Piperidine CXCR7 receptor modulators

Abstract

The present invention relates to piperidine derivatives of formula (I) ##STR00001##
wherein Ar.sup.1, Ar.sup.2, R.sup.Ar1, R.sup.1, R.sup.2, and R.sup.3 are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.

Claims

1. A compound of formula (I) ##STR00034## wherein the two substituents of the piperidine ring: R.sup.1—CO— and —NH—CO—Ar.sup.1—Ar.sup.2, are in relative trans-configuration; Ar.sup.1 represents an unsubstituted 5-membered heteroarylene group containing one sulfur ring atom and one or two nitrogen ring atoms, wherein the —NH—CO— group and Ar.sup.2 are attached in meta arrangement to ring atoms of Ar.sup.1; Ar.sup.2 represents phenyl, or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from fluoro, chloro, methyl, cyano, methoxy, or (C.sub.1)fluoroalkyl; R.sup.1 represents R.sup.N1R.sup.N2N—, wherein R.sup.N1 represents hydrogen; (C.sub.1-6)alkyl; (C.sub.1-6)alkyl which is mono-substituted with hydroxy; (C.sub.1-3)alkoxy; 2-hydroxy-ethoxy; —CO—NH.sub.2; —SO.sub.2—(C.sub.1-3)alkyl; cyano; (C.sub.1-3)fluoroalkoxy; —NR.sup.N3R.sup.N4, wherein R.sup.N3 and R.sup.N4 independently represent hydrogen or (C.sub.1-4)alkyl; (C.sub.2-6)alkynyl; (C.sub.2-5)fluoroalkyl; (C.sub.1-4)alkoxy; 2-(2-oxo-pyrrolidin-1-yl)-ethyl; a group -L.sup.1-Cy.sup.1; wherein L.sup.1 represents a direct bond, —(C.sub.1-3)alkylene-, or —(C.sub.3-5)cycloalkylene-; and Cy.sup.1 represents (C.sub.3-6)cycloalkyl, wherein said (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; wherein said (C.sub.3-6)cycloalkyl independently is unsubstituted; or mono-substituted with fluoro, methyl, or hydroxy, —CO—(C.sub.1-4)alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro; a group -L.sup.2-Ar.sup.3, wherein L.sup.2 represents a direct bond, —(C.sub.1-4)alkylene-; *—(C.sub.3-5)cycloalkylene-(C.sub.0-2)alkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar.sup.3 is attached; *—(C.sub.1-2)alkylene-(C.sub.3-5)cycloalkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar.sup.3 is attached; or —(C.sub.1-3)alkylene- which is mono-substituted with hydroxy, trifluoromethyl, or —CO—(C.sub.1-4)alkoxy; and Ar.sup.3 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, hydroxy, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; and R.sup.N2 independently represents hydrogen, (C.sub.1-4alkyl, or (C.sub.2-3)fluoroalkyl; or R.sup.N1 and R.sup.N2 together with the nitrogen atom to which they are attached to form a 4- to 6-membered ring selected from azetidinyl, pyrrolidinyl or piperidinyl; each independently unsubstituted; or mono-substituted with fluoro, methyl, or hydroxy; or di-substituted with fluoro; or mono-substituted with Ar.sup.4, wherein Ar.sup.4 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; or morpholinyl; R.sup.2 represents hydrogen; (C.sub.1-6)alkyl; (C.sub.2-6)alkyl which is mono-substituted with (C.sub.1-3)alkoxy, or hydroxy; (C.sub.3-5)alkenyl; cyano-methyl; (C.sub.2-3)fluoroalkyl; (C.sub.3-8)cycloalkyl-(C.sub.0-3)alkyl; wherein the (C.sub.3-8)cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C.sub.1-3)alkyl, fluoro, hydroxy, hydroxy-(C.sub.1-3)alkyl, (C.sub.1-3)alkoxy, or (C.sub.1-3)fluoroalkyl; thietan-3-yl; (C.sub.3-8)cycloalkenyl-(C.sub.1-3)alkyl; or Ar.sup.5—CH.sub.2— wherein Ar.sup.5 represents phenyl, or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; and R.sup.3 represents hydrogen, or methyl; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) as defined for claim 1 which are also compounds of Formula (I.sub.S), wherein the two substituents of the piperidine ring: R.sup.1—CO— and —NH—CO—Ar.sup.1—Ar.sup.2, are in relative trans-configuration, wherein the absolute configuration of the two chiral carbon atoms in position 3 and 4 of the piperidine ring is (3S,4S): ##STR00035## or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2; wherein R.sup.3 represents hydrogen; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3; wherein Ar.sup.1 represents [1,3,4]thiadiazol-2,5-diyl or isothiazol-3,5-diyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4; wherein Ar.sup.2 represents phenyl which is mono-, di- or tri-substituted; wherein one or two of said substituents is/are independently selected from fluoro, chloro, and methyl, and the remaining, if present, is/are fluoro; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1; wherein R.sup.1 represents R.sup.N1R.sup.N2N—, wherein R.sup.N1 represents (C.sub.1-6)alkyl; (C.sub.1-6)alkyl which is mono-substituted with hydroxy; (C.sub.1-3)alkoxy; 2-hydroxy-ethoxy; —CO—NH.sub.2; —SO.sub.2—(C.sub.1-3)alkyl; cyano; (C.sub.1-3)fluoroalkoxy; —NR.sup.N3R.sup.N4, wherein R.sup.N3 and R.sup.N4 independently represent hydrogen or (C.sub.1-4)alkyl; (C.sub.2-6)alkynyl; (C.sub.2-s)fluoroalkyl; 2-(2-oxo-pyrrolidin-1-yl)-ethyl; a group -L.sup.1-Cy.sup.1; wherein L.sup.1 represents a direct bond, —(C.sub.1-3)alkylene-, or —(C.sub.3-5)cycloalkylene-; and Cy.sup.1 represents (C.sub.3-6)cycloalkyl, wherein said (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; wherein said (C.sub.3-6)cycloalkyl independently is unsubstituted: or mono-substituted with fluoro, methyl, hydroxy, CO—(C.sub.1-4)alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro; a group -L.sup.2-Ar.sup.3, wherein L.sup.2 represents a —(C.sub.1-4)alkylene-; —(C.sub.3-5)cycloalkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom; *—(C.sub.3-5)cycloalkylene-(C.sub.1-2)alkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar.sup.3 is attached; *—(C.sub.1-2)alkylene-(C.sub.3-5)cycloalkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar.sup.3 is attached; or —(C.sub.1-3)alkylene- which is mono-substituted with hydroxy or trifluoromethyl; and Ar.sup.3 represents phenyl, or 5-membered heteroaryl containing one oxygen atom and one or two nitrogen atoms, or 6-membered heteroaryl containing one or two nitrogen atoms; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; and R.sup.N2 independently represents hydrogen, or (C.sub.1-4)alkyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1; wherein R.sup.1 represents R.sup.N1R.sup.N2N—, wherein R.sup.N1 represents (C.sub.3-6)cycloalkyl, wherein said (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; wherein said (C.sub.3-6)cycloalkyl independently is unsubstituted, or mono-substituted with fluoro, methyl, or hydroxy, or di-substituted with fluoro, or tri-substituted with methyl and two fluoro; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkylene-, wherein said (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; (C.sub.3-6)cycloalkyl-(C.sub.3-5)cycloalkylene-; phenyl-(C.sub.1-4)alkylene- wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; phenyl-(C.sub.1-3)alkylene- wherein said —(C.sub.1-3)alkylene- is mono-substituted with hydroxy; phenyl-(C.sub.3-5)cycloalkylene-; wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, hydroxy, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; phenyl-(C.sub.3-5)cycloalkylene-(C.sub.1-2)alkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-substituted with halogen; phenyl-(C.sub.1-2)alkylene-(C.sub.3-5)cycloalkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom; 5-membered heteroaryl-(C.sub.1-3)alkylene-, wherein said 5-membered heteroaryl contains one oxygen atom and one or two nitrogen atoms; and wherein said 5-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; 6-membered heteroaryl-(C.sub.1-4)alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; 6-membered heteroaryl-(C.sub.1-3)alkylene-, wherein said —(C.sub.1-3)alkylene- is mono-substituted with hydroxy or trifluoromethyl; wherein said 6-membered heteroaryl contains one or two nitrogen atoms; or 6-membered heteroaryl-(C.sub.3-5)cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; 6-membered heteroaryl-(C.sub.3-5)cycloalkylene-(C.sub.1-2)alkylene- wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted; and R.sup.N2 independently represents hydrogen, or (C.sub.1-4)alkyl; or R.sup.N1 represents (C.sub.1-3)alkyl; and R.sup.N2 represents hydrogen, or methyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 5; wherein R.sup.1 represents R.sup.N1R.sup.N2N—, wherein R.sup.N1 represents (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkylene-, wherein said (C.sub.3-6)cycloalkyl optionally contains one ring oxygen atom; phenyl-(C.sub.1-4)alkylene- wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; phenyl-(C.sub.3-5)cycloalkylene- wherein said (C.sub.3-5)cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, hydroxy, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; 6-membered heteroaryl-(C.sub.1-4)alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; 6-membered heteroaryl-(C.sub.3-5)cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; and R.sup.N2 independently represents hydrogen, or (C.sub.1-4)alkyl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 5; wherein R.sup.1 represents R.sup.N1R.sup.N2N—, wherein R.sup.N1 represents 6-membered heteroaryl-(C.sub.1-4)alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; 6-membered heteroaryl-(C.sub.3-5)cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, or (C.sub.1-3)fluoroalkoxy; wherein, in case Ar.sup.3 represents pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide; and R.sup.N2 independently represents hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 7; wherein R.sup.2 represents (C.sub.3-8)cycloalkyl-(C.sub.1-3)alkyl, wherein the (C.sub.3-8)cycloalkyl is unsubstituted; or mono-substituted wherein the substituent is (C.sub.1-3)alkyl, fluoro, or (C.sub.1-3)fluoroalkyl; or di-substituted with fluoro; or (C.sub.3-8)cycloalkyl, wherein the (C.sub.3-8)cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C.sub.1-3)alkyl, or fluoro; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 8; wherein R.sup.2 represents unsubstituted (C.sub.3-8)cycloalkyl-(C.sub.1-3)alkyl; or unsubstituted (C.sub.3-6)cycloalkyl; or (C.sub.3-8)cycloalkyl, wherein the (C.sub.3-8)cycloalkyl is di-substituted with fluoro; or (C.sub.3-8)cycloalkyl-(C.sub.1-3)alkyl; wherein the (C.sub.3-8)cycloalkyl is mono-substituted with methyl, fluoro, or (C.sub.1)fluoroalkyl; or di-substituted with fluoro; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 which is: (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; wherein said compound is in free form.

15. The compound according to claim 1 which is (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide; wherein said compound is in pharmaceutically acceptable salt form.

16. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

17. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 11, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

18. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 12, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

19. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 13, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

20. A method for the treatment of cancer; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof.

21. A method of treating tumors comprising administering an effective amount of the compound of formula (Ia) according to claim 11, or a pharmaceutically acceptable salt thereof, wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating the CXCL11/CXCL12 receptor pathway.

22. A method for the treatment of fibrosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof.

23. A method for the treatment of autoimmune disorders which have an inflammatory component selected from inflammatory demyelinating diseases, multiple sclerosis (MS), Guillain Barré syndrome, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), lupus nephritis, and auto-immune encephalomyelitis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof.

24. A method for the treatment of inflammatory diseases selected from lung inflammatory diseases selected from asthma, chronic obstructive pulmonary disorder (COPD), and acute lung injury; and atherosclerosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof.

25. A method for the treatment of cancer; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13, or a pharmaceutically acceptable salt thereof.

26. A method of treating tumors comprising administering an effective amount of the compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein said effective amount leads to a change of tumor properties, and wherein said modification is achieved by modulating the CXCL11/CXCL12 receptor pathway.

27. A method for the treatment of fibrosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13, or a pharmaceutically acceptable salt thereof.

28. A method for the treatment of autoimmune disorders which have an inflammatory component selected from inflammatory demyelinating diseases, multiple sclerosis (MS), Guillain Barré syndrome, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), lupus nephritis, and auto-immune encephalomyelitis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13, or a pharmaceutically acceptable salt thereof.

29. A method for the treatment of inflammatory diseases selected from lung inflammatory diseases selected from asthma, chronic obstructive pulmonary disorder (COPD), and acute lung injury; and atherosclerosis; comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in claim 13, or a pharmaceutically acceptable salt thereof.

Description

EXPERIMENTAL PART

(1) I. Chemistry

(2) All temperatures are stated in ° C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen or argon. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time t.sub.R is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given.

(3) NMR Spectroscopy

(4) Bruker Avance II spectrometer equipped with a 400 MHz (.sup.1H) Ultrashield™ Magnet and a BBO 5 mm probehead or a PAXTI 1 mm probehead, or a Bruker Avance III HD Ascend 500 MHz (′H), magnet equipped with DCH cryoprobe. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet, triplet, quartet, multiplet and br to broad, respectively. Coupling constants J are reported in Hz. In case NMR spectra are measured using 1 mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured with double irradiation for suppression of the DMSO and H.sub.2O peaks. In that case only a selection of representative NMR peaks of the compound is given.

(5) Quality Control (QC) Analytical LC-MS:

(6) Equipment and Conditions:

(7) Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Columns: Acquity UPLC CSH C18 1.7 μm 2.1×50 mm or Acquity UPLC HSS T3 C18 1.8 μm 2.1×50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60° C. Eluents: A1: H2O+0.05% FA; B1: AcCN+0.045% FA. Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 mL/min. Detection: UV 214 nm and ELSD, and MS, tR is given in min.

(8) Analytical LC-MS

(9) Equipment:

(10) Binary gradient pump Agilent G4220A or equivalent with mass spectrometry detection (single quadrupole mass analyser, Thermo Finnigan MSQPlus or equivalent)

(11) Conditions:

(12) Method A (acidic conditions): Column: Zorbax SB-aq (3.5 μm, 4.6×50 mm); conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient: 95% B.fwdarw.5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

(13) Method B (acidic conditions): Column: Waters XBridge C18 (2.5 μm, 4.6×30 mm); conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient: 95% B.fwdarw.5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

(14) Method C (acidic conditions): Column: Waters BEH C18 (2.5 μm, 3.0×50 mm); conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]; gradient: 95% B.fwdarw.5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.

(15) Method D (basic conditions): Column: Waters BEH C18 (2.5 μm, 3.0×50 mm); conditions: MeCN [eluent A]; H.sub.2O+0.05% NH.sub.4OH [eluent B]; gradient: 95% B.fwdarw.5% B over 1.9 min (flow 1.6 mL/min), Detection: UV/Vis+MS.

(16) Preparative LC-MS

(17) Equipment:

(18) Binary gradient pump Gilson 333/334 or equivalent with mass spectrometry detection (single quadrupole mass analyser, Thermo Finnigan MSQPlus or equivalent)

(19) Conditions:

(20) Method E (basic conditions): Column: Waters XBridge C18 (10 μm, 30×75 mm); conditions: MeCN [eluent A]; water+0.5% NH.sub.4OH (25% aq.) [eluent B]; gradient: 95% B.fwdarw.5% B, over 6.5 min (flow: 75 mL/min). Detection: UV/Vis+MS

(21) Method F (acidic conditions): column: Waters XBridge C18 (10 μm, 30×75 mm); conditions: MeCN [eluent A]; water+0.5% formic acid [eluent B]; gradient: 95% B.fwdarw.5% B, over 6.5 min (flow: 75 mL/min). Detection: UV/Vis+MS

(22) Chiral Analytical Chromatography

(23) Equipment:

(24) HPLC: Dionex HPG-3200SD pump with a Dionex DAD-3000 UV detector.

(25) SFC: CO.sub.2 supply: Aurora Fusion A5 Evolution; pump: Agilent G4302A; UV detector: Agilent G1315C.

(26) Conditions:

(27) HPLC: Columns: ChiralPak AY-H, 5 μm, 250×4.6 mm or Regis (R,R) Whelk-01 250×4.6 mm, 5 μm; eluent: A: Hept, 0.05% DEA, B: Ethanol, 0.05% DEA, flow 0.8 to 1.2 mL/min.

(28) SFC Column: Regis (R,R) Whelk-01, 4.6×250 mm, 5 μM; eluent: A: 60% CO.sub.2, B: 40% DCM/EtOH/DEA 50:50:0.1

(29) Chiral Preparative Chromatography

(30) Equipment:

(31) HPLC: 2 Varian SD1 pump with a Dionex DAD-3000 UV detector.

(32) SFC: CO.sub.2 supply: Maximator DLE15-GG-C; pumps: 2 SSI HF CP 300; UV detector: Dionex DAD-3000.

(33) Conditions:

(34) HPLC: Columns: ChiralPak IA, IB, IC, IE, or IF, 5 μm, 20×250 mm, or Regis (R,R) Whelk-01, 21.1×250 mm, 5 μm; eluent: appropriate mixture of A (0% to 90% Hept) and B (10% to 100% EtOH, 0.1% DEA), flow: appropriate flow of 16, 23 or 34 mL/min.

(35) SFC: Columns: Regis (R,R) Whelk-01, 30×250 mm, 5 μm or ChiralPak IC, 30×250 mm, 5 μm; eluent: appropriate mixture of A (60% to 70% CO.sub.2), and B (30% to 40% of DCM/EtOH/DEA 50:50:0.1), flow 160 mL/min.

Abbreviations (as Used Hereinbefore or Hereinafter)

(36) aq. aqueous atm atmosphere BSA bovine serum albumin Boc butyloxycarbonyl BB building-block CDI carbonyl diimidazole COMU 1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate d days dba dibenzylidene acetone DCC dicyclohexyl carbodiimide DCM dichloromethane DEA diethylamine DIPEA diisopropyl-ethylamine, Hunig's base, ethyl-diisopropylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide EDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide eq. equivalent(s) Et ethyl EtOAc ethyl acetate EtOH ethanol Ex. example(s) h hour(s) HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate Hept heptane HOBt 1-hydroxybenzotriazole HOAT 7-Aza-1-hydroxybenzotriazole HPLC high performance liquid chromatography HV high vacuum conditions .sup.iBu isobutyl .sup.iPr isopropyl KO.sup.tBu potassium tert-butoxide LC-MS liquid chromatography mass spectrometry LiHMDS Lithium bis(trimethylsilyl)amide Lit. Literature Me methyl MeCN acetonitrile MeOH methanol mL milliliter MTBE methyl-tert-butyl ether min minute(s) Nr number NaOAc sodium acetate NBS N-Bromosuccinimide NMP N-methylpyrrolidone .sup.nPr n-propyl OAc acetate Ph phenyl PPh.sub.3 triphenyl phosphine POCl.sub.3 Phosphorus (V) oxychloride prep. Preparative PyBOP benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluoro-phosphate rac racemic RT room temperature s second(s) sat. Saturated Selectfluor® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: supercritical fluid chromatography soln. solution tBu tert-butyl=tertiary butyl TBTU 2-(1H-benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography T.sub.3P Propylphosphonic anhydride t.sub.R retention time

Preparation of Esters and Carboxylic Acids of Structure A-4 Used for the Synthesis of Building-Blocks 1.07 to 1.17 and Examples 3.001 to 3.022

A-4.01: 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.01a: 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(37) The title compound A-4.01a is prepared in analogy to the procedure described in Eur. J. Org. Chem. 2006, 4852-4860, by stirring a solution of ethyl nitroacetate (1.36 mL, 12 mmol), 2-ethynyl-1,3,5-trifluorobenzene (312 mg, 2 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.156 mL, 1.4 mmol) in NMP (1.2 mL), at 65° C. overnight. The solvent is evaporated and the product used in the next step without further purification, LC-MS method A: t.sub.R=1.07 min.

