805 (13.70), 7.823 (5.29), 7.941 (10.76), 8.214 (12.49), 8.464 (10.82), 8.704 (0.47), 8.784 (10.72).

    Example Compound 17


    cis-4-[({[(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid



    [0504] 



    [0505] tert-Butyl cis-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexane-1-carboxylate (intermediate 53A, 190 mg, 210 µmol) was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 110 mg (62 % yield) of the title compound.

    [0506] LC-MS (method 4): Rt = 4.47 min; MS (ESIpos): m/z = 849 [M+H]+

    [0507] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.022 (0.83), 0.006 (1.66), 1.234 (1.39), 1.275 (0.53), 1.491 (2.58), 1.605 (16.00), 1.648 (8.81), 1.673 (8.69), 1.763 (9.17), 2.297 (3.65), 2.361 (0.73), 2.638 (0.56), 4.637 (4.73), 4.805 (0.50), 5.252 (1.82), 5.392 (1.89), 7.589 (5.24), 7.607 (5.98), 7.814 (13.64), 7.944 (13.72), 8.217 (15.39), 8.457 (12.23), 8.776 (11.73), 12.133 (0.48).

    Example Compound 18


    trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl} benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid



    [0508] 



    [0509] tert-Butyl trans-4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]cyclohexane-1-carboxylate (intermediate 55A, 189 mg, 209 µmol) was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 121 mg (94 % purity, 64 % yield) of the title compound.

    [0510] LC-MS (method 4): Rt = 4.48 min; MS (ESIpos): m/z = 849 [M+H]+

    [0511] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.75), 0.005 (1.63), 1.190 (0.66), 1.234 (1.15), 1.360 (8.78), 1.454 (2.90), 1.659 (2.14), 1.759 (9.21), 1.863 (8.45), 2.033 (0.88), 2.075 (1.12), 2.167 (3.86), 2.387 (1.15), 2.426 (1.45), 2.518 (3.02), 2.521 (3.23), 2.524 (3.17), 2.615 (1.03), 2.655 (1.09), 4.398 (3.71), 4.573 (0.54), 5.241 (1.96), 5.389 (2.05), 7.563 (0.69), 7.577 (1.03), 7.599 (6.37), 7.613 (7.00), 7.760 (1.39), 7.785 (10.20), 7.806 (6.97), 7.820 (6.13), 7.940 (14.97), 8.215 (16.00), 8.454 (13.74), 8.778 (13.13), 12.109 (0.78).

    Example Compound 19


    [({[(2-chloro-5-1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yllbenzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]acetic acid



    [0512] 



    [0513] tert-Butyl [({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy} carbonyl) oxy]acetate (intermediate 57A, 115 mg, 137 µmol)was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10µm acetonitrile:water +0,01%TFA 10:90->95:5). Fractions containing the desired product were combined and freeze-dried to give 34.0 mg (97 % purity, 31 % yield) of the title compound.

    [0514] LC-MS (method 4): Rt = 4.18 min; MS (ESIpos): m/z = 781 [M+H]+

    [0515] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (1.08), 0.117 (0.99), 1.170 (0.48), 1.184 (0.97), 1.198 (0.48), 1.234 (0.97), 1.516 (2.26), 1.658 (1.97), 1.767 (9.02), 4.204 (0.50), 4.218 (0.54), 4.475 (1.18), 4.524 (16.00), 4.688 (1.39), 5.210 (0.93), 5.312 (1.82), 5.444 (1.93), 7.539 (0.44), 7.603 (4.58), 7.619 (5.41), 7.689 (0.62), 7.780 (7.71), 7.808 (5.37), 7.824 (4.85), 7.947 (14.20), 8.223 (15.38), 8.321 (0.39), 8.444 (15.83), 8.771 (12.83), 13.240 (1.08).

    Example 20


    4-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] butanoic acid



    [0516] 



    [0517] tert-Butyl 4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]butanoate (intermediate 59A, 230 mg, 299 µmol) was dissolved in 30% TFA in DCM (10 mL) and the mixture was stirred at ambient temperature for 7 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 2:1-ethyl acetate methanol 80:20). 60.9 mg (100 % purity, 29 % yield) of the title compound were isolated.

    [0518] LC-MS (Method 4): Rt = 3.89 min; MS (ESIpos): m/z = 713 [M+H]+

    [0519] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.500 (0.44), 1.760 (2.79), 2.242 (1.98), 3.820 (16.00), 4.037 (1.23), 7.613 (0.94), 7.627 (1.05), 7.825 (1.70), 7.843 (1.21), 7.858 (1.12), 8.557 (2.18), 8.830 (2.26).

    Example 21


    3-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoic acid



    [0520] 



    [0521] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoate (intermediate 61A, 160 mg, 204 µmol) was dissolved in 30% TFA in DCM (8 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 78.3 mg (100 % purity, 53 % yield) of the title compound were isolated.

    [0522] LC-MS (Method 4): Rt = 4.10 min; MS (ESIpos): m/z = 727 [M+H]+

    [0523] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.47), 0.008 (0.47), 1.034 (0.97), 1.064 (12.20), 1.145 (0.70), 1.493 (0.48), 1.644 (0.43), 1.762 (1.81), 2.524 (1.47), 3.823 (16.00), 4.035 (1.24), 7.612 (1.00), 7.632 (1.26), 7.841 (2.64), 7.864 (1.27), 8.564 (2.70), 8.828 (2.75).

    Example 22


    trans (2E)-4-(1-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy}carbonyl)oxy]cyclohexyl}oxy)-4-oxobut-2-enoic acid



    [0524] 



    [0525] tert-Butyl trans-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (intermediate 62A, 188 mg, 214 µmol ) was dissolved in 30% TFA in DCM (15 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 125 mg (100 % purity, 71 % yield) were isolated.

    [0526] LC-MS (Method 4): Rt = 4.11 min; MS (ESIpos): m/z = 823 [M+H]+

    [0527] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.71), 0.008 (16.00), 0.146 (1.67), 1.236 (1.47), 1.511 (6.79), 1.766 (5.25), 1.863 (5.63), 2.328 (0.85), 2.366 (1.19), 2.670 (1.02), 2.710 (1.26), 3.431 (8.97), 4.560 (2.15), 4.810 (2.39), 5.255 (1.16), 5.400 (1.19), 6.626 (1.16), 6.666 (10.85), 6.676 (11.39), 6.715 (1.23), 7.621 (3.17), 7.641 (3.92), 7.841 (7.23), 7.866 (3.72), 8.577 (7.03), 8.844 (7.03), 13.178 (0.89).

    Example 23


    cis-4-[({[[2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid



    [0528] 



    [0529] tert-butyl cis-4-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylate (intermediate 63A, 300 mg, 371 µmol ) was dissolved in 30% TFA in DCM (15 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 51.4 mg (100 % purity, 18 % yield) of the title compound were obtained.

    [0530] LC-MS (Method 4): Rt = 4.07 min; MS (ESIpos): m/z = 753 [M+H]+

    [0531] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.489 (0.54), 1.609 (2.64), 1.643 (1.72), 1.677 (1.68), 1.767 (1.77), 2.301 (0.79), 3.824 (16.00), 4.636 (1.05), 5.399 (0.41), 7.613 (1.19), 7.628 (1.36), 7.849 (3.12), 8.573 (2.84), 8.842 (2.82).

    Example 24


    trans -4-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylic acid



    [0532] 



    [0533] tert-Butyl trans-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexane-1-carboxylate (intermediate 64A, 200 mg, 247 µmol) was dissolved in 30% TFA in DCM (10 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 53.1 mg (100 % purity, 29 % yield) of the title compound were obtained.

    [0534] LC-MS (Method 4): Rt = 4.04 min; MS (ESIpos): m/z = 753 [M+H]+

    [0535] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.360 (1.47), 1.461 (0.56), 1.655 (0.41), 1.763 (1.63), 1.861 (1.32), 2.172 (0.75), 3.823 (16.00), 4.393 (0.69), 7.624 (1.30), 7.638 (1.48), 7.825 (2.02), 7.847 (1.26), 7.863 (1.15), 8.576 (2.69), 8.845 (2.67).

    Example 25


    (12E)-1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-1,5,11-trioxo-4,6,10-trioxa-2-azatetradec-12-en-14-oic acid



    [0536] 



    [0537] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propyl (2E)-but-2-enedioate (intermediate 65A, 200 mg, 238 µmol) was dissolved in 30% TFA in DCM (12 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 8.10 mg (100 % purity, 4 % yield) of the title compound were obtained.

    [0538] LC-MS (Method 4): Rt = 4.00 min; MS (ESIpos): m/z = 783 [M+H]+

    [0539] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.72), -0.007 (7.75), 0.006 (5.08), 0.116 (0.66), 1.225 (1.22), 1.236 (1.36), 1.259 (0.63), 1.285 (0.81), 1.297 (0.83), 1.337 (0.74), 1.494 (0.46), 1.760 (1.58), 1.908 (0.98), 1.917 (1.05), 1.929 (1.49), 1.941 (1.10), 2.040 (1.53), 2.358 (0.42), 2.362 (0.61), 2.365 (0.42), 2.518 (0.85), 2.522 (0.59), 2.632 (0.42), 2.635 (0.61), 2.639 (0.41), 3.820 (16.00), 4.124 (1.36), 4.144 (1.64), 4.156 (2.17), 6.622 (0.46), 6.653 (1.90), 6.674 (2.34), 6.706 (0.68), 7.612 (0.98), 7.628 (1.14), 7.829 (1.68), 7.843 (1.31), 7.860 (1.03), 8.560 (2.30), 8.834 (2.17).

    Example 26


    1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-1,5,11-trioxo-4,6,10-trioxa-2-azatetradecan-14-oic acid



    [0540] 



    [0541] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propyl butanedioate (intermediate 68A, 190 mg, 226 µmol) was dissolved in 30% TFA in DCM (10 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 36.1 mg (100 % purity, 20 % yield) of the title compound were obtained.

    [0542] LC-MS (Method 4): Rt = 3.96 min; MS (ESIpos): m/z = 785 [M+H]+

    [0543] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.397 (0.45), 1.491 (0.52), 1.664 (0.46), 1.765 (1.77), 1.847 (1.27), 1.857 (1.82), 1.867 (1.36), 2.426 (0.45), 2.456 (3.27), 2.467 (3.22), 2.575 (0.52), 3.822 (16.00), 4.027 (2.34), 4.036 (1.52), 4.090 (1.44), 5.249 (0.40), 5.405 (0.42), 7.620 (1.13), 7.634 (1.29), 7.832 (1.98), 7.847 (1.31), 7.861 (1.22), 8.568 (2.47), 8.839 (2.62).

    Example 27


    1-[10-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-9-(1-cyanocyclopropyl)-6,10-dioxo-2,5,7-trioxa-9-azadecanan-1-oyl] cyclopropane-1-carboxylic acid



    [0544] 



    [0545] tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl ethyl(methyl)propanedioate (intermediate 69A, 167 mg, 195 µmol) was dissolved in 30% TFA in DCM (15 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 24.6 mg (100 % purity, 16 % yield) of the title compound were obtained.

