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USE OF SGC ACTIVATORS FOR THE TREATMENT OF OPHTHALMOLOGIC DISEASES

20220241273 · 2022-08-04

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention relates to substituted pyrazolo piperidine carboxylic acids, their salts and their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of ophthalmologic diseases, including non-proliferative diabetic retinopathy (NPDR), diabetic macular edema (DME), retinal ganglion cell/photoreceptor neurodegeneration and cataract.

    Claims

    1. A method for the oral treatment and/or prophylaxis of an eye disease comprising administering an effective amount of an sGC activator of formula (I) ##STR00152## in which R.sup.1 represents hydrogen or halogen, R.sup.2 represents hydrogen or halogen, R.sup.3 represents chloro or trifluoromethyl, R.sup.4 represents hydrogen, C.sub.1-C.sub.4-alkyl, R.sup.5 represents a group of the formula ##STR00153## where # is the point of attachment to the aromatic or heteroaromatic 6 ring system; wherein m is 0-4 R.sup.6 represents C.sub.1-C.sub.6-alkyl, optionally substituted by one or more substituent independently selected from the group consisting of methyl, trifluoromethoxy, nitril, amido, C.sub.2-C.sub.6-halogenoalkyl, optionally substituted by 1 to 5 fluoro substituents, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-methyl, optionally substituted by 1 to 5 fluoro substituents or a trifluoromethyl group, C.sub.1-C.sub.6-alkylcarbonyl, optionally substituted by 1 to 3 fluoro substituents, C.sub.3-C.sub.6-cycloalkyl-carbonyl, optionally substituted by 1 to 3 fluoro substituents or (C.sub.1-C.sub.6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, C.sub.3-C.sub.6-cycloalkyl, (C.sub.3-C.sub.6)-cycloalkoxy-carbonyl, mono-(C.sub.1-C.sub.4)-alkylaminocarbonyl, (C.sub.1-C.sub.4)-alkylsulfonyl or oxetanyl, spiro[2.2]pentan-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl, R.sup.7 represents C.sub.1-C.sub.4-alkylcarbonyl, optionally substituted by a C.sub.3-C.sub.6-cycloalkyl group, R.sup.8 represents C.sub.2-C.sub.4-alkyl, C.sub.2-C.sub.4-halogenoalkyl substituted by 1 to 6 fluoro substituents, R.sup.11 represents hydrogen or fluoro substituent X.sub.1 represents nitrogen or carbon or C—F X.sub.2 represents nitrogen or carbon and the salts thereof, the solvates thereof and the solvates of the salts thereof, to a patient in need of said method.

    2. The method according to claim 1, wherein the sGC activator is an SGC activator of formula (I-A) ##STR00154## in which R.sup.1 represents hydrogen or halogen, R.sup.2 represents hydrogen or halogen, R.sup.3 represents chloro or trifluoromethyl, R.sup.4 represents hydrogen or C.sub.1-C.sub.4-alkyl R.sup.5 represents optionally substituted C.sub.1-C.sub.6-alkyl R.sup.11 represents hydrogen or fluoro substituent X.sub.1 represents nitrogen or carbon X.sub.2 represents nitrogen or carbon and the salts thereof, the solvates thereof and the solvates of the salts thereof.

    3. The method according to claim 1, wherein the sGC activator is selected from the group consisting of ##STR00155## ##STR00156## or one of the salts thereof, solvates thereof or solvates of the salts thereof.

    4. The method according to claim 1, wherein the sGC activator is an SGC activator of formula (I-D) ##STR00157## and salts, solvates and solvates of the salts thereof.

    5. The method according to claim 1, wherein the sGC activator is an SGC activator of formula (I-E) ##STR00158## and salts, solvates and solvates of the salts thereof.

    6. The method according to claim 1, wherein the eye disease is associated with neurovascular unit damage or retinal ganglion cell/photoreceptor neurodegeneration.

    7. The method according to claim 1, wherein the eye disease is selected from a list consisting of non-proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, retinal artery occlusion, retinopathy of prematurity, ocular ischemic syndrome, radiation retinopathy, anterior ischemic optic neuritis, anti-VEGF therapy driven ischemia, ocular neuropathies and choroidal ischemic diseases.

    8. The method according to claim 1, wherein the eye disease is selected from a list consisting of non-proliferative diabetic retinopathy, optic neuropathies and cataract.

    9. The method according to claim 1, wherein the eye disease is non-proliferative diabetic retinopathy.

    10. The method according to claim 1, wherein the eye disease is selected from a list of optic neuropathies consisting of glaucomatous optic neuropathy, ischemic optic neuropathy, traumatic optic neuropathy, non-arteritic anterior ischemic optic neuropathy, optic neuropathy, leber's hereditary optic neuropathy, methanol associated optic neuropathy and age-related macular degeneration.

    11. The method according to claim 10, wherein the optic neuropathy is glaucomatous optic neuropathy.

    12. A method for the oral treatment and/or prophylaxis of an eye disease comprising administering an effective amount of a combination to a patient in need thereof, the combination comprising at least one sGC activator according to claim 1 and at least one compound selected from the group consisting of inhibitors of phosphodiesterases 1, 2 and/or 5, calcium, vitamin D and metabolites of vitamin D, bisphosphonates, selected from etidronate, clodronate, tiludronate, teriparatide, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate, strontium ranelate, active ingredients suitable for hormone replacement therapy in osteoporosis, selected from estrogen and a combination of estrogen and progesterone, selective estrogen receptor modulators, parathyroid hormone and analogs of parathyroid hormone, modulators of receptor activator of nuclear factor kappa-B ligand, sclerostin inhibitors, and TGF-β inhibitors.

    13. A method for the oral treatment and/or prophylaxis of an eye disease comprising administering a pharmaceutical composition to a patient in need thereof, the pharmaceutical composition comprising an effective amount of at least one sGC activator according to claim 1 and one or more inert non-toxic pharmaceutically suitable excipients.

    14. A method for the oral treatment and/or prophylaxis of an eye disease comprising administering an effective amount of a pharmaceutical composition to a patient in need thereof, the pharmaceutical composition comprising the combination according to claim 12 and one or more inert non-toxic pharmaceutically suitable excipients.

    15. A method for the oral treatment and/or prevention of an eye disease selected from a list consisting of non-proliferative diabetic retinopathy, optic neuropathies and cataract in humans and animals comprising administering an effective amount of at least one sGC activator according to claim 1 to a human or animal in need thereof.

    Description

    SPECIFIC EMBODIMENTS

    [0624] 1. sGC activator of formula (I) for use in the oral treatment and/or prophylaxis of an eye disease

    ##STR00084## [0625] in which [0626] R.sup.1 represents hydrogen or halogen, [0627] R.sup.2 represents hydrogen or halogen, [0628] R.sup.3 represents chloro or trifluoromethyl, [0629] R.sup.4 represents hydrogen, C.sub.1-C.sub.4-alkyl, [0630] R.sup.5 represents a group of the formula

    ##STR00085## [0631] where # is the point of attachment to the aromatic or heteroaromatic 6 ring system; wherein m is 0-4 [0632] R.sup.6 represents [0633] C.sub.1-C.sub.6-alkyl, optionally substituted by one or more substituent independently selected from the group consisting of methyl, trifluoromethoxy, nitril, amido, [0634] C.sub.2-C.sub.6-halogenoalkyl, optionally substituted by 1 to 5 fluoro substituents, [0635] C.sub.3-C.sub.6-cycloalkyl, [0636] C.sub.3-C.sub.6-cycloalkyl-methyl, optionally substituted by 1 to 5 fluoro substituents or a trifluoromethyl group, [0637] C.sub.1-C.sub.6-alkylcarbonyl, optionally substituted by 1 to 3 fluoro substituents, [0638] C.sub.3-C.sub.6cycloalkyl-carbonyl, optionally substituted by 1 to 3 fluoro substituents or [0639] (C.sub.1-C.sub.6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, C.sub.3-C.sub.6-cycloalkyl, [0640] (C.sub.3-C.sub.6)-cycloalkoxy-carbonyl, [0641] mono-(C.sub.1-C.sub.4)-alkylaminocarbonyl, [0642] (C.sub.1-C.sub.4)-alkylsulfonyl or [0643] oxetanyl, [0644] spiro[2.2]pentan-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl, [0645] R.sup.7 represents C.sub.1-C.sub.4-alkylcarbonyl, optionally substituted by a C.sub.3-C.sub.6-cycloalkyl group, [0646] R.sup.8 represents C.sub.2-C.sub.4-alkyl, C.sub.2-C.sub.4-halogenoalkyl substituted by 1 to 6 fluoro substituents, [0647] R.sup.11 represents hydrogen or fluoro substituent [0648] X.sub.1 represents nitrogen or carbon or C—F [0649] X.sub.2 represents nitrogen or carbon [0650] and salts, solvates and solvates of the salts thereof. [0651] 2. sGC activator for use according to Claim 1, whereas the sGC activator is corresponding to the following formula (I-A)

    ##STR00086## [0652] in which [0653] R.sup.1 represents hydrogen or halogen, [0654] R.sup.2 represents hydrogen or halogen, [0655] R.sup.3 represents chloro or trifluoromethyl, [0656] R.sup.4 represents hydrogen or C.sub.1-C.sub.4-alkyl [0657] R.sup.5 represents optionally substituted C.sub.1-C.sub.6-alkyl [0658] R.sup.11 represents hydrogen or fluoro substituent [0659] X.sub.1 represents nitrogen or carbon [0660] X.sub.2 represents nitrogen or carbon [0661] and the salts thereof, the solvates thereof and the solvates of the salts thereof. [0662] 3. sGC activator for use according to Claim 1, whereas the sGC activator is selected from the group consisting of

    ##STR00087## ##STR00088## ##STR00089## ##STR00090## [0663] and salts, solvates and solvates of the salts thereof. [0664] 4. sGC activator for use according to Claim 1, whereas the sGC activator is selected from the group consisting of

    ##STR00091## ##STR00092## ##STR00093## [0665] and salts, solvates and solvates of the salts thereof. [0666] 5. sGC activator for use according to Claim 1, whereas the sGC activator is selected from the group consisting of

    ##STR00094## ##STR00095## [0667] and salts, solvates and solvates of the salts thereof. [0668] 6. sGC activator for use according to Claim 1, whereas the sGC activator is ((I-D)

    ##STR00096## [0669] and salts, solvates and solvates of the salts thereof. [0670] 7. sGC activator for use according to Claim 1, whereas the sGC activator is ((I-D-R)

    ##STR00097## [0671] and salts, solvates and solvates of the salts thereof. [0672] 8. sGC activator for use according to Claim 1, whereas the sGC activator is corresponding to the following formula (I-H)

    ##STR00098## [0673] and salts, solvates and solvates of the salts thereof. [0674] 9. sGC activator for use according to Claim 1, whereas the sGC activator is corresponding to the following formula (I-E)

    ##STR00099## [0675] and solvates thereof. [0676] 10. sGC activator for use according to Claim 1, whereas the sGC activator is corresponding to the following formula (I-E-R)

    ##STR00100## [0677] and solvates thereof. [0678] 11. sGC activator for use according to Claim 1, whereas the sGC activator is corresponding to the following formula (I-E-R hemihydrate)

    ##STR00101## [0679] 12. sGC activator for use according to any of claims 1 to 11, whereas the eye disease is associated with neurovascular unit damage, lens opacity (cataract) or retinal ganglion cell/photoreceptor neurodegeneration. [0680] 13. sGC activator for use according to any of Claims 1 to 12, whereas the eye disease is selected from a list consisting of non-proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, retinal artery occlusion, retinopathy of prematurity, ocular ischemic syndrome, radiation retinopathy, anterior ischemic optic neuritis, anti-VEGF therapy driven ischemia, ocular neuropathies and choroidal ischemic diseases. [0681] 14. sGC activator for use according to any of Claims 1 to 13, whereas the eye disease is selected from a list consisting of non-proliferative diabetic retinopathy, optic neuropathies and cataract. [0682] 15. sGC activator for use according to any of Claims 1 to 14, whereas the eye disease is non-proliferative diabetic retinopathy. [0683] 16. sGC activator for use in non-proliferative diabetic retinopathy according to Claim 15, whereas the diabetic retinopathy severity score (DRSS) is between 35 to 53. [0684] 17. sGC activator for use in non-proliferative diabetic retinopathy according to Claim 15, whereas the diabetic retinopathy severity score (DRSS) is between 43 to 53. [0685] 18. sGC activator for use in non-proliferative diabetic retinopathy according to Claim 15, characterized in that the disease progression is stopped and the retinal function is restored to healthier status (reversal of disease progression). [0686] 19. sGC activator for use in non-proliferative diabetic retinopathy according to Claim 15, whereas non-proliferative diabetic retinopathy is complicated by ischemic macular edema. [0687] 20. sGC activator for use according to Claim 19, whereas ischemic macular edema is caused by DR, branch retinal vein occlusion or radiation retinopathy. [0688] 21. sGC activator for use according to any of Claims 1 to 11, whereas the eye disease is selected from a list of optic neuropathies consisting of glaucomatous optic neuropathy, ischemic optic neuropathy, traumatic optic neuropathy, non-arteritic anterior ischemic optic neuropathy, optic neuropathy, leber's hereditary optic neuropathy, methanol associated optic neuropathy and age-related macular degeneration. [0689] 22. sGC activator for use according to Claim 21, wherein the optic neuropathy is glaucoma optic neuropathy. [0690] 23. sGC activator for use according to Claim 21, whereas the glaucomatous optic neuropathy is caused by acute closed angle glaucoma. [0691] 24. sGC activator for use according to Claims 1 to 11, whereas the eye disease is associated with cataract formation. [0692] 25. sGC activator for use according to Claim 24, whereas the cataract formation cause is selected from a list consisting of age-related cataract, diabetes induced cataract, steroid induced cataract, traumatic cataract, congenital cataract. [0693] 26. sGC activator for use according to any of Claim 24, whereas the cataract formation cause is diabetes induced cataract secondary to type 1 or type 2 diabetes. [0694] 27. sGC activator for use according to any of Claim 24, whereas the cataract formation cause is diabetes induced cataract secondary to type 1 diabetes. [0695] 28. Combination for use according to any of Claims 1 to 27 comprising at least one sGC activator according to any of Claims 1 to 11 and at least one compound selected from the group consisting of inhibitors of phosphodiesterases 1, 2 and/or 5, calcium, vitamin D and metabolites of vitamin D, bisphosphonates, selected from etidronate, clodronate, tiludronate, teriparatide, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate, strontium ranelate, active ingredients suitable for hormone replacement therapy in osteoporosis, selected from estrogen and a combination of estrogen and progesterone, selective estrogen receptor modulators, parathyroid hormone and analogs of parathyroid hormone, modulators of receptor activator of nuclear factor kappa-B ligand, sclerostin inhibitors, and TGF-β inhibitors. [0696] 29. Combination for use according to Claim 28, wherein the at least one inhibitor of phosphodiesterase 5 is selected from the group consisting of sildenafil, vardenafil, tadalafil and avanafil. [0697] 30. Combination for use according to any of Claims 1 to 27 comprising at least one sGC activator according to any of Claims 1 to 11 and at least one mineralocorticoid-receptor antagonist selected from the group consisting of spironolactone, eplerenone or finerenone. [0698] 31. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising at least one sGC activator according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients. [0699] 32. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising at least one sGC activator according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients wherein the formulation is in form of an osmotic release system. [0700] 33. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising a sGC activator according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula I, (I-A), (I-B), (I-C), (I-D), (I-D-R), (I-E), (I-E-R), (I-F), (I-G), (I-H), (I-I), (I-J), (I-K), preferably ((I-D), (I-D-R) or (I-E), (I-E-R) or (I-H) or (I-I) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg. [0701] 34. Pharmaceutical composition for use in the oral treatment and/or prophylaxis of an eye disease, wherein the eye diseases is NPDR, comprising a sGC activator according to according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula ((I-D), (I-D-R), (I-E), (I-E-R) or (I-H) or (I-I) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg. [0702] 35. Pharmaceutical composition for use in the oral treatment and/or prophylaxis of an eye disease, wherein the eye diseases is NPDR, comprising a sGC activator according to according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula ((I-D), (I-D-R), (I-E) or (I-E-R) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg. [0703] 36. Pharmaceutical composition for use in the oral treatment and/or prophylaxis of an eye disease, wherein the eye diseases is NPDR, comprising a sGC activator according to according to any of Claims 1 to 11 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula ((I-D), (I-D-R), (I-E) or (I-E-R) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg, also most preferably 4 mg to 45 mg or 4 to 90 mg or 4 to 180 mg. [0704] 37. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising a combination according to Claims 28 or 29 and one or more inert non-toxic pharmaceutically suitable excipients. [0705] 38. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising a combination according to Claims 28 or 29 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula formula I, (I-A), (I-B), (I-C), (I-D), (I-D-R), (I-E), (I-E-R), (I-F), (I-G), (I-H), (I-I), (I-J), (I-K), preferably ((I-D), (I-D-R) or (I-E), (I-E-R) or (I-H) or (I-I) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg. [0706] 39. Pharmaceutical composition for use according to any of Claims 1 to 27 comprising a combination according to Claims 28 or 29 and one or more inert non-toxic pharmaceutically suitable excipients, characterized in that the sGC activator is selected form the group consisting of compound of formula ((I-D), (I-D-R) or (I-E), (I-E-R) and that the sGC activator is present in an amount of 0.1 mg to 500 mg, preferably 1 mg to 120 mg, most preferable 2.5 mg to 50 mg or 2.5 mg to 60 mg, also most preferably 4 mg to 45 mg or 4 to 90 mg or 4 to 180 mg. [0707] 40. Method for the treatment and/or prevention of an eye disease selected from a list consisting of non-proliferative diabetic retinopathy and diabetic macular edema in humans and animals by administration of an effective amount of at least one sGC activator according to any of Claims 1 to 11 or a pharmaceutical composition as defined in any of Claims 31 to 39. [0708] 41. Method for the treatment and/or prevention of an eye disease selected from a list consisting of non-proliferative diabetic retinopathy and diabetic macular edema in humans and animals by administration of an effective amount of at least one sGC activator selected from the group consisting of a compound of formula ((I-D), (I-D-R) or (I-E), (I-E-R) or a pharmaceutical composition as defined in any of Claims 31 to 39. [0709] 42. Method for the oral treatment and/or prevention of an eye disease selected from a list consisting of non-proliferative diabetic retinopathy, optic neuropathies and cataract in humans and animals by administration of an effective amount of at least one sGC activator according to any of Claims 1 to 11 or a pharmaceutical composition as defined in any of Claims 31 to 39. [0710] 43. Method for the oral treatment and/or prevention of an eye disease selected from a list consisting of non-proliferative diabetic retinopathy, glaucoma optic neuropathy, whereas the eye disease is associated with cataract formation and diabetic macular edema in humans and animals by administration of an effective amount of at least one sGC activator according to any of Claims 1 to 10 or a pharmaceutical composition as defined in any of Claims 31 to 39.

    EXPERIMENTAL SECTION

    [0711]

    TABLE-US-00002 TABLE 1 Abbreviations The following table lists the abbreviations used herein. Abbreviation Meaning BH.sub.3•THF Borane-tetrahydrofuran BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl br broad (.sup.1H-NMR signal) CI chemical ionisation d doublet (.sup.1H-NMR signal) d day(s) DAD diode array detector dd double-doublet DMF N,N-dimethylformamide DMSO dimethylsulfoxide ESI electrospray (ES) ionisation EtOAc Ethyl acetate h hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, CAS 148893-10-1 HPLC high performance liquid chromatography LC-MS liquid chromatography mass spectrometry m multiplet (.sup.1H-NMR signal) M molar min minute(s) MS mass spectrometry MTBE methyl-tert-butylether NaBH.sub.4 Sodium borohydride, sodium tetrahydroborate NaHCO.sub.3 Sodium hydrogen carbonate Na.sub.2SO.sub.4 Sodium sulphate NMR nuclear magnetic resonance spectroscopy: chemical shifts (δ) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise stated. PDA Photo Diode Array Pd.sub.2dba.sub.3 Tris(dibenzylideneacetone)dipalladium (0), CAS 51364-51-3 Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphane)palladium(0), CAS 14221-01-3 quant. quantitative rac racemic R.sub.t, Rt retention time (as measured either with HPLC or UPLC) in minutes RuPhos Pd G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, CAS 1445085-77-7 s singlet (.sup.1H-NMR signal) SFC Supercritical Fluid Chromatography SQD Single-Quadrupole-Detector t triplet (.sup.1H-NMR signal) td triple-doublet (.sup.1H-NMR signal) TFA trifluoroacetic acid THF tetrahydrofuran UPLC ultra performance liquid chromatography X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, CAS 564483-18-7

    [0712] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. All publications mentioned herein are incorporated by reference in their entirety.