A-4.01: 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid

(38) To a solution of ester A-4.01a (542 mg, 2 mmol) in THF (4 mL) is added LiOH.H.sub.2O (12 mmol) dissolved in 10 mL water. After stirring for 64 h, a 4M solution HCl (10 mmol) is added, followed by water (1.5 mL). The precipitated product is filtered, washed with water (2×2.5 mL) and DCM (2×2.5 mL) and dried under HV. The title compound is obtained as a white powder, LC-MS method A: t.sub.R=0.83 min; [M+H].sup.+=407.05; .sup.1H NMR (400 MHz, DMSO) δ: 14.3 (bs, 1H), 7.54 (t, J=9.3 Hz, 2H), 7.19 (s, 1H).

A-4.02: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.02a: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(39) The title compound is prepared according to the procedure A-4.01a, starting from 2-chloro-1-ethynyl-4-fluoro-benzene; LC-MS method A: t.sub.R=1.15 min.

A-4.02: 5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carboxylic Acid

(40) The title compound is prepared according to the procedure A-4.01b, starting from ester A-4.02a; LC-MS method A: t.sub.R=0.9 min; 1H NMR (500 MHz, DMSO) δ: 8.00 (m, 1H), 7.73 (m, 1H), 7.45 (m, 1H), 7.14 (s, 1H).

A-4.03: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.03a: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(41) The title compound is prepared according to the procedure A-4.01a, starting from 4-chloro-1-ethynyl-2-fluoro-benzene; LC-MS method A: t.sub.R=1.18 min.

A-4.03: 5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic Acid

(42) The title compound is prepared according to the procedure A-4.01b, starting from ester A-4.03a; LC-MS method D: t.sub.R=0.93 min; .sup.1H NMR (500 MHz, DMSO) δ: 8.03 (m, 1H), 7.77 (m, 1H), 7.52-7.54 (m, 1H), 7.18-7.19 (m, 1H).

A-4.04: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.04a: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(43) The title compound is prepared according to the procedure A-4.01a, starting from 2-ethynyl-1,3-difluorobenzene; LC-MS method A: t.sub.R=1.06 min.

A-4.04: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid

(44) The title compound is prepared according to the procedure A-4.01b, starting from ester A-4.04a; LC-MS method A: t.sub.R=0.84 min; .sup.1H NMR (500 MHz, DMSO) δ: 7.65 (m, 1H), 7.35 (m, 2H), 6.91 (s, 1H).

A-4.05: 3-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic Acid Ethyl Ester

(45) The title compound is prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030. To a solution of 2,4-difluorobenzamidoxime (344 mg, 2 mmol) dissolved in THF (5 mL) is added ethyl 2-chloro-2-oxoacetate (0.279 mL, 2.5 mmol), followed by DIPEA (0.437 mL, 2.5 mmol). The reaction mixture is stirred at 75° C. for 3 h. The mixture is then quenched with water (25 mL) and extracted with EtOAc (25 mL). The organic layer is dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give the desired product as a yellow solid. LC-MS method C: t.sub.R=1.01 min. 1H NMR (400 MHz, DMSO) δ: 8.15 (m, 1H), 7.62 (m, 1H), 7.37 (m, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

A-4.06: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid Lithium Salt

(46) The title compound is prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030.

A-4.06a: Ethyl 2-((2-(2,4-difluorophenyl)-2-oxoethyl)amino)-2-oxoacetate

(47) To a solution of 2,4-difluorophenacylamine hydrochloride (415 mg, 2 mmol) in DCM (8 mL) and TEA (0.591 mL, 4.2 mmol), cooled to 0° C., is added ethyl chlorooxoacetate (0.226 mL, 2.02 mmol). The reaction mixture is stirred 1 h30 at 0° C. and then quenched with water (10 mL), extracted twice with DCM (2×10 mL). The combined organic layers are dried over MgSO.sub.4, and the solvent is evaporated to give the title compound as a brown oil. LC-MS method C: t.sub.R=0.82 min; [M+H].sup.+=272.20.

A-4.06b: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid Ethyl Ester

(48) POCl.sub.3 (0.52 mL, 5.58 mmol) is added dropwise to a solution of A-4.06a (480 mg, 1.77 mmol), dissolved in toluene (5 mL). The mixture is stirred overnight at 110° C. After cooling the solution to 0° C., it is quenched by dropwise addition of water (2 mL) and then it is neutralized with sat. aq. NaHCO.sub.3 and extracted with DCM (20 mL). The organic layer is evaporated and the product is purified by prep. LC-MS method F. LC-MS method D: t.sub.R=1.01 min; [M+H].sup.+=253.98.

A-4.06: 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid Lithium Salt

(49) To a solution of ester A-4.06b (574 mg, 2.13 mmol) in THF (10 mL) is added 1 M LiOH aq. sol. (6.4 mL, mg, 6.4 mmol). After stirring for 1 hour, the solvents are evaporated under reduced pressure to give the title compound as a beige powder, LC-MS method D: t.sub.R=0.65 min; [M+H].sup.+=226.30.

A-4.07: 5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic Acid Lithium Salt

A-4.07a: 5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic Acid Ethyl Ester

(50) The title compound is prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030.

(51) To a solution of 2,4-difluorobenzoic acid hydrazide (2.65 g, 15.4 mmol) in 50 mL DCM is added TEA (9.67 mL, 69.4 mmol). The mixture is cooled to 0° C. and ethyl chlorooxoacetate (2.44 mL, 21.2 mmol) is added. The mixture is stirred 2 h at 0° C. Then, toluene-4-sulfonyl chloride (4.40 g, 23.1 mmol) is added and stirring is continued overnight at RT. A sat. aq. NaHCO.sub.3 solution (50 mL) is added and the reaction mixture is extracted twice with DCM (2×50 mL). The combined organic layers are dried over MgSO.sub.4, filtered and evaporated. The residue is purified by flash chromatography using a gradient of eluent heptane/AcOEt (9:1 to 4:1) to give a light yellow solid. LC-MS method A: t.sub.R=0.80 min; [M+H].sup.+=255.13, [M+H+MeCN].sup.+=296.10.

A-4.07: 5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic Acid Lithium Salt

(52) To a solution of ester A-4.07a (25.4 mg, 0.1 mmol) in THF (0.2 mL) is added LiOH hydrate (5 mg, 0.1 mmol) dissolved in water (0.2 mL). After stirring for 1 hour, the solvents are evaporated under reduced pressure to give the title compound as a white powder, LC-MS method D: t.sub.R=0.41 min; .sup.1H NMR (400 MHz, DMSO) δ: 8.07 (m, 1H), 7.58 (m, 1H), 7.34 (m, 1H).

A-4.08: 1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid

A-4.08a: 1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid Ethyl Ester

(53) To a solution of ethyl 2-diazo-3-oxopropanoate (obtained according to procedure described in Journal of the American Chemical Society, 2011, 133(4), 1044-1051) (1.6 g, 8.85 mmol) in EtOH (3.15 mL) is added glacial acetic acid (1.27 mL, 22.1 mmol) followed by 2,4-difluoroaniline (1.22 g, 9.47 mmol). After stirring overnight, the reaction mixture is concentrated and the residue is diluted with cold water (40 mL). The precipitate is filtered, washed with cold water (10 mL) and dried under HV to afford the title compound as a beige solid. LC-MS method A: t.sub.R=0.8 min; [M+H]+=254.12.

A-4.08: 1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid

(54) To a solution of ester A-4.08a (1.93 g, 7.62 mmol) in THF (16 mL) is added LiOH hydrate (11.4 mmol) dissolved in water (16 mL). After stirring for 45 min, THF is evaporated and the aq. residue is cooled to 0° C. A 1M HCl solution is added until pH=2. The precipitated product is filtered, washed with water (15 mL), and dried under HV. The title compound is obtained as a beige powder, LC-MS method A: t.sub.R=0.61 min; [M+H].sup.+=225.96, [M+H+MeCN].sup.+=267.10.

A-4.09: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic Acid

A-4.09a: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic Acid Ethyl Ester

(55) The title compound is prepared following a procedure analogous to that described in WO 2012/168315. Ethyl 2-amino(hydroxyimino)acetate (2.27 g, 16.7 mmol) dissolved in 2,6-dimethylpyridine (5.88 mL, 50 mmol) is treated dropwise with a solution of 2,4-difluorobenzoyl chloride (1.39 mL, 11.1 mmol) in DCM (30 mL). The reaction mixture is stirred overnight. The beige suspension is dissolved with DCM (150 mL) and washed with water (50 mL), then 1M HCl (50 mL) and brine (50 mL). The organic layer is dried over MgSO.sub.4, filtered and the solvent evaporated. The intermediate white powder ethyl 2-(2,4-difluorobenzamido)-2-(hydroxyimino)acetate is then heated 1 h at 200° C. in a DrySyn metal block (from Asynt Ltd.). After cooling down, the title compound is purified by flash chromatography using a gradient of 2% to 20% EtOAc in n-heptane as eluent. LC-MS method A: t.sub.R=0.85 min; [M+H].sup.+=255.02.

A-4.09: 5-(2,4-Difluoro-phenyl)-[1,2,4]oxadiazole-3-carboxylic Acid

(56) To compound A-4.09a (3.84 g, 14.1 mmol) dissolved in THF (25 mL) and water (25 mL), is added LiOH.H2O (799 mg, 19 mmol) and the mixture is stirred for 1 h. THF is evaporated and the aq. phase is diluted with water (50 mL), cooled to 0° C. and acidified to pH 2-3 with an aq. 1M HCl solution. The precipitated product is filtered, washed with water (20 mL) and dried under HV. LC-MS method A: t.sub.R=0.57; 1H NMR (400 MHz, DMSO) δ: 8.27 (m, 1H), 7.67 (m, 1H), 7.41 (m, 1H).

A-4.10: 3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic Acid

A-4.10a: 3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic Acid Ethyl Ester

(57) The title compound is prepared in analogy to the preparation described in Bioorganic & Medicinal Chemistry Letters 18 (2008), 4521-4524.

(58) 2,4-Difluorobenzaldehyde oxime (prepared according to procedure described in Bioorganic & Medicinal Chemistry Letters, 20 (2010), 1272-1277) (4.25 g, 24.4 mmol) is dissolved in THF (50 mL). Then pyridine (2.46 mL, 30.5 mmol) is added. The mixture is heated up to 60° C. and N-chlorosuccinimide (3.58 g, 26.8 mmol) is added. The reaction mixture is stirred at 60° C. for 45 min and then TEA (4.11 mL, 29.2 mmol) and ethyl propiolate (2.72 mL, 26.8 mmol) are added. The reaction mixture is stirred overnight at 60° C. and then concentrated under HV. The residue is taken up in DCM (100 ml) and diluted with aq. 1M HCl (100 mL). The separated organic phase is washed with water (100 mL). The organic phase is dried over MgSO.sub.4, filtered and the solvent is evaporated under HV. The crude is purified by flash chromatography using n-Heptan/EtOAc 9/1 as eluent to yield the title compound. LC-MS method A: t.sub.R=0.92 min.

A-4.10: 3-(2,4-Difluoro-phenyl)-isoxazole-5-carboxylic Acid

(59) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.10a. LC-MS method A: t.sub.R=0.68 min. 1H NMR (400 MHz, DMSO) δ: 14.48 (bs, 1H), 7.99-8.05 (m, 1H), 7.50-7.56 (m, 2H), 7.30 (m, 1H).

A-4.11: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.11a: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic Acid Methyl Ester

(60) To a solution of methyl 5-(4-fluorophenyl)isoxazole-3-carboxylate (246 mg, 1.11 mmol) in tetramethylene sulfone (4 mL, 41.6 mmol) is added Selectfluor® (498 mg, 1.33 mmol). The reaction mixture is stirred at 150° C. overnight. DCM (20 mL) and water (20 mL) are added. After separation of the layers, the aq. phase is extracted with DCM (20 mL). The combined organic layer are washed with water (3×20 mL), dried over MgSO.sub.4, filtered and evaporated. The crude product is purified by flash chromatography using n-heptane to n-heptane/ethyl acetate (7:3) as eluent to yield the title compound. LC-MS method A: t.sub.R=1.01 min.

A-4.11: 4-Fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic Acid

(61) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.11a. LC-MS method A: t.sub.R=0.79 min.

A-4.12: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic Acid A-4.12a: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic Acid Ethyl Ester

(62) The title compound is prepared according to the procedure A-4.11, starting from 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester. LC-MS method A: t.sub.R=1.01 min.

A-4.12: 5-(2,4-Difluoro-phenyl)-4-fluoro-isoxazole-3-carboxylic Acid

(63) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.12a. LC-MS method A: t.sub.R=0.76 min.

A-4.13: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

A-4.13a: 2,4-Dioxo-4-(2-trifluoromethyl-phenyl)-butyric Acid Ethyl Ester

(64) To a solution of sodium ethoxide (21% in EtOH) (2.16 mL, 5.79 mmol) at RT is added diethyl oxalate (0.929 mL, 6.84 mmol) in one portion. A solution of 2-(trifluoromethyl)acetophenone (0.797 mL, 5.26 mmol) in THF (3 mL) is added dropwise to the reaction mixture. The brown RM is stirred 1 h at RT. The reaction is slowly quenched by dropwise addition of 1M HCl (8 mL). THF is evaporated. The residue is partitioned between DCM (10 mL) and sat. NaHCO3 solution (10 mL) and the aq. phase is extracted with DCM (2×10 mL), dried over MgSO4, filtered and evaporated to yield the title compound as an orange oil; LC-MS method A: t.sub.R=1.00 min. [M+H].sup.+=289.16.

A-4.13b: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(65) Hydroxylamine hydrochloride (0.372 mL, 5.46 mmol) is added to a solution of 2,4-dioxo-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester (1500 mg, 5.2 mmol) in EtOH (20 mL). The mixture is heated to 70° C. overnight. To the hot mixture, water (10 mL) is added dropwise. After addition, the mixture is allowed to cool down to RT. DCM (10 mL) and sat. NaHCO3 solution (10 mL) are added and the aq. phase is extracted with DCM (2×10 mL), dried over MgSO4, filtered and evaporated. The crude product is purified by LC-MS method E. LC-MS method A: t.sub.R=1.01 min. [M+H].sup.+=286.17.

A-4.13: 5-(2-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

(66) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.13b. LC-MS method A: t.sub.R=0.80 min. [M+H+MeCN].sup.+=299.13.

A-4.14: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.14a: 4-(2,6-Difluoro-phenyl)-2,4-dioxo-butyric Acid Ethyl Ester

(67) The title compound is prepared according to the procedure A-4.13a, starting from 1-(2,6-difluorophenyl)ethan-1-one. LC-MS method A: t.sub.R=1.00 min.

A-4.14b: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(68) The title compound is prepared according to the procedure A-4.13b, starting from building block A-4.14a. LC-MS method A: t.sub.R=0.97 min. [M+H].sup.+=254.20.

A-4.14: 5-(2,6-Difluoro-phenyl)-isoxazole-3-carboxylic Acid

(69) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.14b. LC-MS method A: t.sub.R=0.74 min. [M+H+MeCN].sup.+=267.14

A-4.15: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

A-4.15a: 2,4-Dioxo-4-(4-trifluoromethyl-phenyl)-butyric Acid Ethyl Ester

(70) The title compound is prepared according to the procedure A-4.13a, starting from 1-(4-(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A: t.sub.R=1.05 min. [M+H].sup.+=288.96.

A-4.15b: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(71) The title compound is prepared according to the procedure A-4.13b, starting from building block A-4.15a. LC-MS method A: t.sub.R=1.05 min. [M+H+MeCN].sup.+=327.06.

A-4.15: 5-(4-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

(72) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.15b. LC-MS method A: t.sub.R=0.85 min.

A-4.16: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

A-4.16a: 2,4-Dioxo-4-(3-trifluoromethyl-phenyl)-butyric Acid Ethyl Ester

(73) The title compound is prepared according to the procedure A-4.13a, starting from 1-(3-(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A: t.sub.R=1.05 min. [M+H].sup.+=289.17.

A-4.16b: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(74) The title compound is prepared according to the procedure A-4.13b, starting from building block A-4.16a. LC-MS method A: t.sub.R=1.05 min. [M+H].sup.+=286.18.

A-4.16: 5-(3-Trifluoromethyl-phenyl)-isoxazole-3-carboxylic Acid

(75) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.16b. LC-MS method A: t.sub.R=0.85 min.

A-4.17: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid

A-4.17a: 2,4-Dioxo-4-(2,3,4-trifluoro-phenyl)-butyric Acid Ethyl Ester

(76) The title compound is prepared according to the procedure A-4.13a, starting from 1-(2,3,4-trifluorophenyl)ethan-1-one. LC-MS method A: t.sub.R=1.04 min. [M+H].sup.+=275.17.

A-4.17b: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid Ethyl Ester

(77) The title compound is prepared according to the procedure A-4.13b, starting from building block A-4.17a. LC-MS method A: t.sub.R=1.02 min.

A-4.17: 5-(2,3,4-Trifluoro-phenyl)-isoxazole-3-carboxylic Acid

(78) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.17b. LC-MS method A: t.sub.R=0.79 min.

A-4.18: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic Acid

A-4.18a: 4-(5-Fluoro-pyridin-2-yl)-2,4-dioxo-butyric Acid Ethyl Ester

(79) The title compound is prepared according to the procedure A-4.13a, starting from 1-(5-fluoropyridin-2-yl)ethan-1-one. LC-MS method A: t.sub.R=0.89 min. [M+H].sup.+=240.25.

A-4.18b: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic Acid Ethyl Ester

(80) The title compound is prepared according to the procedure A-4.13b, starting from building block A-4.18a. LC-MS method A: t.sub.R=0.85 min. [M+H].sup.+=237.28.

A-4.18: 5-(5-Fluoro-pyridin-2-yl)-isoxazole-3-carboxylic Acid

(81) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.18b. LC-MS method A: t.sub.R=0.59 min. [M+H].sup.+=209.37.

A-4.19: 4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid

A-4.19a: 4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid Ethyl Ester

(82) 2-Acetoxy-2′,4′-difluoroacetophenone (200 mg, 0.934 mmol) is dissolved in p-xylene (10 mL). Ethyl oxamate (437 mg, 3.74 mmol) and boron trifluoride diethyl etherate (0.248 mL, 0.934 mmol) are added. The reaction mixture is heated to 150° C. for 20 h.

(83) The reaction mixture is diluted with EtOAc (40 mL) and washed with saturated NaHCO.sub.3 solution (20 mL). After separation of the layers the aq. layer is extracted with EtOAc (2×20 mL). The combined organic layers are dried over MgSO.sub.4, filtered and evaporated. The crude product is purified by LC-MS method E. LC-MS method A: t.sub.R=0.96 min. [M+H].sup.+=254.11.