    [0546] LC-MS (Method 4): Rt = 4.03 min; MS (ESIpos): m/z = 783 [M+H]+

    [0547] 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.79), -0.006 (9.82), 0.006 (6.98), 0.117 (0.79), 1.280 (7.07), 1.397 (2.03), 1.492 (0.48), 1.646 (0.50), 1.765 (1.75), 2.362 (0.64), 2.635 (0.69), 3.545 (0.50), 3.820 (16.00), 4.227 (3.99), 5.886 (0.43), 7.616 (0.98), 7.633

    Example 28


    1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatetradecan-14-oic acid



    [0548] 



    [0549] tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]ethyl pentanedioate (intermediate 70A, 200 mg, 238 µmol ) was dissolved in 30% TFA in DCM (12 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01% TFA 10:90->95:5). 131 mg (100 % purity, 70 % yield) of the title compound were obtained.

    [0550] LC-MS (Method 4): Rt = 3.84 min; MS (ESIpos): m/z = 785 [M+H]+

    [0551] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.372 (0.41), 1.503 (0.58), 1.681 (1.89), 1.699 (2.52), 1.717 (1.98), 1.736 (1.17), 1.762 (1.78), 2.205 (1.76), 2.223 (3.23), 2.241 (1.68), 2.290 (1.30), 2.309 (2.32), 2.327 (1.62), 2.366 (0.46), 3.821 (16.00), 4.177 (2.15), 4.220 (1.47), 7.612 (0.96), 7.632 (1.15), 7.791 (0.40), 7.835 (2.02), 7.866 (1.14), 8.561 (2.51), 8.834 (2.41).

    Example 29


    1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,10-trioxa-2-azatetradecan-14-oic acid



    [0552] 



    [0553] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'azol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropyl butanedioate (intermediate 71A, 300 mg, 345 µmol ) was dissolved in 30% TFA in DCM (16 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 91.1 mg (100 % purity, 32 % yield) of the title compound were obtained.

    [0554] LC-MS (Method 4): Rt = 4.13 min; MS (ESIpos): m/z = 813 [M+H]+

    [0555] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.62), 0.008 (0.76), 0.851 (10.99), 0.934 (0.59), 1.500 (0.44), 1.762 (1.66), 2.463 (2.83), 3.785 (3.21), 3.822 (16.00), 3.866 (1.89), 7.610 (0.90), 7.631 (1.11), 7.842 (3.25), 7.860 (1.33), 8.563 (2.40), 8.831 (2.28).

    Example 30


    [({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy}carbonyl)oxy]acetic acid



    [0556] 



    [0557] tert-Butyl [({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]acetate (intermediate 72A, 230 mg, 310 µmol) was dissolved in 30% TFA in DCM (15 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.- cyclohexane ethyl acetate 4:1). 45.3 mg (100 % purity, 21 % yield) of the title compound were isolated.

    [0558] LC-MS (Method 4): Rt = 3.82 min; MS (ESIneg): m/z = 683 [M-H]-

    [0559] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.75), 0.008 (1.76), 1.512 (0.46), 1.682 (0.44), 1.766 (1.61), 2.328 (0.41), 2.524 (1.93), 2.670 (0.45), 3.818 (16.00), 3.906 (0.42), 4.533 (2.86), 7.621 (0.78), 7.643 (0.97), 7.815 (1.45), 7.846 (1.05), 7.869 (0.96), 8.551 (4.10), 8.569 (0.45), 8.824 (4.02).

    Example 31


    1-{[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl}cyclopropane-1-carboxylic acid



    [0560] 



    [0561] tert-Butyl 1-{[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl}cyclopropane-1-carboxylate (intermediate 77A, 210 mg, 269 µmol ) was dissolved in 30% TFA in DCM (9.0 mL) and the mixture was stirred at ambient temperature for 7 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). The crude product was purified by flash chromatography on silica gel (gradient cyclohexane.-cyclohexane ethyl acetate 4:1). 62 mg (100 % purity, 32 % yield) of the title compound were isolated.

    [0562] LC-MS (Method 4): Rt = 3.99 min; MS (ESIpos): m/z = 725 [M+H]+

    [0563] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.54), 0.008 (0.58), 0.921 (2.34), 1.117 (2.55), 1.491 (0.54), 1.659 (0.45), 1.759 (1.82), 3.823 (16.00), 4.153 (0.70), 7.613 (1.00), 7.634 (1.26), 7.833 (2.10), 7.864 (1.19), 8.565 (2.97), 8.835 (2.83).

    Example 32


    cis-(2E)-4-({-4-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl) amino] methoxy} carbonyl)oxy] cyclohexyl}oxy) -4-oxobut-2-enoic acid



    [0564] 



    [0565] tert-Butyl (1S,4S)-4-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclohexyl (2E)-but-2-enedioate (intermediate 78A, 73 mg, 83 µmol) was dissolved in 30% TFA in DCM (7.0 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).39.5 mg (100 % purity, 58 % yield) of the title compound were isolated.

    [0566] LC-MS (Method 4): Rt = 4.10 min; MS (ESIpos): m/z = 823 [M+H]+

    [0567] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.40), -0.022 (0.42), -0.008 (3.14), 0.008 (3.57), 1.235 (0.86), 1.457 (0.99), 1.467 (0.55), 1.506 (0.53), 1.695 (4.74), 1.767 (2.39), 3.568 (0.44), 3.818 (16.00), 4.584 (0.83), 4.857 (0.94), 6.684 (5.76), 6.687 (5.79), 7.619 (1.04), 7.639 (1.25), 7.845 (3.70), 7.865 (1.33), 8.574 (2.46), 8.845 (2.38).

    Example 33


    1-{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid



    [0568] 



    [0569] tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy] ethyl butanedioate (intermediate 79A,130 mg, 157 µmol) was dissolved in 30% TFA in DCM (15.0 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).109 mg (95 % purity, 86 % yield) of the title compound were isolated.

    [0570] LC-MS (Method 4): Rt = 3.96 min; MS (ESIpos): m/z = 771 [M+H]+

    [0571] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.501 (0.48), 1.669 (0.43), 1.767 (1.73), 2.444 (2.28), 2.455 (3.01), 2.473 (2.80), 3.822 (16.00), 4.184 (2.35), 4.213 (1.52), 7.617 (0.96), 7.637 (1.19), 7.843 (2.31), 7.868 (1.18), 8.564 (2.63), 8.837 (2.53).

    Example 34


    (11E)-1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-1,5,10-trioxo-4,6,9-trioxa-2-azatridec-11-en-13-oic acid



    [0572] 



    [0573] tert-Butyl 2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy} carbonyl)oxy]ethyl (2E)-but-2-enedioate(intermediate 80A, 74.0 mg, 89.7 µmol) was dissolved in 30% TFA in DCM (7.4 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).54.9 mg (94 % purity, 69 % yield) of the title compound were isolated.

    [0574] LC-MS (Method 4): Rt = 4.01 min; MS (ESIpos): m/z = 769 [M+H]+

    [0575] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.28), 0.008 (1.19), 1.496 (0.55), 1.683 (0.50), 1.758 (1.64), 2.323 (0.73), 2.327 (1.00), 2.332 (0.77), 2.366 (0.89), 2.523 (3.51), 2.665 (0.68), 2.670 (0.93), 2.674 (0.71), 2.710 (0.75), 3.820 (16.00), 4.309 (3.05), 6.665 (2.39), 6.672 (2.67), 7.603 (1.09), 7.625 (1.12), 7.839 (2.55), 7.861 (1.12), 8.556 (2.62), 8.833 (2.23), 13.218 (0.52).

    Example 35


    1-{[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl}cyclopropane-1-carboxylic acid



    [0576] 



    [0577] tert-Butyl 1-{[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]methyl} cyclopropane-1-carboxylate (intermediate 81A, 200 mg, 228 µmol) was dissolved in 30% TFA in DCM (20.0 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).135 mg (95 % purity, 68 % yield) of the title compound were isolated.

    [0578] LC-MS (Method 4): Rt = 4.43 min; MS (ESIpos): m/z = 821 [M+H]+

    [0579] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.67), 0.921 (10.12), 1.114 (11.51), 1.186 (1.08), 1.234 (1.08), 1.501 (2.38), 1.640 (1.98), 1.754 (8.17), 2.328 (0.96), 2.367 (1.08), 2.670 (0.99), 2.711 (1.15), 4.167 (2.60), 4.275 (1.08), 5.265 (1.67), 5.395 (1.73), 7.589 (4.33), 7.609 (5.32), 7.795 (10.58), 7.820 (5.45), 7.935 (14.42), 8.210 (16.00), 8.446 (13.80), 8.763 (11.91), 12.471 (1.33).

    Example 36


    3-[({[(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propanoic acid



    [0580] 



    [0581] tert-Butyl 3-[({[(2-chloro-5- {1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propanoate (intermediate 83A,192 mg, 225 µmol) was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).134 mg (100 % purity, 75 % yield) of the title compound were isolated.

    [0582] LC-MS (Method 4): Rt = 4.28 min; MS (ESIpos): m/z = 795 [M+H]+

    [0583] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.79), 1.505 (2.52), 1.638 (2.12), 1.756 (8.75), 2.073 (12.12), 2.328 (0.62), 2.367 (0.65), 2.671 (1.31), 2.711 (0.76), 4.191 (5.65), 4.345 (0.86), 5.163 (0.47), 5.271 (1.76), 5.386 (1.85), 7.558 (0.47), 7.594 (4.25), 7.614 (5.32), 7.783 (7.52), 7.805 (6.74), 7.826 (5.60), 7.935 (14.80), 8.208 (16.00), 8.211 (15.98), 8.446 (13.07), 8.768 (12.06), 12.416 (1.42).

    Example 37


    4-[({[(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl} benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]butanoic acid



    [0584] 



    [0585] tert-Butyl 4-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]butanoate (intermediate 84A, 190 mg, 220 µmol) was dissolved in 30% TFA in DCM (19 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).139 mg (96 % purity, 75 % yield) of the title compound were isolated.

    [0586] LC-MS (Method 4): Rt = 4.33 min; MS (ESIpos): m/z = 809 [M+H]+

    [0587] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.62), 1.508 (2.36), 1.639 (2.19), 1.755 (13.94), 1.768 (14.21), 2.226 (6.06), 2.244 (10.41), 2.261 (6.12), 2.329 (1.14), 2.367 (0.63), 2.671 (0.52), 2.711 (0.48), 4.036 (6.76), 4.185 (0.78), 5.257 (1.74), 5.380 (1.83), 7.590 (4.72), 7.610 (5.76), 7.793 (9.88), 7.822 (5.85), 7.935 (14.31), 8.209 (16.00), 8.446 (12.78), 8.770 (11.49), 12.122 (0.66).

    Example 38


    4-({(1R,2R)-2-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol] -4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobutanoic acid



    [0588] 



    [0589] tert-Butyl (1R,2R)-2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl butanedioate (intermediate 85A,87.0 mg, 100 µmol) was dissolved in 30% TFA in DCM (8.0 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).32.3 mg (100 % purity, 40 % yield) of the title compound were isolated.