    [0713] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

    Experimental Section—General Part

    [0714] All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

    [0715] The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil® or KP-NH© in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

    [0716] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

    [0717] In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process.

    [0718] Unless specified in more detail, additions to names and structural formulae, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF.sub.3COOH”, “x Na*” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.

    [0719] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.

    [0720] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

    [0721] The .sup.1H-NMR data of selected compounds are listed in the form of .sup.1H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ.sub.1 (intensity.sub.1), δ.sub.2 (intensity.sub.2), . . . , δ.sub.i (intensity.sub.i), . . . , δ.sub.n (intensity.sub.n).

    [0722] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A .sup.1H-NMR peaklist is similar to a classical .sup.1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical .sup.1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of “by-product fingerprints”. An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical .sup.1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (cf. Research Disclosure Database Number 605005, 2014, 1 Aug. 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter “MinimumHeight” can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter “MinimumHeight”<1%.

    [0723] In NMR spectra of mixtures of stereoisomers, numbers mentioned with “/” indicate that the stereoisomers show separate signals for the respective hydrogen atom, i.e. “ . . . / . . . (2s, 1H)” means that one hydrogen atom is represented by 2 singlets, each singlet from one or more different stereoisomer(s).

    [0724] IUPAC names of the following intermediates and example compounds were generated using the ACD/Name software (batch version 14.00; Advanced Chemistry Development, Inc.) or the naming tool implemented in the BIOVIA Draw software (version 4.2 SP1; Dassault Systèemes SE).

    [0725] Analytical LC-MS Methods

    [0726] Method 1

    [0727] MS instrument type: SHIMADZU LCMS-2020, Column: Kinetex EVO C18 30*2.1 mm, 5 um, mobile phase A: 0.0375% TFA in water (v/v), B: 0.01875% TFA in Acetonitrile (v/v), gradient: 0.0 min 0% B.fwdarw.0.8 min 95% B.fwdarw.1.2 min 95% B.fwdarw.1.21 min 5% B.fwdarw.1.55 min 5% B, flow rate: 1.5 mL/min, oven temperature: 50° C.;

    [0728] UV detection: 220 nm & 254 nm.

    [0729] Method 2

    [0730] HPLC instrument type: SHIMADZU LCMS-2020, Column: Kinetex EVO C18 50*4.6 mm, 5 um, mobile phase A: 0.0375% TFA in water (v/v), B: 0.018750% TFA in Acetonitrile (v/v), gradient: 0.0 min 10% B.fwdarw.2.4 min 80% B.fwdarw.3.7 min 80% B.fwdarw.3.71 min 10% B.fwdarw.4.0 min 10% B, flow rate: 1.5 mL/min, oven temperature: 50° C.; UV detection: 220 nm & 215 nm & 254 nm.

    [0731] Method 3 (LC-MS)

    [0732] Instrument MS: Thermo Scientific FT-MS; Instrument type 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.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50° C.; flow rate: 0.90 ml/min; UV-Detection: 210 nm/Optimum Integration Path 210-300 nm.

    [0733] Method 4 (LC-MS)

    [0734] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; Eluent A: 1 l water+0.25 ml formic acid, Eluent B: 11 Acetonitrile+0.25 ml formic acid; Gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UV-Detection: 210 nm.

    [0735] Method 5 (LC-MS)

    [0736] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; Eluent A: 1 l water+0.25 ml formic acid, Eluent B: 1 l Acetonitrile+0.25 ml formic acid; Gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UV-Detection: 210 nm.

    [0737] Method 6 (LC-MS)

    [0738] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μm 50×2.1 mm; Eluent A: 1 l water+0.25 ml formic acid, Eluent B: 1 l Acetonitrile+0.25 ml formic acid; Gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.1.7 min 5% A.fwdarw.3.0 min 5% A oven: 50° C.; flow rate: 1.20 ml/min; UV-Detection: 205-305 nm.

    [0739] Method 7 (LC-MS)

    [0740] Instrument: Waters Single Quad MS System; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7μ 50×2.1 mm; Eluent A: 1 l water+1.0 mL (25% aqueous Ammonia)/L, Eluent B: 1 l Acetonitrile; Gradient: 0.0 min 92% A.fwdarw.0.1 min 92% A.fwdarw.1.8 min 5% A.fwdarw.3.5 min 5% A; oven: 50° C.; flow rate: 0.45 mL/min; UV-Detection: 210 nm.

    [0741] Method 8 (LC-MS)

    [0742] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; Eluent A: 1 l Water+0.100 ml 99% ige Formic acid, Eluent B: 1 l Acetonitrile+0.100 ml 99% ige Formic acid; Gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A Oven: 50° C.; Flow: 0.40 ml/min; UV-Detection: 210 nm.

    [0743] Method 9 (LC-MS):

    [0744] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; Eluent A: 1 l Water+0.100 ml 99% ige Formic acid, Eluent B: 1 l Acetonitrile+0.100 ml 99% ige Formic acid; Gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A Oven: 50° C.; Flow: 0.35 ml/min; UV-Detection: 210 nm.

    [0745] Preparative HPLC Methods

    [0746] Instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 μm 100×30 mm, UV-detection 200-400 nm, room temperature, At-Column Injection (complete injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile/water (80 vol. %/20 vol. %); flow: 80 ml/min, gradient profile: 0 to 2 min: eluent A 47 ml/min, eluent B 23 ml/min; 2 to 10 min: eluent A from 47 ml/min to 23 ml/min, eluent B from 23 ml/min to 47 ml/min; 10 to 12 min eluent A 0 ml/min and eluent B 70 ml/min; eluent C and eluent D have a constant flow of 5 ml/min each over the whole running time.

    [0747] Microwave: Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.

    [0748] When compounds according to the invention are purified by preparative HPLC by the above-described methods in which the eluents contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.

    [0749] In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process. Unless specified in more detail, additions to names and structural formulae, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF.sub.3COOH”, “x Na*” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.

    [0750] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.

    [0751] Enantiomer 1 is an enantiomer which eluted first out of the column.

    [0752] Enantiomer 2 is an enantiomer which eluted second out of the column.

    [0753] Diastereomeric mixture 1 defines a compound where its starting material is defined as Enantiomer 1 and is reacted with a building block containing at least one chiral center and where the configuration is not defined

    [0754] Diastereomeric mixture 2 defines a compound where its starting material is defined as Enantiomer 2 and is reacted with a building block containing at least one chiral center and where the configuration is not defined

    [0755] Diastereomer 1 and Diastereomer 2 defines the two compounds resulting from the chiral separation of the diastereomeric mixture 1 described above.

    [0756] Diastereomer 3 and Diastereomer 4 defines the two compounds resulting from the chiral separation of the diastereomeric mixture 2 described above.

    [0757] Stereoisomer 1 defines a compound where its starting material is defined as Enantiomer 1 and is reacted with a building block containing at least one chiral center and where the configuration is defined Stereoisomer 2 defines a compound where its starting material is defined as Enantiomer 2 and is reacted with a building block containing at least one chiral center and where the configuration is defined

    Starting Compounds and Intermediates

    Intermediate 1A

    Example 1A

    Tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (Racemate)

    [0758] ##STR00102##

    [0759] To a solution of tert-butyl 3-oxopiperidine-1-carboxylate [CAS No. 989-36-7] (300 g, 1.51 mol) in tetrahydrofuran (1.50 L) and Methanol (300 mL) was added benzyl hydrazinecarboxylate [CAS No. 5331-43-1] (250 g, 1.51 mol) at 25° C., then, the mixture was stirred at 25° C. for 1 h. Afterwards NaBH.sub.4 (114 g, 3.01 mol) was added in portions to the mixture at 25° C. and stirred at 25° C. for 2 h. The reaction mixture was cooled to 10° C., and sat. NH.sub.4Cl was added dropwise to pH˜6. The mixture was extracted with EtOAc (300 mL*2) and concentrated in vacuo. The residue was dissolved in MTBE (300 mL) and petroleum ether (300 mL) was added. The mixture was filtrated off and the precipitate was washed with petroleum ether (100 mL) affording the title compound (400 g, 1.14 mol, 76.0% yield) as a white solid.

    [0760] LC-MS: (Method 1) R.sub.t4=0.832 min, MS (M-100+1=250.4).

    Example 2A

    Tert-butyl 3-hydrazinopiperidine-1-carboxylate acetic acid adduct (Racemate)

    [0761] ##STR00103##

    [0762] To a solution of tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (prepared in analogy to Example 1A, 1.20 kg, 3.43 mol) in ethanol (11.0 L) was added acetic acid (415 g, 6.91 mol, 395 mL) and Pd/C (120 g, 20% purity) under H.sub.2 (15 Psi). The mixture was stirred at 25° C. for 12 h. The mixture was filtrated and the precipitate was washed with ethanol (11.0 L) to give a solution of the title compound in ethanol (945 g, acetic acid salt) as a black liquid, the filtrate was used for the next step without purification.

    [0763] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.52 (s, 5H), 3.59 (d, J=6.0 Hz, 12H), 3.30-3.24 (m, 2H), 2.75-2.71 (m, 2H), 1.38-1.34 (m, 1H), 1.20-1.18 (m, 1H), 1.10 (s, 9H)

    [0764] LC-MS: (Method 1) R.sub.t=0.263 min, MS (M-56+1=160.2)

    Example 3A

    Ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate

    [0765] ##STR00104##

    [0766] A solution of ethyl 4,4-difluoro-3-oxobutanoate [CAS No. 352-24-9] (120 g, 722 mmol) and (diethoxymethoxy)ethane (240 ml, 1.4 mol) in acetic acid anhydride (200 ml, 2.2 mol) was stirred overnight at 140° C. and evaporated to dryness affording 155 g (quant.) of the titlte compound which was used in the next step without further purification.

    [0767] .sup.1H-NMR (600 MHz, CDCl.sub.3) δ [ppm]: 1.306 (6.05), 1.318 (16.00), 1.330 (14.48), 1.341 (4.56), 1.428 (5.99), 1.436 (5.01), 1.440 (12.20), 1.448 (9.25), 1.451 (6.31), 1.460 (4.48), 2.095 (1.59), 2.225 (1.56), 4.247 (1.97), 4.260 (5.79), 4.271 (5.85), 4.277 (1.55), 4.283 (2.00), 4.289 (4.40), 4.301 (4.37), 4.308 (2.03), 4.313 (1.64), 4.320 (5.74), 4.332 (5.78), 4.340 (1.60), 4.344 (2.01), 4.351 (4.21), 4.364 (4.20), 4.375 (1.37), 6.262 (1.79), 6.339 (1.35), 6.352 (3.56), 6.429 (2.63), 6.442 (1.72), 6.519 (1.28), 7.867 (5.48), 7.880 (7.31).

    Example 4A

    Tert-butyl 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (Racemate)

    [0768] ##STR00105##

    [0769] To a mixture of tert-butyl 3-hydrazinopiperidine-1-carboxylate acetic acid (Example 2A, 945 g, 3.43 mol) in ethanol (20.0 L) was added ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (prepared in analogy to Example 3A, 840 g, 3.78 mol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated. The residue was poured into saturated NaHCO.sub.3 aqueous solution (10.0 L), and extracted with Ethyl acetate (10.0 L*2). The combined organic layer was washed with brine (10.0 L), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluted with Petroleum ether:Ethyl acetate (50:1-25:1-10:1, R.sub.f=0.3) affording 530 g (41.4% yield) of the title compound.

    [0770] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.84 (s, 1H), 7.51 (t, J=12.8 Hz, 1H), 4.47-4.41 (m, 1H), 4.30-4.10 (m, 4H), 3.19-3.13 (m, 1H), 2.69 (s, 1H), 2.15-2.10 (m, 2H), 1.83-1.78 (m, 1H), 1.60-1.55 (m, 1H), 1.40 (s, 9H), 1.32-1.29 (m, 3H)

    [0771] LC-MS (Method 1) R.sub.t=0.992 min, MS (M-56+1=318.0).

    Example 5A

    Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (Racemate)

    [0772] ##STR00106##

    [0773] Tert-butyl 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (prepared in analogy to Example 4A, 593 g, 1.59 mol) was added to a solution of hydrogen chloride in dioxane (4 M, 2.50 L), the mixture was stirred at 25° C. for 12 h. The mixture was evaporated and the residue was dissolved in 1.00 L water and extracted with MTBE 500 mL. The aqueous phase was separated and adjusted pH to 8-9 with NaHCO.sub.3. The aqueous phase was extracted with dichloromethane (1.00 L×2), and the combined organic phases were washed with brine (1.00 L), dried over Na.sub.2SO.sub.4 and concentrated to give 350 g (80.6% yield) of the title compound.

    [0774] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.87 (s, 1H), 7.54 (t, J=12.8 Hz, 1H), 4.55-4.54 (m, 1H), 4.34-4.28 (m, 2H), 3.25-3.03 (m, 3H), 2.71-2.65 (m, 1H), 2.19-1.86 (m, 4H), 1.63-1.60 (m, 1H), 1.35 (t, J=7.2 Hz, 3H)

    [0775] LC-MS: (Method 1) R.sub.t=0.644 min, MS (M+1)=274.6

    [0776] In analogy to Example 5A, ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (Racemate) was prepared using different protecting groups. The two enantiomers were separated by SFC [sample preparation: 20 g were dissolved in 500 ml methanol; injection volume: 15 ml; column: Daicel AZ SCF 20 μm, 400×50 mm; eluent: carbone dioxide/methanol/aqueous ammonia (1%) 80:19:1 to 60:39:1; flow rate: 400 ml/min; temperature: 40° C.; UV detection: 220 nm]. After separation, 8.1 g of enantiomer 1 (Example 6A), which eluted first, and 8.0 g of enantiomer 2 (Example 7A), which eluted later, were isolated.

    Example 6A

    Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0777] For separation conditions see Example 5A.

    [0778] Analytical SFC: R.sub.t=0.980 min, e.e. =100% [Column Chiralpak IC-3: 50×4.6 mm; eluent: CO.sub.2/[methanol+0.2% diethyl amine]: 90:10 flow rate: 3.0 ml/min; temperature: 25° C.; UV detection: 220 nm].

    [0779] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.00 (s, 1H), 7.75-7.44 (m, 1H), 4.50-4.36 (m, 1H), 4.33-4.18 (m, 2H), 3.10-2.95 (m, 1H), 2.91-2.76 (m, 2H), 2.48-2.33 (m, 2H), 2.08-1.94 (m, 2H), 1.81-1.66 (m, 1H), 1.62-1.40 (m, 1H), 1.37-1.21 (m, 3H).

    Example 7A

    Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0780] For separation conditions see Example 5A.

    [0781] Analytical SFC: R.sub.t=1.227 min, e.e. =97% [Column Chiralpak IC-3: 50×4.6 mm; eluent: C.sub.02/[methanol+0.2% diethyl amine]: 90:10 flow rate: 3.0 ml/min; temperature: 25° C.; UV detection: 220 nm].

    [0782] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 8.01 (s, 1H), 7.75-7.43 (m, 1H), 4.50-4.37 (m, 1H), 4.27 (q, 2H), 3.09-2.97 (m, 1H), 2.94-2.81 (m, 2H), 2.47-2.34 (m, 2H), 2.06-1.92 (m, 2H), 1.79-1.66 (m, 1H), 1.60-1.41 (m, 1H), 1.29 (t, 3H).

    Example 8A

    2-Bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene

    [0783] ##STR00107##

    [0784] A solution of 2-bromo-4-chlorophenol [CAS No. 695-96-5] (10.0 g, 48.2 mmol) in acetone (75 ml) was treated with potassium carbonate (13.3 g, 96.4 mmol) and potassium iodide (12.0 g, 72.3 mmol) and 1-(chloromethyl)-4-methoxybenzene (7.55 g, 48.2 mmol). The resulting mixture was stirred −19 hours at 70° C. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 13.8 g (86% yield) of the title compound.

    [0785] LC-MS (Method 3): R.sub.t=2.48 min; MS (ESIneg): m/z=324 [M−H].sup.−

    [0786] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 3.349 (10.98), 5.124 (16.00), 6.949 (0.87), 6.954 (8.36), 6.957 (2.68), 6.965 (2.83), 6.968 (8.92), 6.973 (1.00), 7.218 (5.23), 7.233 (6.21), 7.380 (0.90), 7.384 (7.80), 7.399 (7.44), 7.402 (4.47), 7.406 (3.89), 7.417 (3.04), 7.421 (3.07), 7.697 (6.51), 7.702 (6.34).

    Example 9A

    Ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0787] ##STR00108##

    [0788] Under argon, a solution of 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared in analogy to Example 8A, 10.0 g, 30.5 mmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared in analogy to Example 6A, Enantiomer 1, 8.34 g, 30.5 mmol) in 1,4-dioxane (100 ml) was treated with caesium carbonate (29.8 g, 91.6 mmol), Pd.sub.2dba.sub.3 (2.80 g, 3.05 mmol) and rac-BINAP (3.80 g, 6.10 mmol) and the resulting mixture was stirred overnight at 100° C. The reaction mixture was combined with a 500 mg test reaction, filtered over celite, rinsed with ethyl acetate and evaporated. The residue was retaken in water and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 10.1 g (60% yield) of the title compound.

    [0789] LC-MS (Method 4): R.sub.4=1.44 min; MS (ESIpos): m/z=520 [M+H].sup.+

    Example 10A Ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0790] ##STR00109##

    [0791] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Example 9A, Enantiomer 1, 10.1 g, 19.4 mmol) in dichloromethane (200 ml) was treated with trifluoroacetic acid and stirred over night at room temperature. The reaction mixture was evaporated. The residue was retaken in ethyl acetate and washed once with water, once with a saturated solution of sodium hydrogencarbonate and finally once with a saturated solution of sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 7.17 g (83% purity, 77% yield) of the title compound.

    [0792] LC-MS (Method 8): R.sub.t4=1.26 min; MS (ESIpos): m/z=400 [M+H].sup.+

    Example 11A

    Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0793] ##STR00110##

    [0794] Under argon, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Example 10A, Enantiomer 1, 7.17 g, 83% purity, 14.9 mmol) in dichloromethane (160 ml) was treated with triethylamine (5.2 ml, 37 mmol) and cooled to 0° C. Trifluoromethanesulfonic anhydride was added dropwise and the resulting mixture was stirred 45 minutes at 0° C. The reaction mixture was diluted with dichloromethane (150 ml) and washed three times with water. The organic phase was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 7.89 g (quant.) of the title compound.

    [0795] LC-MS (Method 4): R.sub.t4=1.47 min; MS (ESIpos): m/z=532 [M+H].sup.+

    Example 12A

    Ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0796] ##STR00111##

    [0797] Under argon, a solution of ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared in analogy to Example 7A, Enantiomer 2, 43.6 g, 160 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared in analogy to Example 8A, 52.3 g, 160 mmol) in 1,4-dioxane (680 ml) was treated with Pd.sub.2(dba).sub.3 (14.6 g, 16.0 mmol), rac-BINAP (19.9 g, 31.9 mmol) and freshly ground caesium carbonate (156 g, 479 mmol) and stirred 18 hours at 100° C. The reaction mixture was diluted with ethyl acetate and a 10% solution of sodium chloride, filtered over Celite and rinsed with ethyl acetate. The aqueous phase of the filtrate was extracted with ethyl acetate. The combined organic layers were washed with a 10% solution of sodium chloride, dried over sodium sulphate and evaporated. The residue was purified flash chromatography over silica gel (dichloromethane/petrol ether 4:1) affording 42 g (82% yield) of the title compound.

    [0798] LC-MS (Method 3): R.sub.t=2.78 min; MS (ESIpos): m/z=520 [M+H].sup.+

    [0799] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.272 (3.65), 1.290 (7.68), 1.307 (3.76), 1.686 (0.44), 1.717 (0.54), 1.852 (0.73), 1.885 (0.50), 1.989 (0.47), 2.019 (0.56), 2.058 (0.99), 2.084 (0.61), 2.587 (0.51), 2.616 (0.89), 2.642 (0.45), 3.030 (0.76), 3.057 (1.51), 3.084 (0.83), 3.447 (0.72), 3.474 (0.69), 3.613 (0.74), 3.640 (0.67), 3.737 (16.00), 4.251 (1.13), 4.269 (3.48), 4.287 (3.45), 4.304 (1.12), 4.624 (0.40), 4.639 (0.48), 4.650 (0.76), 4.661 (0.51), 5.035 (6.45), 6.872 (3.47), 6.893 (5.67), 6.947 (0.98), 6.952 (0.85), 6.968 (1.72), 6.974 (1.67), 7.017 (2.84), 7.039 (1.57), 7.305 (3.66), 7.326 (3.43), 7.340 (0.56), 7.380 (0.41), 7.439 (0.93), 7.463 (0.64), 7.476 (0.48), 7.569 (1.65), 7.699 (0.76), 8.044 (3.66).