A-4.19: 4-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid

(84) The title compound is prepared according to the procedure A-4.09, starting from building block A-4.19b. LC-MS method A: t.sub.R=0.69 min. [M+H].sup.+=226.23.

A-4.20: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid

A-4.20a: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid Ethyl Ester

(85) The title compound is prepared according to the procedure A-4.08a, starting from ethyl 2-diazo-3-oxopropanoate and 2,4,6-trifluoroaniline. LC-MS method A: t.sub.R=0.84 min. [M+H].sup.+=272.29.

A-4.20: 1-(2,4,6-Trifluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic Acid

(86) The title compound is prepared according to the procedure A-4.08, starting from building block A-4.20a. LC-MS method A: t.sub.R=0.65 min. [M+H].sup.+=244.24.

A-4.21: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic Acid

A-4.21a: 5-(2,4-Difluorophenyl)-3-methylisothiazole

(87) Pd(PPh.sub.3).sub.4 (892 mg, 0.77 mmol) is added to a degassed solution of 5-bromo-3-methylisothiazole (1446 mg, 7.72 mmol), 2,4,difluorophenylboronic acid (1462 mg, 9.26 mmol) and K.sub.3PO.sub.4 (8355 mg, 748 mmol) in dioxane (64 mL) and water (10 mL). The resulting solution is stirred for 24 h at 90° C. under argon. The resulting mixture is diluted with DCM (100 mL) and washed with H.sub.2O (100 mL). The organic layer is separated and the aq. phase is extracted twice with DCM (2×100 mL). The combined organic layers are dried over anhydrous sodium sulfate and filtered. The resulting mixture is concentrated under vacuum. The crude is purified by flash silicagel chromatography using n-heptan to n-heptan/EtOAc 85:15 as eluent to yield the title compound as a white powder. LC-MS method A: t.sub.R=1.01 min. [M+H].sup.+=212.19.

A-4.21b: 3-Bromomethyl-5-(2,4-difluoro-phenyl)-isothiazole

(88) A mixture of 5-(2,4-difluorophenyl)-3-methylisothiazole (1042 mg, 4.93 mmol), N-bromosuccinimide (966 mg, 5.43 mmol) and benzoyl peroxide (119 mg, 0.49 mmol) in trifluorotoluene (40 mL) is refluxed for 30 h. More NBS (500 mg, 2.8 mmol), benzoyl peroxide (80 mg, 0.33 mmol) are added and the mixture is then refluxed 2 h. It is diluted with DCM (100 mL) and water (100 mL). The organic layer is separated and the aq. layer is extracted with DCM (100 mL). The combined organic layers are dried over anhydrous sodium sulfate, concentrated, and purified by flash silicagel chromatography using DCM/n-heptan 1:1 as eluent to yield the title compound as a sticky oil. LC-MS method A: t.sub.R=1.06 min. [M+H].sup.+=292.09.

A-4.21c: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic Acid Ethyl Ester

(89) A suspension of 3-bromomethyl-5-(2,4-difluoro-phenyl)-isothiazole (1150 mg, 3.96 mmol) in water (10 mL) at reflux is treated with small portions of potassium permanganate (860 mg, 5.39 mmol) over 30 minutes. The reaction mixture is stirred for 5 h. During this time the purple coloration turns to a colorless liquid with a black suspension, which is filtered through a Whatmann GF/A filtered and evaporated. The crude is diluted with DCM (25 mL) and sat. HCl 1N (25 mL) The aq. phase is extracted thrice with DCM (3×25 mL). The combined organic extracts are dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude contains mainly starting material. The black residue is diluted in ethanol (200 ml) and 4N HCl in dioxane (25 mL) is added. The reaction mixture is refluxed overnight. The black slurry turns to a clear solution and the corresponding ester has been formed. The solution is concentrated in vacuo. The crude is purified by flash silicagel chromatography using n-heptan to n-heptan/EtOAc 95:5 as eluent to yield the title compound as a white powder. LC-MS method A: t.sub.R=1.06 min. [M+H].sup.+=270.17.

A-4.21: 5-(2,4-Difluoro-phenyl)-isothiazole-3-carboxylic Acid

(90) A solution of 5-(2,4-difluoro-phenyl)-isothiazole-3-carboxylic acid ethyl ester (216 mg, 0.8 mmol) in EtOH/1N aq. NaOH (4 mL) is stirred for 24 h at RT. The reaction mixture is washed with EtOAc (10 mL). The aq. phase is made acidic with 1N HCl (5 mL) and then extracted five times with DCM (5×10 mL). The combined extracts are dried over MgSO4, filtered and concentrated in vacuo to yield the title compound as a white powder. LC-MS method A: t.sub.R=0.84 min. [M+H].sup.+=241.83.

(91) General Method A for the Synthesis of Compounds of Formula (I)

(92) Buildings Blocks:

(93) Preparation of Building Blocks of Structure 1.

(94) ##STR00024##

BB 1.01: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.01a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic Acid Methyl Ester

(95) To a solution of rac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester (3.0 g, 11.3 mmol) in DCM (56.4 mL) at RT is added cyclohexanone (1.42 mL, 13.5 mmol) followed by acetic acid (0.966 mL, 16.9 mmol) and sodium triacetoxyborohydride (3.39 g, 15.2 mmol). After stirring for 5 h, additional cyclohexanone (0.23 mL, 2.3 mmol), acetic acid (0.17 mL, 2.8 mmol) and sodium triacetoxyborohydride (590 mg, 2.8 mmol) are added. The reaction mixture is stirred overnight. The reaction mixture is diluted with DCM (200 mL) and treated with aq. sat. NaHCO.sub.3 (250 mL). The organic phase is dried over MgSO.sub.4 and evaporated. The crude title compound is used in the next step without further purification; LC-MS method D t.sub.R=1.09 min; [M+H].sup.+=341.19.

1.01b: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic Acid Methyl Ester

(96) rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic acid methyl ester 1.01a (3.85 g, 11.3 mmol) is dissolved in MeOH (56.5 mL). A 4M solution of HCl in dioxane (56.5 mL, 226 mmol) is added and the reaction is stirred for 1 h. The reaction mixture is concentrated, dissolved in DCM (250 mL) and treated with aq. sat. NaHCO.sub.3 (200 mL). The organic layer is separated and the aq. phase is extracted with DCM (150 mL). The combined organic layers are dried over MgSO.sub.4 and evaporated. The crude title compound is obtained as a yellow oil; LC-MS method D t.sub.R=0.79 min; [M+H].sup.+=241.20.

1.01c: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(97) To a solution of rac-(3R*,4R*)-4-amino-1-cyclohexyl-piperidine-3-carboxylic acid methyl ester 1.01b (2.64 g, 10.4 mmol) in DMF (56.7 mL) at RT is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acid (2.42 g, 10.4 mmol). DIPEA (5.83 mL, 33.4 mmol) is then added followed by HATU (4.16 g, 10.9 mmol). The reaction mixture is stirred overnight (17 h). The reaction mixture is concentrated, dissolved in DCM (300 mL) and treated with aq. sat. NaHCO.sub.3 (225 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The crude residue is purified by prep. LC-MS under basic conditions (method E). The title compound is obtained as white powder; LC-MS method D t.sub.R=1.15 min; [M+H].sup.+=448.19.

1.01: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(98) rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester 1.01c (2.24 g, 5 mmol) is dissolved in THF (30.6 mL) at RT. Aq. 1M NaOH solution (15 mL, 15 mmol) is then added and the mixture stirred for 6.5 h. The reaction mixture is acidified to around pH=3 with a 2M HCl solution (7.75 mL) and evaporated. The resulting suspension is filtered, washed twice with water (2×4 mL) and dried under HV. The title compound is obtained as a white powder; LC-MS method D t.sub.R=0.61 min; [M+H].sup.+=433.89.

(99) Preparation of Building-Blocks of Structure 1 Used as Intermediates in the Preparation of Examples 1.001 to 1.199

(100) The following intermediates are prepared in analogy to BB 1.01:

BB 1.02: rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.02c: rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(101) The title compound is prepared according to the procedure 1.01c, starting from building block 1.01b and building block A-4.08; LC-MS method D: t.sub.R=1.03 min; [M+H].sup.+=448.15.

1.02: rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

(102) The title compound is prepared according to the procedure 1.01, starting from building block 1.02c; LC-MS method D: t.sub.R=0.54 min; [M+H].sup.+=433.88.

BB 1.03: rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.03a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopentyl-piperidine-3-carboxylic Acid Methyl Ester

(103) The title compound is prepared according to the procedure 1.01a, starting from rac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester and cyclopentanone; LC-MS method D: t.sub.R=1.0 min; [M+H].sup.+=327.18.

1.03b: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylic Acid Methyl Ester

(104) The title compound is prepared according to the procedure 1.01b, starting from building block 1.03a; LC-MS method D: t.sub.R=0.71 min; [M+H].sup.+=227.18.

1.03c: rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(105) The title compound is prepared according to the procedure 1.01c, starting from building block 1.03b and building block A-4.08; LC-MS method D: t.sub.R=0.95 min; [M+H].sup.+=433.9.

1.03: rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

(106) The title compound is prepared according to the procedure 1.01, starting from building block 1.03c; LC-MS method D: t.sub.R=0.49 min; [M+H].sup.+=420.07.

BB 1.04: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.04a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid Methyl Ester

(107) The title compound is prepared according to the procedure 1.01a, starting from rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester and cyclopropanecarbaldehyde; LC-MS method D: t.sub.R=0.94 min; [M+H].sup.+=313.18.

1.04b: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid Methyl Ester

(108) The title compound is prepared according to the procedure 1.01b, starting from building block 1.04a; LC-MS method D: t.sub.R=0.64 min; [M+H].sup.+=213.21.

1.04c: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic Acid Methyl Ester

(109) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.08; LC-MS method D: t.sub.R=0.89 min; [M+H].sup.+=420.1.

1.04: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic Acid

(110) The title compound is prepared according to the procedure 1.01, starting from building block 1.04c; LC-MS method D: t.sub.R=0.48 min; [M+H].sup.+=406.09.

BB 1.05: rac-(3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic Acid

1.05a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-(2-methyl-cyclopentyl)-piperidine-3-carboxylic Acid Methyl Ester

(111) The title compound is prepared according to the procedure 1.01a, starting from rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester and 2-methyl-cyclopentanone; LC-MS method D: t.sub.R=1.16 min; [M+H].sup.+=341.2.

1.05b: rac-(3R*,4R*)-4-Amino-1-(2-methyl-cyclobentyl)-piperidine-3-carboxylic acid methyl Ester

(112) The title compound is prepared according to the procedure 1.01b, starting from building block 1.05a; LC-MS method D: t.sub.R=0.83 min; [M+H].sup.+=241.19.

1.05c: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(113) The title compound is prepared according to the procedure 1.01c, starting from building block 1.05b and building block A-4.08; LC-MS method D: t.sub.R=1.08 min; [M+H].sup.+=448.15.

1.05: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid

(114) The title compound is prepared according to the procedure 1.01, starting from building block 1.05c; LC-MS method D: t.sub.R=0.53 min; [M+H].sup.+=433.82.

BB 1.06: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.06c: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(115) The title compound is prepared according to the procedure 1.01c, starting from building block 1.03b and building block A-4.01; LC-MS method D: t.sub.R=1.06 min; [M+H].sup.+=452.13.

1.06: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(116) The title compound is prepared according to the procedure 1.01, starting from building block 1.06c; LC-MS method D: t.sub.R=0.55 min; [M+H].sup.+=438.1.

BB 1.07: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.07c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(117) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.01; LC-MS method D: t.sub.R=1.0 min; [M+H].sup.+=438.11.

1.07: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(118) The title compound is prepared according to the procedure 1.01, starting from building block 1.07c; LC-MS method D: t.sub.R=0.53 min; [M+H].sup.+=424.09.

BB 1.08: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.08c: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(119) The title compound is prepared according to the procedure 1.01c, starting from building block 1.05b and building block A-4.01; LC-MS method D: t.sub.R=1.09 min; [M+H].sup.+=448.14.

1.08: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(120) The title compound is prepared according to the procedure 1.01, starting from building block 1.08c; LC-MS method D: t.sub.R=0.53 min; [M+H].sup.+=433.82.

BB 1.09: rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.09c: rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(121) The title compound is prepared according to the procedure 1.01c, starting from building block 1.01b and building block A-4.10; LC-MS method D: t.sub.R=1.11 min; [M+H].sup.+=448.14.

1.09: rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

(122) The title compound is prepared according to the procedure 1.01, starting from building block 1.09c; LC-MS method D: t.sub.R=0.58 min; [M+H].sup.+=433.88.

BB 1.10: rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.10c: rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(123) The title compound is prepared according to the procedure 1.01c, starting from building block 1.03b and building block A-4.10; LC-MS method D: t.sub.R=1.03 min; [M+H].sup.+=433.88.

1.10: rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

(124) The title compound is prepared according to the procedure 1.01, starting from building block 1.10c; LC-MS method D: t.sub.R=0.54 min; [M+H].sup.+=420.12.

BB 1.11: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.11c: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(125) The title compound is prepared according to the procedure 1.01c, starting from building block 1.01b and building block A-4.01; LC-MS method D: t.sub.R=1.14 min; [M+H].sup.+=465.9.

1.11: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(126) The title compound is prepared according to the procedure 1.01, starting from building block 1.11c; LC-MS method D: t.sub.R=0.59 min; [M+H].sup.+=452.1.

BB 1.12: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.12c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(127) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.10; LC-MS method D: t.sub.R=0.98 min; [M+H].sup.+=420.11.

1.12: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

(128) The title compound is prepared according to the procedure 1.01, starting from building block 1.12c; LC-MS method D: t.sub.R=0.52 min; [M+H].sup.+=406.07.

BB 1.13: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.13c: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(129) The title compound is prepared according to the procedure 1.01c, starting from building block 1.05b and building block A-4.10; LC-MS method D: t.sub.R=1.15 min; [M+H].sup.+=448.14.

1.13: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic Acid

(130) The title compound is prepared according to the procedure 1.01, starting from building block 1.13c; LC-MS method D: t.sub.R=0.59 min; [M+H].sup.+=433.87.

BB 1.14: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.14c: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(131) The title compound is prepared according to the procedure 1.01c, starting from building block 1.01b and building block A-4.09; LC-MS method D: t.sub.R=1.07 min; [M+H].sup.+=449.03.

1.14: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(132) The title compound is prepared according to the procedure 1.01, starting from building block 1.14c; LC-MS method D: t.sub.R=0.55 min; [M+H].sup.+=435.1.

BB 1.15: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.15c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic Acid Methyl Ester

(133) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.09; LC-MS method D: t.sub.R=0.93 min; [M+H].sup.+=421.1.

1.15: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(134) The title compound is prepared according to the procedure 1.01, starting from building block 1.15c; LC-MS method D: t.sub.R=0.49 min; [M+H].sup.+=407.05.

BB 1.16: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.16c: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(135) The title compound is prepared according to the procedure 1.01c, starting from building block 1.03b and building block A-4.09; LC-MS method D: t.sub.R=0.99 min; [M+H].sup.+=435.1.

1.16: rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(136) The title compound is prepared according to the procedure 1.01, starting from building block 1.16c; LC-MS method D: t.sub.R=0.51 min; [M+H].sup.+=421.1.

BB 1.17: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.17c: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic Acid Methyl Ester

(137) The title compound is prepared according to the procedure 1.01c, starting from building block 1.05b and building block A-4.09; LC-MS method D: t.sub.R=1.12 min; [M+H].sup.+=449.02.

1.17: rac-(3R*,4R*)-1-(2-Methyl-cyclopentyl)-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic Acid

(138) The title compound is prepared according to the procedure 1.01, starting from building block 1.17c; LC-MS method D: t.sub.R=0.56 min; [M+H].sup.+=435.1.

BB 1.18: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(139) The title compound is prepared according to the procedure 1.01c, starting from building block 1.01b and building block A-4.07; LC-MS method D: t.sub.R=1.05 min; [M+H].sup.+=449.08.

BB 1.19: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.19c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(140) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and 5-(2,4-dichlorophenyl)-1,2-oxazole-3-carboxylic acid; LC-MS method A: t.sub.R=0.75 min; [M+H].sup.+=451.98.

1.19: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(141) The title compound is prepared according to the procedure 1.01, starting from building block 1.19c; LC-MS method A: t.sub.R=0.70 min; [M+H].sup.+=438.11.

BB 1.20: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.20c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(142) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.13; LC-MS method A: t.sub.R=0.73 min; [M+H].sup.+=452.11.

1.20: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(143) The title compound is prepared according to the procedure 1.01, starting from building block 1.20c; LC-MS method A: t.sub.R=0.67 min; [M+H].sup.+=438.22.

BB 1.21: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.21c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(144) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.14; LC-MS method A: t.sub.R=0.68 min; [M+H].sup.+=420.11.

1.21: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(145) The title compound is prepared according to the procedure 1.01, starting from building block 1.21c; LC-MS method A: t.sub.R=0.62 min; [M+H].sup.+=406.22.

BB 1.22: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.22c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(146) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.15; LC-MS method A: t.sub.R=0.75 min; [M+H].sup.+=452.07.

1.22: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(147) The title compound is prepared according to the procedure 1.01, starting from building block 1.22c; LC-MS method A: t.sub.R=0.70 min; [M+H].sup.+=438.25.

BB 1.23: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.23c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(148) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.16; LC-MS method A: t.sub.R=0.74 min; [M+H].sup.+=452.09.

1.23: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(149) The title compound is prepared according to the procedure 1.01, starting from building block 1.23c; LC-MS method A: t.sub.R=0.69 min; [M+H].sup.+=438.25.

BB 1.24: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.24c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(150) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.17; LC-MS method A: t.sub.R=0.72 min; [M+H].sup.+=438.16.

1.24: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(151) The title compound is prepared according to the procedure 1.01, starting from building block 1.24c; LC-MS method A: t.sub.R=0.66 min; [M+H].sup.+=424.15.

BB 1.25: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.25c: rac-(R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(152) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and 5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carboxylic acid; LC-MS method A: t.sub.R=0.69 min; [M+H].sup.+=432.29.

1.25: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(153) The title compound is prepared according to the procedure 1.01, starting from building block 1.25c; LC-MS method A: t.sub.R=0.67 min; [M+H].sup.+=418.07.

BB 1.26: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

1.26c: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(154) The title compound is prepared according to the procedure 1.01c, starting from building block 1.04b and building block A-4.18; LC-MS method A: t.sub.R=0.59 min; [M+H].sup.+=403.16.

1.26: rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(155) The title compound is prepared according to the procedure 1.01, starting from building block 1.26c; LC-MS method A: t.sub.R=0.54 min; [M+H].sup.+=389.22.

(156) General Procedures for the Preparation of Examples 1.001 to 1.199:

(157) Method A:

(158) To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26) (0.1 mmol) in 1 mL DMF is added the respective amine (commercially available) (0.12 to 0.15 mmol). DIPEA (0.3 mmol; 0.6 mmol if the amine is an hydrochloride salt) is then added followed by HATU (0.105 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified by prep. LC-MS with method E.