    [0590] LC-MS (Method 4): Rt = 4.16 min; MS (ESIpos): m/z = 811 [M+H]+

    [0591] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.236 (0.46), 1.320 (0.89), 1.651 (1.39), 1.756 (1.73), 1.966 (0.89), 2.085 (0.46), 2.384 (1.39), 2.422 (2.03), 2.449 (4.39), 2.517 (2.36), 2.611 (0.93), 2.652 (0.84), 3.266 (2.32), 3.820 (16.00), 4.791 (0.68), 4.950 (0.89), 7.611 (0.93), 7.626 (1.10), 7.831 (1.60), 7.859 (1.14), 8.557 (1.90), 8.826 (1.90), 12.182 (0.84).

    Example 39


    (12E)-1-{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-8,8-dimethyl-1,5,11-trioxo-4,6,1 0-trioxa-2-azatetradec-12-en-14-oic acid



    [0592] 



    [0593] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropyl (2E)-but-2-enedioate (intermediate 86A, 280 mg, 323 µmol) was dissolved in 30% TFA in DCM (16 mL) and the mixture was stirred at ambient temperature for 15 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5).88.2 mg (100 % purity, 34 % yield) of the title compound were isolated.

    [0594] LC-MS (Method 4): Rt = 4.18 min; MS (ESIpos): m/z = 811 [M+H]+

    [0595] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.892 (12.63), 0.925 (0.51), 0.982 (0.62), 1.379 (0.40), 1.483 (0.45), 1.668 (0.40), 1.759 (1.55), 2.521 (0.46), 3.823 (16.00), 3.915 (5.04), 6.687 (5.15), 7.604 (1.07), 7.619 (1.19), 7.843 (3.36), 7.854 (1.45), 8.561 (2.50), 8.830 (2.39).

    Example 40


    1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-12,12-dimethyl-1,5,10-trioxo-4,6,9-trioxa-2-azatridecan-13-oic acid



    [0596] 



    [0597] 1-tert-Butyl 4- {2-[({[{2-chloro-5-[2'-methyl-5'-(pentaauoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy] ethyl} 2,2-dimethylbutanedioate (intermediate 87A, 55.3 mg, 64.7 µmol) was dissolved in 30% TFA in DCM (5 mL) and the mixture was stirred at ambient temperature for 5 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 10.9mg (100 % purity, 21 % yield) of the title compound were isolated. LC-MS (Method 4): Rt = 4.07 min; MS (ESIpos): m/z = 799 [M+H]+

    [0598] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.51), 0.843 (0.46), 0.855 (0.88), 0.866 (0.41), 1.129 (14.61), 1.167 (0.78), 1.237 (3.81), 1.490 (0.53), 1.671 (0.42), 1.769 (1.56), 3.824 (16.00), 4.158 (2.44), 4.216 (0.82), 5.254 (0.41), 5.416 (0.41), 7.623 (1.28), 7.637 (1.49), 7.840 (2.01), 7.854 (1.28), 7.868 (1.12), 8.572 (2.76), 8.845 (2.61).

    Example 41


    3-[({[(2-Chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoic acid



    [0599] 



    [0600] Benzyl 3-[({[(2-chloro-5-{1-[2-chloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}benzoyl)(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]-2,2-dimethylpropanoate (intermediate 89A, 415 mg, 454 µmol) was dissolved in ethyl acetate (200 mL) under an argon atmosphere. 10% Palladium on charcoal (22.0 mg) was added and the mixture was hydrogenated over 6h at ambient pressure at room temperature. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was distilled. The crude product was purified by preparative HPLC (RP C-18 10 µm water-acetonitrile gradient with 0.01% TFA in both eluents, 90:10->5:95). 299 mg (100 % purity,80 % yield) of the title compound were obtained.

    [0601] LC-MS (Method 4): Rt = 4.54 min; MS (ESIpos): m/z = 823 [M+H]+

    [0602] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (4.00), 1.063 (16.00), 1.235 (0.82), 1.513 (0.87), 1.640 (0.77), 1.756 (3.11), 3.363 (1.74), 4.037 (1.81), 5.277 (0.68), 5.400 (0.59), 7.588 (1.42), 7.608 (1.78), 7.762 (0.76), 7.801 (4.81), 7.822 (2.28), 7.935 (4.90), 8.213 (5.67), 8.446 (4.01), 8.755 (4.30).

    Example 42


    (2E)-4-({(1S,2S)-2-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl}oxy)-4-oxobut-2-enoic acid



    [0603] 



    [0604] tert-Butyl (1S,2S)-2-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]cyclopentyl (2E)-but-2-enedioate (intermediate 90A, 57.6 mg, 66.6 µmol) was dissolved in 30% TFA in DCM (6 mL) and the mixture was stirred at ambient temperature for 8 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 27.1 mg (100 % purity, 50 % yield) of the title compound were isolated.

    [0605] LC-MS (Method 4): Rt = 4.21 min; MS (ESIpos): m/z = 809 [M+H]+

    [0606] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.236 (0.46), 1.494 (0.43), 1.643 (1.35), 1.694 (1.37), 1.756 (1.86), 2.033 (0.85), 2.070 (0.66), 2.572 (0.40), 3.820 (16.00), 4.884 (0.65), 5.065 (0.80), 6.612 (0.70), 6.638 (1.67), 6.674 (1.68), 6.699 (0.77), 7.606 (0.90), 7.619 (1.06), 7.835 (1.83), 7.856 (1.23), 8.554 (2.09), 8.825 (1.88).

    Example 43


    3-[({[{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propanoic acid



    [0607] 



    [0608] tert-Butyl 3-[({[{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzoyl}(1-cyanocyclopropyl)amino]methoxy}carbonyl)oxy]propanoate (intermediate 91A, 250 mg, 331 µmol) was dissolved in 30% TFA in DCM (12 mL) and the mixture was stirred at ambient temperature for 8 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). The crude product was purified by flash chromatography on silica gel (gradient cyclohexane:ethyl acetate 2:1->ethyl acetate: methanol 4:1). 42.9 mg (100 % purity, 19 % yield) of the title compound were isolated. LC-MS (Method 4): Rt = 3.85 min; MS (ESIpos): m/z = 699 [M+H]+

    [0609] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.494 (1.33), 1.650 (1.10), 1.759 (4.94), 2.085 (16.00), 2.344 (0.66), 2.355 (0.41), 2.384 (0.45), 2.423 (0.73), 2.613 (0.57), 2.652 (1.15), 3.421 (6.26), 3.598 (0.49), 3.608 (0.83), 3.619 (0.50), 3.697 (0.41), 3.807 (2.81), 4.191 (2.93), 4.348 (0.56), 5.259 (0.89), 5.393 (0.98), 7.618 (2.64), 7.631 (3.04), 7.787 (0.65), 7.820 (4.69), 7.850 (3.42), 7.864 (3.28), 8.557 (6.79), 8.830 (7.19), 12.411 (0.42).

    Example 44


    1-{2-Chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oic acid



    [0610] 



    [0611] tert-Butyl 1-{2-chloro-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]phenyl}-2-(1-cyanocyclopropyl)-11,11-dimethyl-1,5-dioxo-4,6,9-trioxa-2-azadodecan-12-oate (intermediate 92A, 108 mg, 131 µmol) was dissolved in 30% TFA in DCM (11 mL) and the mixture was stirred at ambient temperature for 10 min. The solvent was distilled, the residue was taken up in acetonitrile and purified by preparative HPLC (RP C-18 10 µm acetonitrile:water +0.01%TFA 10:90->95:5). 80.0 mg (100 % purity, 79 % yield) of the title compound were isolated.

    [0612] LC-MS (Method 4): Rt = 4.24 min; MS (ESIpos): m/z = 771 [M+H]+

    [0613] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.68), 1.029 (10.00), 1.076 (1.10), 1.760 (1.36), 2.515 (0.65), 2.518 (0.72), 2.521 (0.57), 2.572 (0.51), 3.391 (0.96), 3.548 (1.76), 3.819 (16.00), 4.119 (0.85), 7.615 (0.76), 7.628 (0.87), 7.826 (1.26), 7.847 (0.95), 7.861

    Physicochemical and biological examples: assessment of prodrug stability and release of parent compound



    [0614] Preparation of the PBS buffer solution pH 7.4: 90g sodium chloride, 13.61 g potassium dihydrogen phosphate, 83.35 g 1M aqueous sodium hydroxide were dissolved in water. More water was added up to a total volume of 1L. This solution was diluted 1:10 with water. Eventually, pH was adjusted to pH 7.4 by the addition of phosphoric acid.

    [0615] Citric acid buffer solution pH 3.0: commercially available citric acid buffer (pH 3) from Fluka (art. No 31046) was used containing 8.47 g of citric acid, 3.49 g of sodium chloride and 0.82 g of sodium hydroxide.

    Physicochemical and Biological Examples


    Assessment of Prodrug Stability and Release of Parent Compound



    [0616] Preparation of the PBS buffer solution pH 7.4: 90g sodium chloride, 13.61 g potassium dihydrogen phosphate, 83.35 g 1M aqueous sodium hydroxide were dissolved in water. More water was added up to a total volume of 1L. This solution was diluted 1:10 with water. Eventually, pH was adjusted to pH 7.4 by the addition of phosphoric acid.

    [0617] Citric acid buffer solution pH 3.0: commercially available citric acid buffer (pH 3) from Fluka (art. No 31046) was used containing 8.47 g of citric acid, 3.49 g of sodium chloride and 0.82 g of sodium hydroxide.

    Biological Example B1


    Measurement of Solubility in Buffer at pH 6.5



    [0618] 2 - 4 mg of the test compound are dissolved in DMSO to reach a concentration of 50 g/L (solution A). To 10 µl of this solution 960 µl PBS buffer pH 6.5 are added (final concentration: 515 µg/l); the mixture is shaken for 24h at rt in a 96 well plate. An aliquot is centrifuged at 42000 rpm für 30 min. The supernatant is diluted with acetonitrile/water (8:2) 1:10 and 1:1000 resp. This diluted samples are analyzed by LC-MSMS. Results are provided in Table 0, below.

    [0619] Calibration: 10 µl of solution A are diluted with 823 µl DMSO (final concentration: 600 µg/ml), which is further diluted with acetonitrile/water 8:2 by a factor of 100 (provides solution B).

    [0620] The calibration curve is obtained from solution B by further diluting with acetonitrile/water 8:2 with target concentrations of 1.2 -12 - 60 - 600 ng/ml and injecting these four solutions for MS measurement.

    [0621] MS method optimization: Solution B is utilized for MS method optimization.

    [0622] PBS-Puffer: 6.18g sodium chloride and 3.96 g sodium dihydrogen phosphate are dissolved in 1L aqua dist., the pH is adjusted to 6.5 with IN sodium hydroxide.

    LC and MS conditions:



    [0623] LC-MSMS optimization: The following configurations were used for optimization

    [0624] AB Sciex TRIPLE QUAD 4500, Agilent 1260 Infinity (G1312B), degasser (G4225A), column oven (G1316C and G1316A), CTC Analytics PAL injection system HTS-xt

    [0625] Eluent A: 0.5 ml formic acid (50% strength)/ L water, Eluent B: 0.5 ml formic acid (50% strength) / L acetonitrile
    time [min]flow [µl/min]%B
    0.00 200 70
    0.08 200 70
    0.09 25 70
    0.60 25 70
    0.65 200 70
    1.10 200 70


    [0626] Autosampler: without auto inject ahead setting; column: stainless steel capillary, oven temperature: 22°C; flow rate: flow gradient, injected volume: 2 µL.