    Example 13A

    Ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0800] ##STR00112##

    [0801] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared in analogy to Example 12A, Enantiomer 2, 67.5 g, 130 mmol) in dichloromethane (1.0 l) was treated with trifluoroacetic acid (100 ml, 1.3 mol) and stirred overnight at room temperature. The reaction mixture was diluted with water (750 ml) and carefully treated with a 10% solution of sodium carbonate (450 ml) until no more carbon dioxide was generated. The organic phase was dried over sodium sulphate and evaporated affording 52 g (90% yield) of the title compound which was used in the next step without further purification.

    [0802] LC-MS (Method 3): R.sub.t4=2.42 min; MS (ESIpos): m/z=400 [M+H].sup.+

    Example 14A

    Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0803] ##STR00113##

    [0804] A solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Example 13A, Enantiomer 2, 52.0 g, 117 mmol) and triethylamine (49 ml, 350 mmol) in dichloromethane (330 ml) was cooled to −50° C. Trifluoromethanesulfonic acid (28 ml, 160 mmol) was added dropwise and the resulting mixture was stirred 1 hour at −50° C. The reaction mixture was then diluted with dichloromethane (330 ml) and water (370 ml). The aqueous phase was extracted with dichloromethane (330 ml). The combined organic layers were washed with (370 ml), dried over sodium sulphate and evaporated.

    [0805] The resulting mixture was purified by flash chromatography (silica gel, dichloromethane/petrol ether 6:4) affording 60 g (96% yield) of the title compound.

    [0806] LC-MS (Method 3): R.sub.t=2.74 min; MS (ESIpos): m/z=532 [M+H].sup.+

    [0807] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: −0.021 (0.65), 1.082 (0.51), 1.270 (7.69), 1.282 (16.00), 1.294 (7.63), 1.772 (0.48), 1.780 (0.51), 1.787 (0.63), 1.793 (0.66), 1.801 (0.62), 1.808 (0.60), 1.910 (1.25), 1.914 (0.99), 1.927 (0.67), 1.932 (0.89), 2.068 (0.72), 2.075 (1.03), 2.086 (2.45), 2.091 (2.40), 2.100 (1.41), 2.792 (0.71), 2.796 (0.83), 2.812 (1.48), 2.816 (1.50), 2.832 (0.83), 2.836 (0.72), 3.142 (1.17), 3.161 (1.04), 3.201 (1.21), 3.219 (2.80), 3.237 (1.83), 3.278 (1.37), 3.285 (1.56), 4.251 (2.26), 4.263 (7.09), 4.275 (7.06), 4.287 (2.20), 4.755 (0.50), 4.765 (0.90), 4.773 (0.89), 4.781 (0.90), 4.791 (0.49), 5.734 (2.17), 7.261 (2.19), 7.265 (2.27), 7.275 (2.69), 7.279 (2.82), 7.391 (4.65), 7.406 (3.75), 7.431 (4.73), 7.435 (4.51), 7.492 (1.26), 7.579 (2.61), 7.666 (1.07), 8.026 (6.37).

    Example 15A

    Tert-butyl 4-(4′-chloro-2′-{3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Enantiomer 2)

    [0808] ##STR00114##

    [0809] Under argon, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Example 14A, Enantiomer 2, 57.0 g, 107 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate [CAS No. 470478-90-1] (49.9 g, 129 mmol) in toluene (600 ml) and ethanol (600 ml) was treated with an aqueous solution of sodium carbonate (160 ml, 2.0 M, 320 mmol) and Tetrakis(triphenylphosphine)palladium(0) (6.19 g, 5.36 mmol). The resulting mixture was stirred 4 hours at 100° C. The reaction mixture was cooled to room temperature, filtered over Celite, washed with ethyl acetate and evaporated. The residue was purified by flash chromatography (silica gel, petrol ether/ethyl acetate 9:1 to 8:2) affording 62 g (89% yield) of the title compound.

    [0810] LC-MS (Method 3): R.sub.t=3.15 min; MS (ESIpos): m/z=644 [M+H].sup.+

    Example 16A

    Ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 2)

    [0811] ##STR00115##

    [0812] A solution of tert-butyl 4-(4′-chloro-2′-{(3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Example 15A, Enantiomer 2, 60.0 g, 93.1 mmol) in dichloromethane (250 ml) was treated with a solution of hydrogen chloride in dioxane (230 ml, 4.0 M, 930 mmol). The resulting mixture was stirred 3 hours at room temperature and evaporated. The residue was co-evaporated twice with diethyl ether (250 ml×2), stirred 4 days in diisopropyl ether. The suspension was filtered, the solid was washed twice with diisopropyl ether affording 57 g (quant.) of the title compound.

    [0813] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=544 [M+H].sup.+

    [0814] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.029 (13.49), 1.044 (13.77), 1.262 (7.53), 1.280 (16.00), 1.297 (7.81), 1.496 (0.79), 1.506 (0.62), 1.527 (0.91), 1.559 (0.40), 1.716 (1.24), 1.749 (0.95), 1.888 (0.84), 1.897 (0.78), 1.918 (0.98), 1.926 (0.93), 1.966 (1.38), 1.995 (0.69), 2.580 (1.54), 2.606 (0.83), 2.992 (1.21), 3.018 (2.69), 3.044 (2.33), 3.063 (1.24), 3.435 (5.96), 3.448 (7.25), 3.460 (5.00), 3.570 (5.78), 3.586 (0.87), 3.601 (1.12), 3.616 (0.85), 4.227 (5.38), 4.238 (6.62), 4.256 (9.26), 4.273 (7.97), 4.291 (2.70), 4.444 (0.41), 4.455 (0.77), 4.470 (0.89), 4.481 (1.31), 4.491 (0.92), 4.507 (0.68), 7.045 (6.02), 7.067 (6.86), 7.074 (5.10), 7.079 (5.42), 7.099 (2.25), 7.104 (1.49), 7.120 (3.55), 7.125 (3.10), 7.164 (6.27), 7.185 (3.37), 7.383 (1.62), 7.483 (6.90), 7.505 (6.40), 7.513 (3.75), 7.643 (1.34), 8.005 (5.77), 9.399 (1.97).

    Example 17A

    Ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0815] ##STR00116##

    [0816] A solution of ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate hydrogen chloride (Example 16A, Enantiomer 2, 52.0 g, 84.3 mmol) in THF was treated with N,N-diisopropylethylamine (59 ml, 340 mmol) and 2-methylpropanal [CAS No. 78-84-2] (38 ml, 420 mmol) and stirred 1 hour at room temperature. Sodium triacetoxyborohydride (71.5 g, 337 mmol) was then added and the resulting mixture was stirred 18 hours at room temperature. The reaction mixture was diluted with an aqueous solution of sodium hydrogen carbonate (10%) and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, petrol ether/ethyl acetate 8:2) affording 47 g (93% yield) of the title compound.

    [0817] LC-MS (Method 9): R.sub.t4=3.42 min; MS (ESIpos): m/z=600 [M+H].sup.+

    Example 18A

    1-(2-Methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

    [0818] ##STR00117##

    [0819] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (350 mg, 1.21 mmol) was placed in 7.4 ml THF and N,N-diisopropylethylamine (320 μl, 1.8 mmol) was added. Then 2-methylpropanal (440 μl, 4.9 mmol) was added and the mixture was stirred for 10 min. Then sodium triacetoxyborohydride (772 mg, 3.64 mmol) was added and the mixture was stirred at 55° C. for 4 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated, aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated. 342 mg of the target compound (79% of theory, purity 97%) were obtained.

    [0820] LC-MS (Method 3): R.sub.t=1.23 min; MS (ESIpos): m/z=345 [M+H].sup.+

    [0821] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.058 (0.55), 0.927 (4.09), 0.938 (4.13), 1.316 (16.00), 2.121 (0.98), 2.133 (0.89), 2.492 (0.99), 2.508 (0.99), 2.559 (2.25), 2.599 (2.62), 3.241 (1.07), 3.249 (1.38), 3.257 (0.98), 6.935 (1.05), 6.949 (1.07), 7.552 (1.15), 7.566 (1.07).

    Example 19A

    1-Propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

    [0822] ##STR00118##

    [0823] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (300 mg, 1.04 mmol) was placed in 6.4 ml of THF and N,N-diisopropylethylamine (270 ul, 1.6 mmol) was added. Propanal (242 mg, 4.16 mmol) was then added and the mixture was stirred for 10 min. Then sodium triacetoxyborohydride (662 mg, 3.12 mmol) was added and the mixture was stirred at 55° C. for 1.5 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The mixture was purified by means of silica gel chromatography (dichloromethane/methanol 100/1, then isocratic dichloromethane/methanol: 50/1). 186 mg of the target compound (53% of theory) were obtained.

    [0824] LC-MS (Method 6): R.sub.t=0.97 min; MS (ESIpos): m/z=331 [M+H].sup.+

    [0825] .sup.1H-NMR (500 MHz, DMSO-d6) δ[ppm]: 0.856 (1.10), 0.871 (2.41), 0.886 (1.18), 1.070 (6.41), 1.258 (16.00), 1.457 (0.59), 1.472 (0.58), 2.250 (0.49), 2.265 (0.64), 2.279 (0.45), 2.453 (0.86), 2.462 (1.15), 2.472 (0.89), 3.181 (0.94), 3.192 (1.13), 3.201 (0.86), 3.916 (1.09), 6.877 (1.01), 6.894 (1.02), 7.490 (1.17), 7.507 (1.04).

    Example 20A

    Ethyl 1-{1-[4-chloro-4′-(4-propylpiperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate trifluoroacetic acid adduct (Enantiomer 2)

    [0826] ##STR00119##

    [0827] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2, 90.0 mg, 169 μmol) and 1-propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (67.1 mg, 203 μmol) were placed under argon in toluene/ethanol (940 μl/940 μl), 2 M sodium carbonate solution (250 μl) and tetrakis(triphenylphosphine)palladium(0) (9.78 mg, 8.46 μmol) were added and the mixture was stirred at 100° C. overnight. Tetrakis(triphenylphosphine)palladium(0) (9.78 mg, 8.46 μmol) was added to the mixture, flushed with argon and stirred at 100° C. for 3 h. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was acidified with 1M hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with the addition of 0.10% trifluoroacetic acid). 43 mg of the target compound were obtained (36% of theory).

    [0828] LC-MS (Method 4): R.sub.t=2.07 min; MS (ESIpos): m/z=586 [M+H].sup.+

    Example 21A

    Ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 2)

    [0829] ##STR00120##

    [0830] A solution of tert-butyl 4-(4′-chloro-2′-{(3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Enantiomer 2, 60.0 g, 93.1 mmol) in dichloromethane (250 ml) was treated with a solution of hydrogen chloride in dioxane (230 ml, 4.0 M, 930 mmol). The resulting mixture was stirred 3 hours at room temperature and evaporated. The residue was co-evaporated twice with diethyl ether (250 ml×2), stirred 4 days in diisopropyl ether. The suspension was filtered, the solid was washed twice with diisopropyl ether affording 57 g (quant.) of the title compound.

    [0831] LC-MS (Method 4): R.sub.t=1.78 min; MS (ESIpos): m/z=544 [M+H].sup.+

    [0832] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.029 (13.49), 1.044 (13.77), 1.262 (7.53), 1.280 (16.00), 1.297 (7.81), 1.496 (0.79), 1.506 (0.62), 1.527 (0.91), 1.559 (0.40), 1.716 (1.24), 1.749 (0.95), 1.888 (0.84), 1.897 (0.78), 1.918 (0.98), 1.926 (0.93), 1.966 (1.38), 1.995 (0.69), 2.580 (1.54), 2.606 (0.83), 2.992 (1.21), 3.018 (2.69), 3.044 (2.33), 3.063 (1.24), 3.435 (5.96), 3.448 (7.25), 3.460 (5.00), 3.570 (5.78), 3.586 (0.87), 3.601 (1.12), 3.616 (0.85), 4.227 (5.38), 4.238 (6.62), 4.256 (9.26), 4.273 (7.97), 4.291 (2.70), 4.444 (0.41), 4.455 (0.77), 4.470 (0.89), 4.481 (1.31), 4.491 (0.92), 4.507 (0.68), 7.045 (6.02), 7.067 (6.86), 7.074 (5.10), 7.079 (5.42), 7.099 (2.25), 7.104 (1.49), 7.120 (3.55), 7.125 (3.10), 7.164 (6.27), 7.185 (3.37), 7.383 (1.62), 7.483 (6.90), 7.505 (6.40), 7.513 (3.75), 7.643 (1.34), 8.005 (5.77), 9.399 (1.97).

    Example 22A

    1-{1-[4-Chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid (Enantiomer 2)

    [0833] ##STR00121##

    [0834] An aqueous solution of lithium hydroxide (4.0 ml, 1.0 M, 4.0 mmol) was added to a solution of ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl) [1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 2, 281 mg, 82% purity, 396 μmol) in a THF/methanol mixture 10:1 (8.8 ml). The resulting mixture was stirred 2 hours at room temperature. The reaction mixture was acidified with an aqueous solution of hydrogen chloride (2 N) and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water gradient) affording 175 mg (86% yield) of the title compound.

    [0835] LC-MS (Method 3): R.sub.t4=0.83 min; MS (ESIpos): m/z=516 [M+H].sup.+

    Example 23A

    Tert-butyl 4-(2′-bromo-4′-chloro[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate

    [0836] ##STR00122##

    [0837] Under argon, a suspension of 2-bromo-4-chloro-1-iodobenzene (518 mg, 1.63 mmol), {4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}boronic acid (500 mg, 1.63 mmol), Pd(PPh.sub.3).sub.4 (94.4 mg, 81.7 μmol) was treated with an aqueous solution of sodium carbonate (2.4 ml, 2.0 M, 4.9 mmol) and heated overnight at 85° C. The reaction mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 390 mg (52% yield) of the title compound.

    [0838] LC-MS (Method 4): R.sub.t=2.82 min; MS (ESIpos): m/z=451 [M+H].sup.+

    [0839] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: −0.008 (0.43), 0.008 (0.47), 1.419 (1.16), 1.428 (16.00), 3.166 (0.88), 3.179 (1.25), 3.192 (1.05), 3.458 (0.93), 3.471 (1.13), 3.483 (0.78), 7.006 (1.04), 7.028 (1.24), 7.258 (1.42), 7.280 (1.16), 7.355 (0.92), 7.376 (1.19), 7.488 (0.68), 7.493 (0.69), 7.508 (0.50), 7.514 (0.52), 7.820 (1.11), 7.826 (1.09).

    Example 24A

    1-(2′-Bromo-4′-chloro[1,1′-biphenyl]-4-yl)piperazine hydrochloride

    [0840] ##STR00123##

    [0841] A solution of tert-butyl 4-(2′-bromo-4′-chloro[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (prepared in analogy to Example 46A, 664 mg, 1.47 mmol) in dichloromethane (8.0 ml) was treated with a solution of hydrogen chloride in dioxane (3.7 ml, 4.0 M, 15 mmol), stirred 2.5 hours and evaporated. The residue was triturated in diethyl ether. The solid was filtered off affording 602 mg (quant.) of the title compound.

    [0842] LC-MS (Method 4): R.sub.t=1.46 min; MS (ESIpos): m/z=351 [M+H].sup.+

    [0843] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.146 (0.66), 1.596 (1.27), 2.329 (0.80), 2.671 (0.82), 3.360 (1.28), 3.437 (12.88), 3.451 (14.96), 3.463 (10.26), 3.568 (1.96), 4.670 (3.35), 5.756 (2.57), 7.002 (0.87), 7.055 (12.43), 7.077 (14.87), 7.294 (16.00), 7.315 (12.89), 7.362 (11.21), 7.382 (14.09), 7.502 (7.29), 7.507 (7.43), 7.522 (5.26), 7.528 (5.74), 7.835 (12.20), 7.840 (11.66), 9.202 (2.59).

    Example 25A

    1-(2′-Bromo-4′-chloro[1,1′-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine

    [0844] ##STR00124##

    [0845] Under argon, a solution of 1-(2′-bromo-4′-chloro[1,1′-biphenyl]-4-yl)piperazine hydrochloride (600 mg, 1.55 mmol) in DMF (7.8 ml) was treated with N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (670 μl, 4.6 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate gradient) affording 536 mg (80% yield) of the title compound.

    [0846] LC-MS (Method 3): R.sub.t4=1.42 min; MS (ESIpos): m/z=433 [M+H].sup.+ (isotope 1) m/z=435 [M+H].sup.+ (isotope 2)

    [0847] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: −0.007 (1.98), 0.008 (2.22), 2.740 (0.98), 2.758 (11.29), 2.770 (14.79), 2.782 (12.18), 3.115 (0.79), 3.128 (0.89), 3.140 (0.72), 3.205 (12.89), 3.212 (13.88), 3.218 (16.00), 3.230 (12.50), 3.236 (11.79), 3.262 (9.39), 3.288 (3.13), 6.914 (0.51), 6.935 (0.60), 6.990 (11.06), 7.011 (13.08), 7.204 (0.54), 7.246 (13.70), 7.267 (11.56), 7.354 (8.19), 7.375 (10.92), 7.485 (5.59), 7.490 (5.77), 7.506 (4.15), 7.511 (4.36), 7.817 (7.70), 7.823 (7.57).

    Example 26A

    Ethyl 1-[1-{4-chloro-4′-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0848] ##STR00125##

    [0849] Under argon, a solution of 1-(2′-bromo-4′-chloro[1,1′-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine (150 mg, 346 μmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (Enantiomer 1, 94.5 mg, 346 μmol) in toluene (3.0 ml) was treated with caesium carbonate (282 mg, 865 μmol) and RuPhos Pd G3 (57.9 mg, 69.2 μmol) and stirred 16 hours at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered over celite and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water+0.5% formic acid gradient) affording 62.7 mg (29% yield) of the title compound.

    [0850] LC-MS (Method 3): R.sub.t=1.8 min; MS (ESIpos): m/z=626 [M+H].sup.+

    Example 27A

    Ethyl 1-[1-{4-chloro-4′-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0851] ##STR00126##

    [0852] Under argon, a solution of 1-(2′-bromo-4′-chloro[1,1′-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine (150 mg, 346 μmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (Enantiomer 2, 94.5 mg, 346 μmol) in toluene (3.0 ml) was treated with caesium carbonate (282 mg, 865 μmol) and RuPhos Pd G3 (57.9 mg, 69.2 μmol) and stirred 16 hours at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered over celite and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water+0.5% formic acid gradient) affording 66.6 mg (30% yield) of the title compound.

    [0853] LC-MS (Method 3): R.sub.t=1.58 min; MS (ESIpos): m/z=626 [M+H].sup.+

    Example 28A

    Tert-butyl 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (Racemate)

    [0854] ##STR00127##

    [0855] Tert-butyl 3-hydrazinopiperidine-1-carboxylate acetic acid (945 g, 3.43 mol) in ethanol (20 L) was treated with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (907 g, 3.78 mol). The resulting mixture was stirred 16 hours at 25° C., diluted with a saturated solution of sodium hydrogencarbonate (2.0 L) and concentrated to ˜5.0 L. The resulting mixture was diluted with water (5.0 L) and extracted with ethyl acetate (5.0 L). The organic phase was washed with a saturated solution of sodium chloride (5.0 L) and evaporated. The residue was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate, 10:1) affording 548 g (41% yield) of the title compound.

    [0856] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.90 (s, 1H), 4.33-3.09 (m, 5H), 3.26-3.12 (m, 1H), 2.89-2.61 (m, 1H), 2.35-2.05 (m, 2H), 1.98-1.78 (m, 1H), 1.71-1.51 (m, 1H), 1.50-1.37 (m, 9H), 1.32 (m, 3H)

    Example 29A

    Ethyl 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Racemate)

    [0857] ##STR00128##

    [0858] Tert-butyl 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (548 g, 1.40 mol) was treated with a solution of hydrogen chloride in dioxane (4 M, 2.38 L), stirred 2 hours at 25° C. and evaporated. The residue was retaken in 1.0 L water and extracted with MTBE (500 mL×1). The aqueous phase was separated and adjusted to pH to 8-9 with a saturated solution of sodium hydrogencarbonate. The aqueous phase was extracted with dichloromethane (1.0 L×2), and the combined organic layers were washed with a saturated solution of sodium chloride (1 L), dried over sodium sulfate and evaporated affording 325 g (80% yield) of the title compound.

    [0859] LC-MS: (Method 1) R.sub.t=0.955 min, MS (M+1)=299.2.

    [0860] The two enantiomers were separated by SFC [325 g, column: Phenomenex-Cellulose-2 (250 mm*50 mm, 10 μm); eluent: CO.sub.2/(methanol+0.1% aqueous ammonia); 75:25, 4.5 min; 1400 min] affording 103.0 g of enantiomer 1 (Example 5A) and 110.1 g of enantiomer 2 (Example 6A).

    Example 30A

    Ethyl 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0861] For separation conditions see Example 29A.