(159) Method B:

(160) To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26) (0.05 mmol) in pyridine (1 mL) at RT is added the respective commercially available amine ((0.1 mmol). POCl.sub.3 (0.1 mmol) is then added and the mixture is stirred at RT for 2 h. Water (50 μL) is added and the resulting solution is evaporated. The crude residue is purified by prep. LC-MS with method E.

(161) Method C:

(162) To a solution of the respective carboxylic acid (BB 1.01 to BB 1.26) (0.07 mmol) and a commercially available amine (0.067 mmol) in 2 mL DCM, is added TEA (0.29 mmol) and T3P 50% in DCM (0.08 mL, 0.135 mmol). The mixture is stirred 24 h at RT and then the reaction mixture is washed with aq. sat. NaHCO.sub.3 and water. The organic solvent is evaporated and the residue is purified by prep HPLC using method E.

Example 1.001: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide

(163) To a solution of rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (43.3 mg, 0.1 mmol) in DMF (1 mL) is added 2-(2-pyridyl)-2-propylamine dihydrochloride (41.8 mg, 0.2 mmol). DIPEA (0.055 mL, 0.32 mmol) is then added followed by HATU (39.9 mg, 0.105 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified by prep. LC-MS with method E. LC-MS method D: t.sub.R=1.07 min; [M+H].sup.+=552.15.

(164) Compounds of Examples 1.001a to 1.199 listed in Table 1 below are prepared by applying one of the above-mentioned general procedures A, B or C to the building blocks BB-1.01-BB-1.26 coupled with commercially available amines of Structure 2.

(165) Enantiomerically pure compounds are obtained by using one of the above mentioned chiral preparative chromatography methods.

(166) TABLE-US-00001 TABLE 1 Examples 1.001-1.199 QC LC-MS Mass Example Found Nr Substance Name t.sub.R (min) [M + H].sup.+ 1.001 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 552 carbonyl]-amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl- ethyl)-amide 1.001a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.66 552.3 amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.001b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.66 552.2 amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.002 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64 551 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.002a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 551.2 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1) 1.002b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 551 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 2) 1.003 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71 501.1 carbonyl]-amino}-piperidine-3-carboxylic acid cyclopentylamide 1.004 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.67 487.4 cyclohexyl-3-(pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide 1.005 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 491.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-hydroxy-ethyl)-methyl- amide 1.006 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 491.1 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-ethyl)-amide 1.007 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71 489.4 carbonyl]-amino}-piperidine-3-carboxylic acid isobutyl-amide 1.008 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66 475.3 carbonyl]-amino}-piperidine-3-carboxylic acid isopropylamide 1.009 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 461.1 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.010 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 447.3 carbonyl]-amino}-piperidine-3-carboxylic acid methylamide 1.011 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 479.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-fluoro-ethyl)-amide 1.012 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.62 461.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethylamide 1.013 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.68 487.3 carbonyl]-amino}-piperidine-3-carboxylic acid cyclopropyl-methyl-amide 1.014 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.54 490.1 carbonyl]-amino}-piperidine-3-carboxylic acid carbamoylmethyl-amide 1.015 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.56 477.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide 1.016 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.63 503.1 cyclohexyl-3-(morpholine-4-carbonyl)-piperidin-4-yl]-amide 1.017 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.72 489.1 carbonyl]-amino}-piperidine-3-carboxylic acid isopropyl-methyl-amide 1.018 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.42 518.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-dimethylamino-ethyl)- methyl-amide 1.019 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71 519.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-ethoxy-ethyl)-methyl- amide 1.020 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66 544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (5-methyl-thiazol-2- ylmethyl)-amide 1.021 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.67 505.1 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-ethyl)-methyl- amide 1.022 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 528.3 carbonyl]-amino}-piperidine-3-carboxylic acid (5-methyl-isoxazol-3- ylmethyl)-amide 1.023 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.4 504.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-dimethylamino-ethyl)- amide 1.024 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.67 475.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethyl-methyl-amide 1.025 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid (pyridin-2-ylmethyl)-amide 1.026 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64 497.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2,2-difluoro-ethyl)-amide 1.027 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 519.3 carbonyl]-amino}-piperidine-3-carboxylic acid (3-methoxy-propyl)-methyl- amide 1.028 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.58 503.3 cyclohexyl-3-((3RS)-3-hydroxy-pyrrolidine-1-carbonyl)-piperidin-4-yl]- amide (mixture of isomers) 1.029 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 528.3 carbonyl]-amino}-piperidine-3-carboxylic acid (3-methyl-isoxazol-5- ylmethyl)-amide 1.030 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3- 0.62 473.3 (azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide 1.031 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 544.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methyl-thiazol-4- ylmethyl)-amide 1.032 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 525.3 carbonyl]-amino}-piperidine-3-carboxylic acid (pyrimidin-2-ylmethyl)- amide 1.033 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (4-methyl-thiazol-5- ylmethyl)-amide 1.034 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57 525.1 carbonyl]-amino}-piperidine-3-carboxylic acid (pyrimidin-4-ylmethyl)- amide 1.035 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 514.3 carbonyl]-amino}-piperidine-3-carboxylic acid (oxazol-5-ylmethyl)-amide 1.036 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.63 491.3 cyclohexyl-3-(3-fluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide 1.037 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 525.3 carbonyl]-amino}-piperidine-3-carboxylic acid (pyrazin-2-ylmethyl)-amide 1.038 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.71 545.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-trifluoromethoxy-ethyl)- amide 1.039 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.62 517.1 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-oxetan-3-ylmethyl- amide 1.040 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 539 amino}-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.041 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 544 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(2-oxo-pyrrolidin-1-yl)- ethyl]-amide 1.042 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 527.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-methyl-1H-pyrazol-3- ylmetyl)-amide 1.043 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.39 513.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1H-imidazol-4-ylmethyl)- amide 1.044 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 517.1 amino}-piperidine-3-carboxylic acid ((2RS)-tetrahydro-furan-2-ylmethyl)- amide (mixture of isomers) 1.045 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 541.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1,5-dimethyl-1H-pyrazol- 3-ylmethyl)-amide 1.046a (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]- 0.78 567.3 amino}-piperidine-3-carboxylic acid ((1S,2R)-2-phenyl-cyclopropyl)- amide or (3R,4R)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- carbonyl]-amino}-piperidine-3-carboxylic acid ((1R,2S)-2-phenyl- cyclopropyl)-amide or (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)- isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1S,2R)-2- phenyl-cyclopropyl)-amide or (3S,4S)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro- phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide (1.sup.st eluted enantiomer) 1.047 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66 543.3 carbonyl]-amino}-piperidine-3-carboxylic acid (3-ethyl-[1,2,4]oxadiazol-5- ylmethyl)-amide 1.048 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid (pyridin-3-ylmethyl)-amide 1.049 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.82 551 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-phenethyl-amide 1.050 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.46 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid (pyridin-4-ylmethyl)-amide 1.051 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 530.3 carbonyl]-amino}-piperidine-3-carboxylic acid (thiazol-2-ylmethyl)-amide 1.052 rac-5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.67 509.3 cyclohexyl-3-(3,3-difluoro-azetidine-1-carbonyl)-piperidin-4-yl]-amide 1.053 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.61 517.4 amino}-piperidine-3-carboxylic acid ((3RS)-tetrahydro-furan-3-ylmethyl)- amide (mixture of isomers) 1.054 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 541.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2,5-dimethyl-2H-pyrazol- 3-ylmethyl)-amide 1.055 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.46 563.2 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(2-hydroxy-ethoxy)- ethyl]-isopropyl-amide 1.056 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 551.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-o-tolyl-ethyl)-amide 1.057 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.78 567.4 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(2-methoxy-phenyl)- ethyl]-amide 1.058 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.81 571 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(2-chloro-phenyl)-ethyl]- amide 1.059 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.77 555.1 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]- amide 1.060 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.8 551.4 amino}-piperidine-3-carboxylic acid ((2RS)-2-phenyl-propyl)-amide (mixture of isomers) 1.061 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.79 549.4 amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl-cyclopropyl)- amide and (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl- cyclopropyl)-amide (mixture of isomers) 1.062 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.82 551 carbonyl]-amino}-piperidine-3-carboxylic acid (2-p-tolyl-ethyl)-amide 1.063 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.59 539 amino}-piperidine-3-carboxylic acid ((1RS)-1-(pyrimidin-4-yl)-ethyl)- amide (mixture of isomers) 1.064 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.74 509.3 carbonyl]-amino}-piperidine-3-carboxylic acid phenylamide 1.065 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.77 544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (4,5-dimethyl-thiazol-2-yl)- amide 1.066 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.81 551.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-m-tolyl-ethyl)-amide 1.067 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57 510.1 carbonyl]-amino}-piperidine-3-carboxylic acid pyridin-3-ylamide 1.068 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.66 544.1 carbonyl]-amino}-piperidine-3-carboxylic acid (4-methyl-thiazol-2- ylmethyl)-amide 1.069 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.73 592.3 amino}-piperidine-3-carboxylic acid ((1RS)-2,2,2-trifluoro-1-pyridin-2-yl- ethyl)-amide (mixture of isomers) 1.070 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.81 563 cyclohexyl-3-((3RS)-3-phenyl-pyrrolidine-1-carbonyl)-piperidin-4-yl]- amide (mixture of isomers) 1.071 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 550.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 1.072 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.69 553 amino}-piperidine-3-carboxylic acid ((R)-2-hydroxy-2-phenyl-ethyl)-amide (mixture of isomers) 1.073 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.69 553.3 amino}-piperidine-3-carboxylic acid ((S)-2-hydroxy-2-phenyl-ethyl)-amide (mixture of isomers) 1.074 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.52 538.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-pyridin-2-yl-ethyl)-amide 1.075 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.57 552.2 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-(2-pyridin-2-yl- ethyl)-amide 1.076 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.58 491.1 amino}-piperidine-3-carboxylic acid ((1RS)-2-hydroxy-1-methyl-ethyl)- amide (mixture of isomers) 1.077 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.67 511.3 amino}-piperidine-3-carboxylic acid ((1RS)-2,2-difluoro-1-methyl-ethyl)- amide (mixture of isomers) 1.078 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.77 515.4 amino}-piperidine-3-carboxylic acid ((1RS)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.079 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 507 carbonyl]-amino}-piperidine-3-carboxylic acid (2-fluoro-1,1-dimethyl- ethyl)-amide 1.080 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.78 557.3 carbonyl]-amino}-piperidine-3-carboxylic acid (3,3,3-trifluoro-1,1- dimethyl-propyl)-amide 1.081 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 567.1 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methanesulfonyl-1,1- dimethyl-ethyl)-amide 1.082 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 493.3 amino}-piperidine-3-carboxylic acid ((1RS)-2-fluoro-1-methyl-ethyl)- amide (mixture of isomers) 1.083 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.69 519.4 amino}-piperidine-3-carboxylic acid ((1RS)-2-ethoxy-1-methyl-ethyl)- amide (mixture of isomers) 1.084 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 517.2 amino}-piperidine-3-carboxylic acid ((3RS)-3-methyl-tetrahydro-furan-3- yl)-amide (mixture of isomers) 1.085 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 543 amino}-piperidine-3-carboxylic acid [(1RS)-1-(5-methyl-[1,3,4]oxadiazol- 2-yl)-ethyl]-amide (mixture of isomers) 1.086 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.74 574 amino}-piperidine-3-carboxylic acid [(1RS)-1-(3,5-difluoro-pyridin-2-yl)- ethyl]-amide (mixture of isomers) 1.087 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.73 537.3 carbonyl]-amino}-piperidine-3-carboxylic acid (3,3-difluoro-1-methyl- cyclobutyl)-amide (mixture of isomers) 1.088 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 505.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-hydroxy-1,1-dimethyl- ethyl)-amide 1.089 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-1- 0.64 564 cyclohexyl-3-((3RS)-3-pyridin-2-yl-pyrrolidine-1-carbonyl)-piperidin-4-yl]- amide (mixture of isomers) 1.090 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.61 539.4 amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.091 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.77 515.4 amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.092 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.72 556.4 amino}-piperidine-3-carboxylic acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide (mixture of isomers) 1.093 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.79 517.4 amino}-piperidine-3-carboxylic acid ((R)-1,2,2-trimethyl-propyl)-amide (mixture of isomers) 1.094 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.66 557 amino}-piperidine-3-carboxylic acid [(R)-1-(5-fluoro-pyrimidin-2-yl)-ethyl]- amide (mixture of isomers) 1.095 rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole- 0.55 461.3 4-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.095a (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.55 461.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide or (3S,4S)- 1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]- amino}-piperidine-3-carboxylic acid dimethylamide (1.sup.st eluted enantiomer) 1.096 rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5 447.2 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.097 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 1 433.3 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.098 (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]- 0.55 461.3 amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 1.099 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.59 465.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.100 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.58 451.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.101 (3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.63 479.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 1.102 rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.62 461 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.103 rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.57 447 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.104 rac-1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid 0.54 473.3 [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide 1.105 rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3- 0.62 491 (azetidine-1-carbonyl)-1-cyclohexyl-piperidin-4-yl]-amide 1.106 rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3- 0.58 477.1 (azetidine-1-carbonyl)-1-cyclopentyl-piperidin-4-yl]-amide 1.107 rac-5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3- 0.57 463.3 (azetidine-1-carbonyl)-1-cyclopropylmethyl-piperidin-4-yl]-amide 1.108 5-(2,4,6-Trifluoro-phenyl)-isoxazole-3-carboxylic acid [(3R*,4R*)-3- 0.62 491.3 (azetidine-1-carbonyl)-1-((1RS,2RS)-2-methyl-cyclopentyl)-piperidin-4- yl]-amide (mixture of isomers) 1.109 rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.6 505 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (2- methoxy-1,1-dimethyl-ethyl)-amide 1.110 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 1.1 491.3 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (2- methoxy-1,1-dimethyl-ethyl)-amide 1.111 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71 537.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.111a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71 537.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 1) 1.111b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71 537.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 2) 1.112 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.68 523 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.113 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.67 509 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy- 1,1-dimethyl-ethyl)-amide 1.113a (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.67 509.1 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 1) 1.113b (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.67 509.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide (enantiomer 2) 1.114 (3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.7 537 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (2- methoxy-1,1-dimethyl-ethyl)-amide (mixture of isomers) 1.115 rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.69 519 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.116 rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.67 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.117 (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.54 538.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.117a (3S,4S)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.54 538.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide or (3R,4R)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H- [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.118 (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.5 524.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.118a (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.51 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide or (3R,4R)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.119 (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.49 510.1 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.120 (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]- 0.53 538.2 amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.121 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63 556.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.121a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61 556.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 1) 1.121b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63 556.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 2) 1.122 (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 542.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.122a (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.58 542.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 1) 1.122b (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 542.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (enantiomer 2) 1.123 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.57 528.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.123a (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.58 528 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide or (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin- 2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.124 (3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.62 556.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.125 (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- 0.61 538.2 amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.125a (3S,4S)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- 0.62 538.2 amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide or (3R,4R)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.126 (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.58 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.127 (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 1 539.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.128 (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 1 525.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.129 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 557.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.129a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 557.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (enantiomer 1) 1.129b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63 557.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (enantiomer 2) 1.130 (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.59 543.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.131 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.59 529 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.132 (3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.62 557.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.133 (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- 0.59 539.3 amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)-amide (mixture of isomers) 1.134 (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.69 515.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.135 (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.66 501.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.136 (3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.64 487.3 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- cyclobutyl-ethyl)-amide (mixture of isomers) 1.137 (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]- 0.68 515.4 amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.138 (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.74 519.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.138a (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.73 519.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (enantiomer 1) 1.138b (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.74 519.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (enantiomer 2) 1.139 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.72 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.139a (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.71 505.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (enantiomer 1) 1.139b (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.73 505.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (enantiomer 2) 1.140 (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- 0.75 515.4 amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide (mixture of isomers) 1.141 (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.73 501.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.142 rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole- 0.64 568.2 4-carbonyl]-amino}-piperidine-3-carboxylic acid [1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.143 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.72 586.1 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.144 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.68 558.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid [1-(5-fluoro- pyridin-2-yl)-cyclopropyl]-amide 1.145 (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.72 549.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl- cyclopropyl)-amide and (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro- phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.146 (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.69 535.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl- cyclopropyl)-amide and (3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro- phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.147 (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]- 0.77 549.4 amino}-piperidine-3-carboxylic acid ((1S*,2R)-2-phenyl-cyclopropyl)- amide and (3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole- 5-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl- cyclopropyl)-amide(mixture of isomers) 1.148 (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.75 535.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl- cyclopropyl)-amide and (3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro- phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.149 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole- 0.56 433.2 5-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 1.150 (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1- 0.61 461.3 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 1.151 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole- 0.65 491.3 5-carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.152 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole- 0.65 520.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl- ethyl)-amide 1.153 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.61 492.3 [1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (2- methoxy-1,1-dimethyl-ethyl)-amide 1.154 (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.57 510 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.154a (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.58 510 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide or (3R,4R)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)- isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin- 2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.155 (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1- 0.61 538.2 ((1RS,2RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.156 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.56 539.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.156a (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.57 539.2 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide or (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)- [1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (2.sup.nd eluted enantiomer) 1.157 (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.53 525.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 1.158 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.52 511.1 [1,2,4]oxadiazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1- pyridin-2-yl-ethyl)-amide (mixture of isomers) 1.159 (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.55 510.9 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.160 (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.56 540.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrazin-2-yl-ethyl)- amide (mixture of isomers) 1.161 (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.71 487.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)- amide (mixture of isomers) 1.162 (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1- 0.74 515.4 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid ((R)-1- cyclobutyl-ethyl)-amide (mixture of isomers) 1.163 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole- 0.66 540.3 5-carbonyl]-amino}-piperidine-3-carboxylic acid [1-(5-fluoro-pyridin-2-yl)- cyclopropyl]-amide 1.164 (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.73 521.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1S*,2R*)-2-phenyl- cyclopropyl)-amide and (3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4- difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-piperidine-3-carboxylic acid ((1R*,2S*)-2-phenyl-cyclopropyl)-amide (mixture of isomers) 1.165 rac-(3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole- 0.55 550.2 4-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide 1.165a (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.54 550.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 1) 1.165b (3R*,4R*)-1-Cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.55 550.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 2) 1.166 rac-(3R*,4R*)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.51 536.1 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin- 2-yl-cyclopropyl)-amide 1.167 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5 522 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin- 2-yl-cyclopropyl)-amide 1.168 (3R*,4R*)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]- 0.54 550.2 amino}-1-((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide (mixture of isomers) 1.169 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.65 568.3 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 1.170 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 554.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 1.170a (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.6 554.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide or (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole- 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide (1.sup.st eluted enantiomer) 1.171 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.59 540.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide 1.171a (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.58 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 1) 1.171b (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.59 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide (enantiomer 2) 1.172 (3R*,4R*)-1-((1RS,2RS)-2-Methyl-cyclopentyl)-4-{[5-(2,4,6-trifluoro- 0.62 568.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyridin-2-yl-cyclopropyl)-amide (mixture of isomers) 1.173 rac-(3R*,4R*)-1-Cyclopentyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.59 536.3 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 1.174 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole- 0.57 522.1 5-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide 1.175 (3R*,4R*)-4-{[3-(2,4-Difluoro-phenyl)-isoxazole-5-carbonyl]-amino}-1- 0.61 550.2 ((1RS,2RS)-2-Methyl-cyclopentyl)-piperidine-3-carboxylic acid (1-pyridin- 2-yl-cyclopropyl)-amide (mixture of isomers) 1.176 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.62 555.3 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.176a (3S,4S)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61 555.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide or (3R,4R)-1-Cyclopentyl-4-{[5-(2,4,6-trifluoro- phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide (2.sup.nd eluted enantiomer) 1.177 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)- 0.63 541.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 1.178 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 0.61 523.1 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.179 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrazin-2-yl- cyclopropyl)-amide 1.180 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.56 523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridazin-3-yl- cyclopropyl)-amide 1.181 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 537.1 amino}-piperidine-3-carboxylic acid (1-pyrazin-2-yl-cyclopropyl)-amide 1.182 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.57 537.1 amino}-piperidine-3-carboxylic acid (1-pyridazin-3-yl-cyclopropyl)-amide 1.183 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 500.3 carbonyl]-amino}-piperidine-3-carboxylic acid (cyano-dimethyl-methyl)- amide 1.184 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.71 565.4 amino}-piperidine-3-carboxylic acid [1-(4,6-dimethyl-pyrimidin-2-yl)- cyclopropyl]-amide 1.185 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 551.4 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(4,6-dimethyl-pyrimidin- 2-yl)-cyclopropyl]-amide 1.186 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 461.3 amino}-piperidine-3-carboxylic acid dimethylamide 1.187a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 538.4 amino}-piperidine-3-carboxylic acid ((S)-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.187b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 538.3 amino}-piperidine-3-carboxylic acid ((S)-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.187c (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 538.3 amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) 1.187d (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 538.2 amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) 1.188a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 552.2 amino}-piperidine-3-carboxylic acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 1) 1.188b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.59 552.2 amino}-piperidine-3-carboxylic acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 2) 1.188c (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 552.2 amino}-piperidine-3-carboxylic acid [(S)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 1) 1.188.d (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.59 552.2 amino}-piperidine-3-carboxylic acid [(S)-1-(6-methyl-pyridin-2-yl)-ethyl]- amide (enantiomer 2) 1.189 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole- 0.70 555 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.189a (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3- 0.70 555.3 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide or (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-dichloro- phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide (1.sup.st eluted enantiomer) 1.190 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)- 0.7 555.2 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 1.191 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole- 0.6 523.4 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.192 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70 555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 1.192a (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70 555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide (enantiomer 1) 1.192b (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)- 0.70 555.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide (enantiomer 2) 1.193 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)- 0.70 555 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 1.193a (3R,4R)-1-Cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)-isoxazole- 0.70 555.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(3- trifluoromethyl-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3- carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (2.sup.nd eluted enantiomer) 1.194a (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)-isoxazole-3- 0.60 541 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluoro- phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide (1st eluted enantiomer) 1.195 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)- 0.60 535.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 1.196 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)-isoxazole- 0.50 506 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 1.197 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 0.6 536.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclobutyl)-amide 1.198 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 0.8 551.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-methoxy-phenyl)- cyclopropyl]-amide 1.199 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,3-difluoro-phenyl)-isoxazole- 0.6 523.2 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide
General Method B for the Synthesis of Compounds of Formula (I)
Buildings Blocks:
Preparation of Building Blocks of Structure B-6