    [0627] Waters Quattro Micro MS, Agilent 1100 (G1312A), degasser (G1322A), column oven (G1316A), CTC Analytics PAL injection system HTS, eluents as above
    time [min]flow [µl/min]%B
    0.00 250 70
    1.50 250 70


    [0628] Autosampler with auto inject ahead setting; column: stainless steel capillary, oven temperature: 22°C, flow rate: flow gradient, injected volume: 5 µL.

    [0629] MS method: Flow Injection Analysis (FIA) for optimization ("MS-OPTI"); ionization mode ABSciex-MS: ESI-pos/neg, Waters-MS: ESI-pos

    HPLC method for MSMS quantification:



    [0630] The following conditions were used for quantification:
    Eluent A, B as above

    ABSciex-MS



    [0631] 
    time [min]% A%B
    0 90 10
    0.5 5 95
    0.84 5 95
    0.85 90 10
    1.22 90 10


    [0632] Autosampler without auto inject ahead setting, column: Waters OASIS HLB, 2,1 x 20 mm, 25 µ, column temperature: 30°C, flow rate: 2.5 mL/min, injected volume: 2 µl, Splitter (before MS) 1:20.

    Waters-MS



    [0633] Gradient as above

    [0634] Autosampler: with auto inject ahead setting, column: stainless steel capillary, column: Waters OASIS HLB, 2,1 x 20 mm, 25 µ, column temperature: 30°C, flow rate: 2,5 mL/min, injected volume: 5 µL, Splitter (before MS) 1:20, MS method: Multiple Reaction Monitoring (MRM).
    Table 0: Solubility of example compounds at pH 6.5
    Example Nomg/mL
    1 5
    2 4
    3 6
    4 2
    5 2
    6 4
    7 3
    8 1
    9 5
    10 3
    11 2
    12 3
    13 7
    14 19
    15 1
    16 2
    17 2
    18 3
    19 42
    20 212
    21 136
    22 17
    23 50
    24 57
    25 98
    26 96
    27 147
    28 76
    29 35
    30 398
    31 168
    32 41
    35 8
    36 16
    37 7
    38 37
    39 43
    40 43
    41 4
    42 38

    Biological Example B2


    Measurement of Stability of Prodrugs in Buffer at pH 7.4



    [0635] Measurement 0.15 mg of the test compound were dissolved in 0.1 mL dimethylsulfoxide and 0.4 mL acetonitrile. For complete dissolution, the HPLC vial with the sample solution was shaken and treated with ultrasound. Then, 1.0 mL of PBS buffer solution pH 7.4 was added and the sample was vortexed.The sample solution was analysed by HPLC (method 8) to determine the amount of the test compound at a particular time over a period of 24 h at 37 °C. The peak areas, given as percentage of total area, are used for quantification. In addition, the reaction mixture was analysed by method 9 (HPLC-MS) at the final timepoint.
    Table 1: Stability of Example Compounds at pH 7.4
    Example Compound No.% Recovery after 24 h
    1 100
    2 98
    3 99
    4 99
    5 99
    6 98
    7 99
    8 98
    9 98
    10 100
    11 100
    12 95
    13 92
    14 100
    15 98
    16 100
    17 100
    18 100
    19 95
    20 83
    21 99
    22 100
    23 100
    24 100
    25 100
    26 100
    27 90
    28 95
    29 100
    30 96
    31 99
    32 100
    33 96
    34 96
    35 100
    36 98
    37 84
    38 98
    39 99
    40 97
    41 99
    42 99
    43 98

    Biological Example B3


    Measurement of Release of Parent Compound in Rat Plasma



    [0636] 1 mg of the test compound was dissolved in 0.5 mL acetonitrile/dimethylsulfoxide 9:1. For complete dissolution the HPLC vial was shaken and treated with ultrasound. 20 µl of this solution were added to 1 mL of rat (Li-heparin plasma, Hannover-Janvier rat, RjHan male) with vortexing at a temperature of 37 °C. Aliquots (100 µL each) were taken at 0.17, 0.5, 1, 1.5, 2 and 4 hours. Each aliquot was transferred to a vial containing 300 µL of acetonitrile/ citric acid buffer pH 3 8:2. These solutions were centrifuged at 5000 rpm for 10 minutes. The supernatant was analysed by HPLC (Method 8) to determine the amount of the test compound. In addition, the reaction mixture was analysed by method 9 (HPLC-MS) at the final timepoint. Both decrease of the prodrug concentration and increase of parent compound concentration were monitored. All data is given as percent area of the prodrug at to.

    [0637] Parent compound A means 2-Chlor-5-{1-[2-chlor-4-(1,1,1,2,3,3,3-heptafluorpropan-2-yl)-6-(trifluormethoxy)phenyl]-1H-pyrazol-4-yl}-N-(1-cyanocyclopropyl)benzamide (CAS-RN 1771742-44-9).



    [0638] Parent compound B means 2-chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(triauoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide (CAS-RN 1621436-41-6)

    Table 2: Degradation of prodrugs in rat plasma: and release of parent drug
     % Recovery of prodrug at different time pointsParent Drug% Parent Drug
    Example No 0.17 h 0.5 h 1 h 1.5 h 2 h 4 h   4 h
    1 12 0 0 0 0 0 A 74
    2 26 0 0 0 0 0 A 73
    3 37 0 0 0 0 0 A 104
    4 0 0 0 0 0 0 A 99
    5 0 0 0 0 0 0 A 102
    6 49 33 22 19 7 0 A 78
    7 44 27 12 0 0 0 A 99
    8 30 0 0 0 0 0 A 110
    9 26 0 0 0 0 0 A 99
    10 50 7 0 0 0 0 A 76
    11 74 41 18 10 0 0 A 101
    12 9 0 0 0 0 0 A 107
    14 0 0 0 0 0 0 A 99
    15 0 0 0 0 0 0 A 102
    16 37 13 0 0 0 0 A 92
    17 41 16 6 0 0 0 A 100
    18 78 52 33 23 16 5 A 95
    19 97 97 96 96 94 95 A 10
    21 0 0 0 0 0 0 B 114
    22 35 0 0 0 0 0 B 74
    23 0 0 0 0 0 0 B 102
    24 65 41 22 12 0 0 B 100
    25 9 0 0 0 0 0 B 72
    26 36 0 0 0 0 0 B 101
    28 0 0 0 0 0 0 B 99
    29 0 0 0 0 0 0 B 103
    30 96 95 93 88 89 70 B 29
    31 5 0 0 0 0 0 B 101
    32 0 0 0 0 0 0 B 100
    33 26 0 0 0 0 0 B 102
    34 25 0 0 0 0 0 B 64
    35 63 29 10 3 0 0 A 99
    36 90 78 67 56 48 28 A 75
    38 36 18 0 0 0 0 B 104
    39 0 0 0 0 0 0 B 81
    40 0 0 0 0 0 0 B 99
    41 25 0 0 0 0 0 A 107
    42 27 5 0 0 0 0 B 84
    43 69 38 20 8 4 0 B 101

    Biological Example B4


    Measurement of Release of Parent Compound in Dog Plasma



    [0639] 1 mg of the test compound was dissolved in 0.5 mL acetonitrile/dimethylsulfoxide 9:1. For complete dissolution the HPLC vial was shaken and treated with ultrasound. 20 µl of this solution were added to 1 mL of dog plasma (Beagle) under vortexing at a temperature of 37 °C. Aliquots (100 µL each) were taken at 0.17, 0.5, 1, 1.5, 2 and 4 hours. Each aliquot was transferred to a vial containing 300 µL of acetonitrile/ citric acid buffer pH 3 80:20. These solutions were centrifuged at 5000 rpm for 10 minutes. The supernatant was analysed by HPLC (Method 8) to determine the amount of the test compound. In addition, the reaction mixture was analysed by method 9 (HPLC-MS) at the final timepoint.

    [0640] Both decrease of the prodrug concentration and increase of parent compound concentration were monitored. All data is given as percent area of the prodrug at to.
    Table 3: Degradation of prodrugs in dog plasma
     % Recovery at indicated time pointsParent Drug% Parent Drug
    Example Compound No. 0.17 h 0.5 h 1 h 1.5 h 2 h 4 h   4 h
    1 100 100 100 88 82 54 A 32

    Biological Example B5


    Evaluation of Pharmacokinetics (in vivo)



    [0641] To evaluate the pharmacokinetics of test substances in vivo, these test substances are dissolved in appropriate formulation vehicles (ethanol, dimethyl sulfoxide, PEG400, glycerol formal etc.), or mixtures thereof. The test substances are then administered to rats or dogs intravenously, orally or subcutaneously. The intravenous application is performed as bolus. Administered doses range usually between 0.1 to 5 mg/kg, however, doses for subcutaneous and oral administration can exceed this range up to doses of 30 mg/kg. Blood samples are retrieved via a catheter, exsanguination or venous puncture in vials containing appropriate anticoagulants, such as lithium heparinate or potassium EDTA. Plasma is generated from the blood via centrifugation. Blood samples are taken over an appropriate time interval, usually lasting up to 144h after administration. If necessary, samples from later time points can also be taken. If possible, time points are chosen so that the initial absorption phase, the maximum plasma concentration (Cmax), and exposure within a certain time interval (AUC(0-t))aer described. Furthermore, it is possible to also retrieve organ-, tissue- and urine samples . The quantitative measurement of the test substances in the samples is performed using calibration curves in the respective matrices. The protein content of the samples is precipitated using acetonitrile or methanol. Thereafter, the samples are separated using HPLC in combination with reversed phase chromatography columns. The HPLC system is coupled to a triple quadrupole mass spectrometer via an electrospray interface. The evaluation of the plasma concentration / time profiles are afterwards evaluated using a validated pharmacokinetics evaluation program.