    [0862] Analytical SFC: R.sub.t=1.345 min, e.e. =99% [Column Cellulose 2-3: 50×4.6 mm; eluent: CO2/[methanol+0.5% diethyl amine]: 95:5 to 60:40 flow rate: 3.0 ml/min; temperature: 35° C.; UV detection: 220 nm, back pressure 100 bar].

    [0863] LCMS (Method 2), R.sub.t=0.906 min, MS (M+1)=292.1.

    [0864] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.89 (s, 1H), 4.50-4.47 (m, 1H), 4.31-4.25 (m, 2H), 3.24-3.05 (m, 4H), 2.70-2.67 (m, 1H), 2.10-2.02 (m, 2H), 1.92-1.79 (m, 1H), 1.74-1.56 (m, 1H), 1.31 (t, J=7.2 Hz, 3H).

    Example 31A

    Ethyl 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2)

    [0865] For separation conditions see Example 29A.

    [0866] Analytical SFC: R.sub.t=1.071 min, e.e. =99% [Column Cellulose 2-3: 50×4.6 mm; eluent: C.sub.02/[methanol+0.5% diethyl amine]: 95:5 to 60:40 flow rate: 3.0 ml/min; temperature: 35° C.; UV detection: 220 nm, back pressure 100 bar].

    [0867] LCMS (Method 2), R.sub.t=0.906 min, MS (M+1)=292.1.

    [0868] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ [ppm]: 7.91 (s, 1H), 4.58-4.41 (m, 1H), 4.35-4.23 (m, 2H), 3.70-3.56 (m, 1H), 3.31-3.12 (m, 2H), 3.11-3.02 (m, 1H), 2.75-2.62 (m, 1H), 2.15-2.02 (m, 2H), 1.92-1.79 (m, 1H), 1.74-1.56 (m, 1H), 1.33 (t, J=7.2 Hz, 3H).

    Example 32A

    Ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0869] ##STR00129##

    [0870] Under argon, a solution of ethyl 1-[piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 75.0 g, 257 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (84.4 g, 257 mmol) in 1,4-dioxane (1.1 l) was treated with Pd.sub.2dba.sub.3 (23.6 g, 25.7 mmol), rac-BINAP (32.1 g, 51.5 mmol) and cesium carbonate (252 g, 772 mmol). The resulting mixture was stirred 3 days at 100° C. and cooled to room temperature. The reaction mixture was diluted with an aqueous solution of sodium chloride (10%) and ethyl acetate, filtered over celite and rinsed with ethyl acetate. The aqueous phase of the filtrate was separated and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride (10%), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, dichloromethane/petrol ether gradient) affording 119 g (71% yield) of the title compound.

    [0871] LC-MS (Method 3): R.sub.t4=2.81 min; MS (ESIpos): m/z=538 [M+H].sup.+

    Example 33A

    Ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0872] ##STR00130##

    [0873] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 119 g, 221 mmol) in dichloromethane (1.8 l) was treated with trifluoroacetic acid (170 ml, 2.2 mol) and the resulting mixture was stirred 3 days at room temperature. Thre reaction mixture was quenched carefully with an aqueous solution of sodium hydrogenocarbonate (10%) until pH=8. The phases were separated. The organic layer was evaporated and the residue was purified by flash chromatography (silica gel, dichloromethane/petrol ether gradient) affording 85 g (90% purity, 92% yield) of the title compound.

    [0874] LC-MS (Method 3): R.sub.t4=2.47 min; MS (ESIpos): m/z=418 [M+H].sup.+

    Example 34A

    Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0875] ##STR00131##

    [0876] Under argon, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 85.0 g, 90% purity, 184 mmol) in dichloromethane (520 ml) was cooled to −50° C. and treated with triethylamine (77 ml, 550 mmol). Trifluoromethanesulfonic anhydride (43 ml, 260 mmol) was added dropwise to the reaction mixture and the resulting solution was stirred 1 hour at −50° C. The reaction mixture was diluted with dichloromethane (520 ml) and ice-cooled water (590 ml). The aqueous layer was extracted with dichloromethane (520 ml). The combined organice layers were washed once with ice-cooled water (590 ml), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, dichloromethane/petrol ether gradient) affording 94 g (93% yield) of the title compound.

    [0877] LC-MS (Method 3): R.sub.t=2.79 min; MS (ESIpos): m/z=550 [M+H].sup.+

    [0878] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.259 (7.63), 1.271 (16.00), 1.282 (7.94), 1.771 (0.45), 1.779 (0.80), 1.786 (0.61), 1.793 (0.61), 1.800 (0.94), 1.807 (0.61), 1.821 (0.45), 1.932 (1.22), 1.955 (0.96), 2.099 (0.77), 2.106 (0.73), 2.120 (1.04), 2.126 (1.33), 2.138 (1.91), 2.820 (0.73), 2.825 (0.87), 2.841 (1.56), 2.845 (1.61), 2.861 (0.93), 2.865 (0.82), 3.140 (1.18), 3.159 (1.09), 3.186 (1.39), 3.204 (2.87), 3.222 (1.78), 3.318 (1.51), 3.324 (1.60), 3.336 (1.08), 3.342 (1.04), 4.247 (2.31), 4.259 (7.26), 4.270 (7.27), 4.282 (2.41), 4.669 (0.70), 4.679 (0.84), 4.686 (1.34), 4.694 (0.96), 4.704 (0.72), 4.711 (0.42), 7.286 (2.29), 7.290 (2.44), 7.300 (2.89), 7.304 (3.11), 7.415 (5.01), 7.430 (4.13), 7.457 (5.11), 7.461 (5.05), 8.123 (6.61).

    Example 35A

    Tert-butyl 4-(4′-chloro-2′-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Enantiomer 1)

    [0879] ##STR00132##

    [0880] Under argon, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 92.1 g, 167 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (78.0 g, 201 mmol) in toluene (840 ml) and ethanol (840 ml) was treatd with an aqueous solution of sodium carbonate (250 ml, 2.0 M, 500 mmol) and Pd(PPh.sub.3).sub.4 (9.68 g, 8.37 mmol) and the resulting mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, filtered over celite, rinsed with ethyl acetate and evaporated. The residue was purified by flash chromatography (silica gel, petrol ether/ethyl acetate gradient) affording 94 g (85% yield) of the title compound.

    [0881] LC-MS (Method 3): R.sub.t=3.19 min; MS (ESIpos): m/z=662 [M+H].sup.+

    [0882] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: −0.008 (0.66), 0.008 (0.84), 1.038 (0.55), 1.088 (0.76), 1.232 (1.60), 1.250 (3.49), 1.268 (1.69), 1.419 (0.77), 1.431 (16.00), 1.989 (0.77), 2.957 (0.43), 3.127 (0.91), 3.140 (1.32), 3.152 (1.09), 3.457 (0.99), 3.470 (1.25), 3.481 (0.88), 4.211 (0.45), 4.228 (1.43), 4.246 (1.38), 4.264 (0.43), 6.985 (1.10), 7.007 (1.20), 7.068 (0.79), 7.073 (1.06), 7.089 (0.49), 7.109 (0.80), 7.114 (0.69), 7.146 (1.34), 7.166 (0.65), 7.433 (1.33), 7.455 (1.19), 8.062 (1.56).

    Example 36A

    Ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 1)

    [0883] ##STR00133##

    [0884] A solution of tert-butyl 4-(4′-chloro-2′-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Enantiomer 1, 93.0 g, 140 mmol) in dichloromethane (290 ml) was treated with a solution of hydrogen chloride in dioxane (350 ml, 4.0 M, 1.4 mol) and stirred 3 hours at room temperature. The reaction mixture was evaporated and the residue co-evaporated with MTBE affording 95 g (quant.) of the title compound which was used in the next step without further purification.

    [0885] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=562 [M+H].sup.+

    Example 37A

    Ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0886] ##STR00134##

    [0887] A solution of ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 1, 95.0 g, 150 mmol) in THF (1.8 l) was treated with N,N-diisopropylethylamine (100 ml, 600 mmol) and 2-methylpropanal [CAS No. 78-84-2] (53.9 g, 748 mmol) and stirred 1 hour at room temperature. Sodium triacetoxyborohydride (127 g, 598 mmol]) was added and the resulting mixture was stirred 18 hours at room temperature. The reaction mixture was diluted with an aqueous solution of sodium hydrogen carbonate (10%) and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (silica gel, petrol ether/ethyl acetate gradient) affording 78 g (84% yield) of the title compound.

    [0888] LC-MS (Method 3): R.sub.t=2.03 min; MS (ESIpos): m/z=618 [M+H].sup.+

    [0889] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.827 (0.53), 0.839 (0.55), 0.867 (0.66), 0.871 (0.81), 0.883 (15.73), 0.894 (16.00), 1.041 (0.92), 1.090 (1.35), 1.241 (4.62), 1.252 (9.48), 1.264 (4.77), 1.554 (0.58), 1.575 (0.64), 1.753 (0.80), 1.775 (0.81), 1.786 (0.63), 1.798 (0.90), 1.809 (1.08), 1.820 (0.88), 1.831 (0.48), 1.889 (0.64), 1.895 (0.58), 1.909 (0.66), 1.916 (0.63), 1.988 (0.94), 1.998 (0.79), 2.015 (0.59), 2.085 (4.57), 2.097 (4.16), 2.467 (3.65), 2.476 (5.06), 2.483 (4.05), 2.595 (0.61), 2.612 (1.08), 2.615 (1.10), 2.631 (0.59), 2.937 (0.86), 2.955 (1.65), 2.972 (0.98), 3.073 (0.84), 3.093 (0.80), 3.156 (3.65), 3.164 (4.72), 3.172 (3.66), 3.212 (0.97), 3.227 (0.83), 4.221 (1.39), 4.233 (4.19), 4.245 (4.15), 4.256 (1.41), 4.362 (0.49), 4.379 (0.85), 4.397 (0.49), 6.949 (3.70), 6.963 (3.93), 7.060 (2.66), 7.063 (3.31), 7.082 (1.52), 7.085 (1.15), 7.095 (2.12), 7.099 (1.92), 7.141 (3.61), 7.154 (2.29), 7.411 (4.15), 7.426 (3.95), 8.049 (4.51).

    Example 38A

    1-(Cyclopropylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

    [0890] ##STR00135##

    [0891] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (380 mg, 1.32 mmol) was dissolved in 8 ml THF and N,N-diisopropylethylamine (340 μl, 2.0 mmol) was added. Then cyclopropanecarbaldehyde (370 mg, 5.27 mmol) was added and the mixture was stirred for 10 min. Then sodium triacetoxyborohydride (838 mg, 3.96 mmol) was added and the mixture was stirred at 55° C. for 4 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 519 mg of the target compound (98% of theory, purity 85%) were obtained.

    [0892] LC-MS (Method 3): R.sub.t=1.18 min; MS (ESIpos): m/z=343 [M+H].sup.+

    [0893] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.089 (0.56), 0.096 (0.58), 0.471 (0.53), 0.483 (0.55), 1.158 (0.59), 1.175 (0.52), 1.259 (16.00), 1.989 (1.00), 3.210 (0.89), 3.216 (0.92), 3.226 (0.55), 6.885 (0.93), 6.900 (0.95), 7.494 (1.10), 7.509 (1.02).

    Example 39A

    Ethyl 1-[1-{4-chloro-4′-[4-(cyclopropylmethyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0894] ##STR00136##

    [0895] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 150 mg, 273 μmol) and 1-(cyclopropylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (112 mg, purity 85%, 278 μmol) were dissolved under argon in toluene/ethanol (1.5/1.5 ml). Tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 13.6 μmol) and 2 M sodium carbonate solution (410 μl, 820 μmol) were added and stirred at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic phase was then dried over sodium sulfate, filtered and evaporated. The residue was dissolved in acetonitrile and a few drops of water and purified by means of prep HPLC (RP18 column, acetonitrile/water gradient with addition of 0.1% TFA). 191 mg of the target compound as TFA adduct (810% of theory) were obtained.

    [0896] LC-MS (Method 3): R.sub.t=2.09 min; MS (ESIpos): m/z=616 [M+H].sup.+

    Example 40A

    1-{1-[4-Chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Enantiomer 1)

    [0897] ##STR00137##

    [0898] A solution of ethyl 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (Enantiomer 1, 290 mg, 516 μmol) in a THF/methanol mixture (10:1) (11 ml) was treated with an aqueous solution of lithium hydroxide (5.2 ml, 1.0 M, 5.2 mmol) and stirred 2.5 hours at room temperature. The reaction mixture was acidified with an aqueous solution of hydrogen chloride (2N) and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water gradient) affording 316 mg (73% yield) of the title compound.

    [0899] LC-MS (Method 3): R.sub.t=1.62 min; MS (ESIpos): m/z=534 [M+H].sup.+

    Example 41A

    2,2,2-trifluoroethyl 1-(1-{4-chloro-4′-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][biphenyl]-2-yl}piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1)

    [0900] ##STR00138##

    [0901] Under argon, a solution of 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Enantiomer 1, 100 mg, 187 μmol) in DMF (1.7 ml) was treated with N,N-diisopropylethylamine (100 μl, 580 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (81 μl, 560 μmol). The resulting mixture was stirred 2 hours at room temperature, acidified with formic acid and purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water+0.1% formic acid gradient) affording 88 mg (67% yield) of the title compound.

    [0902] LC-MS (Method 3): R.sub.t=3.01 min; MS (ESIpos): m/z=698 [M+H].sup.+

    Experimental Section—Example Compounds

    Example 1

    1-[1-{4-Chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 1)

    [0903] ##STR00139##

    [0904] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared in analogy to Example 11A, Enantiomer 1, 80.0 mg, 147 μmol) and 1-(2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18A 62.8 mg, 97% purity, 177 μmol) were placed under argon in toluene/ethanol (820/820 μl). 2 M sodium carbonate solution (220 μl, 2.0 M, 440 μmol) and tetrakis(triphenylphosphine)palladium(0) (8.52 mg, 7.37 μmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and 1 M hydrochloric acid was added. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried with sodium sulfate, filtered off and evaporated. The crude mixture was dissolved with THF/ethanol (2.0/0.2 ml), 1 M lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred at room temperature overnight. A 1 M lithium hydroxide solution (740 μl, 740 μmol) was added again. After about 6 h the reaction mixture was evaporated at 50° C. The residue was dissolved in acetonitrile/water/0.25 ml trifluoroacetic acid and purified by preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.10% trifluoroacetic acid). The crude product was purified by means of thick layer chromatography (dichloromethane/methanol/formic acid: 10/1/0.1). The silica gel mixture was stirred with dichloromethane/1 M hydrochloric acid in dioxane (10/1) in ethanol, filtered off and carefully evaporated at 30° C. and lyophilized. 34 mg of the target compound (36% of theory, purity 95%) were obtained.

    [0905] LC-MS (Method 6): R.sub.t=1.23 min; MS (ESIpos): m/z=572 [M−HCl+H].sup.+

    [0906] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 1.004 (15.87), 1.015 (16.00), 1.500 (0.51), 1.521 (0.57), 1.728 (0.73), 1.750 (0.61), 1.897 (0.57), 1.917 (0.62), 1.975 (0.79), 2.122 (0.42), 2.133 (0.84), 2.144 (1.02), 2.156 (0.79), 2.571 (0.47), 2.587 (0.91), 2.610 (0.52), 3.004 (0.84), 3.022 (2.01), 3.026 (2.20), 3.038 (3.72), 3.048 (2.50), 3.065 (0.75), 3.154 (2.66), 3.161 (2.75), 3.169 (2.36), 3.177 (1.88), 3.224 (0.84), 3.237 (0.70), 3.589 (1.41), 3.602 (1.80), 3.825 (1.02), 3.841 (0.78), 3.866 (1.05), 3.882 (0.75), 4.223 (2.57), 4.445 (0.68), 4.463 (0.97), 4.481 (0.57), 7.045 (0.55), 7.055 (3.63), 7.070 (3.72), 7.084 (2.72), 7.087 (3.09), 7.110 (1.47), 7.113 (1.11), 7.123 (2.19), 7.127 (2.02), 7.163 (3.67), 7.177 (2.19), 7.215 (0.46), 7.428 (0.83), 7.495 (4.24), 7.510 (4.02), 7.515 (2.07), 7.602 (0.82), 7.959 (4.79), 9.484 (0.54).

    Example 2

    1-[1-{4-Chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid (Enantiomer 2)

    [0907] ##STR00140##

    [0908] Method A

    [0909] A solution of ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared in analogy to Example 17A, Enantiomer 2, 50.8 g, 84.6 mmol) in a THF/methanol mixture 9:1 (1.01) was treated with an aqueous solution of lithium hydroxide (850 ml, 1.0 M, 850 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated, diluted with dichloromethane (1.5 l) and adjusted to pH=2 with an aqueous solution of hydrogen chloride (2N). The resulting suspension was stirred 45 minutes at room temperature. The solid was filtered, washed with water and dried under vacuum affording 43 g (90% yield) of the title compound.

    [0910] LC-MS (Method 7): R.sub.t=1.27 min; MS (ESIpos): m/z=572 [M+H].sup.+

    [0911] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 1.002 (15.68), 1.013 (16.00), 1.080 (0.57), 1.092 (1.18), 1.103 (0.63), 1.498 (0.74), 1.519 (0.83), 1.719 (1.03), 1.741 (0.88), 1.902 (0.78), 1.908 (0.74), 1.922 (0.88), 1.928 (0.83), 1.943 (0.45), 1.978 (1.13), 1.994 (0.74), 2.102 (0.71), 2.112 (0.85), 2.123 (0.70), 2.571 (1.40), 2.591 (0.77), 2.882 (1.10), 3.018 (1.27), 3.035 (3.01), 3.053 (2.14), 3.239 (2.40), 3.254 (2.32), 3.368 (1.13), 3.379 (1.40), 3.391 (1.33), 3.403 (0.92), 3.493 (0.76), 4.463 (0.65), 4.482 (1.12), 4.500 (0.62), 7.033 (4.22), 7.048 (4.45), 7.074 (3.47), 7.077 (4.04), 7.100 (1.85), 7.103 (1.52), 7.113 (2.53), 7.117 (2.34), 7.162 (4.18), 7.175 (2.71), 7.439 (1.03), 7.481 (4.88), 7.495 (4.57), 7.526 (2.04), 7.613 (0.91), 7.952 (5.28).

    [0912] Method B

    [0913] 1-{1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (prepared in analogy to Example 3, Enantiomer 2, 31.2 mg, 51.3 μmol) were dissolved in 17 ml of dichloromethane and 1 ml of methanol. The solution was shaken once with 1.5 ml of saturated, aqueous sodium bicarbonate solution. The phases were separated. 5 ml of dichloromethane and 3 ml of methanol were added to the organic phase. The organic phase was then dried over sodium sulfate, filtered, evaporated and purified by preparative HPLC (RP18 column, acetonitrile/water gradient, neutral without acid addition). Product fractions were combined and lyophilized. 22 mg of the target compound (74% of theory) were obtained.

    [0914] LC-MS (Method 3): R.sub.t=1.73 min; MS (ESIpos): m/z=572 [M+H].sup.+

    [0915] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.887 (15.60), 0.898 (16.00), 1.493 (0.64), 1.514 (0.70), 1.695 (0.89), 1.718 (0.74), 1.799 (0.48), 1.811 (0.88), 1.822 (1.12), 1.833 (0.92), 1.844 (0.48), 1.890 (0.68), 1.910 (0.74), 1.977 (0.93), 1.995 (0.62), 2.118 (3.91), 2.130 (3.66), 2.516 (5.14), 3.017 (1.09), 3.035 (2.76), 3.053 (1.94), 3.181 (5.03), 3.185 (5.02), 3.267 (1.53), 4.473 (0.55), 4.491 (0.96), 4.509 (0.54), 6.963 (3.96), 6.977 (4.06), 7.048 (3.13), 7.051 (3.31), 7.081 (1.60), 7.084 (1.26), 7.095 (2.21), 7.098 (1.89), 7.152 (3.52), 7.165 (2.42), 7.434 (4.45), 7.448 (4.50), 7.533 (1.51), 7.621 (0.67), 7.930 (4.14).

    Example 3

    1-{1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 2)

    [0916] ##STR00141##

    [0917] Method A

    [0918] A suspension of 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (prepared in analogy to Example 2, Enantiomer 2, 43.5 g, 76.0 mmol) in diethyl ether (870 ml) was treated with a solution of hydrogen chloride in diethyl ether (84 ml, 1.0 M, 84 mmol). The resulting mixture was stirred overnight at room temperature and evaporated affording 46.1 g (quant.) of the title compound.