(167) ##STR00025##

BB 2.01: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Dimethylamide

2.01a: rac-(3R*,4R*)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(168) To a solution of rac-(3R*,4R*)-4-amino-1-benzyl-piperidine-3-carboxylic acid methyl ester (10.00 g, 33.4 mmol) in DMF (200 mL) is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (7.74 g, 33.4 mmol). DIPEA (24.5 mL, 140 mmol) is then added followed by HATU (13.32 g, 35 mmol). The reaction mixture is stirred for 1 h. The reaction mixture is concentrated, diluted with DCM (750 mL) and treated with aq. sat. NaHCO.sub.3 (600 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The crude residue is purified by prep. LC-MS in basic conditions to give the title compound; LC-MS method D t.sub.R=1.14 min; [M+H].sup.+=456.18.

2.01b: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl ester 3-methyl Ester

(169) To a solution of rac-(3R*,4R*)-1-benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester 2.01a (11.33 g, 24.9 mmol) in ethyl acetate (250 mL) under argon is added 10% wet palladium on activated charcoal (2.647, 2.49 mmol) and di-tert-butyl-dicarbonate (6.03 g, 27.4 mmol). After degassing the reaction flask, the mixture is hydrogenated for 5 h at RT. The catalyst is filtered, washed with EtOAc and the solvent is evaporated. The crude residue is purified by prep. LC-MS with basic conditions to give the title compound; LC-MS method D t.sub.R=1.11 min; [M+H].sup.+=465.90.

2.01c: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(170) rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 2.01b (8.71 g, 18.7 mmol) is dissolved in THF (114 mL). Aq. 1M NaOH solution (56.1 mL, 56.1 mmol) is then added and the mixture stirred at RT for 3 h. The reaction mixture is acidified to around pH=3 with 2M aq. HCl solution (30 mL) and concentrated. The resulting suspension is filtered, washed twice with water (2×14 mL) and dried under HV. The title compound is obtained as a white powder; LC-MS method D t.sub.R=0.66 min; [M+H].sup.+=452.17.

2.01d: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylic Acid Tert-Butyl Ester

(171) To a solution of rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 2.01c (5 g, 11 mmol) in DMF (58 mL) at RT is added a 2M solution of dimethylamine in THF (22 mL, 44 mmol). DIPEA (6.15 mL, 35.2 mmol) is then added followed by HATU (4.4 g, 11.6 mmol). The reaction mixture is stirred at RT for 4 h. The volatiles are evaporated and the crude mixture is purified by prep. LC-MS with basic conditions to give the title compound; LC-MS method D t.sub.R=1.01 min; [M+H].sup.+=479.23.

2.01: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Dimethylamide

(172) rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester 2.01d (4.53 g, 9.47 mmol) is dissolved in MeOH (47.3 mL) at RT. A 4M solution of HCl in dioxane (47.3 mL, 189 mmol) is added and the reaction mixture is stirred at RT for 1 h. The solvents are evaporated to give the title compound; LC-MS method D t.sub.R=0.75 min; [M+H].sup.+=379.11.

(173) Preparation of Building-Blocks of General Formula (B-6) Used as Intermediates in the Preparation of Examples 2.001 to 2.108

(174) The following intermediates are prepared in analogy to BB 2.01:

BB 2.02: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl-Phenethyl-Amide Hydrochloride

2.02b: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(methyl-phenethyl-carbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(175) The title compound is prepared according to the procedure 2.01d, starting from building block 2.01c and N-methyl-2-phenylethylamine; LC-MS method D: t.sub.R=1.17 min; [M+H].sup.+=569.14.

2.02: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl-Phenethyl-Amide Hydrochloride

(176) The title compound is prepared according to the procedure 2.01, starting from building block 2.02b; LC-MS method D: t.sub.R=0.92 min; [M+H].sup.+=469.18.

BB 2.03: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyridin-2-yl-ethyl)-amide Hydrochloride

2.03b: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(177) The title compound is prepared according to the procedure 2.01d, starting from building block 2.01c and 1-(2-pyridyl)ethylamine; LC-MS method D: t.sub.R=1.01 min; [M+H].sup.+=556.13.

2.03: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyridin-2-yl-ethyl)-amide Hydrochloride

(178) The title compound is prepared according to the procedure 2.01, starting from building block 2.03b; LC-MS method D: t.sub.R=0.77 min; [M+H].sup.+=456.09.

BB 2.04: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Hydrochloride

2.04a: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(179) The title compound is prepared by chiral preparative HPLC of rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester using a column ChiralPak IC, 5 μm, 20×250 mm; with a mixture of A (25% Hept) and B (75% EtOH, 0.1% DEA) as eluent and a flow of 34 mL/min. Chiral HPLC: t.sub.R=7.3 min.

2.04b: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(180) The title compound is prepared according to the procedure 2.01c, starting from building block 2.04a; LC-MS method A: t.sub.R=0.77 min; [M+H].sup.+=452.04.

2.04c: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(181) The title compound is prepared according to the procedure 2.01d, starting from 2.04b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LC-MS method A: t.sub.R=0.94 min; [M+H].sup.+=569.19.

2.04: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Hydrochloride

(182) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.04c; LC-MS method A: t.sub.R=0.62 min; [M+H].sup.+=469.23.

BB 2.05: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Dimethylamide Hydrochloride

2.05a: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(183) The title compound is prepared by chiral preparative HPLC of rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester using a column ChiralPak IC, 5 μm, 20×250 mm; with a mixture of A (25% Hept) and B (75% EtOH, 0.1% DEA) as eluent and a flow of 34 mL/min. Chiral HPLC: t.sub.R=5.9 min.

2.05b: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(184) The title compound is prepared according to the procedure 2.01c, starting from building block 2.05a; LC-MS method D: t.sub.R=0.62 min; [M+H].sup.+=452.17.

2.05c: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-piperidine-1-carboxylic Acid Tert-Butyl Ester

(185) The title compound is prepared according to the procedure 2.01d, starting from 2.05b and dimethylamine solution 2 M in THF; LC-MS method D: t.sub.R=1.00 min; [M+H].sup.+=479.16.

2.05: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Dimethylamide Hydrochloride

(186) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.05c; LC-MS method D: t.sub.R=0.75 min; [M+H].sup.+=379.15.

BB 2.06: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [(R)-1-(1-oxy-pyridin-2-yl)-ethyl]-amide Hydrochloride

2.06b: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(187) The title compound is prepared according to the procedure 2.01d, starting from building block 2.01c and (R)-1-(pyridin-2-yl)ethanamine; LC-MS method A: t.sub.R=0.87 min; [M+H].sup.+=556.26.

2.06c: 2-((R)-1-((3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)ethyl)pyridine-1-oxide

(188) To a solution of 2.06b (90 mg, 0.162 mmol) in DCM (3 mL) at 0° C. is added portionwise 3-chloroperbenzoic acid (47.2 mg, 0.211 mmol). The reaction mixture is stirred at RT for 1 h. The mixture is diluted with DCM and washed with aq. sat. NaHCO.sub.3. The org phase is dried over MgSO4, filtered and concentrated to give the tittle compound as a white powder; LC-MS method A: t.sub.R=0.96 min; [M+H].sup.+=572.28.

2.06: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [(R)-1-(1-oxy-pyridin-2-yl)-ethyl]amide Hydrochloride

(189) The title compound is prepared according to the procedure 2.01, starting from building block 2.06c; LC-MS method A: t.sub.R=0.63 min; [M+H].sup.+=472.19.

BB 2.07: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide Hydrochloride

2.07b: Rac-Tert-Butyl (3R*,4R*)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-3-((1-(pyridin-2-yl)cyclopropyl)carbamoyl)piperidine-1-carboxylate

(190) The title compound is prepared according to the procedure 2.01d, starting from building block 2.01c and 1-(pyridin-2-yl)cyclopropan-1-amine; LC-MS method A: t.sub.R=0.88 min; [M+H].sup.+=568.26.

2.07c: rac-2-(1-((3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl)pyridine 1-oxide

(191) The title compound is prepared according to the procedure 2.06c, starting from building block 2.07b; LC-MS method A: t.sub.R=0.91 min; [M+H].sup.+=584.27.

2.07: (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide Hydrochloride

(192) The title compound is prepared according to the procedure 2.01, starting from building block 2.07c; LC-MS method A: t.sub.R=0.63 min; [M+H].sup.+=484.19.

BB 2.08: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide Hydrochloride

2.08b: tert-butyl (3S,4S)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-3-((1-(pyridin-2-yl)cyclopropyl)carbamoyl)piperidine-1-carboxylate

(193) The title compound is prepared according to the procedure 2.01d, starting from building block 2.04b and 1-(pyridin-2-yl)cyclopropan-1-amine; LC-MS method A: t.sub.R=0.82 min; [M+H].sup.+=568.02.

2.08c: 2-(1-((3S,4S)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl)pyridine 1-oxide

(194) The title compound is prepared according to the procedure 2.06c, starting from building block 2.08b; LC-MS method A: t.sub.R=0.87 min; [M+H].sup.+=583.99.

2.08: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]-amide Hydrochloride

(195) The title compound is prepared according to the procedure 2.01, starting from building block 2.08c; LC-MS method A: t.sub.R=0.58 min; [M+H].sup.+=484.06.

BB 2.09: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-cyano-cyclobutyl)-amide Hydrochloride

2.09b: rac-(3R*,4R*)-3-(1-Cyano-cyclobutylcarbamoyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1-carboxylic Acid Tert-Butyl Ester

(196) The title compound is prepared according to the procedure 2.01d, starting from building block 2.01c and 1amino-cyclobutane carbonitrile; LC-MS method A: t.sub.R=1.03 min; [M+H].sup.+=550.02.

2.09: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-cyano-cyclobutyl)-amide Hydrochloride

(197) The title compound is prepared according to the procedure 2.01, starting from building block 2.09b; LC-MS method A: t.sub.R=0.70 min; [M+H].sup.+=430.2.

BB 2.10: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Hydrochloride

2.10c: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(198) The title compound is prepared according to the procedure 2.01d, starting from 2.05b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LC-MS method A: t.sub.R=0.86 min; [M+H].sup.+=569.19.

2.10: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Hydrochloride

(199) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.10c; LC-MS method A: t.sub.R=0.61 min; [M+H].sup.+=469.19.

BB 2.11: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Ethyl-Methyl-Amide Hydrochloride

2.11c: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(ethyl-methyl-carbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(200) The title compound is prepared according to the procedure 2.01d, starting from 2.05b and N-ethylmethylamine; LC-MS method A: t.sub.R=0.99 min; [M+H].sup.+=493.18.

2.11: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Ethyl-Methyl-Amide Hydrochloride

(201) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.11c; LC-MS method A: t.sub.R=0.69 min; [M+H].sup.+=393.18.

BB 2.12: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid methyl-(2-pyridin-2-yl-ethyl)-amide Hydrochloride

2.12c: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-piperidine-1-carboxylic Acid Tert-Butyl Ester

(202) The title compound is prepared according to the procedure 2.01d, starting from 2.05b and N-methyl-2-(pyridin-2-yl)ethan-1-amine; LC-MS method A: t.sub.R=0.78 min; [M+H].sup.+=570.17.

2.12: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid methyl-(2-pyridin-2-yl-ethyl)-amide Hydrochloride

(203) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.12c; LC-MS method A: t.sub.R=0.57 min; [M+H].sup.+=470.18.

BB 2.13: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (2-pyridin-2-yl-ethyl)-amide Hydrochloride

2.13c: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(2-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(204) The title compound is prepared according to the procedure 2.01d, starting from 2.05b and 2-(pyridin-2-yl)ethan-1-amine; LC-MS method A: t.sub.R=0.76 min; [M+H].sup.+=557.15.

2.13: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (2-pyridin-2-yl-ethyl)-amide Hydrochloride

(205) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.12c; LC-MS method A: t.sub.R=0.56 min; [M+H].sup.+=456.18.

BB 2.14: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

2.14a: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(206) To a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester 4.06c (3.7 g, 13.6 mmol) in DMF (100 mL) is added 5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carboxylic acid sodium salt (3.73 g, 14.1 mmol). TEA (7.56 mL, 54.3 mmol) is then added followed by HATU (6.2 g, 16.3 mmol). The reaction mixture is stirred for 1 h. The reaction mixture is concentrated, diluted with DCM (250 mL) and treated with aq. sat. NaHCO.sub.3 (250 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The crude residue is purified by flash chromatography using n-heptan/EtOAc 3:1 as eluent to deliver (3R,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as a white powder. This compound is dissolved in EtOH (40 mL) and EtOAc (20 mL). Sodium ethoxide 95% powder (3.44 g, 48 mmol) is added at once to and the resulting mixture is stirred under an argon atmosphere at RT for 4 d. The reaction mixture is quenched with sat. aq. NH.sub.4Cl (100 mL) and extracted thrice with DCM (3×100 mL). The combined organic extracts are dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude is purified by prep-LC-MS, under basic conditions (method E) followed by chiral preparative SFC in order to remove traces of the [R,R]-isomer (Column: Regis (R,R) Whelk-01, 30×250 mm, 5 μm or ChiralPak IC, 30×250 mm, 5 μm; eluent: mixture of A (65% CO.sub.2), and B (35% of DCM/EtOH/DEA 50:50:0.1), flow 160 mL/min. t.sub.R=1.18 min.) The title product is obtained as a white powder; LC-MS method A: t.sub.R=1.07 min; [M+H].sup.+=496.96.

2.14b: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)1,3,4-thiadiazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(207) The title compound is obtained by treatment of (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with sodium hydroxide followed by HCl according to procedure 2.01c; LC-MS method A: t.sub.R=0.94 min; [M+H].sup.+=468.88.

2.14c: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(208) The title compound is prepared according to the procedure 2.01d, starting from 2.14b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LC-MS method D: t.sub.R=0.94 min; [M+H].sup.+=585.34.

2.14: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(209) The title compound is prepared according to the procedure 2.01 described above, starting from building block 2.14c; LC-MS method A: t.sub.R=0.67 min; [M+H].sup.+=486.24

(210) General Procedures for the Preparation of Examples 2.001 to 2.109:

(211) Method D:

(212) To a solution of the respective amine (BB 2.01 to BB 2.14) (0.1 mmol) in DCM (mL) is added a commercially available aldehyde or ketone (0.12 to 1 mmol) followed by sodium triacetoxyborohydride (0.13 to 0.4 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is then diluted with DCM or chloroform (3 mL) and treated with aq. sat. NaHCO.sub.3 (2 mL). The organic phase is dried over Na.sub.2SO.sub.4, filtered and the solvent is evaporated. The crude residue is purified by prep. LC-MS using method E.

(213) Method E:

(214) To a solution of the respective amine (BB 2.01 to BB 2.14) (0.1 mmol) in DMF (mL) is added a commercially available aldehyde or ketone (0.2 to 1 mmol) followed by sodium triacetoxyborohydride (0.23 mmol). The reaction mixture is stirred overnight at RT. 150 μL water are added and the product is purified by prep. LC-MS using method E.

(215) Method F:

(216) To the respective amine (BB 2.01 to BB 2.14) (0.5 mmol) and a commercially available ketone (0.6 mmol) and titanium(IV) isopropoxide (1 mmol) are stirred under argon at 80° C. for 4.5 h. Methanol (1.18 mL) is added followed by sodium borohydride (1.5 mmol) in one portion. The reaction mixture is stirred at RT for 1 h. Water (1.2 mL) is added. The resulting suspension is filtered, washed with 9 mL DCM/MeOH 3/1 and the solvents are evaporated. The crude residue is purified by prep. LC-MS using method E.

(217) Method G:

(218) The respective amine (BB 2.01 to BB 2.14) (0.1 mmol) is dissolved in water (0.7 mL). DIPEA (0.3 mmol) is added followed by a commercially available epoxide (0.4 mmol). The reaction mixture is stirred at 100° C. for 17 h. The solvent is evaporated and the crude mixture is dissolved in 1 mL MeOH/DMF and purified by prep. LC-MS using method E.