    [0642] Exposure of parent compound A within a certain time interval displayed as AUC(0-t) in tables 4-6 was used to assess conversion of prodrug to drug and absorption of prodrug compared to parent in vivo, respectively. Comparison of exposures after intravenous administration of parent compound A and prodrugs showed the amount of prodrug which was converted into parent. Comparison of exposures after subcutaneous or oral administration of parent and prodrugs additionally showed altered absorption characteristics of prodrugs compared to parent. Relative bioavailability (Frel) was used to describe the exposure of parent after prodrug administration compared to the exposure of parent after direct administration of compound A which was normalised to 100%.
    Table 4: AUC of parent compound A after intravenous administration of example prodrugs and after intravenous administration of parent compound A
     UnitsConcentration of Parent Compound A
    after admin. of Parent Compound AExample Compound 4Example Compound 3Example Compound 1Parent Compound AExample Compound 1
    Admin Route   iv bolus
    Species   Rat Dog
    AUC(0-144 h)norm kg·h/L 11 5.4 5.6 8.5    
    AUC(0-72 h)norm kg·h/L         6.0 4.6
    after admin. of   Example 6
    Admin Route   iv bolus Example 8 Example 17 Example 18    
    Species   Rat
    AUC(0-144 h)norm kg·h/L 7.1
    AUC(0-72 h)norm kg·h/L   5.1 4.4 4.1    
    after admin. of   Example 6          
    Table 5: AUC of parent compound A after subcutaneous administration of example prodrugs and after subcutaneous administration of parent compound A
     UnitsConcentration of Parent Compound A
    after admin. of Parent Compound AExample Compound 4Example Compound 3Example Compound 1Parent Compound AExample Compound 1
    Admin Route   sc
    Species   Rat Dog
    AUC(0-144 h)norm kg·h/L 1.7 6.8 3.8 6.4    
    AUC(0-384 h)norm kg·h/L         1.0 17
    Frel % 100 413 233 387 100 1688
      Units Concentration of Parent Compound A  
    after admin. of   Example 6 Example 8 Example 17 Example 18 Example 18**
    Admin Route   sc
    Species   Rat Dog
    AUC(0-144 h)norm kg·h/L 9.0 2.2 3.1 5.6  
    AUC(0-384 h)norm kg·h/L         11.8
    Frel % 526 127 184 329 1178
    Frel calculated based on AUC(0-t)norm
    ∗∗Test substance was dissolved in triacetin
    Table 6: AUC of parent compound A after oral administration of example prodrugs and after oral administration of parent compound A
     UnitsConcentration of Parent Compound A
    after admin. of Example Compound 1Parent compound A
    Admin Route   po
    Species   Rat
    Dose Admin   20
    Unit Dose Admin   mg/kg
    AUC(0-24)norm kg·h/L 1.4 0.37
    F % 54 14
    F calculated based on AUC(0-24)norm

    Biological Example B6


    Measurement of the Antiparasitic Activity after Administration of a Prodrug to Rats



    [0643] Compounds were dissolved in the appropriate volume of glycerol formal (p.a.) just before application to the animals (dose volume was adjusted to 0.03 mL/kg bodyweight). 5 rats per group were either injected intraperitoneally or subcutaneously.

    [0644] Rats were infested with 30 Dermacentor variabilis nymphs on study days -2, 7, 14, 21, 28, 35 and 30 adult Ctenocephalides fleas on study days -1, 8, 15, 22, 29, 36.

    [0645] Parasite counts were performed on study days 2, 9, 16, 23, 30, 37.

    [0646] Percent efficacy was calculated as arithmetic mean parasite numbers as life attached tick numbers and live flea numbers of the respective study group in comparison to parasite counts on a placebo-treated control group. Infestation of groups with less than 75% efficacy on two consecutive counting occasions will terminated for the respective parasite.

    [0647] Both SC prodrug treatments (example 1 and example 4) are superior in their flea and tick efficacy on rats over the parent drug also injected subcutaneously.
    Table 7: In-vivo Efficacy of parent compound A and prodrug examples formulations applied i.p. or sc in rats
    ExampleDose mg/kg]Applicat. typeParasiteSD2SD9SD16SD23SD30SD37SD42
    Parent Compound A 10 ip CF A 84 68 71 na na na na
    DV N 96 87 83 93 53 32 na
    sc CF A 53 44 na na na na na
    DV N 72 61 na na na na na
    Example 13.33 sc CF A 100 100 100 99 81 75 79
    Compound 1     DV N 99 100 100 100 77 90 81
    Example Compound 2 13.98 sc CF A 99 93 99 97 66 76 69
    DV N 98 98 96 99 99 97 82
    Example 3 13.36 sc CF A 97 97 93 86 76 72 na
    DV N 99 99 100 77 57 49 na
    Example 4 13.98 sc CF A 99 93 99 97 66 76 na
    DV N 98 98 96 99 99 97 na
    Example 6 13.95 sc CF A 100 100 94 73 59 100 na
    DV N 100 100 100 78 58 31 na
    Example 7 13.98 sc CF A 100 98 99 91 86 66 na
    DV N 99 100 96 98 89 46 na
    Example 18 13.08 sc CF A 100 97 94 82 76 75 na
    DV N 100 100 100 82 74 47 na
    Example 35 13.65 sc CF A 100 100 98 87 70 49 na
    DV N 100 99 80 97 80 53 na
    Example 36 13.25 sc CF A no data 100 93 99 80 67 na
    DV N no data 96 88 99 89 68 na
    CF = Ctenocphalides felis; DV = Dermacentor variabilis; A = adult; N = nymph

    Biological Example B7


    Measurement of the Antiparasitic Activity after Administration of a Prodrug to Dogs



    [0648] Compounds were dissolved in the appropriate volume of glycerol formal (p.a.) just before application to the animals (dose volume was adjusted to 0.1 ml/kg bodyweight). Dogs were were injected intravenously respective subcutaneously (see table 8 for details).

    [0649] Dogs were infested with ectoparasites according to table on study 1 day prior to counting for fleas, 2 days prior to counting for RS, IR, DV tickss and 3 days prior to counting for AA ticks. For this purpose, dogs were placed in an individually labeled box with grid windows. The ticks were released onto the back of the dogs and were allowed to disperse and move into the hair without disturbance. The dog remained in the box for approximately 120 minutes with the lid closed and the light switched off in the room. For flea infestations, flea containers were opened in the animal's cage and fleas were applied on the dog's back between the shoulders.

    [0650] Parasite counts were performed as indicated in Table 8.. Tick counts including removal of I. ricinus, R. sanguineus and D. variabilis were conducted 48(±4) hours after the infestation. Tick counts including removal of A. americanum were conducted 72(±4) hours after the infestation. Flea counts were conducted 24(±4) hours after the infestation.

    [0651] On each parasite assessment day percent efficacy was calculated as arithmetic mean parasite numbers as life attached and live free tick numbers and live flea numbers of the respective study group in comparison to parasite counts on a placebonon-treated control group.

    [0652] Based on the results of these infestations a five months efficacy of the prodrug "1" against D. variabilis as least sensitive species could be reached.
    Table 8: In-vivo Efficacy of parent and prodrug formulations applied iv or sc in dogs
         % Efficacy in study month
    CompoundtreatmentDose [mg/kg]StudyParasite123456
    A iv 2x5 1 CF 100 100 100 100 100 100
    A iv 2x5 1 DV 98 99 100 95 98 84
    A iv 2x5 1 IR 100 100 100 100 98 98
    A iv 2x5 1 RS 100 100 100 100 100 99
    A iv 2x5 2 AA 100 99 99 99 95 98
    A sc 5 3 DV           19
    A sc 5 3 IR           3
    A sc 5 3 RS           50
    A sc 5 3 AA           90
    1 sc 13.33 (= 10 parent) 4 DV       96 100 77



    Claims

    1. Compounds of formula (I)

    wherein

    Q is O or absent;

    L1 is linear C2-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from halogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a moiety (CH2)n-X-(CH2)m wherein n and m are independently 0, 1 or 2 and X is C3-C7-cycloalkanediyl, which is optionally substituted with C1-C4 alkyl; or L1 is absent; with the proviso that in the case of L1 being absent, Q is also absent;

    L2 is C=O or absent,

    L3 is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; or is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2; or is C3-C7-cycloalkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4-alkyl and halogen;

    Y is selected from T1



    wherein

    R1, R2 and R3 are each independently selected from hydrogen, halogen, cyano, nitro, linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, linear or branched halogen-substituted C1-C6-alkyl, halogen-substituted C1-C6-alkoxy, halogen substituted C3-C6-cycloalkyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, N-C1-C6-alkylamino, N,N-di-C1-C6-alkylamino, N-C1-C3-alkoxy-C1-C4-alkylamino and 1-pyrrolidinyl

    or T2

    wherein

    Z1 and Z2 are each independently selected from hydrogen, halogen, cyano, nitro, linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-alkylcarbonyl, halogen-substituted linear or branched C1-C6-alkyl, halogen-substituted C1-C6-alkoxy, halogen substituted C3-C6-cycloalkyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, N-C1-C6-alkylamino, N,N-di-C1-C6-alkylamino, N-C1-C3-alkoxy-C1-C4-alkylamino and 1-pyrrolidinyl; and

    Z3 represents hydrogen or linear C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl or hetaryl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, amino, C1-C3-alkyl, C1-C3-alkoxy, hydroxycarbonyl, alkoxycarbonyl, alkylcarbamoyl, cycloalkylcarbamoyl and phenyl

    and the salts thereof
     
    2. Compounds according to claim 1,
    wherein

    Q is O;

    L2 is C=O;

    L3 is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2; and

    L1 has the meaning as defined in claim 1;

    and the salts thereof.
     
    3. Compounds according to claim 1 or 2,
    wherein

    Q is O;

    L2 is C=O;

    L3 is a group (CH2)n-(CH=CH)-CH2)m, wherein n and m are 0; and

    L1 has the meaning as defined in claim 1;

    and the salts thereof.
     
    4. Compounds according to claim 1,
    wherein

    Q is O

    L2 is C=O

    L3 is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and

    L1 has the meaning as defined in claim 1;

    and the salts thereof.
     
    5. Compounds according to claim 1,
    wherein

    Q is O;

    L2 is absent;

    L3 is linear C1-C4 alkanediyl, which is optionally substituted with one or more groups independently selected from C1-C4 alkyl, C3-C6 cycloalkyl and halogen, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded; and

    L1 has the meaning as defined in claim 1;

    and the salts thereof.
     
    6. Compounds according to claim 1,
    wherein

    L1, L2 and Q are absent; and

    L3 has the meaning as defined in claim 1;

    and the salts thereof.


     
    7. Compounds according to any one of the preceding claims,
    wherein one or more of the following conditions apply

    Q is O;

    and/or

    L1 is linear C2-C4 alkanediyl, which is optionally substituted with one or more C1-C4 alkyl groups, wherein two C1-C4-alkyl substituents may form a ring together with the carbon atom to which they are bonded

    and/or

    L2 is C=O

    and/or

    L3 is a group (CH2)n-(CH=CH)-CH2)m, which is optionally substituted with up to 2 groups independently selected from C1-C4 alkyl, C3-C5 cycloalkyl and halogen, wherein n and m are independently 0, 1 or 2, preferably n and m are 0;

    and the salts thereof.
     
    8. Compounds according to any one of the preceding claims,
    wherein

    Y is selected from T1



    wherein

    R1, R2 and R3 are each independently selected from hydrogen, halogen, linear or branched C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, linear or branched halogen-substituted C1-C3-alkyl, halogen-substituted C1-C3-alkoxy, halogen substituted C3-C6-cycloalkyl, and 1-pyrrolidinyl, preferably R1, R2 and R3 are each independently selected from halogen, linear or branched halogen-substituted C1-C3-alkyl, and halogen-substituted C1-C3-alkoxy;

    or T2

    wherein

    Z1 represents linear or branched C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy, preferably Z1 represents linear or branched C1-C3-alkyl or C3-C6-cycloalkyl, which may independently of one another be substituted with 1 to 5 halogen substituents;

    Z2 represents halogen, cyano, nitro, amino, or linear or branched C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylsulphanyl, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy, preferably Z2 represents linear or branched C1-C3-alkyl, which may be substituted with 1 to 5 halogen substituents, preferably with 1 to 3 halogen substituents, more preferably trifluoromethyl or Z2 represents nitro, methylsulphanyl, methylsulphinyl, methylsulphonyl, fluorine, chlorine, bromine, iodine; and

    Z3 represents hydrogen or linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl or hetaryl, which may independently of one another be substituted with 1 to 5 substituents selected from hydroxy, halogen, cyano, nitro, C1-C3-alkyl, and C1-C3-alkoxy, preferably Z3 represents hydrogen or linear or branched C1-C6-alkyl which may be substituted with 1 to 5 substituents selected from hydroxy, halogen, C1-C3-alkyl, and C1-C3-alkoxy:

    and the salts thereof.
     