    [0919] LC-MS (Method 3): R.sub.t=1.72 min; MS (ESIpos): m/z=572 [M+H].sup.+

    [0920] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 1.026 (15.64), 1.037 (16.00), 1.497 (0.56), 1.519 (0.61), 1.722 (0.78), 1.743 (0.65), 1.903 (0.59), 1.910 (0.53), 1.924 (0.66), 1.930 (0.61), 1.978 (0.82), 1.994 (0.50), 2.142 (0.45), 2.154 (0.91), 2.165 (1.11), 2.176 (0.89), 2.187 (0.45), 2.557 (0.64), 2.577 (1.02), 2.594 (0.55), 2.992 (1.81), 3.002 (2.77), 3.012 (1.87), 3.018 (1.15), 3.036 (2.40), 3.054 (1.60), 3.133 (1.12), 3.148 (1.19), 3.168 (0.53), 3.237 (0.88), 3.250 (0.76), 3.338 (0.81), 3.360 (1.42), 3.379 (0.88), 3.580 (1.61), 3.791 (0.89), 3.819 (1.25), 3.844 (0.81), 4.463 (0.89), 4.474 (0.97), 4.481 (1.26), 4.488 (0.99), 4.499 (0.88), 7.051 (3.56), 7.065 (3.77), 7.077 (2.72), 7.080 (3.14), 7.103 (1.42), 7.106 (1.13), 7.116 (2.00), 7.120 (1.84), 7.165 (3.40), 7.178 (2.22), 7.443 (0.84), 7.489 (4.04), 7.504 (3.79), 7.531 (1.66), 7.618 (0.72), 7.954 (4.33), 10.519 (0.49).

    [0921] Method B

    [0922] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared in analogy to Example 14A, Enantiomer 2, 80.0 mg, 150 μmol) and 1-(2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18A 64.1 mg, 97% purity, 180 μmol) were dissolved under argon in toluene/ethanol (0.83/0.83 ml). Tetrakis(triphenylphosphine)palladium(0) (8.69 mg, 7.52 μmol) and 2 M sodium carbonate solution (226 μl, 452 μmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was acidified with 1 M hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The crude product was dissolved in THF/ethanol (3.9/0.39 ml), 1 M aqueous lithium hydroxide solution (1.5 ml, 1.5 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, the residue was dissolved in acetonitrile/TFA/water and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. The residue was mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30° C. (twice) and then lyophilized. 53 mg of the target compound (55% of theory, purity 95%) were obtained.

    [0923] LC-MS (Method 4): R.sub.t=0.91 min; MS (ESIpos): m/z=572 [M−HCl+H].sup.+

    [0924] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.004 (15.46), 1.020 (16.00), 1.491 (0.44), 1.522 (0.50), 1.722 (0.68), 1.753 (0.55), 1.890 (0.47), 1.920 (0.55), 1.967 (0.84), 2.129 (0.76), 2.146 (0.96), 2.163 (0.76), 2.582 (0.91), 2.613 (0.48), 2.999 (0.86), 3.010 (1.71), 3.025 (3.88), 3.041 (2.30), 3.131 (0.88), 3.161 (1.25), 3.177 (2.08), 3.213 (1.75), 3.242 (1.16), 3.467 (1.06), 3.496 (0.84), 3.503 (0.60), 3.519 (0.54), 3.525 (0.50), 3.549 (0.75), 3.555 (0.84), 3.572 (1.57), 3.582 (1.48), 3.589 (1.38), 3.601 (2.78), 3.608 (1.89), 3.633 (0.44), 3.640 (0.41), 3.811 (0.94), 3.847 (1.32), 3.878 (0.71), 4.329 (0.49), 4.439 (0.46), 4.466 (0.73), 4.477 (0.52), 4.839 (0.49), 7.047 (3.30), 7.070 (3.64), 7.082 (2.61), 7.087 (3.29), 7.104 (1.46), 7.109 (0.86), 7.124 (2.34), 7.129 (2.03), 7.160 (3.99), 7.181 (1.96), 7.388 (0.88), 7.490 (4.02), 7.512 (3.81), 7.519 (2.20), 7.650 (0.72), 7.959 (3.78), 9.708 (0.41).

    [0925] [α].sub.D.sup.20=−73.05°, c=0.465 g/100 cm.sup.3, trichloromethane.

    [0926] Enantiomer 2 has an absolute configuration of R as shown in example 3A below.

    1-{3(R)-1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride

    Example 3A

    1-{3(R)-1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride Hemihydrate

    [0927] ##STR00142##

    [0928] 100 mg 1-{1-[4-Chloro-4′-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (Enantiomer 2) (example 3) were solved at 60° C. in 3.5 ml 2-propanol, wherein the 2-propanol was dosed portionwise in 100 μl-portions at 60° C. until a clear solution was obtained. Afterwards the vessel was closed with a septum and placed into a slowly cooling sand bath from 60° C. to room temperature over the weekend -> small amounts of solids were detected. Thereafter the septum was provided with a canula, in order to slowly let the solvent evaporate. After 4 weeks crystals were collected and inspected under a microscope.

    [0929] Single Crystal X-Ray Structure Analysis:

    [0930] The Crystal structure determination was carried out using a Bruker diffractometer (QS-no.: 02506) equipped with an Apex II-CCD area detector, an IμS-microsource with CuKa radiation, mirrors as monochromator and a Cryostream low temperature device (T=110 K). Fullsphere data collection, omega and phi scans.

    [0931] Programs used: Data collection and reduction Apex II v2014.11.0 (Bruker AXS, 2014), absorption correction/scaling SADABS. Crystal structure solution was achieved using direct methods as implemented in SHELXTL Version 6.14 (Bruker AXS, 2003) and visualized using XP program. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL Version 6.14 (Bruker AXS, 2003). All non hydrogen atoms were refined including anisotropic displacement parameters.

    TABLE-US-00003 Correct Inverted Chirality Check* structure structure Flack Parameter (standard deviation) 0.094 (0.009) 0.906 (0.009) wR2-value (with Flack Parameter) 0.2357 0.2522 Chirality R(C22) S(C22) *H. D. Flack, Acta Cryst., 1983, A39, 876-881 H. D. Flack, G. Bernardinelli, J. Appl. Cryst., 2000, 33, 1143-1148 S. Parsons, H. D. Flack, T. Wagner, Acta Cryst., 2013, B69, 249-259.

    TABLE-US-00004 TABLE 1 Crystal data and structure refinement for example 3A Identification code example 3A Empirical formula C60 H76 Cl4 F4 N10 O5 Formula weight 1235.10 Temperature 110 K Wavelength 1.54178 Å Crystal system Trigonal Space group P3.sub.221 Unit cell dimensions a = 9.8693(5) Å α = 90°. b = 9.8693(5) Å β = 90°. c = 54.159(3) Å γ = 120°. Volume 4568.5(5) Å.sup.3 Z 3 Density (calculated) 1.347 Mg/m.sup.3 Absorption coefficient 2.341 mm.sup.−1 F(000) 1950 Crystal size 0.14 × 0.10 × 0.06 mm.sup.3 Theta range for data collection 4.899 to 63.664°. Index ranges −11 ≤ h ≤ 10, −10 ≤ k ≤ 11, −62 ≤ l ≤ 61 Reflections collected 27868 Independent reflections 4640 [R(int) = 0.0378] Completeness to 95.9% theta = 63.664° Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.87 and 0.74 Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 4640/11/593 Goodness-of-fit on F.sup.2 1.047 Final R indices [I > 2sigma(I)] R1 = 0.0848, wR2 = 0.2336 R indices (all data) R1 = 0.0864, wR2 = 0.2357 Absolute structure parameter 0.094(9) Extinction coefficient n/a Largest diff. peak and hole 0.601 and −0.650 e.Math.Å.sup.−3

    TABLE-US-00005 TABLE 2 Bond lengths [Å] and angles [°] for example 3A. Cl(2)—C(3) 1.767(13) O(1′)—C(29′) 1.17(2) Cl(2′)—C(3′) 1.772(13) O(2′)—C(29′) 1.36(2) F(1)—C(30) 1.341(7)  O(2′)—H(2B) 0.8400 F(2)—C(30) 1.339(7)  N(1)—C(10) 1.416(9)  F(1′)—C(30′) 1.339(7)  N(1)—C(16) 1.434(12) F(2′)—C(30′) 1.38(2) N(1)—C(13) 1.470(10) O(1)—C(29) 1.22(2) N(2)—C(14) 1.497(9)  O(2)—C(29) 1.30(2) N(2)—C(15) 1.498(9)  O(2)—H(2A)    0.8400 N(2)—C(17) 1.512(8)  N(2)—H(2C)    1.0000 C(8)—C(9) 1.378(13) N(3)—C(25) 1.46(2) C(8)—H(8A)    0.9500 N(3)—C(21) 1.46(5) C(9)—C(10) 1.390(15) N(3)—C(1) 1.47(3) C(9)—H(9A)    0.9500 N(4)—C(26) 1.30(3) C(10)—C(11) 1.390(16) N(4)—N(5) 1.32(3) C(11)—C(12) 1.391(11) N(4)—C(22) 1.47(2) C(11)—H(11A)    0.9500 N(5)—C(28) 1.37(2) C(12)—H(12A)    0.9500 N(3′)—C(1′) 1.38(3) C(13)—C(14) 1.524(10) N(3′)—C(21′) 1.44(4) C(13)—H(13A)    0.9900 N(3′)—C(25′) 1.46(2) C(13)—H(13B)    0.9900 N(4′)—N(5′) 1.38(3) C(14)—H(14A)    0.9900 N(4′)—C(26′) 1.42(3) C(14)—H(14B)    0.9900 N(4′)—C(22′) 1.46(2) C(15)—C(16) 1.519(10) N(5′)—C(28′) 1.32(2) C(15)—H(15A)    0.9900 C(1)—C(6) 1.35(3) C(15)—H(15B)    0.9900 C(1)—C(2) 1.42(4) C(16)—H(16A)    0.9900 C(2)—C(3) 1.37(3) C(16)—H(16B)    0.9900 C(2)—H(2D)    0.9500 C(17)—C(18) 1.499(10) C(3)—C(4) 1.33(2) C(17)—H(17A)    0.9900 C(4)—C(5) 1.390(19) C(17)—H(17B)    0.9900 C(4)—H(4A)    0.9500 C(18)—C(20) 1.509(11) C(5)—C(6) 1.41(2) C(18)—C(19) 1.538(10) C(5)—H(5A)    0.9500 C(18)—H(18A)    1.0000 C(6)—C(7) 1.506(17) C(19)—H(19A)    0.9800 C(7)—C(8) 1.36(2) C(19)—H(19B)    0.9800 C(7)—C(12) 1.382(19) C(19)—H(19C)    0.9800 C(7)—C(6′) 1.58(2) C(20)—H(20A)    0.9800 C(20)—H(20B)    0.9800 C(4′)—C(5′) 1.392(19) C(20)—H(20C)    0.9800 C(4′)—H(4B)    0.9500 C(21)—C(22) 1.541(7)  C(5′)—C(6′) 1.40(2) C(21)—H(21A)    0.9900 C(5′)—H(5B)    0.9500 C(21)—H(21B)    0.9900 C(21′)—C(22′) 1.59(2) C(22)—C(23) 1.56(2) C(21′)—H(21C)    0.9900 C(22)—H(22A)    1.0000 C(21′)—H(21D)    0.9900 C(23)—C(24) 1.52(3) C(22′)—C(23′) 1.52(2) C(23)—H(23A)    0.9900 C(22′)—H(22B)    1.0000 C(23)—H(23B)    0.9900 C(23′)—C(24′) 1.52(2) C(24)—C(25) 1.52(2) C(23′)—H(23C)    0.9900 C(24)—H(24A)    0.9900 C(23′)—H(23D)    0.9900 C(24)—H(24B)    0.9900 C(24′)—C(25′) 1.55(2) C(25)—H(25A)    0.9900 C(24′)—H(24C)    0.9900 C(25)—H(25B)    0.9900 C(24′)—H(24D)    0.9900 C(26)—C(27) 1.42(2) C(25′)—H(25C)    0.9900 C(26)—C(30) 1.500(7)  C(25′)—H(25D)    0.9900 C(27)—C(28) 1.34(3) C(26′)—C(27′) 1.35(3) C(27)—C(29) 1.50(3) C(26′)—C(30′) 1.46(3) C(28)—H(28A)    0.9500 C(27′)—C(28′) 1.41(2) C(30)—H(30A)    1.0000 C(27′)—C(29′) 1.50(3) C(1′)—C(2′) 1.39(3) C(28′)—H(28B)    0.9500 C(1′)—C(6′) 1.42(2) C(30′)—H(30B)    1.0000 C(2′)—C(3′) 1.39(3) O(1W)—H(1W)    0.9010 C(2′)—H(2E)    0.9500 O(1W)—H(1W)#1    0.9010 C(3′)—C(4′) 1.36(2) C(29)—O(2)—H(2A) 109.5 C(29′)—O(2′)—H(2B) 109.5 C(10)—N(1)—C(16) 117.9(8)  C(1)—C(2)—H(2D) 120.8 C(10)—N(1)—C(13) 113.5(6)  C(4)—C(3)—C(2) 123.8(15) C(16)—N(1)—C(13) 109.6(5)  C(4)—C(3)—Cl(2) 120.9(12) C(14)—N(2)—C(15) 109.2(5)  C(2)—C(3)—Cl(2) 115.1(14) C(14)—N(2)—C(17) 108.8(5)  C(3)—C(4)—C(5) 117.5(14) C(15)—N(2)—C(17) 113.0(5)  C(3)—C(4)—H(4A) 121.3 C(14)—N(2)—H(2C) 108.6 C(5)—C(4)—H(4A) 121.3 C(15)—N(2)—H(2C) 108.6 C(4)—C(5)—C(6) 121.0(15) C(17)—N(2)—H(2C) 108.6 C(4)—C(5)—H(5A) 119.5 C(25)—N(3)—C(21)  107(2) C(6)—C(5)—H(5A) 119.5 C(25)—N(3)—C(1) 116.5(18) C(1)—C(6)—C(5) 119.5(15) C(21)—N(3)—C(1) 112.2(18) C(1)—C(6)—C(7) 112.0(17) C(26)—N(4)—N(5)  113(2) C(5)—C(6)—C(7) 128.4(16) C(26)—N(4)—C(22)  127(2) C(8)—C(7)—C(12) 115.2(8)  N(5)—N(4)—C(22)  120(2) C(8)—C(7)—C(6) 109.3(13) N(4)—N(5)—C(28)  104(2) C(12)—C(7)—C(6) 135.5(15) C(1′)—N(3′)—C(21′) 112.1(19) C(8)—C(7)—C(6′) 136.3(13) C(1′)—N(3′)—C(25′) 117.2(19) C(12)—C(7)—C(6′) 108.4(14) C(21′)—N(3′)—C(25′) 119.2(19) C(7)—C(8)—C(9) 124.1(12) N(5′)—N(4′)—C(26′)  109(2) C(7)—C(8)—H(8A) 118.0 N(5′)—N(4′)—C(22′) 118.1(15) C(9)—C(8)—H(8A) 118.0 C(26′)—N(4′)—C(22′)  128(2) C(8)—C(9)—C(10) 120.2(13) C(28′)—N(5′)—N(4′) 106.9(15) C(8)—C(9)—H(9A) 119.9 C(6)—C(1)—C(2)  119(2) C(10)—C(9)—H(9A) 119.9 C(6)—C(1)—N(3) 120.5(18) C(9)—C(10)—C(11) 117.3(8)  C(2)—C(1)—N(3)  120(2) C(9)—C(10)—N(1) 121.7(10) C(3)—C(2)—C(1) 118.4(19) C(11)—C(10)—N(1) 120.9(9)  C(3)—C(2)—H(2D) 120.8 C(10)—C(11)—C(12) 120.2(11) C(10)—C(11)—H(11A) 119.9 H(16A)—C(16)—H(16B) 107.9 C(12)—C(11)—H(11A) 119.9 C(18)—C(17)—N(2) 115.7(5)  C(7)—C(12)—C(11) 123.0(13) C(18)—C(17)—H(17A) 108.4 C(7)—C(12)—H(12A) 118.5 N(2)—C(17)—H(17A) 108.4 C(11)—C(12)—H(12A) 118.5 C(18)—C(17)—H(17B) 108.4 N(1)—C(13)—C(14) 110.8(6)  N(2)—C(17)—H(17B) 108.4 N(1)—C(13)—H(13A) 109.5 H(17A)—C(17)—H(17B) 107.4 C(14)—C(13)—H(13A) 109.5 C(17)—C(18)—C(20) 114.1(6)  N(1)—C(13)—H(13B) 109.5 C(17)—C(18)—C(19) 108.2(6)  C(14)—C(13)—H(13B) 109.5 C(20)—C(18)—C(19) 110.6(6)  H(13A)—C(13)—H(13B) 108.1 C(17)—C(18)—H(18A) 107.9 N(2)—C(14)—C(13) 110.7(6)  C(20)—C(18)—H(18A) 107.9 N(2)—C(14)—H(14A) 109.5 C(19)—C(18)—H(18A) 107.9 C(13)—C(14)—H(14A) 109.5 C(18)—C(19)—H(19A) 109.5 N(2)—C(14)—H(14B) 109.5 C(18)—C(19)—H(19B) 109.5 C(13)—C(14)—H(14B) 109.5 H(19A)—C(19)—H(19B) 109.5 H(14A)—C(14)—H(14B) 108.1 C(18)—C(19)—H(19C) 109.5 N(2)—C(15)—C(16) 110.4(6)  H(19A)—C(19)—H(19C) 109.5 N(2)—C(15)—H(15A) 109.6 H(19B)—C(19)—H(19C) 109.5 C(16)—C(15)—H(15A) 109.6 C(18)—C(20)—H(20A) 109.5 N(2)—C(15)—H(15B) 109.6 C(18)—C(20)—H(20B) 109.5 C(16)—C(15)—H(15B) 109.6 H(20A)—C(20)—H(20B) 109.5 H(15A)—C(15)—H(15B) 108.1 C(18)—C(20)—H(20C) 109.5 N(1)—C(16)—C(15) 112.1(7)  H(20A)—C(20)—H(20C) 109.5 N(1)—C(16)—H(16A) 109.2 H(20B)—C(20)—H(20C) 109.5 C(15)—C(16)—H(16A) 109.2 N(3)—C(21)—C(22)  106(3) N(1)—C(16)—H(16B) 109.2 N(3)—C(21)—H(21A) 110.4 C(15)—C(16)—H(16B) 109.2 C(22)—C(21)—H(21A) 110.4 N(3)—C(21)—H(21B) 110.4 N(4)—C(26)—C(30)  124(2) C(22)—C(21)—H(21B) 110.4 C(27)—C(26)—C(30) 127.8(16) H(21A)—C(21)—H(21B) 108.6 C(28)—C(27)—C(26) 102.7(18) N(4)—C(22)—C(21)  110(2) C(28)—C(27)—C(29)  133(2) N(4)—C(22)—C(23) 106.8(16) C(26)—C(27)—C(29) 124.0(19) C(21)—C(22)—C(23)  105(2) C(27)—C(28)—N(5) 112.9(19) N(4)—C(22)—H(22A) 111.7 C(27)—C(28)—H(28A) 123.6 C(21)—C(22)—H(22A) 111.7 N(5)—C(28)—H(28A) 123.6 C(23)—C(22)—H(22A) 111.7 O(1)—C(29)—O(2)  123(2) C(24)—C(23)—C(22) 108.9(13) O(1)—C(29)—C(27) 125.0(19) C(24)—C(23)—H(23A) 109.9 O(2)—C(29)—C(27)  112(2) C(22)—C(23)—H(23A) 109.9 F(2)—C(30)—F(1) 104.4(13) C(24)—C(23)—H(23B) 109.9 F(2)—C(30)—C(26) 112.1(18) C(22)—C(23)—H(23B) 109.9 F(1)—C(30)—C(26) 110.6(17) H(23A)—C(23)—H(23B) 108.3 F(2)—C(30)—H(30A) 109.9 C(23)—C(24)—C(25) 112.6(13) F(1)—C(30)—H(30A) 109.9 C(23)—C(24)—H(24A) 109.1 C(26)—C(30)—H(30A) 109.9 C(25)—C(24)—H(24A) 109.1 N(3′)—C(1′)—C(2′) 119.2(17) C(23)—C(24)—H(24B) 109.1 N(3′)—C(1′)—C(6′) 120.3(18) C(25)—C(24)—H(24B) 109.1 C(2′)—C(1′)—C(6′)  120(2) H(24A)—C(24)—H(24B) 107.8 C(1′)—C(2′)—C(3′) 118.4(18) N(3)—C(25)—C(24) 107.3(15) C(1′)—C(2′)—H(2E) 120.8 N(3)—C(25)—H(25A) 110.3 C(3′)—C(2′)—H(2E) 120.8 C(24)—C(25)—H(25A) 110.3 C(4′)—C(3′)—C(2′) 125.1(15) N(3)—C(25)—H(25B) 110.3 C(4′)—C(3′)—Cl(2′) 118.0(12) C(24)—C(25)—H(25B) 110.3 C(2′)—C(3′)—Cl(2′) 116.8(12) H(25A)—C(25)—H(25B) 108.5 C(3′)—C(4′)—C(5′) 114.4(13) N(4)—C(26)—C(27) 107.8(18) C(3′)—C(4′)—H(4B) 122.8 C(5′)—C(4′)—H(4B) 122.8 C(23′)—C(24′)—H(24D) 108.8 C(4′)—C(5′)—C(6′) 125.3(14) C(25′)—C(24′)—H(24D) 108.8 C(4′)—C(5′)—H(5B) 117.3 H(24C)—C(24′)—H(24D) 107.7 C(6′)—C(5′)—H(5B) 117.3 N(3′)—C(25′)—C(24′) 106.9(15) C(5′)—C(6′)—C(1′) 116.2(16) N(3′)—C(25′)—H(25C) 110.3 C(5′)—C(6′)—C(7) 109.8(15) C(24′)—C(25′)—H(25C) 110.3 C(1′)—C(6′)—C(7) 131.7(15) N(3′)—C(25′)—H(25D) 110.3 N(3′)—C(21′)—C(22′)  109(2) C(24′)—C(25′)—H(25D) 110.3 N(3′)—C(21′)—H(21C) 109.9 H(25C)—C(25′)—H(25D) 108.6 C(22′)—C(21′)—H(21C) 109.9 C(27′)—C(26′)—N(4′) 105.4(19) N(3′)—C(21′)—H(21D) 109.9 C(27′)—C(26′)—C(30′) 134.7(19) C(22′)—C(21′)—H(21D) 109.9 N(4′)—C(26′)—C(30′)  120(3) H(21C)—C(21′)—H(21D) 108.3 C(26′)—C(27′)—C(28′) 108.0(15) N(4′)—C(22′)—C(23′) 108.7(16) C(26′)—C(27′)—C(29′) 128.4(19) N(4′)—C(22′)—C(21′) 111.0(16) C(28′)—C(27′)—C(29′) 123.1(17) C(23′)—C(22′)—C(21′) 117.6(19) N(5′)—C(28′)—C(27′) 110.3(16) N(4′)—C(22′)—H(22B) 106.3 N(5′)—C(28′)—H(28B) 124.8 C(23′)—C(22′)—H(22B) 106.3 C(27′)—C(28′)—H(28B) 124.8 C(21′)—C(22′)—H(22B) 106.3 O(1′)—C(29′)—O(2′) 126.1(19) C(22′)—C(23′)—C(24′) 107.4(15) O(1′)—C(29′)—C(27′) 124.4(16) C(22′)—C(23′)—H(23C) 110.2 O(2′)—C(29′)—C(27′) 109.4(19) C(24′)—C(23′)—H(23C) 110.2 F(1′)—C(30′)—F(2′) 107.3(18) C(22′)—C(23′)—H(23D) 110.2 F(1′)—C(30′)—C(26′) 111.2(19) C(24′)—C(23′)—H(23D) 110.2 F(2′)—C(30′)—C(26′) 112.0(17) H(23C)—C(23′)—H(23D) 108.5 F(1′)—C(30′)—H(30B) 108.7 C(23′)—C(24′)—C(25′) 114.0(14) F(2′)—C(30′)—H(30B) 108.7 C(23′)—C(24′)—H(24C) 108.8 C(26′)—C(30′)—H(30B) 108.7 C(25′)—C(24′)—H(24C) 108.8 H(1W)—O(1W)—H(1W)#1 107.2