(219) Method H:

(220) To an ice cold solution of the respective amine (BB 2.01 to BB 2.14) (0.1 mmol) and K.sub.2CO.sub.3 (0.2 mmol) in acetone (5 mL) is added a commercially available alkyl bromide (0.11 mmol). The mixture is stirred 18 h at RT. Another equivalent of alkyl bromide is added and the mixture is stirred 18 h at 50° C. The reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is purified by Prep HPLC using method E.

Example 2.001 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic Acid Dimethylamide

(221) To a solution of rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (BB 2.01) (41.5 mg, 0.1 mmol) in DCM (0.5 mL) is added acetone (27.8 mg, 0.036 mL, 0.48 mmol) followed by sodium triacetoxyborohydride (61 mg, 0.27 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is then diluted with chloroform (3 mL) and treated with aq. sat. NaHCO.sub.3 (2 mL). The organic phase is dried over Na.sub.2SO.sub.4, filtered and the solvent is evaporated. The crude residue is purified by prep. LC-MS using method E. LC-MS QC method: t.sub.R=0.56 min; [M+H].sup.+=421.1.

(222) Compounds of Examples 2.001 to 2.108 listed in Table 2 below are prepared by applying one of the above-mentioned general procedures D, E, F, G, or H to the building blocks BB-2.01 BB-2.14 or BB-8.01-BB-8.02 coupled with commercially available aldehydes, ketones, alkyl halogenides or epoxydes.

(223) Enantiomerically pure compounds are obtained by using one of the above mentioned preparative chiral chromatography methods.

(224) TABLE-US-00002 TABLE 2 Examples 2.001-2.108 QC LC-MS Mass Example Found Nr Substance Name t.sub.R (min) [M + H].sup.+ 2.001 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.56 421.1 1-isopropyl-piperidine-3-carboxylic acid dimethylamide 2.002 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.54 407.3 1-ethyl-piperidine-3-carboxylic acid dimethylamide 2.003 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.75 511 1-isopropyl-piperidine-3-carboxylic acid methyl-phenethyl-amide 2.004 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.73 497.3 1-ethyl-piperidine-3-carboxylic acid methyl-phenethyl-amide 2.005 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.78 537.4 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-phenethyl-amide 2.006 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.77 523.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl- phenethyl-amide 2.007 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.57 498 isopropyl-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 2.008 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.55 484.1 ethyl-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.009 (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.59 524.5 carbonyl]-amino}-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl- ethyl)-amide (mixture of isomers) 2.010 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 510.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl- ethyl)-amide (mixture of isomers) 2.011 (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.55 525.9 carbonyl]-amino}-piperidine-3-carboxylic acid [(R)-1-(1-oxy-pyridin-2- yl)-ethyl]-amide (mixture of isomers) 2.013 (3R*,4R*)-1-((1RS)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)- 0.61 447.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.014 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.58 477.3 ((1RS,2RS)-2-hydroxymethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.015 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.68 475.3 ((1RS,2RS)-2-ethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.016 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.61 447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.016a (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.61 447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic acid dimethylamide, mixture of isomers 1 2.016b (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6 447.3 ((1RS,2RS)-2-methyl-cyclobutyl)-piperidine-3-carboxylic acid dimethylamide, mixture of isomers 2 2.017 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.65 461.1 (1RS)-1-(2,2-dimethyl-cyclobutyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.018 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.67 475.3 ((1RS)-3,3-dimethyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.019 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.59 447.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.019a (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.59 447.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide or (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- amino}-piperidine-3-carboxylic acid dimethylamide (1.sup.st eluted enantiomer) 2.020 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.65 449.1 1-(2,2-dimethyl-propyl)-piperidine-3-carboxylic acid dimethylamide 2.021 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.64 449 1-(3-methyl-butyl)-piperidine-3-carboxylic acid dimethylamide 2.022 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.68 463.4 1-(3,3-dimethyl-butyl)-piperidine-3-carboxylic acid dimethylamide 2.023 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63 461.3 ((1RS,2RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.023a (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63 461.3 ((1RS,RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide, mixture of isomere 1 2.023b (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63 461.3 ((1RS,RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid dimethylamide, mixture of isomers 2 2.024 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.72 489.3 ((1RS)-3,3-dimethyl-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.025 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.66 473.3 1-spiro[3.3]hept-2-yl-piperidine-3-carboxylic acid dimethylamide 2.026 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.61 479.3 ((1RS,4RS)-4-fluoro-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.027 rac-(3R*,4R*)-1-(4,4-Difluoro-cyclohexyl)-4-{[5-(2,4-difluoro-phenyl)- 0.63 497.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.028 rac-(3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.56 433.4 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.029 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.58 433 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.030 rac-(3R*,4R*)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.66 461.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.031 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.64 461.3 1-(3,3-dimethyl-cyclobutyl)-piperidine-3-carboxylic acid dimethylamide 2.032 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.67 491 ((1RS,3RS)-3-methoxy-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.033 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.67 491 ((1RS,2RS)-2-methoxy-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.034 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.63 447.3 1-(1-methyl-cyclopropylmethyl)-piperidine-3-carboxylic acid dimethylamide 2.035 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.67 461 1-(1-methyl-cyclobutylmethyl)-piperidine-3-carboxylic acid dimethylamide 2.036 rac-(3R*,4R*)-1-Cyclopent-1-enylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.66 459.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.037 (3R*,4R*)-(1RS,2RS,4RS)-1-Bicyclo[2.2.1]hept-2-yl-4-{[5-(2,4-difluoro- 0.64 473.3 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.038 rac-(3R*,4R*)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 0.62 447.3 3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.039 rac-(3R*,4R*)-1-(2-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)- 0.62 447.1 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.040 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.63 479.3 ((1RS,2RS)-2-fluoro-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.045 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.58 433.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.046 (3R,4R)-1-((1RS)-1-Cyclopropyl-ethyl)-4-{[5-(2,4-difluoro-phenyl)- 0.62 447.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.047 (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.68 473 (1RS)-1-spiro[2.4]hept-4-yl-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.048 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.61 477.3 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.049 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.56 451 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic acid dimethylamide (mixture of isomers) 2.050 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.79 567.4 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid methyl- phenethyl-amide (mixture of isomers) 2.051 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.75 541 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic acid methyl-phenethyl-amide (mixture of isomers) 2.052 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.72 513 1-(2-hydroxy-ethyl)-piperidine-3-carboxylic acid methyl-phenethyl- amide 2.053 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.59 554.2 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid ((1RS)- 1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.054 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.57 528 ((1RS,2RS)-2-hydroxy-1-methyl-propyl)-piperidine-3-carboxylic acid ((1RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 2.055 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2- 0.6 527.1 methoxy-ethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.056 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.58 497 ethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.057 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.58 502.2 ((1,1,2,2,2-d.sub.5-ethyl)-piperidine)-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.058 rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)isoxazole-3-carbonyl]-amino}- 0.71 469 (BB 2.02) piperidine-3-carboxylic acid methyl-phenethyl-amide 2.059 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.58 469.27 (BB 2.04) piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.060 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60 567 ((1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide (mixture of stereoisomers) 2.061 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.60 538.4 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy- pyridin-2-yl)-cyclopropyl]-amide 2.062 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 552.2 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide 2.062a (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 552.2 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide (Enantiomer 1) 2.062b (3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.65 552.17 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyridin-2-yl)- cyclopropyl]-amide (Enantiomer 2) 2.063 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.60 538.4 amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyridin-2-yl)-cyclopropyl]- amide 2.064 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 498 carbonyl]-amino}-piperidine-3-carboxylic acid (1-cyano-cyclobutyl)- amide 2.065 (3S,4S)-1-Cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.70 551 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.066 (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 537.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.067 (3S,4S)-1-(1-Difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluoro- 0.60 573 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide 2.068 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(4- 0.70 577 fluoro-benzyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.069 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.70 539.1 (2,2-dimethyl-propyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.070 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60 525.2 isobutyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.071 (3S,4S)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.70 559.1 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.072 (3S,4S)-1-Cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 537.4 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.073 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60 511.2 isopropyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.074 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.60 523.1 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.075 (3S,4S)-1-Cyclopropyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 509.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.076 (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 461.3 carbonyl]-amino}-piperidine-3-carboxylic acid ethyl-methyl-amide 2.077 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 447 carbonyl]-amino}-piperidine-3-carboxylic acid ethyl-methyl-amide 2.078 (3R,4R)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.50 538.1 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-(2-pyridin-2-yl- ethyl)-amide 2.079 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.50 524 carbonyl]-amino}-piperidine-3-carboxylic acid methyl-(2-pyridin-2-yl- ethyl)-amide 2.080 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.50 510.2 carbonyl]-amino}-piperidine-3-carboxylic acid (2-pyridin-2-yl-ethyl)- amide 2.081 (3R,4R)-1-Benzyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.70 469.3 amino}-piperidine-3-carboxylic acid dimethylamide 2.082 (3R,4R)-1-(2-Chloro-benzyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.70 503.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 2.083 (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(2- 0.70 487.3 fluoro-benzyl)-piperidine-3-carboxylic acid dimethylamide 2.084 (3S,4S)-1-((1RS)-2,2-Difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro- 0.60 559.1 phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide (mixture of isomers) 2.085 (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1- 0.60 472.4 methyl-1H-pyrrol-3-ylmethyl)-piperidine-3-carboxylic acid dimethylamide 2.086 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.60 483.4 methyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.087 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(3- 0.60 529 fluoro-propyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.088 rac-(3R*,4R*)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.60 523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.089 (3S,4S)-1-(3,3-Difluoro-cyclobutyl)-4-{[5-(2,4-difluoro-phenyl)- 0.7 559 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin- 2-yl-cyclopropyl)-amide 2.090 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1- 0.6 537.1 methyl-cyclopropylmethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2- yl-cyclopropyl)-amide 2.091 (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- 0.5 522 [1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic acid (1- pyridin-2-yl-cyclopropyl)-amide 2.092 (3S,4S)-1-Cyclopentyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 0.5 536.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl- cyclopropyl)-amide 2.093 (3S,4S)-1-Allyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 509.2 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.094 (3S,4S)-1-Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 549.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.095 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.5 511.2 propyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.096 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}- 0.6 469 (BB 8.02) piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 2.097 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.6 523.1 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.098 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.6 537.1 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.099 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-1- 0.6 511.4 isopropyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.100 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-1-(1- 0.6 541.3 fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.101 (3S,4S)-1-(3,3-Difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)- 0.6 573 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin- 2-yl-cyclopropyl)-amide 2.102 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6 541 thietan-3-yl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.103 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.6 549 spiro[2.3]hex-5-yl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.104 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 1.0 486.4 (BB 2.14) amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 2.105 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2- 0.6 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.106 (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 0.6 558.1 amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid (1- pyrimidin-2-yl-cyclopropyl)-amide 2.107 (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2-carbonyl]- 0.6 514.1 amino}-1-ethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 2.108 (3S,4S)-1-(Cyclopropyl-(d.sub.2-methyl))-4-{[5-(2,4-difluoro-phenyl)- 0.6 525.3 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin- 2-yl-cyclopropyl)-amide
General Method C for the Synthesis of Compounds of Formula (I)
Buildings Blocks:
Preparation of Building Blocks of Structure C-3

(225) ##STR00026##

BB 3.01: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic acid Dimethylamide

3.01a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic Acid

(226) rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic acid methyl ester 1.01a (2.85 g, 7.35 mmol) is dissolved in THF (45 mL) at RT. Aq. 1M NaOH solution (22.1 mL, 22.1 mmol) is then added and the mixture stirred at RT for 72 h. The reaction mixture is acidified to around pH=3 with a 2M HCl solution (12 mL) and evaporated. The resulting suspension is dissolved with DCM, the organic phase is dried over MgSO.sub.4 and the solvents are evaporated to give the title compound; LC-MS method D t.sub.R=0.54 min; [M+H].sup.+=327.23.

3.01b: rac-((3R*,4R*)-1-Cyclohexyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamic acid tert-butyl Ester

(227) To a solution of rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic acid 3.01a (2.4 g, 7.35 mmol) in DMF (36.8 mL) is added a 40% solution of dimethylamine in water (2.79 mL, 22.1 mmol). DIPEA (4.11 mL, 23.5 mmol) is then added followed by HATU (2.93 g, 7.72 mmol). The reaction mixture is stirred for 2 h. The reaction mixture is concentrated, dissolved in DCM (150 mL) and treated with aq. sat. NaHCO.sub.3 (150 mL). The organic layer is separated and the aq. phase is further extracted with DCM (3×150 mL). The combined organic phases are dried over MgSO.sub.4 and evaporated. The crude residue is purified by prep. LC-MS with basic conditions (method E). The title compound is obtained; LC-MS method D t.sub.R=0.91 min; [M+H].sup.+=353.96.

3.01: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic Acid Dimethylamide

(228) rac-((3R*,4R*)-1-Cyclohexyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamic acid tert-butyl ester (2.08 g, 5.88 mmol) is dissolved in MeOH (29.5 mL) at RT. A 4M solution of HCl in dioxane (29.5 mL, 118 mmol) is added and the reaction is stirred at RT for 1 h. The reaction mixture is concentrated, dissolved in DCM (150 mL) and treated with aq. sat. NaHCO.sub.3 (50 mL). The organic layer is separated and the aq. phase is extracted twice with DCM (2×100 mL) and twice with chloroform (2×100 mL). The combined organic phases are dried over MgSO.sub.4, filtered and the solvent is evaporated to give the crude title compound; LC-MS method D t.sub.R=0.68 min; [M+H].sup.+=254.24.

(229) Preparation of Building-Blocks of General Formula (C-3) Used as Intermediates in the Preparation of Examples 3.001 to 3.022

(230) The following intermediates are prepared in analogy to BB 3.01:

BB 3.02: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide, Dihydrochloride

3.02b: rac-[(3R*,4R*)-1-Cyclohexyl-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Tert-Butyl Ester

(231) The title compound is prepared according to the procedure 3.01b, starting from building block 3.01a and 1-(2-pyridyl)cyclopropylamine dihydrochloride; LC-MS method D: t.sub.R=0.97 min; [M+H].sup.+=443.21.

3.02: rac-(3R*,4R*)-4-Amino-1-cyclohexyl-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide, Dihydrochloride

(232) The title compound is prepared according to the procedure 3.01, starting from building block 3.02b; LC-MS method D: t.sub.R=0.77 min; [M+H].sup.+=343.17.

BB 3.03: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylic Acid Dimethylamide

3.03a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopentyl-piperidine-3-carboxylic Acid

(233) The title compound is prepared according to the procedure 3.01a, starting from building block 1.03a; LC-MS method D: t.sub.R=0.51 min; [M+H].sup.+=313.08.

3.03b: rac-((3R*,4R*)-1-Cyclopentyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamic Acid Tert-Butyl Ester

(234) The title compound is prepared according to the procedure 3.01b, starting from building block 3.03a and a 40% solution of dimethylamine in water; LC-MS method D: t.sub.R=0.82 min; [M+H].sup.+=340.16.

3.02: rac-(3R*,4R*)-4-Amino-1-cyclopentyl-piperidine-3-carboxylic Acid Dimethylamide

(235) The title compound is prepared according to the procedure 3.01, starting from building block 3.03b; LC-MS method D: t.sub.R=0.59 min; [M+H].sup.+=240.18.

BB 3.04: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide, Dihydrochloride

3.04a: rac-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid

(236) The title compound is prepared according to the procedure 3.01a, starting from building block 1.04a; LC-MS method D: t.sub.R=0.47 min; [M+H].sup.+=299.13.

3.04b: rac-[(3R*,4R*)-1-Cyclopropylmethyl-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Tert-Butyl Ester

(237) The title compound is prepared according to the procedure 3.01b, starting from building block 3.04a and 1-(2-pyridyl)cyclopropylamine dihydrochloride; LC-MS method D: t.sub.R=0.85 min; [M+H].sup.+=415.17.

3.04 rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide, Dihydrochloride

(238) The title compound is prepared according to the procedure 3.01, starting from building block 3.04b; LC-MS method D: t.sub.R=0.64 min; [M+H].sup.+=315.18.

BB 3.05: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Dihydrochloride

3.05b: rac-[(3R*,4R*)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Tert-Butyl Ester

(239) The title compound is prepared according to the procedure 3.01b, starting from building block 3.04a and 1-(2-pyrimidyl)cyclopropylamine hydrochloride; LC-MS method A: t.sub.R=0.64 min; [M+H].sup.+=416.34.

3.05 rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide, Dihydrochloride

(240) The title compound is prepared according to the procedure 3.01, starting from building block 3.04b; LC-MS method A: t.sub.R=0.38 min; [M+H].sup.+=316.34.

(241) General Procedures for the Preparation of Compounds 3.001 to 3.022:

(242) Method I:

(243) To a solution of the respective amine (BB 3.01 to BB 3.05) (0.08 mmol) in 0.7 mL DMF is added the respective carboxylic acid (commercially available or of Structure A-4) (0.08 mmol). DIPEA (0.336 mmol) is then added followed by HATU (0.084 mmol). The reaction mixture is stirred 21 h at RT. Up to 0.28 mmol of a 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the clear solution is directly purified by prep. LC-MS with method E.

(244) Method J:

(245) A solution of the respective amine (BB 3.01 to BB 3.05) (0.3 mmol) in toluene (0.4 mL) at 0° C. under argon is treated with a 2M solution of trimethylaluminium in toluene (0.3 mmol). After stirring for 30 min at 0° C., a solution of an ester of Structure A-4 (L1=O-alkyl) (0.1 mmol) in toluene (0.4 mL) is added and the mixture stirred at RT for 4 to 22 hours. The reaction mixture is quenched with a 1.25M solution of HCl in methanol (0.6 mmol) and the solvents are evaporated. The crude residue is purified by prep. LC-MS using method E.

Example 3.001: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Dimethylamide

(246) To a solution of rac-(3R*,4R*)-4-amino-1-cyclohexyl-piperidine-3-carboxylic acid dimethylamide (20.3 mg, 0.08 mmol) in DMF (0.7 mL) is added 5-(2,6-difluoro-phenyl)-isoxazole-3-carboxylic acid (18 mg, 0.08 mmol). DIPEA (0.044 mL, 0.256 mmol) is then added followed by HATU (31.9 mg, 0.084 mmol). The reaction mixture is stirred 21 h at RT. Up to 0.28 mmol of a 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the clear solution is directly purified by prep. LC-MS with method E. LC-MS method D: t.sub.R=0.61 min; [M+H].sup.+=461.

(247) Compounds of Examples 3.002 to 3.022 listed in Table 3 below are prepared by applying one of the above-mentioned general procedures I or J to the building blocks BB-3.01 BB-3.05 coupled with respective carboxylic acid or ester of Structure A-4 (L.sup.1=OH or O-alkyl), which is commercially available or prepared according to/in analogy to the methods described above.

(248) Enantiomerically pure compounds are obtained using one of the above mentioned chiral preparative chromatography methods.