    9. Compounds according to any one of the preceding claims,
    wherein

    Y is selected from T1



    wherein

    R1 is halogen, preferably fluorine, bromine or chlorine, more preferably chlorine;

    R2 is linear or branched C1-C3-alkyl substituted with 1 to 7 halogen, preferably linear or branched C1-C3-alkyl substituted with 1 to 7 fluorine, more preferably CF3, C2F5 or C3F7; and

    R3 is C1-C3-alkoxy substituted with 1 to 3 halogen, preferably C1-C3-alkoxy substituted with 1 to 3 fluorine, more preferably OCF3, OC2F5 or OC3F7;

    or T2

    wherein

    Z1 represents linear or branched C1-C3-alkyl or C3-C6-cycloalkyl, substituted with 1 to 5 halogen substituents, preferably trifluoromethyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl or pentafluoroethyl, more preferably trifluoromethyl or pentafluoroethyl;

    Z2 represents linear or branched C1-C3-alkyl substituted with 1 to 3 halogen substituents, or

    Z2 represents nitro, methylsulphanyl, methylsulphinyl, methylsulphonyl, fluorine, chlorine, bromine, iodine; preferably Z2 represents linear or branched C1-C3-alkyl substituted with 1 to 3 fluorine, more preferably trifluoromethyl; and

    Z3 represents hydrogen or linear or branched C1-C6-alkyl, preferably linear or branched C1-C6-alkyl, more preferably hydrogen, methyl, ethyl, or n-propyl;

    and the salts thereof.
     
    10. Compounds according to any one of the preceding claims, wherein T1 is represented by one of the following groups T1-1, T1-2 or T1-3:


     
    11. Pharmaceutical composition comprising at least one compound according to any of the preceding claims, which optionally comprises at least one further component selected from auxiliaries, excipients, solvents and/or at least one additional pharmaceutically active agent.
     
    12. Pharmaceutical composition according to claim 11 for use in subcutaneous or oral application.
     
    13. Compounds or the pharmaceutical compositions according to any one of the preceding claims for use in controlling parasites on animals, preferably for controlling insects and arachnids, preferably selected from the group of Chelicerata, such as preferably ticks, flees, acari and mites, preferably on companion animals such as cats and dogs.
     
    14. Process for preparing the compounds according to any of the preceding claims comprising the step of reacting a compound (A)

    with a group (B)

    wherein

    Y, Q, L1, L2 and L3 have the meaning as defined in any one of the preceding claims and wherein PG1 represents a protecting group or hydrogen to form the compounds according to formula (I), and wherein in cases wherein PG1 is not hydrogen, deprotection is carried out to form the compounds (I);

    wherein the process may further comprise the preliminary step of preparing the group (B) by

    i) reacting a compound (IIa) with a compound (IIIa) to form compound (Va), wherein PG2 is a protecting group or hydrogen, and wherein in cases wherein PG2 is not hydrogen (Va) is obtained by selectively cleaving PG2:

    wherein L1 and L3 have the meaning as defined in any one of the preceding claims and wherein PG1 represents a protecting group or hydrogen;
    or

    ii) reacting a compound (VI) with compound (IIIb) to form compound (Vb) , wherein PG2 is a protecting group or hydrogen, and wherein in cases wherein PG2 is not hydrogen (Vb) is obtained by selectively cleaving PG2:

    wherein L1, L2 and L3 have the meaning as defined in any one of the preceding claims and wherein PG1 represents a protecting group or hydrogen.


     
    15. Intermediate compounds according to formula (B),

    wherein

    Q is O;

    L2 is C=O;

    L1 and L3 have the meaning as defined in any one of the preceding claims and

    PG1 represents a tert-butyl group

    or
    according to formula (C),

    wherein Y, Q, L1, L2 and L3 have the meaning as defined in any one of the preceding claims and wherein PG1 represents a tert-butyl group.
     


    Ansprüche

    1. Verbindungen der Formel (I)

    wobei

    Q O ist oder fehlt;

    L1 ein lineares C2-C4-Alkandiyl ist, das gegebenenfalls mit einer oder mehreren Gruppen substituiert ist, die unabhängig voneinander aus Halogen, C1-C4-Alkyl und C3-C6-Cycloalkyl ausgewählt sind, wobei zwei C1-C4-Alkylsubstituenten zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Ring bilden können; oder

    eine funktionelle Gruppe (CH2)n-X-(CH2)m ist, wobei n und m unabhängig voneinander 0, 1 oder 2 sind und

    X ein C3-C7-Cycloalkandiyl ist, das gegebenenfalls mit C1-C4-Alkyl substituiert ist; oder

    L1 fehlt;

    mit der Bedingung, dass in dem Fall, dass L1 fehlt, Q ebenfalls fehlt;

    L2 C=O ist oder fehlt,

    L3 ein lineares C1-C4-Alkandiyl ist, das gegebenenfalls mit einer oder mehreren Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C6-Cycloalkyl und Halogen ausgewählt sind, wobei zwei C1-C4-Alkylsubstituenten zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Ring bilden können; oder eine Gruppe (CH2)n-(CH=CH)-CH2)m ist, die gegebenenfalls mit bis zu 2 Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C5-Cycloalkyl und Halogen ausgewählt sind, wobei n und m unabhängig voneinander 0, 1 oder 2 sind; oder

    ein C3-C7-Cycloalkandiyl ist, das gegebenenfalls mit einer oder mehreren Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl und Halogen ausgewählt sind;

    Y ausgewählt ist aus T1

    wobei

    R1, R2 und R3 jeweils unabhängig voneinander ausgewählt sind aus Wasserstoff, Halogen, Cyano, Nitro, linearem oder verzweigtem C1-C6-Alkyl, C3-C6-Cycloalkyl, C1-C6-Alkoxy, linearem oder verzweigtem halogensubstituierten C1-C6-Alkyl, halogensubstituiertem C1-C6-Alkoxy, halogensubstituiertem C3-C6-Cycloalkyl, C1-C6-Alkylsulphanyl, C1-C6-Alkylsulphinyl, C1-C6-Alkylsulphonyl, N,N-di-C1-C6-alkylamino, N-C1-C3-Alkoxy-C1-C4-alkylamino und 1-Pyrrolidinyl

    oder T2

    wobei

    Z1 und Z2 jeweils unabhängig voneinander ausgewählt sind aus Wasserstoff, Halogen, Cyano, Nitro, linearem oder verzweigtem C1-C6-Alkyl, C3-C6-Cycloalkyl, C1-C6-Alkoxy, C1-C6-Alkylcarbonyl, halogensubstituiertem linearen oder verzweigten C1-C6-Cycloalkyl, halogensubstituiertem C1-C6-Alkoxy, halogensubstituiertem C3-C6-Cycloalkyl, C1-C6-Alkylsulfanyl, C1-C6-Alkylsulfinyl, C1-C6-Alkylsulfonyl, N-C1-C6-Alkylamino, N,N-di-C1-C6-Alkylamino, N- C1-C3-Alkoxy-C1-C4-alkylamino und 1-Pyrrolidinyl; und

    Z3 für Wasserstoff oder lineares C1-C6-Alkyl, C1-C3-Cycloalkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, Aryl oder Hetaryl steht, die unabhängig voneinander mit 1 bis 5 Substituenten, ausgewählt aus Hydroxy, Halogen, Cyano, Nitro, Amino, C1-C3-Alkyl, C1-C3-Alkoxy, Hydroxycarbonyl, Alkoxycarbonyl, Alkylcarbamoyl, Cycloalkylcarbamoyl und Phenyl substituiert sein können und deren Salzen.


     
    2. Verbindungen nach Anspruch 1,
    wobei

    Q O ist;

    L2 C=O ist;

    L3 eine Gruppe (CH2)n-(CH=CH)-CH2)m ist, die gegebenenfalls mit bis zu 2 Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C5-Cycloalkyl und Halogen ausgewählt sind, wobei n und m unabhängig voneinander 0, 1 oder 2 sind; und

    L1 die in Anspruch 1 definierte Bedeutung hat;

    und deren Salze.


     
    3. Verbindungen nach Anspruch 1 oder 2,
    wobei

    Q O ist;

    L2 C=O ist;

    L3 eine Gruppe (CH2)n-(CH=CH)-CH2)m ist, wobei n und m 0 sind; und

    L1 die in Anspruch 1 definierte Bedeutung hat;

    und deren Salze.


     
    4. Verbindungen nach Anspruch 1,
    wobei

    Q O ist

    L2 C=O ist

    L3 ein lineares C1-C4-Alkandiyl ist, das gegebenenfalls mit einer oder mehreren Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C6-Cycloalkyl und Halogen ausgewählt sind, wobei zwei C1-C4-Alkylsubstituenten zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Ring bilden können; und

    L1 die in Anspruch 1 definierte Bedeutung hat; und deren Salze.


     
    5. Verbindungen nach Anspruch 1,
    wobei

    Q O ist;

    L2 fehlt;

    L3 ein lineares C1-C4-Alkandiyl ist, das gegebenenfalls mit einer oder mehreren Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C6-Cycloalkyl und Halogen ausgewählt sind, wobei zwei C1-C4-Alkylsubstituenten zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Ring bilden können; und

    L1 die in Anspruch 1 definierte Bedeutung hat; und deren Salze.


     
    6. Verbindungen nach Anspruch 1, wobei

    L1, L2 und Q fehlen; und

    L3 die in Anspruch 1 definierte Bedeutung hat; und deren Salze.


     
    7. Verbindungen nach einem der vorhergehenden Ansprüche, wobei eine oder mehrere der folgenden Bedingungen gelten

    Q ist O;

    und/oder

    L1 ist ein lineares C2-C4-Alkandiyl, das gegebenenfalls mit einer oder mehreren C1-C4-Alkylgruppen substituiert ist, wobei zwei C1-C4-Alkylsubstituenten zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen Ring bilden können

    und/oder

    L2 ist C=O

    und/oder

    L3 ist eine Gruppe (CH2)n-(CH=CH)-CH2)m, die gegebenenfalls mit bis zu 2 Gruppen substituiert ist, die unabhängig voneinander aus C1-C4-Alkyl, C3-C5-Cycloalkyl und Halogen ausgewählt sind, wobei n und m unabhängig voneinander 0, 1 oder 2 sind, vorzugsweise n und m 0 sind;

    und deren Salze.