    [0932] Symmetry transformations used to generate equivalent atoms: #1 y−1,x+1,−z+1

    TABLE-US-00006 TABLE 3 Torsion angles [°] for example 3A C(26)—N(4)—N(5)—C(28)   4(2) C(12)—C(7)—C(8)—C(9)  2.5(13) C(22)—N(4)—N(5)—C(28) −173.4(17)  C(6)—C(7)—C(8)—C(9) −178.9(9)  C(26′)—N(4′)—N(5′)—C(28′)   0(2) C(6′)—C(7)—C(8)—C(9) 178.8(11) C(22′)—N(4′)—N(5′)—C(28′) −157.8(16)  C(7)—C(8)—C(9)—C(10)  −1.1(13) C(25)—N(3)—C(1)—C(6) 148.8(17) C(8)—C(9)—C(10)—C(11)  −1.0(11) C(21)—N(3)—C(1)—C(6)  −87(3) C(8)—C(9)—C(10)—N(1) −179.4(7)  C(25)—N(3)—C(1)—C(2)  −25(3) C(16)—N(1)—C(10)—C(9) −176.9(7)  C(21)—N(3)—C(1)—C(2) .sup. 99(3) C(13)—N(1)—C(10)—C(9) −46.9(9)  C(6)—C(1)—C(2)—C(3)   9(3) C(16)—N(1)—C(10)—C(11)  4.8(10) N(3)—C(1)—C(2)—C(3) −177.2(18)  C(1)—C(2)—C(3)—C(4) .sup. −7(3) C(13)—N(1)—C(10)—C(11) 134.9(8)  C(1)—C(2)—C(3)—C1(2) 178.6(14) C(9)—C(10)—C(11)—C(12)  1.5(12) C(2)—C(3)—C(4)—C(5)   5(3) N(1)—C(10)—C(11)—C(12) 179.9(7)  Cl(2)—C(3)—C(4)—C(5) 178.8(12) C(8)—C(7)—C(12)—C(11)  −1.9(13) C(3)—C(4)—C(5)—C(6) .sup. −4(2) C(6)—C(7)—C(12)—C(11) 179.9(11) C(2)—C(1)—C(6)—C(5) .sup. −8(3) C(6′)—C(7)—C(12)—C(11) −179.2(10)  N(3)—C(1)—C(6)—C(5) 178.0(16) C(10)—C(11)—C(12)—C(7)  0.0(14) C(2)—C(1)—C(6)—C(7) 169.6(16) C(10)—N(1)—C(13)—C(14) 167.0(7)  N(3)—C(1)—C(6)—C(7) .sup. −5(2) C(16)—N(1)—C(13)—C(14) −58.8(8)  C(4)—C(5)—C(6)—C(1)   6(2) C(15)—N(2)—C(14)—C(13) −55.6(7)  C(4)—C(5)—C(6)—C(7) −171.3(14)  C(17)—N(2)—C(14)—C(13) −179.3(6)  C(1)—C(6)—C(7)—C(8) 148.5(14) N(1)—C(13)—C(14)—N(2) 57.9(8) C(5)—C(6)—C(7)—C(8) −34.4(18) C(14)—N(2)—C(15)—C(16) 55.1(8) C(1)—C(6)—C(7)—C(12) −33.3(19) C(17)—N(2)—C(15)—C(16) 176.4(6)  C(5)—C(6)—C(7)—C(12) 143.8(15) C(10)—N(1)—C(16)—C(15) −168.9(6)  C(13)—N(1)—C(16)—C(15) 59.3(7) C(30)—C(26)—C(27)—C(29)   2(3) N(2)—C(15)—C(16)—N(1) −58.4(8)  C(26)—C(27)—C(28)—N(5)   2(2) C(14)—N(2)—C(17)—C(18) 178.4(6)  C(29)—C(27)—C(28)—N(5) 176.9(18) C(15)—N(2)—C(17)—C(18) 56.9(8) N(4)—N(5)—C(28)—C(27)  −3.6(19) N(2)—C(17)—C(18)—C(20) 58.0(8) C(28)—C(27)—C(29)—O(1) 146.4(19) N(2)—C(17)—C(18)—C(19) −178.5(6)  C(26)—C(27)—C(29)—O(1)  −39(3) C(25)—N(3)—C(21)—C(22)  −75(3) C(28)—C(27)—C(29)—O(2)  −31(3) C(1)—N(3)—C(21)—C(22)  156(2) C(26)—C(27)—C(29)—O(2)  143(2) C(26)—N(4)—C(22)—C(21)  131(3) N(4)—C(26)—C(30)—F(2) .sup. 53(2) N(5)—N(4)—C(22)—C(21)  −52(3) C(27)—C(26)—C(30)—F(2) −124(2)  C(26)—N(4)—C(22)—C(23) −116(2)  N(4)—C(26)—C(30)—F(1)  −63(2) N(5)—N(4)—C(22)—C(23) .sup. 61(2) C(27)—C(26)—C(30)—F(1)  120(2) N(3)—C(21)—C(22)—N(4) −177(2)  C(21′)—N(3′)—C(1′)—C(2′)  112(2) N(3)—C(21)—C(22)—C(23) .sup. 68(3) C(25′)—N(3′)—C(1′)—C(2′)  −31(3) N(4)—C(22)—C(23)—C(24) −173.8(14)  C(21′)—N(3′)—C(1′)—C(6′)  −71(2) C(21)—C(22)—C(23)—C(24)  −57(2) C(25′)—N(3′)—C(1′)—C(6′) 146.4(17) C(22)—C(23)—C(24)—C(25)  53.5(18) N(3′)—C(1′)—C(2′)—C(3′) 180.0(19) C(21)—N(3)—C(25)—C(24) .sup. 67(2) C(6′)—C(1′)—C(2′)—C(3′)   3(3) C(1)—N(3)—C(25)—C(24) −166.6(17)  C(1′)—C(2′)—C(3′)—C(4′)   2(3) C(1′)—C(2′)—C(3′)—Cl(2′) 179.1(15) C(23)—C(24)—C(25)—N(3) −56.8(19) C(2′)—C(3′)—C(4′)—C(5′) .sup. −4(3) N(5)—N(4)—C(26)—C(27) .sup. −3(2) Cl(2′)—C(3′)—C(4′)—C(5′) 179.0(12) C(22)—N(4)—C(26)—C(27) 174.2(19) C(3′)—C(4′)—C(5′)—C(6′)   1(2) N(5)—N(4)—C(26)—C(30) 179.8(15) C(4′)—C(5′)—C(6′)—C(1′)   4(3) C(22)—N(4)—C(26)—C(30) .sup. −3(3) C(4′)—C(5′)—C(6′)—C(7) 168.4(15) N(4)—C(26)—C(27)—C(28)   1(2) N(3′)—C(1′)—C(6′)—C(5′) 177.6(19) C(30)—C(26)—C(27)—C(28) 177.7(15) C(2′)—C(1′)—C(6′)—C(5′) .sup. −5(3) N(4)—C(26)—C(27)—C(29) −175.0(16)  N(3′)—C(1′)—C(6′)—C(7) .sup. 17(3) C(2′)—C(1′)—C(6′)—C(7) −166.3(19)  N(5′)—N(4′)—C(26′)—C(27′) .sup. −1(2) C(8)—C(7)—C(6′)—C(5′) −39.2(19) C(22′)—N(4′)—C(26′)—C(27′)  154(2) C(12)—C(7)—C(6′)—C(5′) 137.2(12) N(5′)—N(4′)—C(26′)—C(30′) −176.3(16)  C(8)—C(7)—C(6′)—C(1′) 122.5(19) C(22′)—N(4′)—C(26′)—C(30′)  −21(3) C(12)—C(7)—C(6′)—C(1′)  −61(2) N(4′)—C(26′)—C(27′)—C(28′)  1.2(19) C(1′)—N(3′)—C(21′)—C(22′) 168.4(18) C(30′)—C(26′)—C(27′)—C(28′) 175.6(19) C(25′)—N(3′)—C(21′)—C(22′)  −49(3) N(4′)—C(26′)—C(27′)—C(29′) −171.1(16)  N(5′)—N(4′)—C(22′)—C(23′) .sup. 65(2) C(30′)—C(26′)—C(27′)—C(29′)   3(3) C(26′)—N(4′)—C(22′)—C(23′)  −88(3) N(4′)—N(5′)—C(28′)—C(27′)   1(2) N(5′)—N(4′)—C(22′)—C(21′)  −66(3) C(26′)—C(27′)—C(28′)—N(5′) .sup. −1(2) C(26′)—N(4′)—C(22′)—C(21′)  141(2) C(29′)—C(27′)—C(28′)—N(5′) 171.6(15) N(3′)—C(21′)—C(22′)—N(4′) 169.0(19) C(26′)—C(27′)—C(29′)—O(1′) 162.9(18) N(3′)—C(21′)—C(22′)—C(23′) .sup. 43(3) C(28′)—C(27′)—C(29′)—O(1′) .sup. −8(3) N(4′)—C(22′)—C(23′)—C(24′) −173.4(15)  C(26′)—C(27′)—C(29′)—O(2′)  −21(2) C(21′)—C(22′)—C(23′)—C(24′)  −46(2) C(28′)—C(27′)—C(29′)—O(2′) 167.6(16) C(22′)—C(23′)—C(24′)—C(25′) .sup. 55(2) C(27′)—C(26′)—C(30′)—F(1′)  132(2) C(1′)—N(3′)—C(25′)—C(24′) −161.9(18)  N(4′)—C(26′)—C(30′)—F(1′)  −54(2) C(21′)—N(3′)—C(25′)—C(24′) .sup. 58(2) C(27′)—C(26′)—C(30′)—F(2′) −108(2)  C(23′)—C(24′)—C(25′)—N(3′)  −59(2) N(4′)—C(26′)—C(30′)—F(2′) .sup. 66(2)

    [0933] Symmetry transformations used to generate equivalent atoms: #1 y−1,x+1,−z+1

    TABLE-US-00007 TABLE 4 Hydrogen bonds for example 3A [Å and °]. D—H d(D—H) d(H . . . A) <DHA d(D . . . A) A O2{circumflex over ( )}a—H2A{circumflex over ( )}a 0.840 2.268 171.52 3.102 Cl1 [x + 1, y − 1, z] O2′{circumflex over ( )}b—H2B{circumflex over ( )}b 0.840 2.219 158.79 3.018 Cl1 [x + 1, y − 1, z] N2—H2C 1.000 2.158 162.74 3.128 Cl1 [y, x, −z + 1] O1W—H1W 0.901 2.448 164.20 3.324 Cl1

    [0934] FIG. 6: Ortep-Plot (50%) with labeling scheme (without disorder), example 3A

    [0935] FIG. 7: Independent molecules in the asymmetric unit (with disorder), example 3A

    [0936] FIG. 8: Configuration of C22, example 3A

    Example 4

    1-{1-[4-Chloro-4′-(4-propylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 2)

    [0937] ##STR00143##

    [0938] Ethyl 1-{1-[4-chloro-4′-(4-propylpiperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 2, 97.0 mg, 139 μmol) was dissolved in THF/ethanol (1.9/0.19 ml). 1 M aqueous lithium hydroxide solution (1.4 ml, 1.4 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, then acidified and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. Then the residue was mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30° C. (twice) and then lyophilized. 68 mg of the target compound (82% of theory) were obtained.

    [0939] LC-MS (Method 4): R.sub.t=1.72 min; MS (ESIpos): m/z=558 [M−HCl+H].sup.+

    [0940] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.927 (7.59), 0.940 (16.00), 0.952 (7.89), 1.474 (0.44), 1.496 (1.25), 1.517 (1.37), 1.538 (0.56), 1.719 (1.74), 1.741 (1.49), 1.753 (0.97), 1.766 (2.44), 1.779 (3.67), 1.786 (2.49), 1.793 (3.59), 1.806 (2.32), 1.818 (0.65), 1.880 (0.45), 1.886 (0.49), 1.900 (1.35), 1.906 (1.24), 1.921 (1.45), 1.927 (1.37), 1.942 (0.70), 1.977 (1.87), 1.992 (1.13), 2.572 (2.30), 2.592 (1.22), 3.016 (2.00), 3.034 (5.57), 3.052 (5.43), 3.058 (5.00), 3.077 (3.34), 3.086 (2.24), 3.115 (2.60), 3.130 (2.85), 3.150 (1.37), 3.215 (1.95), 3.548 (4.23), 3.569 (5.69), 3.827 (2.12), 3.851 (3.24), 3.876 (1.87), 4.023 (0.52), 4.329 (0.46), 4.459 (1.32), 4.470 (1.47), 4.477 (2.13), 4.484 (1.51), 4.495 (1.26), 4.842 (0.83), 7.053 (8.27), 7.068 (8.76), 7.076 (6.37), 7.079 (6.96), 7.102 (3.18), 7.105 (2.52), 7.115 (4.43), 7.119 (3.97), 7.165 (7.58), 7.179 (4.92), 7.443 (1.92), 7.486 (9.24), 7.500 (8.36), 7.530 (3.79), 7.618 (1.70), 7.952 (9.70), 11.078 (0.84).

    Example 5

    1-(1-{4-Chloro-4′-[4-(cyclopropylmethyl)piperazin-1-yl][biphenyl]-2-yl}piperidin-3-yl)-5-(difluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 2)

    [0941] ##STR00144##

    [0942] A solution of 1-{1-[4-chloro-4′-(piperazin-1-yl)[1,1′-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (Enantiomer 2, 175 mg, 339 μmol) in acetonitrile (3.1 ml) was treated with cyclopropanecarboxaldehyde (180 μl, 2.4 mmol) and sodium triacetoxyborohydride (216 mg, 1.02 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with water and purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water gradient) and evaporated. The residue was stirred in an aqeuous solution of hydrogen chloride and lyophilized affording 193 mg (94% yield) of the title compound.

    [0943] LC-MS (Method 4): R.sub.t=1.71 min; MS (ESIpos): m/z=570 [M−HCl+H].sup.+

    [0944] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.008 (3.75), 0.404 (1.78), 0.416 (7.42), 0.428 (7.54), 0.441 (2.23), 0.667 (5.71), 0.687 (6.02), 1.163 (1.94), 1.492 (1.30), 1.524 (1.42), 1.721 (2.07), 1.754 (1.58), 1.889 (1.40), 1.918 (1.60), 1.969 (2.29), 2.329 (0.68), 2.368 (0.70), 2.584 (2.75), 2.613 (1.40), 2.672 (0.72), 2.712 (0.80), 2.999 (2.19), 3.026 (4.93), 3.053 (7.20), 3.069 (7.86), 3.161 (7.98), 3.216 (2.87), 3.242 (2.05), 3.629 (14.26), 3.644 (16.00), 3.864 (4.63), 3.893 (4.81), 3.919 (3.11), 4.440 (1.32), 4.468 (2.19), 4.494 (1.18), 7.054 (9.40), 7.076 (11.45), 7.081 (9.08), 7.086 (9.54), 7.103 (3.93), 7.124 (6.28), 7.128 (5.61), 7.163 (11.39), 7.183 (5.71), 7.394 (2.53), 7.490 (11.05), 7.512 (10.19), 7.525 (5.19), 7.655 (2.09), 7.958 (11.99), 10.563 (0.64).

    Example 6

    1-[1-[5-Chloro-2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(difluoromethyl)pyrazole-4-carboxylic Acid (Enantiomer 1)

    [0945] ##STR00145##

    [0946] An aqueous solution of lithium hydroxide (1.0 ml, 1.0 M, 1.0 mmol) was added to a solution of ethyl 1-[1-[5-chloro-2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(difluoromethyl)pyrazole-4-carboxylate (Enantiomer 1, 62.7 mg, 100 μmol) in a THF/Methanol mixture (10:1, 2.2 mL). The reaction mixture was stirred overnight at room temperature. An aqeuous solution of hydrogen chloride (6N) was then added and the resulting mixture was extracted with dichloromethane. The combined organic layers were evaporated affording 57.9 mg (90% purity, 93% yield) of the title compound.

    [0947] LC-MS (Method 4): R.sub.t=2.68 min; MS (ESIpos): m/z=598 [M+H].sup.+

    [0948] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.886 (0.89), 1.117 (0.75), 1.128 (1.08), 1.170 (2.21), 1.183 (0.78), 1.237 (0.99), 1.271 (0.42), 1.356 (1.93), 1.489 (1.60), 1.520 (1.83), 1.700 (2.49), 1.743 (5.12), 1.752 (5.38), 1.760 (12.17), 1.769 (5.24), 1.776 (4.32), 1.794 (0.56), 1.864 (0.59), 1.885 (1.74), 1.916 (2.02), 1.978 (2.75), 2.329 (0.70), 2.367 (0.92), 2.578 (2.44), 2.671 (0.96), 2.711 (1.13), 2.810 (13.27), 3.005 (2.68), 3.032 (7.52), 3.058 (5.17), 3.262 (4.51), 3.283 (4.75), 3.310 (4.28), 3.585 (8.11), 3.601 (15.55), 3.618 (10.01), 4.459 (1.48), 4.486 (2.61), 4.513 (1.41), 5.754 (12.15), 7.002 (6.93), 7.024 (7.45), 7.059 (8.88), 7.064 (10.57), 7.086 (4.82), 7.091 (3.41), 7.107 (7.47), 7.112 (6.51), 7.155 (12.55), 7.175 (6.93), 7.387 (3.10), 7.452 (12.64), 7.473 (11.21), 7.518 (5.80), 7.649 (2.54), 7.954 (16.00).