(249) TABLE-US-00003 TABLE 3 Examples 3.001a-3.022 QC LC-MS Mass Example Found Nr Substance Name t.sub.R (min) [M + H].sup.+ 3.001 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,6-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.61 461 amino}-piperidine-3-carboxylic acid dimethylamide 3.002 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 443 amino}-piperidine-3-carboxylic acid dimethylamide 3.003 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2- 0.54 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 3.003a (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2- 0.54 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (enantiomer 1) 3.003b (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2- 0.54 462 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide (enantiomer 2) 3.004 rac-(3R*,4R*)-4-{[5-(2-Chloro-4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.67 477.1 1-cyclohexyl-piperidine-3-carboxylic acid dimethylamide 3.005 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.63 479.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 3.006 rac-(3R*,4R*)-4-{[5-(4-Chloro-2-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}- 0.69 477 1-cyclohexyl-piperidine-3-carboxylic acid dimethylamide 3.007 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.56 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 3.009 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3-carbonyl] 0.62 532.2 amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide 3.010 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.57 551 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 3.011 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2-difluoro-phenyl)-oxazole-2-carbonyl]- 0.61 550.3 amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide 3.012 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2- 0.56 551.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 3.013 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3- 0.56 504.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 3.014 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3- 0.58 504.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 3.015 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2- 0.56 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 3.016 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- 0.5 523.1 [1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin- 2-yl-cyclopropyl)-amide 3.016a (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]oxadiazole-2- 0.51 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide or (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- [1,3,4]oxadiazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin- 2-yl-cyclopropyl)-amide (1.sup.st eluted enantiomer) 3.017 rac-(3R*,4R*)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.57 447.3 amino}-piperidine-3-carboxylic acid dimethylamide 3.018 rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.61 461.3 amino}-piperidine-3-carboxylic acid dimethylamide 3.019 rac-(3R*,4R*)-1-Cyclohexyl-4-{[3-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-5- 0.59 462.3 carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 3.020a (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61 541.28 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide (enantiomer 1) 30.20b (3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3- 0.61 541.41 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide (enantiomer 2) 3.021 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole- 0.60 523.4 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 3.022 rac-(3R*,4R*)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro- 0.60 541 isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 3.022a (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazole-3- 0.60 541.4 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoro- isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide (1.sup.st eluted enantiomer)
General Method D for the Synthesis of Piperidines of Formula (I)
Buildings Blocks:
Preparation of Building Blocks of Structure 1

(250) ##STR00027##

BB-4.01 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.01a: 4-((S)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(251) In a dry flask equipped with a Dean-Stark trap and reflux condenser, 4-oxopiperidine-1,3-dicarboxylic acid-1-t-butyl ester 3-methyl ester (10 g, 35 mmol) is dissolved in toluene (500 mL). (S)-(−)-α-methylbenzylamine (6.36 g, 52.5 mmol) and p-toluenesulfonic acid monohydrate (0.34 g, 1.75 mmol) are added and the mixture is heated to reflux for 3 h. The mixture is then cooled to RT, washed three times with aq. sat. NaHCO.sub.3 (3×100 mL) and dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield the product as a thick yellow oil. LC-MS method A: t.sub.R=1.01 min; [M+H].sup.+=375.18. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 9.28 (d, J=7.4 Hz, 1H), 7.25-7.38 (m, 5H), 4.63 (quint, J=6.7 Hz, 1H), 4.19 (q, J=7 Hz, 2H), 4.07 (s, 2H) 3.46-3.38 (m, 1H) 3.33-3.26 (m, 1H), 2.43-35 (m, 1H), 2.09-1.99 (m, 1H), 1.50 (d, J=7.4 Hz, 3H), 1.43 (s, 9H), 1.29 (t, J=7.0 Hz, 3H).

4.01b: (3S,4S)-4-((S)-1-Phenyl-ethylamino)-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(252) Sodium borohydride (5.19 g, 137 mmol) is added portionwise under N.sub.2 to a solution of isobutyric acid (68.1 mL, 734 mmol) in toluene (22 mL) at 0° C. The mixture is further stirred at RT for 20 min. The mixture is cooled again to 0° C. A solution of 4-((S)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (13 g, 34.7 mmol) in toluene (50 mL) is slowly added and the resulting mixture is stirred for 60 min at 0° C. Additional sodium borohydride (817 mg, 21.6 mmol) is added in five portions over a 4 h period. Water (100 mL) is added carefully and the reaction mixture is stirred for 15 min at RT. A 3M aq.NaOH solution is added to bring the mixture to pH 10. The reaction mixture is extracted with EtOAc (3×150 mL), the combined organic layers are dried with MgSO.sub.4 and the solvent is evaporated under reduced pressure. The resulting yellow oil is purified on a plug of silica gel and chromatographied with heptane/EtOAc 2:1 to give a yellowish oil. This oil is dissolved in dry ethanol (50 mL) under N.sub.2 and the resulting solution is transferred to a solution prepared in advance by mixing sodium ethoxyde in ethanol (20 mL of 21 w %, 52 mmol) and EtOAc (7.6 mL, 78 mmol). The resulting solution is stirred at 50° C. under N.sub.2 for 15 h. The solvent is removed under reduced pressure, brine (150 mL) is added and the pH of the resulting solution is brought to pH=10 with 1 N aq. NaOH. The resulting mixture is extracted with EtOAc (3×100 mL). The combined organic layers are dried over MgSO.sub.4 and concentrated under reduced pressure. The resulting oil is purified by flash chromatography over 100 g of silica gel with Heptane/EtOAc system (10:0 to 1:1 gradient) as eluent. The combined fractions are concentrated and dried under vacuum over night to obtain a pale yellow oil. This oil is dissolved in diethyl ether (10 mL) and 4 N HCl in dioxane (1.45 mL, 5.8 mmol) is added dropwise. The solution is stirred for 30 min and a precipitate is formed during this time. The precipitation is completed by adding heptane (28.7 mL) and storing the mixture at 0° C. for 1 h. The precipitate is isolated by filtration and washed with heptane to yield 2.57 g of an off-white solid. The solid is suspended in acetonitrile (4.6 mL) and heated to reflux until the solid has dissolved completely. The solution is then cooled to 0° C. overnight. The resulting crystals are isolated by filtration and washed 3× with 1.15 mL portions of cold acetonitrile to yield the hydrochloride salt as a colorless solid. The salt is then stirred in aq. 10% NaHCO.sub.3 solution (25 mL) and extracted with DCM (2×20 mL). Evaporation of the organic layers under reduced pressure yields the title product as a colorless oil. LC-MS method A: t.sub.R=0.73 min; [M+H].sup.+=377.29 .sup.1H NMR (400 MHz, CDCl3) δ: 7.79-7.40 (m, 5H), 4.13-4.24 (m, 3H), 3.70-4.09 (m, 2H), 2.82-2.99 (m, 2H), 2.58-2.72 (m, 1H), 2.21-2.38 (m, 1H), 1.62-1.76 (m, 1H), 1.45 (m, 9H), 1.20-1.35 (m, 7H), 1.02-1.14 (m, 1H).

4.01c: (3S,4S)-4-Amino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(253) A solution of (3S,4S)-4-((S)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.833 g, 5.06 mmol) in MeOH (7 mL) is added to a suspension of palladium on activated charcoal (10%) (183 mg, 0.172 mmol) and ammonium formate (2.63 g, 40.5 mmol) in MeOH (40 mL) under N.sub.2. The mixture is refluxed for 6 h. After the reaction is complete (disappearance of the peak but also exchange of the ethyl- for the methyl ester) the cooled solution is filtered through Celite, and the filtrate is concentrated to obtain the title product as a slightly yellow oil. LC-MS method A: t.sub.R=0.53 min; [M+H].sup.+=259.23. .sup.1H NMR (400 MHz, CDCl3) δ: 3.87-3.49 (m, 4H), 3.70 (s, 3H), 3.31 (m, 1H), 2.43-1.75 (m, 5H), 1.43 (s, 9H).

4.01d: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(254) To a solution of (3S,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1 g, 3.87 mmol) in DMF (8 mL) at RT is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (1.3 g, 5.81 mmol). DIPEA (2.12 mL, 12.4 mmol) is then added followed by HATU (1.55 g, 4.06 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is concentrated, dissolved in DCM (100 mL) and treated twice with aq. sat. NaHCO.sub.3 (100 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The crude residue is purified by flash chromatography over 40 g of silica gel with heptane/EtOAc system (1:0 to 3:1) as eluent to yield the title compound as white powder; LC-MS method A: t.sub.R=0.94 min; [M+H].sup.+=466.04. .sup.1H NMR (400 MHz, CDCl3) δ: 7.23-7.36 (m, 1H), 7.96 (m, 1H), 6.96-7.12 (m, 3H), 6.79-6.91 (m, 1H), 4.29-4.51 (m, 2H), 4.00-4.22 (m, 1H), 3.64-3.78 (m, 3H), 2.85-3.09 (m, 2H), 2.50-2.68 (m, 1H), 2.10-2.27 (m, 1H), 1.42-1.69 (m, 11H), 1.21-1.38 (m, 1H).

4.01e: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester Hydrochloride

(255) (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1152 mg, 2.48 mmol) is dissolved in DCM (15 mL). HCl in dioxane 4M (12.4 mL, 49.5 mmol) is added dropwise. The mixture is stirred at RT for 1 hour. The solvents are evaporated and the residue is dried on HV to deliver the title crude compound as a white powder. LC-MS method A: t.sub.R=0.61 min; [M+H].sup.+=366.18.

4.01f: (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(256) To a suspension of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester hydrochloride (0.99 g, 2.48 mmol) in DCM (20 mL) at RT is added cyclohexanone (0.75 mL, 6.9 mmol) followed by acetic acid (0.44 mL, 7.7 mmol) and sodium triacetoxyborohydride (1.58 g, 7.45 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is diluted with DCM (30 mL) and treated with aq. sat. NaHCO.sub.3 twice (50 mL). The organic phase is dried over MgSO.sub.4 and evaporated. The crude title compound is obtained; LC-MS method A: t.sub.R=0.71 min; [M+H].sup.+=448.17.

4.01: (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(257) (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester (1214 mg, 2.71 mmol) is dissolved in THF (14 mL) and 1 M aq. LiOH solution (6.98 mL, 6.98 mmol) is added. The mixture is stirred overnight at RT. 1M aq. HCl solution (6.98 mL, 6.98 mmol) is added and the reaction is stirred for 5 min. The solvents are evaporated to give the title compound as a yellow solid. LC-MS method A: t.sub.R=0.66 min; [M+H].sup.+=434.06.

(258) Preparation of Building Blocks of Structure 1 Used as Intermediates in the Preparation of Examples 4.001 to 4.102.

(259) The following carboxylic acids are prepared in analogy to example BB-4.01:

(260) ##STR00028##

BB-4.02: (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.02a: 4-((R)-1-Phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl Ester 3-ethyl Ester

(261) The title compound is prepared according to reaction 4.01a described above using 4-oxopiperidine-1,3-dicarboxylic acid-1-t-butyl ester 3-ethyl ester and (R)-(−)-α-methylbenzylamine; LC-MS method A: t.sub.R=1.01 min; [M+H].sup.+=375.28.

4.02b: (3R,4R)-4-(R)-1-Phenyl-ethylamino)-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(262) The title compound is prepared according to reaction 4.01b described above by reduction of 4-((R)-1-phenyl-ethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with a mixture of sodium borohydride and isobutyric acid followed by epimerisation with sodium ethoxide in EtOH and EtOAc; LC-MS method A: t.sub.R=0.72 min; [M+H].sup.+=377.27.

4.02c: (3R,4R)-4-amino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(263) The title compound is prepared according to reaction 4.01c described above by treatment of (3R,4R)-4-(R)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with palladium on activated charcoal (10%)) and ammonium formate in MeOH; LC-MS method A: t.sub.R=0.52 min; [M+H].sup.+=259.22.

4.02d: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(264) The title compound is prepared according to reaction 4.01d by treatment of (3R,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acid; LC-MS A: t.sub.R=0.94 min; [M+H].sup.+=466.02.

4.02e: (3R,4R)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester Hydrochloride

(265) The title compound is prepared according to reaction 4.01e by treatment of (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester with HCl in Dioxane 4M; LC-MS method A: t.sub.R=0.61 min; [M+H].sup.+=366.14.

4.02f: (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(266) The title compound is prepared according to reaction 4.01f by treatment of (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclohexanone and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.72 min; [M+H].sup.+=448.19.

4.02: (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(267) The title compound is prepared according to reaction 4.01 by treatment of (3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.66 min; [M+H].sup.+=434.07.

BB-4.03: (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.03f: (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(268) The title compound is prepared according to reaction 4.01f by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclopropanecarbaldehyde and sodium triacetoxyborohydride; LC-MS method D: t.sub.R=1.02 min; [M+H].sup.+=420.12.

4.03: (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(269) The title compound is prepared according to reaction 4.01 by treatment of (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method D: t.sub.R=0.54 min; [M+H].sup.+=405.79.

BB-4.04: (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.04f: (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(270) The title compound is prepared according to reaction 4.01f by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclopentanone and sodium triacetoxyborohydride; LC-MS method D: t.sub.R=1.04 min; [M+H].sup.+=434.14.

4.04g: (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(271) The title compound is prepared according to reaction 4.01 by treatment of (3S,4S)-1-cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method D: t.sub.R=0.56 min; [M+H].sup.+=420.09.

BB-4.05: (3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.05f: (3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Ethyl Ester

(272) The title compound is prepared by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ethyl ester hydrochloride with bromoacetonitrile and DIPEA in EtOH; LC-MS method A: t.sub.R=0.95 min; [M+H].sup.+=419.19.

4.05: (3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(273) The title compound is prepared according to reaction 4.01 by treatment of (3S,4S)-1-cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ethyl ester with 1 M aq. LiOH solution. LC-MS method D: t.sub.R=0.81 min; [M+H].sup.+=391.20.

BB-4.06: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic Acid

4.06c: (3R,4S)-4-Amino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(274) The title compound is prepared according to reaction 4.01c described above by treatment of (3R,4S)-4-(R)-1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with palladium hydroxide on activated charcoal 20%)) and hydrogen in EtOH at 20 bar and 80° C.; LC-MS method D: t.sub.R=0.81 min; [M+H].sup.+=273.21

4.06d: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(275) The title compound is prepared according to reaction 4.01d by treatment of (3S,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic Acid followed by epimerization with sodium ethoxyde in ethanol; LC-MS A: t.sub.R=0.96 min; [M+H].sup.+=480.17.

4.06e: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Ethyl Ester Hydrochloride

(276) The title compound is prepared according to reaction 4.01e by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with HCl in dioxane 4M; LC-MS method A: t.sub.R=0.70 min; [M+H].sup.+=380.18.

4.06f: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic Acid Ethyl Ester

(277) The title compound is prepared by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid ethyl ester hydrochloride with 1-fluorocyclopropane-1-carbaldehyde and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.78 min; [M+H].sup.+=452.19.

4.06: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic Acid

(278) The title compound is prepared according to reaction 4.01 by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1-fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid ethyl ester with 1 M aq. LiOH solution. LC-MS method D: t.sub.R=0.69 min; [M+H].sup.+=424.20.

BB-4.07: (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.07f: (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(279) The title compound is prepared according to reaction 4.01f by treatment of (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclopropanecarbaldehyde and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.7 min; [M+H].sup.+=420.14.

4.07: (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(280) The title compound is prepared according to reaction 4.01 by treatment of (3R,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.64 min; [M+H].sup.+=406.06.

BB-4.08 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.08f: (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(281) The title compound is prepared according to reaction 4.01f by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclobutanone and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.76 min; [M+H].sup.+=420.21.

4.08: (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(282) The title compound is prepared according to reaction 4.01g by treatment of (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.64 min; [M+H].sup.+=406.33.

BB-4.09 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.09f: (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(283) The title compound is prepared according to reaction 4.01f by treatment of (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with cyclobutanone and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.77 min; [M+H].sup.+=419.83.

4.09: (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(284) The title compound is prepared according to reaction 4.01g by treatment of (3R,4R)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.69 min; [M+H].sup.+=406.22.

BB-4.10: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic Acid

4.10f: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic Acid Methyl Ester

(285) The title compound is prepared according to reaction 4.01f by treatment of (3S,4S)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester hydrochloride with acetaldehyde and sodium triacetoxyborohydride; LC-MS method A: t.sub.R=0.66 min; [M+H].sup.+=394.35.

4.10: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic Acid

(286) The title compound is prepared according to reaction 4.01g by treatment of (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.62 min; [M+H].sup.+=380.96.

BB-4.11: rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

4.11a: 4-Amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic Acid Methyl Ester

(287) A solution of LiHMDS 1M in THF (6.73 mL, 6.73 mmol, 1.1 eq) is added dropwise at −78° C. to a solution of 1-tert-butylpiperidin-4-one (1000 mg, 6.12 mmol) in THF (10 mL) under argon. The mixture is stirred at this temperature for 1 h. Then methyl cyanoformate (0.486 mL, 6.12 mmol) is added and the reaction is stirred at −78° C. for 1 h. MeOH (30 mL) is added at −78° C., followed by ammonium acetate (4813 mg, 61.2 mmol). the mixture is stirred at this temperature for a 15 minutes and then allowed to warm to RT and stirred for 18 h. The solvents are evaporated under reduced pressure. The residue is taken up in DCM (25 mL) and washed with sat. aq. NaHCO.sub.3 (25 mL). The aq. phase is extracted twice with DCM (2×25 mL). The organic phase is washed with brine (25 mL). The combined organic layers are dried over MgSO.sub.4, filtered and concentrated to deliver the crude title compound as a yellowish oil; LC-MS method A: t.sub.R=0.43 min; [M+H].sup.+=213.46.

4.11b: rac-[R*,R*]-Methyl-4-amino-1-(tert-butyl)piperidine-3-carboxylate and rac-[R*,S*]-methyl 4-amino-1-(tert-butyl)piperidine-3-carboxylate

(288) A solution of 4-amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic Acid Methyl Ester (1.29 g, 6.12 mmol) in methanol (10 mL) is treated with NaBH.sub.3CN (774 mg, 12.3 mmol) and AcOH (1.06 mL, 9.25 mmol) at 0° C. Then the reaction is let to warm to RT. The reaction is stirred at 50° C. for 1 h. NaBH.sub.3CN (387 mg, 6.15 mmol, 1 eq) is added and the reaction is heated at 50° C. for 18 h. MeOH is evaporated under reduced pressure and the residue is taken up in DCM (20 mL) and washed with sat. aq. NaHCO.sub.3 (20 mL). The aq. phases are extracted twice (2×15 mL) with DCM and the organic phases are combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield the crude title product as a yellowish oil; LC-MS method A: t.sub.R=0.21 min; [M+H].sup.+=215.34.

4.11c: rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid Methyl Ester

(289) A solution of rac-[R*,R*]-methyl 4-amino-1-(tert-butyl)piperidine-3-carboxylate and rac-[R*,S*]-methyl 4-amino-1-(tert-butyl)piperidine-3-carboxylate (659 mg, 3.08 mmol) in DCM (5 mL), is treated with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (714 mg, 3.08 mmol), HATU (2338 mg, 3.08 mmol), and DIPEA (0.526 mL, 3.08 mmol). The reaction mixture is stirred at RT for 1 h30. DCM (10 mL) and sat. aq. NaHCO.sub.3 solution (10 mL) are added to the mixture. The organic phase is separated, the aq. phase is extracted with DCM (2×10 mL), the combined organic phases are dried over MgSO.sub.4, filtered and evaporated. The crude is purified by prep. LC-MS with method E to obtain the title compound as a colorless oil; LC-MS method A: t.sub.R=0.71 min; [M+H].sup.+=422.33.