     
    8. Verbindungen nach einem der vorhergehenden Ansprüche, wobei
    Y ausgewählt ist aus T1

    wobei

    R1, R2 und R3 jeweils unabhängig voneinander ausgewählt sind aus Wasserstoff, Halogen, linearem oder verzweigtem C1-C3-Alkyl, C3-C6-Cycloalkyl, C1-C3-Alkoxy, linearem oder verzweigtem halogensubstituierten C1-C3-Alkyl, halogensubstituiertem C1-C3-Alkoxy, halogensubstituiertem C3-C6-Cycloalkyl und 1-Pyrrolidinyl, vorzugsweise R1, R2 und R3 jeweils unabhängig voneinander ausgewählt sind aus Halogen, linearem oder verzweigtem halogensubstituierten C1-C3-Alkyl und halogensubstituiertem C1-C3-Alkoxy;

    oder T2

    wobei

    Z1 für lineares oder verzweigtes C1-C3-Alkyl, C3-C6-Cycloalkyl, C1-C3-Alkoxy steht, die unabhängig voneinander mit 1 bis 5 Substituenten, ausgewählt aus Hydroxy, Halogen, Cyano, Nitro, C1-C3-Alkyl und C1-C3-Alkoxy, substituiert sein können,

    Z1 vorzugsweise für lineares oder verzweigtes C1-C3-Alkyl oder C3-C6-Cycloalkyl steht, die unabhängig voneinander mit 1 bis 5 Halogensubstituenten substituiert sein können;

    Z2 für Halogen, Cyano, Nitro, Amino oder lineares oder verzweigtes C1-C6-Alkyl, C1-C6-Alkylcarbonyl, C1-C6-Alkylsulphanyl, C1-C6-Alkylsulphinyl, C1-C6-Alkylsulphonyl steht, die unabhängig voneinander mit 1 bis 5 Substituenten, ausgewählt aus Hydroxy, Halogen, Cyano, Nitro, C1-C3-Alkyl und Ci-C-Alkoxy, substituiert sein können;

    Z2 vorzugsweise für lineares oder verzweigtes C1-C3-Alkyl steht, das mit 1 bis 5 Halogensubstituenten, vorzugsweise mit 1 bis 3 Halogensubstituenten, besonders bevorzugt Trifluormethyl, substituiert sein kann, oder Z2 für Nitro, Methylsulphanyl, Methylsulphinyl, Methylsulphonyl, Fluor, Chlor, Brom, Jod steht; und

    Z3 für Wasserstoff oder lineares oder verzweigtes C1-C6-Alkyl, C3-C6-Cycloalkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, Aryl oder Hetaryl steht, die unabhängig voneinander mit 1 bis 5 Substituenten, ausgewählt aus Hydroxy, Halogen, Cyano, Nitro, C1-C3-Alkyl und C1-C3-Alkoxy, substituiert sein können, Z3 vorzugsweise für Wasserstoff oder lineares oder verzweigtes C1-C6-Alkyl steht, das mit 1 bis 5 Substituenten, ausgewählt aus Hydroxy, Halogen, C1-C3-Alkyl und C1-C3-Alkoxy, substituiert sein kann; und deren Salze.


     
    9. Verbindungen nach einem der vorhergehenden Ansprüche, wobei
    Y ausgewählt ist aus T1

    wobei

    R1 ein Halogen ist, vorzugsweise Fluor, Brom oder Chlor, besonders bevorzugt Chlor;

    R2 ein lineares oder verzweigtes C1-C3-Alkyl ist, das mit 1 bis 7 Halogenen substituiert ist, vorzugsweise ein lineares oder verzweigtes C1-C3-Atkyl, das mit 1 bis 7 Fluoren substituiert ist, besonders bevorzugt CF3, C2F5 oder C3F7; und

    R3 ein C1-C3-Alkoxy ist, das mit 1 bis 3 Halogenen substituiert ist, vorzugsweise C1-C3-Alkoxy, das mit 1 bis 3 Fluoren substituiert ist, besonders bevorzugt OCF3, OC2F5 oder OC3F7;

    oder T2



    wobei

    Z1 für ein lineares oder verzweigtes C1-C3-Alkyl oder C3-C6-Cycloalkyl steht, das mit 1 bis 5 Halogensubstituenten, vorzugsweise Trifluormethyl, 1-Chlorcyclopropyl, 1-Fluorcyclopropyl oder Pentafluorethyl, besonders bevorzugt Trifluormethyl oder Pentafluorethyl, substituiert ist;

    Z2 für ein lineares oder verzweigtes C1-C3-Alkyl steht, das mit 1 bis 3 Halogensubstituenten substituiert ist, oder

    Z2 für Nitro, Methylsulphanyl, Methylsulphinyl, Methylsulphonyl, Fluor, Chlor, Brom, Jod steht; Z2 vorzugsweise für ein lineares oder verzweigtes C1-C3-Alkyl steht, das mit 1 bis 3 Fluoren, besonders bevorzugt Trifluormethyl, substituiert ist; und

    Z3 für Wasserstoff oder lineares oder verzweigtes C1-C6-Alkyl steht, vorzugsweise lineares oder verzweigtes C1-C6-Alkyl, besonders bevorzugt Wasserstoff, Methyl, Ethyl oder n-Propyl;

    und deren Salze.


     
    10. Verbindungen nach einem der vorhergehenden Ansprüche, wobei T1 durch eine der folgenden Gruppen TI-1, TI-2 oder TI-3 vertreten wird:


     
    11. Pharmazeutische Zusammensetzung, umfassend mindestens eine Verbindung nach einem der vorhergehenden Ansprüche, die gegebenenfalls mindestens einen weiteren Bestandteil, ausgewählt aus Hilfsstoffen, Trägerstoffen, Lösungsmitteln und/oder mindestens einem zusätzlichen pharmazeutischen Wirkstoff, umfasst.
     
    12. Pharmazeutische Zusammensetzung nach Anspruch 11 zur Verwendung bei subkutaner oder oraler Anwendung.
     
    13. Verbindungen oder pharmazeutische Zusammensetzungen nach einem der vorhergehenden Ansprüche zur Verwendung bei der Bekämpfung von Parasiten auf Tieren, vorzugsweise zur Bekämpfung von Insekten und Spinnentieren, vorzugsweise ausgewählt aus der Gruppe der Cheliceraten, wie vorzugsweise Zecken, Flöhen, Acari und Milben, vorzugsweise an Haustieren wie Katzen und Hunden.
     
    14. Verfahren zur Herstellung der Verbindungen nach einem der vorhergehenden Ansprüche, umfassend den Schritt der Reaktion einer Verbindung (A)

    mit einer Gruppe (B)

    wobei

    Y, Q, L1, L2 und L3 die in einem der vorhergehenden Ansprüche definierte Bedeutung haben und wobei PG1 für eine Schutzgruppe oder Wasserstoff steht, um die Verbindungen gemäß Formel (I) zu bilden, und wobei in Fällen, in denen PG1 kein Wasserstoff ist, eine Entschützung durchgeführt wird, um die Verbindungen (I) zu bilden;

    wobei das Verfahren ferner den vorläufigen Schritt des Herstellens der Gruppe (B) umfassen kann, durch

    i) Reaktion einer Verbindung (IIa) mit einer Verbindung (IIIa), um Verbindung (Va) zu bilden, wobei PG2 eine Schutzgruppe oder Wasserstoff ist, und wobei in Fällen, in denen PG2 kein Wasserstoff ist, (Va) durch selektives Abspalten von PG2 erhalten wird:

    wobei L1 und L3 die in einem der vorhergehenden Ansprüche definierte Bedeutung haben und wobei PG1 für eine Schutzgruppe oder Wasserstoff steht;
    oder

    ii) Reaktion einer Verbindung (VI) mit Verbindung (IIIb), um Verbindung (Vb) zu bilden, wobei PG2 eine Schutzgruppe oder Wasserstoff ist, und wobei in Fällen, in denen PG2 kein Wasserstoff ist, (Vb) durch selektives Abspalten von PG2 erhalten wird:

    wobei L1, L2 und L3 die in einem der vorhergehenden Ansprüche definierte Bedeutung haben und wobei PG1 für eine Schutzgruppe oder Wasserstoff steht.


     
    15. Zwischenverbindungen nach Formel (B),

    wobei

    Q O ist;

    L2 C=O ist;

    L1 und L3 die in einem der vorhergehenden Ansprüche definierte Bedeutung haben und

    PG1 für eine tert-Butylgruppe steht oder

    nach Formel (C),

    wobei Y, Q, L1, L2 und L3 die in einem der vorhergehenden Ansprüche definierte Bedeutung haben und wobei PG1 für eine tert-Butylgruppe steht:


     


    Revendications

    1. Composés de formule (I)

    Q est O ou absent ;

    L1 est un alcanediyle linéaire en C2 à C4, qui est éventuellement substitué par un ou plusieurs groupes choisis indépendamment parmi un halogène, un alkyle en C1 à C4 et un cycloalkyle en C3 à C6, dans lequel deux substituants alkyle en C1 à C4 peuvent former un cycle conjointement avec l'atome de carbone auquel ils sont liés ; ou

    est une fraction (CH2)n-X-(CH2)m dans laquelle

    n et m sont indépendamment 0, 1 ou 2 et

    X est un cycloalcanediyle en C3 à C7, qui est éventuellement substitué par un alkyle en C1 à C4 ; ou

    L1 est absent ;

    à condition que dans le cas où L1 est absent, Q soit également absent ;

    L2 est C=O ou est absent,

    L3 est un alcanediyle en C1 à C4 linéaire, qui est éventuellement substitué par un ou plusieurs groupes choisis indépendamment parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C6 et un halogène, dans lequel deux substituants alkyle en C1 à C4 peuvent former un cycle conjointement avec l'atome de carbone auquel ils sont liés ; ou est un groupe (CH2)n-(CH=CH)-CH2)m, qui est éventuellement substitué par un maximum de 2 groupes indépendamment choisis parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C5 et un halogène, où

    n et m sont indépendamment 0, 1 ou 2 ; ou

    est un cycloalcanediyle en C3 à C7, qui est éventuellement substitué par un ou plusieurs groupes indépendamment choisis parmi un alkyle en C1 à C4 et un halogène ;

    Y est choisi dans T1

    R1, R2 et R3 sont chacun indépendamment choisis parmi un hydrogène, un halogène, un groupe cyano, un groupe nitro, un alkyle en C1 à C6 linéaire ou ramifié, un cycloalkyle en C3 à C6, un alcoxy en C1 à C6, un alkyle en C1 à C6 linéaire ou ramifié substitué par un halogène, un alcoxy en C1 à C6 substitué par un halogène, un cycloalkyle en C3 à C6 substitué par un halogène, un alkylsulfanyle en C1 à C6, un alkylsulfinyle en C1 à C6, un alkylsulfonyle en C1 à C6, un N-C1-C6-alkylamino, un N,N-di-C1-C6-alkylamino, un N-C1-C3-alcoxy-C1-C4-alkylamino et un 1-pyrrolidinyle

    ou T2

    Z1 et Z2 sont chacun indépendamment choisis parmi un hydrogène, un halogène, un groupe cyano, un groupe nitro, un alkyle en C1 à C6 linéaire ou ramifié, un cycloalkyle en C3 à C6, un alcoxy en C1 à C6, un alkylcarbonyle en C1 à C6, un alkyle en C1 à C6 linéaire ou ramifié substitué par un halogène, un alcoxy en C1 à C6 substitué par un halogène, un cycloalkyle en C3 à C6 substitué par un halogène, un alkylsulfanyle en C1 à C6, un alkylsulfinyle en C1 à C6, un alkylsulfonyle en C1 à C6, un N-C1-C6-alkylamino, un N,N-di-C1-C6-alkylamino, un N-C1-C3-alcoxy-C1-C4-alkylamino et un 1-pyrrolidinyle ; et

    Z3 représente un hydrogène ou un alkyle en C1 à C6 linéaire, un cycloalkyle en C3 à C6; un alcényle en C2 à C6 un alcynyle en C2 à C6, un aryle ou un hétaryle, qui peuvent indépendamment les uns des autres être substitués par 1 à 5 substituants choisis parmi les groupes hydroxy, halogène, cyano, nitro, amino, un alkyle en C1 à C3, un alcoxy en C1 à C3, un hydroxycarbonyle, un alcoxycarbonyle, un alkylcarbamoyle, un cycloalkylcarbamoyle et un phényle et les sels de ceux-ci


     
    2. Composés selon la revendication 1,

    Q est O ;

    L2 est C=O ;

    L3 est un groupe (CH2)n-(CH=CH)-CH2)m, qui est éventuellement substitué par un maximum de 2 groupes indépendamment choisis parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C5 et un halogène, où

    n et m sont indépendamment 0, 1 ou 2 ; et

    L1 a la signification telle que définie dans la revendication 1 ;

    et les sels de ceux-ci.