    Example 7

    1-[1-[5-Chloro-2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(difluoromethyl)pyrazole-4-carboxylic Acid (Enantiomer 2)

    [0949] ##STR00146##

    [0950] An aqueous solution of lithium hydroxide (1.1 ml, 1.0 M, 1.1 mmol) was added to a solution of ethyl 1-[1-[5-chloro-2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(difluoromethyl)pyrazole-4-carboxylate (Enantiomer 2, 66.6 mg, 106 μmol) in a THF/Methanol mixture (10:1, 2.2 mL). The reaction mixture was stirred overnight at RT. An aqueous solution of hydrogen chloride (6N) was then added and the resulting mixture was extracted with dichloromethane. The combined organic layers were evaporated affording 54.7 mg (90% purity, 77% yield) of the title compound.

    [0951] LC-MS (Method 4): R.sub.t=2.67 min; MS (ESIpos): m/z=598 [M+H].sup.+

    [0952] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.886 (0.65), 0.948 (0.41), 1.092 (0.48), 1.107 (0.60), 1.116 (1.02), 1.128 (0.84), 1.169 (2.79), 1.183 (1.08), 1.236 (0.93), 1.271 (0.60), 1.356 (1.02), 1.489 (1.77), 1.521 (2.07), 1.700 (2.77), 1.743 (5.62), 1.751 (5.95), 1.760 (12.78), 1.768 (5.69), 1.776 (4.73), 1.794 (0.61), 1.864 (0.69), 1.885 (1.93), 1.916 (2.20), 1.978 (3.01), 1.988 (2.81), 2.328 (0.80), 2.367 (0.80), 2.580 (2.29), 2.670 (1.00), 2.711 (0.89), 2.823 (13.80), 3.004 (2.83), 3.031 (7.94), 3.057 (5.49), 3.260 (4.30), 3.301 (4.33), 3.325 (4.15), 3.585 (5.71), 3.601 (12.71), 3.618 (6.10), 3.731 (4.95), 4.021 (0.52), 4.038 (0.47), 4.457 (1.62), 4.484 (2.81), 4.511 (1.47), 5.754 (11.96), 7.013 (6.70), 7.034 (7.14), 7.061 (9.75), 7.066 (11.52), 7.088 (5.10), 7.093 (3.57), 7.108 (7.87), 7.113 (6.81), 7.156 (13.10), 7.176 (7.16), 7.387 (3.31), 7.456 (13.47), 7.477 (11.85), 7.518 (6.20), 7.649 (2.72), 7.954 (16.00).

    Example 8

    1-[1-{4-Chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid (Enantiomer 1)

    [0953] ##STR00147##

    [0954] An aqueous solution of lithium hydroxide (1.21, 1.0 M, 1.2 mol) was added to a solution of ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 77.0 g, 125 mmol) in a THF/methanol mixture (9:1) (1.5 l). The resulting mixture was stirred overnight at room temperature and acidified to pH-2 with an aqueous solution of hydrogen chloride (2N). The reaction mixture was diluted with dichloromethane. The organic layer was washed with water and evaporated affording 74 g (quant.) of the title compound which was used in the next step without further purification.

    [0955] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=590 [M+H].sup.+

    [0956] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.830 (0.48), 0.841 (0.49), 1.009 (16.00), 1.020 (16.00), 1.045 (0.89), 1.094 (1.29), 1.187 (0.45), 1.363 (0.58), 1.528 (0.64), 1.549 (0.68), 1.750 (2.54), 1.755 (2.82), 1.760 (5.81), 1.766 (2.92), 1.771 (2.27), 1.919 (0.75), 1.926 (0.61), 1.940 (0.72), 1.946 (0.67), 2.003 (0.92), 2.019 (0.59), 2.105 (0.70), 2.117 (0.84), 2.128 (0.67), 2.579 (0.64), 2.863 (1.29), 2.981 (1.01), 2.998 (1.83), 3.016 (1.09), 3.051 (1.01), 3.069 (0.93), 3.216 (1.08), 3.238 (1.70), 3.256 (1.35), 3.573 (0.51), 3.594 (2.25), 3.604 (4.74), 3.615 (1.96), 4.383 (0.57), 4.394 (0.64), 4.400 (0.96), 4.407 (0.64), 4.418 (0.51), 7.033 (4.04), 7.048 (4.15), 7.082 (3.12), 7.085 (3.80), 7.099 (1.74), 7.102 (1.19), 7.113 (2.42), 7.116 (2.08), 7.155 (4.12), 7.168 (2.53), 7.473 (4.69), 7.488 (4.22), 8.020 (5.33).

    Example 9

    1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 1)

    [0957] ##STR00148##

    [0958] Method A

    [0959] A solution of 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Enantiomer 1, 78.0 g, 132 mmol) in diethyl ether (1.5 1) was treated with a solution of hydrogen chloride in diethyl ether (150 ml, 150 mmol). The resulting mixture was stirred overnight at room temperature and evaporated affording 82 g (quant.) of the title compound.

    [0960] LC-MS (Method 3): R.sub.t=1.77 min; MS (ESIpos): m/z=590 [M−HCl+H].sup.+

    [0961] .sup.1H-NMR (400 MHz, DMSO-d6) δ[ppm]: −0.839 (0.40), 1.013 (0.67), 1.029 (15.68), 1.039 (16.00), 1.057 (0.67), 1.081 (1.77), 1.092 (3.56), 1.104 (1.68), 1.360 (0.54), 1.520 (0.54), 1.540 (0.60), 1.741 (0.73), 1.750 (0.52), 1.761 (0.83), 1.921 (0.56), 1.927 (0.52), 1.941 (0.61), 1.947 (0.58), 2.004 (0.77), 2.020 (0.52), 2.147 (0.46), 2.158 (0.88), 2.169 (1.10), 2.180 (0.89), 2.192 (0.47), 2.578 (0.57), 2.984 (0.91), 2.995 (1.90), 3.004 (3.37), 3.016 (1.95), 3.044 (0.88), 3.062 (0.77), 3.119 (0.77), 3.125 (0.78), 3.135 (1.02), 3.145 (0.85), 3.151 (0.86), 3.244 (0.80), 3.258 (0.71), 3.361 (1.04), 3.368 (0.87), 3.380 (3.28), 3.391 (1.89), 3.403 (1.41), 3.570 (1.41), 3.589 (1.33), 3.603 (0.52), 3.785 (0.79), 3.814 (0.99), 3.838 (0.75), 4.383 (0.46), 4.394 (0.53), 4.400 (0.79), 4.407 (0.55), 4.418 (0.46), 7.055 (3.42), 7.070 (3.66), 7.085 (2.44), 7.089 (3.02), 7.105 (1.54), 7.108 (1.13), 7.118 (2.11), 7.121 (1.92), 7.157 (3.63), 7.171 (2.19), 7.485 (3.98), 7.500 (3.68), 8.023 (4.23), 10.650 (0.49).

    [0962] Method B

    [0963] Ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 149 mg, 241 μmol) was dissolved in THF/ethanol (6.3/0.63 ml). 1 M aqueous lithium hydroxide solution (2.4 ml, 2.4 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, then acidified and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. Then the residue was dissolved in acetonitrile, mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30° C. (thrice) and then lyophilized. 130 mg of the target compound (85% of theory) were obtained.

    [0964] LC-MS (Method 3): R.sub.t=1.81 min; MS (ESIpos): m/z=590 [M−HCl+H].sup.+

    [0965] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 1.014 (15.69), 1.025 (16.00), 1.522 (0.64), 1.543 (0.70), 1.747 (0.89), 1.769 (0.75), 1.916 (0.67), 1.935 (0.74), 2.003 (0.95), 2.020 (0.62), 2.133 (0.48), 2.144 (0.96), 2.155 (1.17), 2.166 (0.94), 2.177 (0.49), 2.588 (0.65), 2.605 (1.20), 2.624 (0.66), 2.968 (0.93), 2.986 (1.83), 3.006 (2.63), 3.017 (3.24), 3.027 (1.95), 3.052 (1.01), 3.070 (0.94), 3.115 (0.97), 3.133 (1.36), 3.148 (1.12), 3.230 (1.08), 3.251 (1.98), 3.273 (2.05), 3.292 (1.01), 3.578 (1.97), 3.597 (1.82), 3.800 (1.79), 3.823 (2.21), 3.841 (2.82), 4.367 (0.59), 4.385 (1.02), 4.403 (0.56), 7.051 (3.88), 7.065 (4.03), 7.092 (3.43), 7.110 (1.41), 7.123 (2.32), 7.155 (3.64), 7.169 (1.99), 7.486 (4.35), 7.501 (3.97), 8.028 (4.91), 10.135 (0.55).

    Example 10

    1-[1-[5-Chloro-2-[4-[4-(cyclopropylmethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(trifluoromethyl)pyrazole-4-carboxylic Acid Hydrochloride (Enantiomer 1)

    [0966] ##STR00149##

    [0967] Ethyl 1-[1-{4-chloro-4′-[4-(cyclopropylmethyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate trifluoroacetic acid (Enantiomer 1, 161 mg, 221 μmol) was dissolved in THF/ethanol (6.8/0.68 ml). 1 M aqueous lithium hydroxide solution (2.6 ml, 2.6 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was evaporated, then acidified and purified using preparative HPLC (RP18 column, acetonitrile/water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. Then the residue was dissolved in acetonitrile, mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30° C. (thrice) and then lyophilized. 134 mg of the target compound (97% of theory) were obtained.

    [0968] LC-MS (Method 3): R.sub.t=1.82 min; MS (ESIpos): m/z=588 [M−HCl+H].sup.+

    [0969] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 0.426 (11.09), 0.434 (11.21), 0.443 (2.91), 0.665 (9.10), 0.678 (9.20), 0.687 (2.36), 1.161 (1.39), 1.169 (2.49), 1.173 (2.48), 1.181 (3.33), 1.193 (2.23), 1.522 (2.23), 1.543 (2.37), 1.565 (0.99), 1.746 (3.16), 1.767 (2.56), 1.903 (0.93), 1.917 (2.39), 1.937 (2.58), 1.957 (1.13), 2.003 (3.29), 2.021 (2.11), 2.585 (2.13), 2.602 (3.93), 2.621 (2.20), 2.972 (3.14), 2.990 (5.91), 3.008 (3.45), 3.054 (9.53), 3.065 (12.33), 3.074 (8.23), 3.131 (3.14), 3.149 (4.65), 3.164 (4.39), 3.184 (7.56), 3.205 (7.92), 3.228 (5.44), 3.248 (3.11), 3.649 (6.16), 3.857 (3.86), 3.878 (3.65), 3.892 (4.10), 3.912 (3.42), 4.373 (2.27), 4.391 (3.67), 4.408 (2.14), 4.718 (2.01), 7.060 (13.16), 7.075 (13.71), 7.092 (11.58), 7.109 (4.98), 7.123 (7.67), 7.158 (11.82), 7.172 (6.72), 7.488 (14.54), 7.502 (13.17), 8.029 (16.00), 10.907 (2.16).

    Example 11

    1-[1-[5-Chloro-2-[4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]phenyl]-3-piperidyl]-5-(trifluoromethyl)pyrazole-4-carboxylic Acid (Enantiomer 1)

    [0970] ##STR00150##

    [0971] An aqueous solution of lithium hydroxide (1.3 ml, 1.0 M, 1.3 mmol) was added to a solution of 2,2,2-trifluoroethyl 1-(1-{4-chloro-4′-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][biphenyl]-2-yl}piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Enantiomer 1, 88.0 mg, 126 μmol) in a THF/methanol mixture (10/1, 2.5 ml). The resulting mixture was stirred 2 hours at room temperature. The reaction mixture was acidified with an aqueous solution of hydrogen chloride (2 N), evaporated and purified by preparative HPLC (RP18 column, eluent: Acetonitrile/water gradient) affording 73.0 mg (93% yield) of the title compound.

    [0972] LC-MS (Method 3): R.sub.t=2.71 min; MS (ESIpos): m/z=616 [M+H].sup.+

    [0973] .sup.1H-NMR (600 MHz, DMSO-d6) δ[ppm]: 1.233 (0.40), 1.356 (7.08), 1.522 (0.63), 1.543 (1.76), 1.563 (1.88), 1.585 (0.83), 1.747 (2.39), 1.768 (2.00), 1.879 (0.71), 1.892 (1.90), 1.898 (1.75), 1.913 (1.92), 1.919 (1.86), 1.934 (0.90), 1.995 (2.40), 2.012 (1.64), 2.183 (1.02), 2.386 (0.47), 2.425 (0.46), 2.588 (1.81), 2.608 (3.38), 2.624 (1.77), 2.654 (0.50), 2.763 (11.02), 2.771 (16.00), 2.779 (11.98), 2.937 (2.72), 2.955 (5.21), 2.973 (3.04), 3.067 (2.64), 3.086 (2.38), 3.175 (10.75), 3.182 (13.42), 3.185 (13.56), 3.192 (10.16), 3.212 (3.33), 3.224 (5.64), 3.241 (8.96), 3.258 (8.54), 3.275 (3.26), 4.353 (1.52), 4.370 (2.62), 4.388 (1.43), 6.871 (0.68), 6.971 (12.63), 6.986 (12.93), 7.067 (9.07), 7.071 (10.95), 7.090 (5.19), 7.094 (3.70), 7.104 (7.44), 7.107 (6.37), 7.147 (12.95), 7.160 (7.73), 7.429 (14.45), 7.443 (12.97), 8.005 (13.58), 13.136 (0.44).

    Comparative Example 174 (WO2012/058132)

    1-{1-[4-Chloro-4′-(4-cyclopropylmethylpiperazin-1-yl)[biphenyl]-2-yl]pyridin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

    [0974] ##STR00151##

    [0975] The compound was synthesized according to the procedures disclosed in WO 2012/058132 (experimental part, pages 58 to 84).

    [0976] B. Assessment of Pharmacological Efficacy and Pharmacokinetic Profile

    [0977] The following abbreviations are used: [0978] ATP adenosine triphosphate [0979] Brij35 polyoxyethylene(23) lauryl ether [0980] BSA bovine serum albumin: [0981] DTT dithiothreitol [0982] TEA triethanolamine

    [0983] Biological Investigations

    [0984] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

    [0985] The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.

    [0986] Examples were tested in selected biological assays one or more times. When tested more than once, data are

    reported as either average values or as median values, wherein [0987] the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and [0988] the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

    [0989] Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values calculated utilizing data sets obtained from testing of one or more synthetic batch.

    [0990] The in vitro activity of the compounds of the present invention can be demonstrated in the following assays.

    [0991] The pharmacological action of the compounds of the invention can be demonstrated in the following assays:

    [0992] B-1. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

    [0993] The cellular activity of the compounds according to the invention was determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

    [0994] Representative MEC values (MEC=minimum effective concentration) and EC.sub.50 values (half maximal effective concentration) for the compounds of the invention are shown in the table below (in some cases as mean values from individual determinations):

    TABLE-US-00008 TABLE 2 Example MEC [nM] EC.sub.50 [nM] 1 2.3 9.2 2 1.0 8.6 3 0.6 2.7 4 0.3 3.2 5 <0.3 3.6 6 1.6 19.3 7 1.6 13.7 8 6.5 40 9 2.2 11.0 10 2.0 10.3 11 0.6 5.2

    [0995] B-2. Determination of Pharmacokinetic Parameters Following Intravenous and Oral Administration

    [0996] The pharmacokinetic parameters of the compounds according to the invention were determined in male Wistar rats and and/or in female beagles and/or in cynomolgus monkeys and/or in male CD-1 mice. Intravenous administration in the case of mice and rats was carried out by means of a species-specific plasma/DMSO formulation, and in the case of dogs and monkeys by means of a water/PEG400/ethanol formulation. In all species, oral administration of the dissolved substance was performed via gavage, based on a water/PEG400/ethanol formulation.

    [0997] An internal standard (which may also be a chemically unrelated substance) was added to the samples of the compounds of the invention, calibration samples and qualifiers, and there followed protein precipitation by means of acetonitrile in excess. Addition of a buffer solution matched to the LC conditions, and subsequent vortexing, was followed by centrifugation at 1000 g. The supernatant was analysed by LC-MS/MS using C18 reversed-phase columns and variable mobile phase mixtures. The substances were quantified via the peak heights or areas from extracted ion chromatograms of specific selected ion monitoring experiments.

    [0998] The plasma concentration/time plots determined were used to calculate the pharmacokinetic parameters such as AUC, C.sub.max, t.sub.1/2 (terminal half-life), F (bioavailability), MRT (mean residence time) and CL (clearance), by means of a validated pharmacokinetic calculation program.

    [0999] Since the substance quantification was performed in plasma, it was necessary to determine the blood/plasma distribution of the substance in order to be able to adjust the pharmacokinetic parameters correspondingly. For this purpose, a defined amount of substance was incubated in K3 EDTA whole blood of the species in question in a rocking roller mixer for 20 min. After centrifugation at 1000 g, the plasma concentration was measured (by means of LC-MS/MS; see above) and determined by calculating the ratio of the C.sub.blood/C.sub.plasma value.

    [1000] Table 3 shows data of representative compounds of the present invention following intravenous administration in rats:

    TABLE-US-00009 TABLE 3 AUCnorm CLplasma t½ MRT Example [kg .Math. h/L] [L/h/kg] [h] [h] 1 1.77 0.56 1.64 2.24 2 7.08 0.14 3.13 3.44 4 1.40 0.72 2.09 2.62 5 1.23 0.81 2.43 2.88 6 2.29 0.44 5.13 4.16 7 7.23 0.14 3.83 4.41 9 5.48 0.18 4.10 5.83 10 1.37 0.73 1.89 2.39 174 (WO2012/ 0.77 1.30 2.33 2.78 058132)

    [1001] Table 4 shows data of representative compounds of the present invention following oral administration (p.o.) in rats:

    TABLE-US-00010 TABLE 4 AUCnorm t½ MRT F Example [kg .Math. h/L] [h] [h] [%] 1 0.57 3.24 6.28 31.4 2 3.77 3.96 6.23 53.3 4 0.84 3.02 5.91 59.9 5 0.70 3.76 7.53 58.2 6 2.11 7.37 14.2 91.7 7 4.04 3.63 7.32 56.1 9 4.50 4.96 8.51 82.1 10 0.52 3.41 4.04 37.4 174 (WO2012/ 0.63 3.60 8.40 81.8 058132)

    [1002] Table 5 shows data of representative compounds of the present invention following intravenous administration (i.v.) in dogs:

    TABLE-US-00011 TABLE 5 AUCnorm CLplasma t½ MRT Example [kg .Math. h/L] [L/h/kg] [h] [h] 2 81.7 0.01 17.7 25.6 9 37.4 0.03 7.86 10.3 174 (WO2012/ 5.00 0.20 10.8 7.23 058132)

    [1003] Table 6 shows data of representative compounds of the present invention following oral administration (p.o.) in dogs:

    TABLE-US-00012 TABLE 6 AUCnorm t½ MRT F Example [kg .Math. h/L] [h] [h] [%] 2 67.7 14.0 21.3 82.8 9 31.7 9.28 13.7 84.8 174 (WO2012/ 2.08 7.05 6.10 41.6 058132)

    [1004] The compounds according to the present invention show low plasma clearance (CLplasma) in all tested species, e.g. examples 2 and 9 show lower CL.sub.plasma (up to 10 times) and therefore much higher exposure (AUCnorm) in comparison to the compounds disclosed in the prior art, e.g. example 174 (WO2012/058132) in rats as well as in dogs (see tables 3 and 5). Examples 2 and 9 also show long half-life and mean residence time (MRT) in all tested species after p.o. (per oral) application (see tables 4 and 6). Due to the lower plasma clearance (CLplasma) of examples 2 and 9 and the resulting higher exposure (AUC.sub.norm) with good bioavailability after p.o. application in all tested species, examples 2 and 9 show superior pharmacokinetic properties versus the compounds disclosed in the prior art, e.g. example 174 (WO2012/058132).

    [1005] B-3. Metabolic Study

    [1006] To determine the metabolic profile of the inventive compounds, they were incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or primary fresh hepatocytes from various animal species (e.g. rats, dogs), and also of human origin, in order to obtain and to compare information about a very substantially complete hepatic phase I and phase II metabolism, and about the enzymes involved in the metabolism.

    [1007] The compounds of the invention were incubated with a concentration of about 0.1-10 μM. To this end, stock solutions of the compounds of the invention having a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1:100 dilution into the incubation mixture. The liver microsomes and recombinant enzymes were incubated at 37° C. in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP.sup.+, 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase. Primary hepatocytes were incubated in suspension in Williams E medium, likewise at 37° C. After an incubation time of 0-4 h, the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15 000×g. The samples thus stopped were either analyzed directly or stored at −20° C. until analysis.

    [1008] The analysis was carried out by high-performance liquid chromatography with ultraviolet and mass spectrometry detection (HPLC-UV-MS/MS). To this end, the supernatants of the incubation samples were chromatographed with suitable C18 reversed-phase columns and variable mobile phase mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid. The UV chromatograms in conjunction with mass spectrometry data serve for identification, structural elucidation and quantitative estimation of the metabolites, and for quantitative metabolic reduction of the compound of the invention in the incubation mixtures.

    [1009] B-4. Caco-2 Permeability Test

    [1010] The permeability of a test substance was determined with the aid of the Caco-2 cell line, an established in vitro model for permeability prediction at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. 175 (3), 880-885). The Caco-2 cells (ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were sown in 24-well plates having an insert and cultivated for 14 to 16 days. For the permeability studies, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco/Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES). In order to determine the apical to basolateral permeability (P.sub.appA-B) of the test substance, the solution comprising the test substance was applied to the apical side of the Caco-2 cell monolayer, and transport buffer to the basolateral side. In order to determine the basolateral to apical permeability (P.sub.appB-A) of the test substance, the solution comprising the test substance was applied to the basolateral side of the Caco-2 cell monolayer, and transport buffer to the apical side. At the start of the experiment, samples were taken from the respective donor compartment in order to ensure the mass balance. After an incubation time of two hours at 37° C., samples were taken from the two compartments. The samples were analyzed by means of LC-MS/MS and the apparent permeability coefficients (P.sub.app) were calculated. For each cell monolayer, the permeability of Lucifer Yellow was determined to ensure cell layer integrity. In each test run, the permeability of atenolol (marker for low permeability) and sulfasalazine (marker for active excretion) was also determined as quality control.

    [1011] B-5. Solubility Determination of Substances in Buffer pH 6.5

    [1012] 2-4 mg of the test compound were dissolved in DMSO to reach a concentration of 50 g/L (solution A, 515 μg/l). To 10 μl of this solution 960 μl PBS buffer pH 6.5 were added; the mixture was shaken for 24 h at rt in a 96 well plate. An aliquot was centrifuged at 42000 rpm for 30 min. The supernatant was diluted with ACN/water (8:2) 1:10 and 1:1000 resp. This diluted samples were analyzed by LC-MSMS.

    [1013] Calibration: 10 μl of solution A were diluted with 823 μl DMSO (final concentration: 600 μg/ml), which was further diluted with ACN/water 8:2 by a factor of 100 (solution B).

    [1014] The calibration curve was obtained from solution B by further diluting with ACN/water 8:2 with target concentrations of 1.2-12-60-600 ng/ml and injecting these four solutions for MS measurement.

    [1015] MS Method Optimization:

    [1016] Solution B was utilized for MS method optimization.

    [1017] PBS-Puffer: 6.18 g sodium chloride and 3.96 g sodium dihydrogen phosphate were dissolved in 1 L aqua dist., the pH was adjusted to 6.5 with 1N sodium hydroxide.

    [1018] LC-MSMS Optimization:

    [1019] The following configurations were used for optimization

    [1020] AB Sciex TRIPLE QUAD 4500, Agilent 1260 Infinity (G1312B), degasser (G4225A), column oven (G1316C or G1316A), CTC Analytics PAL injection system HTS-xt or HTC-xt.

    [1021] Eluent A: 0.5 ml formic acid (50% ig)/L water, Eluent B: 0.5 ml formic acid (50% ig)/L acetonitrile

    TABLE-US-00013 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

    [1022] Autosampler: without auto inject ahead setting

    [1023] column: stainless steel capillary

    [1024] oven temperature: 22° C.

    [1025] flow rate: flow gradient

    [1026] injected volume: 2 μl

    [1027] Water Quattro Micro MS, Agilent 1100 (G1312A), degasser (G1322A), column oven (G1316A), CTC Analytics PAL injection system HTS, eluents as above

    TABLE-US-00014 time [min] flow [μl/min] % B 0.00 250 70 1.50 250 70

    [1028] Autosampler: with auto inject ahead setting

    [1029] column: stainless steel capillary

    [1030] oven temperature: 22° C.

    [1031] flow rate: flow gradient

    [1032] injected volume: 5 μl [1033] MS method: Flow Injection Analysis (FIA) for optimization (“MS-OPTI”); Ionization mode ABSciex-MS: ESI-pos/neg, Waters-MS: ESI-pos

    [1034] HPLC method for MSMS quantification:

    [1035] Eluent A, B as above

    [1036] ABSciex-MS

    TABLE-US-00015 time [min] % A % B 0 90 10 0.5 5 95 0.84 5 95 0.85 90 10 1.22 90 10

    [1037] Autosampler: without auto inject ahead setting

    [1038] column: Waters OASIS HLB, 2.1×20 mm, 25μ

    [1039] column temperature: 30° C.

    [1040] flow rate: 2.5 ml

    [1041] injected volume: 2 μl

    [1042] Splitter (before MS) 1:20

    [1043] Waters-MS

    TABLE-US-00016 time [min] % A % B 0 90 10 0.5 5 95 0.84 5 95 0.85 90 10 1.5 90 10

    [1044] Autosampler: with auto inject ahead setting

    [1045] column: Waters OASIS HLB, 2.1×20 mm, 25μ

    [1046] column temperature: 30° C.

    [1047] flow rate: 2.5 ml

    [1048] injected volume: 5 μl

    [1049] Splitter (before MS) 1:20

    [1050] MS method: Multiple Reaction Monitoring (MRM)

    [1051] B-6. Determination of Solubility from Solid

    [1052] For each solvent, an Eppendorf plastic vial was charged with 0.5-1 mg of the test compound (exact weight), 2-3 glass pearls (diameter 3 mm) and 1.0 ml of the respective solvent. The vial was closed and shaken at RT for 24 h (1400 rpm; Thermomixer, Eppendorf). Thereafter, 230 μl each of the solution/suspension was transferred into one or more centrifuge vials (Beckman Coulter) and were centrifuged at 42000 rpm for 30 min (Beckman Coulter Optima L90). At least 100 μl of the supernatant were withdrawn and further diluted with DMSO in two dilution strength: 1:5 and 1:50 (the latter obtained from the 1:5 dilution step by subsequent DMSO addition). This liquid handling was done either manually or with the help of a pipetting robot (Lissy, Zinsser Analytic).

    [1053] For HPLC quantification, calibration solutions of the test compound in DMSO were prepared. Starting from an initial concentration of 600 μg/ml, three calibration solutions were prepared: 100 μg/ml, 20 μg/ml and 2.5 μg/ml (manually or via Lissy).

    [1054] Both calibration solutions and the supernatant were analyzed by HPLC/UV-detection at an appropriate wave length. The solubility was determined using the linear calibration curve.

    [1055] HPLC Systems:

    [1056] Hewlett Packard/Agilent HPLC systems, G1311A+G1316A+G1315B as well as G1312A+G1316A+G1315A

    [1057] injector system: CTC-Analytik HTC PAL

    [1058] or with a Agilent UPLC System (G7117C, G7116B, G7167B and G7120)

    [1059] oven temperature: 30° C., detection: 210 and/or 254 nm, injected volume: 20 μl

    [1060] eluent A: 0.1% TFA in water, eluent B: 0.1% TFA in acetonitrile

    [1061] column: ZORBAX Extend-C18, 3.0×50 mm, 3.5 μm

    [1062] Gradient:

    TABLE-US-00017 time [min] A [%] B [%] Flow rate: [ml/min] 0.0 98 2 1.5 0.2 98 2 1.5 3.3 10 90 1.5 4.0 10 90 1.5 4.1 98 2 2.5 4.7 98 2 2.5 5.0 98 2 1.5

    [1063] B-7 Evaluation of Acute Changes in Rat Retinal Structure after Retinal Ischemia Reperfusion (I/R) Prophylactic Settings

    [1064] Six male Wistar Unilever rats were used per experimental group. On induction day, rats were anesthetized with an intraperitoneal injection of Rompun® and Ketavet® before the pupils of the right eyes (oculus dextrus, OD) were dilated with Alcain eye drops and in addition treated with Vigamox® eye drops. The left eye (oculus sinister, OS) is covered with Bepanthen® eye cream. Under deep anesthesia, the retina and the optic nerve were examined by optical coherence tomography (OCT) as a baseline measurement. 15 minutes before induction, group 2 received an intravenous (IV) bolus of compound (e.g. example 3, formula I-E-R) (i.v. 3 mg/kg in rat plasma). Then, the anterior chamber was punctured with a 30 G needle. Through a tube, 0.9% NaCl solution was pumped into the anterior chamber with a pressure 120 mm Hg. The pressure is regulated with a blood pressure cuff. The intraocular pressure (IOP) was elevated for 45 min. The procedure was successful as the eyeballs discolored because of vascular obstruction. After 45 min, the needle was removed, eye cream was put on the right eye and the animal could wake up. Compound (e.g. example 3, formula I-E-R) or its vehicle (Transcutol/Cremophor EL/H2O (10%/20%/70%) were orally applied, once daily (QD). The application volume was 5 mL/kg. Treatment was initiated 2 days before induction day and continued 6 days after induction. In addition, at the day of induction (day 3), 15 minutes before the induction, group 2 received compound in rat plasma IV treatment.

    [1065] On day 7 following induction, an OCT and ERG examinations were done. At day 7 post induction, under deep anesthesia, the eyes were collected for histopathology and preserved in Davidson's solution. The eye sections were stained with hematoxylin and eosin staining.

    [1066] Functional read-out of retinal electrical signal in response to light stimulation “b-wave amplitude (μv)”

    represents inner retinal function. The retinal function ERG (Electroretinography) was tested at day 7 post induction according to the method disclosed in McCulloch et al., 2015. IR animals at day 7 had significantly lower b wave amplitude compared to age matched normal animals (Non IR), which reflects the development of the retinal ischemic damage phenotype. Animals which received compound (e.g. example 3, formula I-E-R) therapy (IR+ compound (e.g. example 3, formula I-E-R)) had significant higher b wave amplitude compared to vehicle treated animals (IR+ Vehicle) and compared to untreated induced animals (IR only) as shown in FIGS. 1A & 1B.

    [1067] Examination of the retina at day 7 post ischemic induction reveals a marked distortion of different retinal layers specially the RPE Photoreceptor layer in IR only group. Animal treated with the compound (e.g. example 3, formula I-E-R) showed a preserved retinal structure in both OCT and histological examination. This was reflected as a preserved retinal function as measure by ERG in compound (e.g. example 3, formula I-E-R) treated animals compared to control (FIG. 1B).

    [1068] The compounds according to the invention, e.g. example 3 protect(s) the retina from acute ischemic damage and preserves retinal function and morphology.

    [1069] B-8 Evaluation of Sub-Chronic Changes in Rat Retinal Structure after Retinal Ischemia Reperfusion (I/R) Therapeutic and Prophylactic Settings

    [1070] Six male Wistar Unilever rats were used per experimental group. On induction day, rats were anesthetized with an intraperitoneal injection of Rompun® and Ketavet® before the pupils of the right eyes were dilated with Alcain eye drops and in addition treated with Vigamox® eye drops. The left eye is covered with Bepanthen® eye cream. Under deep anesthesia, the retina and the optic nerve were examined by optical coherence tomography (OCT) as a baseline measurement. The induction was done as the anterior chamber was punctured with a 30 G needle. Through a tube, 0.9% NaCl solution was pumped into the anterior chamber with a pressure 120 mm Hg. The pressure is regulated with a blood pressure cuff. The intraocular pressure (IOP) was elevated for 45 min. The procedure was successful as the eyeballs discolored because of vascular obstruction. After 45 min, the needle was removed, eye cream was put on the right eye and the animal could wake up. Compound (e.g. example 3, formula I-E-R) or its vehicle were orally applied, once daily (QD). The application volume was 5 mL/kg. In prophylactic setting, animals started the treatment 2 days before induction and received an intravenous (IV) bolus of compound (e.g. example 3, formula I-E-R) (i.v. 3 mg/kg in rat plasma) 15 minutes before induction. Treatment continued then after for 21 days. In the therapeutic setting, animals received an intravenous (IV) bolus of compound (e.g. example 3, formula I-E-R) (i.v. 3 mg/kg in rat plasma) 15 minutes after induction. Treatment continued then after for 21 days; once daily (3 mg/kg, PO QD). At day 7 and day 21, the retina and the optic nerve were examined by optical coherence tomography (OCT). The retinal function was evaluated by the ERG (Electroretinography) at day 7 and day 21 post induction according to the method disclosed in McCulloch et al., 2015. Functional read-out of retinal electrical signal in response to light stimulation “b-wave amplitude (μv)” represents inner retinal function. Then the eyes were collected for histopathology and preserved in Davidson's solution. The eye sections were stained with hematoxylin and eosin staining. The total retinal thickness and the inner plexiform layer thickness was measured at 1000 μm distances from the optic nerve using (Microscope Software ZEN, Zeiss, Germany).

    [1071] Neuroprotection: The inner plexiform layer (IPL) functions as a relay station for the vertical-information-carrying nerve cells, the bipolar cells, to connect the photoreceptor cells to the ganglion cells. The IPL layer thickness was measured in histological sections stained with (H&E).

    [1072] Animals exposed to retinal ischemia (IR only) showed a progressive reduction of the retinal thickness (retinal degeneration) compared to baseline. Compound (e.g. example 3, formula I-E-R) treated animals showed a significantly higher retinal thickness compared to IR only animals at 3 weeks. This was reflected as significant difference in retinal function measured by ERG between IR and compound (e.g. example 3, formula I-E-R) treated animals (FIG. 2).

    [1073] At day 7 and day 21, the retina and the optic nerve were examined by optical coherence tomography (OCT). The mean total retinal thickness was maintained at 1- and 3-weeks post induction compared to IR only animal that experienced a progressive degeneration of the retina consistent with the histopathological finding, FIG. 3.

    [1074] The IPL thickness was reduced in vehicle treated animals and preserved in compound (e.g. example 3, formula I-E-R) treated animals in both prophylactic (FIG. 4A) and therapeutic settings (FIG. 4B). Retinas of IR only animals showed photoreceptors structural changes with accumulation of homogenous structures in the sub-photoreceptor space. In animals treated received compound (e.g. example 3, formula I-E-R) therapy, the retinal structure was preserved, and the photoreceptors integrity was intact.

    [1075] The compounds according to the invention, e.g. example 3 protect(s) the retinal structure and maintains retinal function in both prophylactic and therapeutic settings.

    [1076] As shown in FIG. 9, the photoreceptors (see arrow in FIG. 9) were degenerated in IR animals (left panel) and protected in compound treated animals (middle and right panel). This was reflected as significant difference in retinal function as measured by ERG between IR and compound treated animals.

    [1077] B-9 Streptozotocin-Induced DR Model in Rat (STZ Rat Model)

    [1078] 135 male 6-week-old male SD rats (200 to 250 g) were randomized to become diabetic or non-diabetic. Following an overnight fast, SD rats were assigned to become diabetic by receiving a single intraperitoneal injection of streptozotocin (55 mg per kg; Sigma-Aldrich, St. Louis, USA) diluted in 0.1M citrate buffer, pH 4.5. Rats were weighed and their blood glucose levels measured (Accu-check Advantage II Blood Glucose Monitor, Roche Diagnostics, USA). Only rats with blood glucose levels greater than 250 mg/dL were considered diabetic (Li et al. 2002). Insulin was administered three times per week to reduce mortality and promote weight gain (2 to 4 units s.c. Humulin NPH, Eli Lilly and Co., Indianapolis, Ind., USA). The pathological events that occur in the early stages of DR were evaluated. Functional read-out of retinal electrical signal in response to light stimulation “b-wave amplitude (μv)” represents inner retinal function. The retinal function ERG (Electroretinography) was tested 2 months after STZ injection according to the method disclosed in McCulloch et al., 2015 and animals were randomized into subgroups with same severity. The animals received treatment after randomization for 2 months and were terminated then after. Treatment was applied by oral gavage, once daily (QD) with a range of doses, including e.g. 5 mg/kg, 15 mg/kg compound (e.g. example 3, formula I-E-R) (STZ+ compound (e.g. example 3, formula I-E-R) or vehicle (STZ+ vehicle (Transcutol/Cremophor EL/H2O (10%/20%/70%))). Diabetic animals at 2 months had significantly lower b wave amplitude compared to age matched normal animals (Non STZ), which reflects the development of DR disease phenotype. Animals which received compound (e.g. 15 mg/kg of example 3, formula I-E-R) therapy (STZ+compound (e.g. example 3, formula I-E-R) had significant higher b wave amplitude compared to vehicle treated animals as shown in FIG. 5.

    [1079] While diabetic animals under vehicle therapy (STZ+vehicle) continue to progress to a more severe form of the disease (i.e. lower levels of b wave values), surprisingly diabetic animals under compound (e.g. example 3, formula I-E-R) therapy (STZ+compound (e.g. example 3, formula I-E-R) prevented disease progression and were significantly better than vehicle treated animals in a chronic diabetic retinopathy model.

    [1080] Treatment is also applied by oral gavage, once daily (QD) with a range of doses, including 0.5 mg/kg, 1.5 mg/kg, 5 mg/kg, 15 mg/kg compound (e.g. example 3, formula I-E-R) (STZ+compound (e.g. example 3, formula I-E-R) or vehicle (STZ+vehicle (Transcutol/Cremophor EL/H2O (10%/20%/70%))).

    [1081] B-10 Stimulation and Activation of Recombinant Soluble Guanylate Cyclase (sGC) In Vitro

    [1082] Investigations on the modulation of recombinant soluble guanylate cyclase (sGC) by the compounds according to the invention with and without sodium nitroprusside, and with and without the heme-dependent sGC inhibitor 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), are carried out by the method described in Hoenicka et al., 1999. The heme-free guanylate cyclase is obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration).

    [1083] As described in WO 2012/139888, combination of sGC activators and 2-(N,N-diethylamino)diazenolate 2-oxide (DEA/NO), an NO donor, show no synergistic effect, i.e. the effect of DEA/NO is not potentiated as is expected with an sGC modulator acting via a heme-dependent mechanism. In addition, the effect of the sGC activator according to the invention is not blocked by 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), a heme-dependent inhibitor of soluble guanylate cyclase, but is in fact increased.

    [1084] Thus, this test is suitable to distinguish between the heme-dependent sGC Stimulators and the heme-independent sGC Activators.

    FIGURES

    [1085] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

    [1086] While the invention is illustrated and described in detail in the drawing and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. Any reference signs should not be construed as limiting the scope.

    [1087] FIG. 1A Compound (example 3, formula I-E-R) reduces ischemia induced retinal dysfunction measured by b wave amplitude in SD rats at one week post induction.

    [1088] FIG. 1B Animal with the compound (example 3, formula I-E-R) showed a preserved retinal structure in both OCT and histological examination.

    [1089] FIG. 2 Compound (example 3, formula I-E-R) reduces ischemia induced retinal dysfunction measured by b wave amplitude in SD rats at one week and 3 weeks post induction.

    [1090] FIG. 3 Compound of (example 3, formula I-E-R) therapy protect retinal structure as measured by optical coherence tomography (OCT) at 1- and 3-weeks post induction compared to IR only animal.

    [1091] FIG. 4A shows changes of the rat retina in a rat IR model following treatment with formula I-E-R of example 3 in a prophylactic setting.

    [1092] FIG. 4B shows changes of the rat retina in a rat IR model following treatment with formula I-E-R of example 3 in a therapeutic setting.

    [1093] FIG. 5 Compound (example 3 of formula I-E-R) reduces diabetic induced retinal dysfunction and diabetic retinopathy progression measured by b wave amplitude in STZ rats.

    [1094] FIG. 6 shows an Ortep-Plot (50%) with labeling scheme (without disorder), as defined in example 3A.

    [1095] FIG. 7 shows independent molecules in the asymmetric unit (with disorder), as defined in example 3A.

    [1096] FIG. 8 shows the configuration of C22, as defined in example 3A.

    [1097] FIG. 9 shows differences in retinal function for compound-treated animals compared to untreated animals.

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    [1144] C. Working Examples of Pharmaceutical Compositions

    [1145] The compounds of the invention can be converted to pharmaceutical preparations as follows:

    [1146] Tablet:

    [1147] Composition:

    [1148] 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

    [1149] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

    [1150] Production:

    [1151] The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

    [1152] Suspension for Oral Administration:

    [1153] Composition:

    [1154] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

    [1155] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

    [1156] Production:

    [1157] The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

    [1158] Solution for Oral Administration:

    [1159] Composition:

    [1160] 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

    [1161] Production:

    [1162] The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

    [1163] Example Solution for Oral Administration:

    [1164] Compound (e.g. example 3, formula I-E-R) is solubilized in vehicle comprising a mixture of Transcutol/Cremophor EL/H.sub.2O (10%/20%/70%).

    [1165] i.v. Solution:

    [1166] The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection containers.