     
    3. Composés selon la revendication 1 ou 2,

    Q est O ;

    L2 est C=O ;

    L3 est un groupe (CH2)n-(CH=CH)-CH2)m, où n et m sont 0 ; et

    L1 a la signification telle que définie dans la revendication 1 ;

    et les sels de ceux-ci.


     
    4. Composés selon la revendication 1,

    Q est O

    L2 est C=O

    L3 est un alcanediyle en C1 à C4 linéaire, qui est éventuellement substitué par un ou plusieurs groupes choisis indépendamment parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C6 et un halogène, où deux substituants alkyle en C1 à C4 peuvent former un cycle conjointement avec l'atome de carbone auquel ils sont liés ; et

    L1 a la signification telle que définie dans la revendication 1 ;

    et les sels de ceux-ci.


     
    5. Composés selon la revendication 1,

    Q est O ;

    L2 est absent ;

    L3 est un alcanediyle en C1 à C4 linéaire, qui est éventuellement substitué par un ou plusieurs groupes choisis indépendamment parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C6 et un halogène, où deux substituants alkyle en C1 à C4 peuvent former un cycle conjointement avec l'atome de carbone auquel ils sont liés ; et

    L1 a la signification telle que définie dans la revendication 1 ;

    et les sels de ceux-ci.


     
    6. Composés selon la revendication 1,
    dans lesquels

    L1, L2 et Q sont absents ; et

    L3 a la signification telle que définie dans la revendication 1 ;

    et les sels de ceux-ci.


     
    7. Composés selon l'une quelconque des revendications précédentes, dans lesquels une ou plusieurs des conditions suivantes s'appliquent

    Q est O ;

    et/ou

    L1 est un alcanediyle en C2 à C4 linéaire, qui est éventuellement substitué par un ou plusieurs groupes alkyle en C1 à C4, où deux substituants alkyle en C1 à C4 peuvent former un cycle conjointement avec l'atome de carbone auquel ils sont liés

    et/ou

    L2 est C=O

    et/ou

    L3 est un groupe (CH2)n-(CH=CH)-CH2)m, qui est éventuellement substitué par un maximum de 2 groupes indépendamment choisis parmi un alkyle en C1 à C4, un cycloalkyle en C3 à C5 et un halogène, où

    n et m sont indépendamment 0, 1 ou 2, de préférence n et m sont 0 ;

    et les sels de ceux-ci.


     
    8. Composés selon l'une quelconque des revendications précédentes, dans lesquels
    Y est choisi dans T1

    R1, R2 et R3 sont chacun indépendamment choisis parmi un hydrogène, un halogène, un alkyle en C1 à C3 linéaire ou ramifié, un cycloalkyle en C3 à C6, un alcoxy en C1 à C3, un alkyle en C1 à C3 linéaire ou ramifié substitué par un halogène, un alcoxy en C1 à C3 substitué par un halogène, un cycloalkyle en C3 à C6 substitué par un halogène et un 1-pyrrolidinyle,

    de préférence R1, R2 et R3 sont chacun indépendamment choisis parmi un halogène, un alkyle en C1 à C3 linéaire ou ramifié substitué par un halogène et un alcoxy en C1 à C3 substitué par un halogène ;

    ou T2

    Z1 représente un alkyle en C1 à C3 linéaire ou ramifié, un cycloalkyle en C3 à C6, un alcoxy en C1 à C3, qui peuvent indépendamment les uns des autres être substitués par 1 à 5 substituants choisis parmi un groupe hydroxy, halogène, cyano, nitro, un alkyle en C1 à C3 et un alcoxy en C1 à C3,

    de préférence Z1 représente un alkyle en C1 à C3 ou un cycloalkyle en C3 à C6 linéaire ou ramifié, qui peuvent indépendamment l'un de l'autre être substitués par 1 à 5 substituants halogène ;

    Z2 représente un halogène, un groupe cyano, nitro, amino, ou un alkyle en C1 à C6 linéaire ou ramifié, un alkylcarbonyle en C1 à C6, un alkylsulfanyle en C1-C6, un alkylsulfinyle en C1 à C6, un alkylsulfonyle en C1 à C6, qui peuvent indépendamment les uns des autres être substitués par 1 à 5 substituants choisis parmi un groupe hydroxy, halogène, cyano, nitro, un alkyle en C1 à C3 et un alcoxy en C1 à C3.

    de préférence Z2 représente un alkyle en C1 à C3 linéaire ou ramifié, qui peut être substitué par 1 à 5 substituants halogène, de préférence par 1 à 3 substituants halogène, plus préférentiellement le trifluorométhyle ou Z2 représente un groupe nitro, le méthylsulfanyle, le méthylsulfinyle, le méthylsulfonyle, le fluor, le chlore, le brome, l'iode ; et

    Z3 représente un hydrogène ou un alkyle en C1 à C6 linéaire ou ramifié, un cycloalkyle en C3 à C6, un alcényle en C2 à C6, un alcynyle en C2 à C6, un aryle ou un hétaryle, qui peuvent être indépendamment les uns des autres substitués par 1 à 5 substituants choisis parmi un groupe hydroxy, halogène, cyano, nitro, un alkyle en C1 à C3 et un alcoxy en C1 à C3, de préférence Z3 représente un hydrogène ou un alkyle en C1-C6 linéaire ou ramifié qui peuvent être substitués par 1 à 5 substituants choisi parmi un groupe hydroxy, halogène, un alkyle en C1 à C3 et un alcoxy en C1 à C3 :
    et les sels de ceux-ci.


     
    9. Composés selon l'une quelconque des revendications précédentes, dans lesquels
    Y est choisi dans T1

    R1 est un halogène, de préférence le fluor, le brome ou le chlore, plus préférentiellement le chlore ;

    R2 est un alkyle en C1 à C3 linéaire ou ramifié substitué par 1 à 7 halogènes, de préférence un alkyle en C1 à C3 linéaire ou ramifié substitué par 1 à 7 fluors, plus préférentiellement CF3, C2F5 ou C3F7 ; et

    R3 est un alcoxy en C1-C3 substitué par 1 à 3 halogènes, de préférence un alcoxy en C1 à C3 substitué par 1 à 3 fluors, plus préférentiellement OCF3, OC2F5 ou OC3F7 ;

    ou T2

    Z1 représente un alkyle en C1 à C3 ou un cycloalkyle en C3 à C6 linéaires ou ramifiés, substitués par 1 à 5 substituants halogène, de préférence le trifluorométhyle, le 1-chlorocyclopropyle, le 1-fluorocyclopropyle ou le pentafluoroéthyle, plus préférentiellement le trifluorométhyle ou le pentafluoroéthyle ;

    Z2 représente un alkyle en C1 à C3 linéaire ou ramifié substitué par 1 à 3 substituants halogène, ou

    Z2 représente un groupe nitro, le méthylsulfanyle, le méthylsulfinyle, le méthylsulfanyle, le fluor, le chlore, le brome, l'iode ; de préférence Z2 représente un alkyle en C1 à C3 linéaire ou ramifié substitué par 1 à 3 fluors, plus préférentiellement le trifluorométhyle ; et

    Z3 représente un hydrogène ou un alkyle en C1 à C6 linéaire ou ramifié, de préférence un alkyle en C1 à C6 linéaire ou ramifié, plus préférentiellement un hydrogène, le méthyle, l'éthyle ou le n-propyle ;

    et les sels de ceux-ci.


     
    10. Composés selon l'une quelconque des revendications précédentes, dans lesquels T1 est représenté par l'un des groupes T1-1, T1-2 ou T1-3 suivants :


     
    11. Composition pharmaceutique comprenant au moins un composé selon l'une quelconque des revendications précédentes, qui comprend éventuellement au moins un autre composant choisi parmi des agents auxiliaires, des excipients, des solvants et/ou au moins un agent pharmaceutiquement actif supplémentaire.
     
    12. Composition pharmaceutique selon la revendication 11 pour.une utilisation dans une application sous-cutanée ou orale.
     
    13. Composés ou compositions pharmaceutiques selon l'une quelconque des revendications précédentes pour une utilisation dans la lutte contre des parasites sur des animaux, de préférence pour lutter contre des insectes et des arachnides, de préférence choisis dans le groupe Chelicerata, notamment de préférence des tiques, des puces, des acariens et des mites, de préférence sur des animaux de compagnie tels que des chats et des chiens.
     
    14. Procédé de préparation des composés selon l'une quelconque des revendications précédentes comprenant l'étape de mise à réagir d'un composé (A)

    avec un groupe (B)

    Y, Q, L1, L2 et L3 ont la signification telle que définie dans l'une quelconque des revendications précédentes et où PG1 représente un groupe protecteur ou un hydrogène pour former les composés selon la formule (I), et dans lequel dans les cas où PG1 n'est pas l'hydrogène, une déprotection est effectuée pour former les composés (I) ;

    dans lequel le procédé peut en outre comprendre l'étape préliminaire de préparation du groupe (B) par

    i) la mise à réagir d'un composé (IIa) avec un composé (IIIa) pour former le composé (Va), où PG2 est un groupe protecteur ou un hydrogène, et dans lequel dans les cas où PG2n'est pas l'hydrogène (Va) est obtenu en clivant sélectivement PG2 :

    où L1 et L3 ont la signification telle que définie dans l'une quelconque des revendications précédentes et où PG1 représente un groupe protecteur ou un hydrogène ;
    ou

    ii) la mise réagir d'un composé (VI) avec un composé (IIIb) pour former le composé (Vb), où PG2 est un groupe protecteur ou un hydrogène, et dans lequel dans les cas où PG2 n'est pas l'hydrogène (Vb) est obtenu en clivant sélectivement PG2 :

    où L1, L2 et L3 ont la signification telle que définie dans l'une quelconque des revendications précédentes et où PG1 représente un groupe protecteur ou un hydrogène.


     
    15. Composés intermédiaires selon la formule (B),

    Q est O ;

    L2 est C=O ;

    L1 et L3 ont la signification telle que définie dans l'une quelconque des revendications précédentes et

    PG1 représente un groupe tert-butyle

    ou

    selon la formule (C),

    où Y, Q, L1, L2 et L3 ont la signification telle que définie dans l'une quelconque des revendications précédentes et où PG1 représente un groupe tert-butyle.


     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description




    Non-patent literature cited in the description