4.11: rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid

(290) The title compound is prepared according to reaction 4.01g by treatment of rac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester with 1 M aq. LiOH solution. LC-MS method A: t.sub.R=0.64 min; [M+H].sup.+=408.35.

Example 4.001: (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-methyl-cyclopropyl)-amide

(291) To a solution of (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (21.7 mg, 0.05 mmol) in DMF (0.55 mL) is added 1-methylcyclopropan-1-amine hydrochloride (11.3 mg, 0.1 mmol). DIPEA (0.028 mL, 0.16 mmol) is then added followed by HATU (20 mg, 0.052 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified by prep. LC-MS with method E. LC-MS method D: t.sub.R=0.66 min; [M+H].sup.+=487.2.

(292) Compounds of Examples 4.001 to 4.102 listed in Table 4 below are prepared by applying one of the above-mentioned general procedures A, B or C to the building blocks BB-4.01 BB-4.11 coupled with commercially available amines or amine BB-9.01 of general structure 2. Enantiomerically pure compounds are obtained using one of the above mentioned chiral preparative chromatography methods.

(293) TABLE-US-00004 TABLE 4 Examples 4.002-4.102 QC LC-MS Mass Example Found Nr Substance Name t.sub.R (min) [M + H].sup.+ 4.001 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.66 487.2 amino}-piperidine-3-carboxylic acid (1-methyl-cyclopropyl)-amide 4.002 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.71 519.2 amino}-piperidine-3-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-amide 4.003 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.72 533.4 amino}-piperidine-3-carboxylic acid (3-methoxy-1,1-dimethyl-propyl)-amide 4.004 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.72 568.1 amino}-piperidine-3-carboxylic acid[1-(5-fluoro-pyridin-2-yl)-cyclopropyl]- amide 4.005 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 461 amino}-piperidine-3-carboxylic acid dimethylamide 4.006 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.73 501.3 amino}-piperidine-3-carboxylic acid (1-methyl-cyclobutyl)-amide 4.007 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 529.3 amino}-piperidine-3-carboxylic acid ((1RS)-1-[1,2,4]oxadiazol-3-yl-ethyl)- amide (mixture of isomers) 4.008 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.71 556.3 amino}-piperidine-3-carboxylic acid [(1RS)-1-(5-fluoro-pyridin-2-yl)-ethyl]- amide (mixture of isomers) 4.009 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.76 515.2 amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide 4.010 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.77 537.4 amino}-piperidine-3-carboxylic acid ((R)-1-phenyl-ethyl)-amide 4.011 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.67 553.4 amino}-piperidine-3-carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide 4.012 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.72 523.4 amino}-piperidine-3-carboxylic acid benzylamide 4.013 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.58 554.2 amino}-piperidine-3-carboxylic acid ((1RS)-2-hydroxy-1-pyridin-2-yl-ethyl)- amide (mixture of isomers) 4.014 (3S,4S)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.77 515.2 amino}-piperidine-3-carboxylic acid ((R)-1-cyclobutyl-ethyl)-amide 4.015 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.73 489 amino}-piperidine-3-carboxylic acid tert-butylamide 4.016 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.73 501.3 amino}-piperidine-3-carboxylic acid (1-methyl-cyclobutyl)-amide 4.017 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.56 433.3 amino}-piperidine-3-carboxylic acid amide 4.018 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.66 487 amino}-piperidine-3-carboxylic acid (1-methyl-cyclopropyl)-amide 4.019 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.65 500.3 amino}-piperidine-3-carboxylic acid (cyano-dimethyl-methyl)-amide 4.020 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.67 553.4 amino}-piperidine-3-carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide 4.021 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.68 553.3 amino}-piperidine-3-carboxylic acid ((R)-2-hydroxy-1-phenyl-ethylyamide 4.022 (3R,4R)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.75 537.4 amino}-piperidine-3-carboxylic acid ((R)-1-phenyl-ethyl)-amide 4.023 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3- 0.55 499.1 carbonyl]-amino}-piperidine-3-carboxylic acid [(1RS)-1-(2H-pyrazol-3yl)- ethyl]-amide (mixture of isomers) 4.024 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.49 510.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-3-yl-ethyl)- amide 4.025 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 523.3 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 4.026 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.43 536.1 amino}-piperidine-3-carboxylic acid (1-pyridin-4-yl-cyclopropyl)-amide 4.027 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.41 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-4-yl-cyclopropyl)- amide 4.028 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.61 536.1 amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide 4.029 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.62 537.3 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 4.030 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 538.2 amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide 4.031 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.59 522.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)- amide 4.032 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 4.033 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 524.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-methyl-1-pyridin-2-yl- ethyl)-amide 4.034 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.64 541.1 amino}-piperidine-3-carboxylic acid [1-methyl-1-methyl-1H-pyrazol-4yl)- ethyl]-amide 4.035 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.65 543.1 amino}-piperidine-3-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol- 3-yl)-ethyl]-amide 4.036 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.69 499.3 amino}-piperidine-3-carboxylic acid bicyclopropyl-1-ylamide 4.037 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.65 517.4 amino}-piperidine-3-carboxylic acid [(1RS)-1-(tetrahydro-furan-2yl)-ethyl]- amide (mixture of isomers) 4.038 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.55 514 amino}-piperidine-3-carboxylic acid [(1RS)-1-(1H-[1,2,4]triazol-3-yl)-ethyl]- amide (mixture of isomers) 4.039 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 471.3 amino}-piperidine-3-carboxylic acid ((1RS)-1-methyl-prop-2-ynyl)-amide (mixture of isomers) 4.04 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.63 514.3 amino}-piperidine-3-carboxylic acid ((1RS)-1-isoxazol-3-yl-ethyl)-amide (mixture of isomers) 4.041 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.56 513.1 amino}-piperidine-3-carboxylic acid [(1RS)-1-(2H-pyrazol-3yl)-ethyl]amide (mixture of isomers) 4.042 (3S,4S)-1-Cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.5 524.1 amino}-piperidine-3-carboxylic acid ((R)-1-pyridin-3-yl-ethyl)-amide 4.043 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.63 527.2 carbonyl]-amino}-piperidine-3-carboxylic acid [1-methyl-1-(1-methyl-1H- pyrazol-4-yl)-ethyl]amide 4.044 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64 529.1 carbonyl]-amino}-piperidine-3-carboxylic acid [1-methyl-1-(5-methyl- [1,2,4]oxadiazol-3-yl)-ethyl]amide 4.045 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.67 485.3 carbonyl]-amino}-piperidine-3-carboxylic acid bicyclopropyl-1-ylamide 4.046 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.64 503.3 carbonyl]-amino}-piperidine-3-carboxylic acid [(1RS)-1-(tetrahydro-furan-2- yl)-ethyl]-amide (mixture of isomers) 4.047 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.53 500.1 carbonyl]-amino}-piperidine-3-carboxylic acid [(1RS)-1-(1H-[1,2,4]triazol-3- yl)-ethyl]-amide (mixture of isomers) 4.048 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.62 457.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1RS)-1-methyl-prop-2-ynyl)- amide (mixture of isomers) 4.049 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.61 500.3 carbonyl]-amino}-piperidine-3-carboxylic acid ((1RS)-1-isoxazol-3-yl-ethyl)- amide (mixture of isomers) 4.050 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 538.4 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyridin-2-yl)- cyclopropyl]amide 4.051 (3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.9 508.3 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 4.052 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-(1- 0.6 541 fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid (1-pyrimidin-2-yl- cyclopropyl)-amide 4.053 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 521.4 carbonyl]-amino)-piperidine-3-carboxylic acid (1-phenyl-cyclopropyl)-amide 4.054 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 540.2 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-fluoro-pyridin-2-yl)- cyclopropyl]-amide 4.055 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 523.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-4-yl-cyclopropyl)- amide 4.056 1-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 517.4 carbonyl]-amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester 4.057 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 535.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-phenyl-cyclobutyl)-amide 4.058 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenylyisoxazole-3- 0.8 541.4 carbonyl]-amino}-piperidine-3-carboxylic acid benzyl-(2-fluoro-ethyl)-amide 4.059 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 551.1 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-methoxy-phenyl)- cyclopropyl]-amide 4.060 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 589.4 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-trifluoromethyl-phenyl)- cyclopropyl]-amide 4.061 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 539.1 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-fluoro-phenyl)- cyclopropyl]-amide 4.062 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.0 539 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(4-fluoro-phenyl)- cyclopropyl]-amide 4.063 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 539 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-fluoro-phenyl)- cyclopropyl]-amide 4.064 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5 510 carbonyl]-amino}-piperidine-3-carboxylic acid (6-methyl-pyridin-2-ylmethyl)- amide 4.065 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.86 543.2 carbonyl]-amino}-piperidine-3-carboxylic acid [2-(2-chloro-phenyl)-ethyl]- amide 4.066 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 461 carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 4.067a 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.7 521.1 cyclopropylmethyl-3((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]- amide or 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- cyclopropylmethyl-3((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]- amide (1.sup.st eluted epimer) 4.067b 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.7 521.1 cyclopropylmethyl-3-((R)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]- amide or 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- cyclopropylmethyl-3-((S)-2-phenyl-azetidine-1-carbonyl)-piperidin-4-yl]- amide (2.sup.nd eluted epimer) 4.068 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 555 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(3-chloro-phenyl)- cyclopropyl]-amide 4.069 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 449.2 carbonyl]-amino}-piperidine-3-carboxylic acid methoxy-methyl-amide 4.070 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 556.1 carbonyl]-amino)-piperidine-3-carboxylic acid [1-(4-methyl-thiazol-2-yl)- cyclobutyl]-amide 4.071 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 461.1 carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 4.072 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 539.4 carbonyl]-amino}-piperidine-3-carboxylic acid [(R,S)-1-(2-methoxy-phenyl)- ethyl]-amide 4.072a (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 539.4 carbonyl]-amino}-piperidine-3-carboxylic acid [(R)-1-(2-methoxy-phenyl)- ethyl]-amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid [(S)-1-(2- methoxy-phenyl)-ethyl]-amide (1.sup.st eluted epimer) 4.073 (R,S)-[((3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 567.2 carbonyl]-amino}-piperidine-3-carbonyl)-amino]-phenyl-acetic acid ethyl ester 4.074 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 551 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-methoxy-phenyl)- cyclopropyl]-amide 4.075 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.8 587.1 carbonyl]-amino}-piperidine-3-carboxylic acid [(R)-1-(3-bromo-phenyl)- ethyl]-amide 4.076 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.7 537 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(2-hydroxy-phenyl)- cyclopropyl]-amide 4.077 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 1.0 539.4 carbonyl]-amino}-piperidine-3-carboxylic acid [1-(1-oxy-pyrimidin-2-yl)- cyclopropyl]-amide 4.078 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 537 cyclopropylmethyl-3-((R,S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)- piperidin-4-yl]-amide 4.078b 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 537.4 cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)-piperidin- 4-yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)- 1-cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-pyrrolidine-1-carbonyl)- piperidin-4-yl]-amide (2.sup.nd eluted epimer) 4.079a 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 523.4 cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4- yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4- yl]-amide (1st eluted epimer) 4.079b 5-(2,4-Difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- 0.6 523 cyclopropylmethyl-3-((R)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4- yl]-amide or 5-(2,4-difluoro-phenyl)-isoxazole-3-carboxylic acid [(3S,4S)-1- cyclopropylmethyl-3-((S)-2-pyrimidin-2-yl-azetidine-1-carbonyl)-piperidin-4- yl]-amide (2nd eluted epimer) 4.080 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 511.1 carbonyl]-amino}-piperidine-3-carboxylic acid ((R,S)-1-pyrimidin-2-yl-ethyl)- amide 4.080a (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 511 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrimidin-2-yl-ethyl)- amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino}-piperidine-3-carboxylic acid ((S)-1-pyrimidin-2-yl-ethyl)- amide (1st eluted epimer) 4.080b (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenylyisoxazole-3- 0.6 511.4 carbonyl]-amino}-piperidine-3-carboxylic acid ((R)-1-pyrimidin-2-yl-ethyl)- amide or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino}-piperidine-3-carboxylic acid ((S)-1-pyrimidin-2-yl-ethyl)- amide (2nd eluted epimer) 4.081 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-5-yl-cyclopropyl)- amide 4.082 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 540.4 amino}-piperidine-3-carboxylic acid [1-(3-fluoro-pyridin-2-yl)-cyclopropyl]- amide 4.083 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 525.1 amino}-piperidine-3-carboxylic acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide 4.084 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 511 amino}-piperidine-3-carboxylic acid ((R,S)-1-pyrimidin-2-yl-ethyl)-amide 4.084b (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 511 amino}-piperidine-3-carboxylic acid ((R)-1-pyrimidin-2-yl-ethyl)-amide or (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- amino}-piperidine-3-carboxylic acid ((S)-1-pyrimidin-2-yl-ethyl)-amide (2nd eluted epimer) 4.085 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.7 551.1 amino}-piperidine-3-carboxylic acid (3-benzyl-oxetan-3-yl)-amide 4.086 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 552 amino}-piperidine-3-carboxylic acid [2-methyl-2-(3-methyl-pyridin-2-yl)- propyl]-amide 4.087 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 538.1 amino}-piperidine-3-carboxylic acid (2-methyl-2-pyridin-2-yl-propyl)-amide 4.088 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.8 535 amino}-piperidine-3-carboxylic acid (1-o-tolyl-cyclopropyl)-amide 4.089 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.7 555.1 amino}-piperidine-3-carboxylic acid [3-(4-fluoro-phenyl)-oxetan-3-yl]amide 4.090 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.7 551 amino}-piperidine-3-carboxylic acid (3-phenyl-oxetan-3-ylmethyl)-amide 4.091 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.8 571.3 amino}-piperidine-3-carboxylic acid [2-(2-chloro-phenyl)-2-methyl-propyl]- amide 4.092 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.8 569.4 amino}-piperidine-3-carboxylic acid [1-(4-chloro-phenyl)-cyclopropylmethyl]- amide 4.093 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 536 amino}-piperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropylmethyl)- amide 4.094 (3R,4R)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.7 571.1 amino}-piperidine-3-carboxylic acid [3-(3-chloro-phenyl)-oxetan-3-yl]-amide 4.095 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl- 0.5 498 piperidine-3-carboxylic acid [(R)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide 4.096 (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-1-ethyl- 0.6 499 piperidine-3-carboxylic acid (1-methyl-1-pyrimidin-2-yl-ethyl)-amide 4.097 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.7 571.4 amino}-piperidine-3-carboxylic acid [3-(3-chloro-phenyl)-oxetan-3-yl]amide 4.098 (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 528 amino}-piperidine-3-carboxylic acid [(R,S)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide 4.098a (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 528 amino}-piperidine-3-carboxylic acid [(R)-1-(3-fluoro-pyridin-2-yl)-ethyl]- amide or (3S,4S)-1-Cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- carbonyl]-amino}-piperidine-3-carboxylic acid [(S)-1-(3-fluoro-pyridin-2yl)- ethyl]-amide (2nd eluted epimer) 4.099 (3R,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5 497.2 carbonyl]-amino)-piperidine-3-carboxylic acid (pyrimidin-2-ylmethyl)-amide 4.100 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.5 497 carbonyl]-amino)-piperidine-3-carboxylic acid (pyrimidin-2-ylmethyl)-amide 4.101 rac-(3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 525.4 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 4.101a (3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 525 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1) 4.101b (3R*,4R*)-1-tert-Butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- 0.6 525 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 2) 4.102 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- 0.6 525 carbonyl]-amino}-piperidine-3-carboxylic acid (1-methyl-1-pyrimidin-2-yl- ethyl)-amide
General Method G for the Synthesis of Piperidines of Formula (I)
Buildings Blocks:
Preparation of building blocks of Structure G-9

(294) ##STR00029##

BB-5.01: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid Dimethylamide

5.01a: 3-Methyl-4-oxo-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(295) A mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1 g, 4 mmol), potassium carbonate (1.1 g, 8 mmol) and iodomethane (1.13 g, 8 mmol) in acetone (12 mL) is heated under reflux for 7 h. The mixture is then cooled to RT and filtered through a fritted filter. The filtrate is concentrated under reduced pressure to yield the title compound as a yellowish oil. LC-MS method A: t.sub.R=0.78 min; [M+H].sup.+=272.21.

5.01b: 4-Benzylamino-3-methyl-3,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(296) A solution of 3-methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.02 g, 3.78 mmol) in toluene (30 mL) is treated with benzylamine (0.51 g, 4.76 mmol) and p-toluenesulfonic acid monohydrate (36 mg). The resulting mixture is heated under reflux for 2 h with a dean-stark condenser. The reaction mixture is extracted three times with aq. sat. NaHCO.sub.3. The organic phase is collected, dried over MgSO.sub.4, filtered and the solvents evaporated to yield the crude product as a yellow oil.

5.01c: rac-(3R*,4R*)-4-Benzylamino-3-methyl-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(297) The crude benzylamino-3-methyl-3,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.23 g, 3.3 mmol) is dissolved in MeCN (15 mL) and cooled to 0° C. AcOH (0.38 mL, 6.6 mmol) is added. Sodium triacetoxyborohydride (3.84 g, 18.1 mmol) is added portionwise. The resulting mixture is stirred at 0° C. for 30 min and at RT for 2 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in DCM (50 mL) and sat. aq. sodium carbonate solution (50 mL) is added slowly. The organic layer is separated, the aq. phase extracted again with DCM (50 mL) and the combined organic layers are washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The two diastereomers are separated using silica gel column chromatography. Evaporation of the lower fraction delivers the trans isomer, as shown by 2D- and NOE NMR study, as a colorless oil. LC-MS method A: t.sub.R=0.67 min; [M+H].sup.+=363.22.

5.01d: rac-(3R*,4R*)-4-Amino-3-methyl-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(298) Dry Pd on activated charcoal 10% (27 mg, 0.0254 mmol) is added to a solution of rac-(3R*,4R*)-4-benzylamino-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.3 g, 0.84 mmol) in MeOH (12 mL). After degassing the reaction flask, the mixture is hydrogenated for 1 h at ambient temperature. The reaction mixture is filtered to remove the catalyst, and then concentrated to give the crude product as a yellow oil. LC-MS method A: t.sub.R=0.53 min; [M+H].sup.+=273.22.

5.01e: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(299) To a solution of rac-(3R*,4R*)-4-amino-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (225 mg, 0.83 mmol) in DMF (5 mL) at RT is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (205 mg, 0.91 mmol). DIPEA (0.283 mL, 1.65 mmol) is then added followed by HATU (346 mg, 0.91 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is purified by prep. LC-MS in basic conditions. The title compound is obtained as a pale yellow solid. LC-MS method A: t.sub.R=1.01 Min; [M+H].sup.+=480.14.

5.01f: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(300) rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (240 mg, 0.5 mmol) is dissolved in THF (4 mL) at RT. Aq. 1M LiOH solution (4 mL, 4 mmol) is then added and the mixture stirred at RT for 72 h. The reaction mixture is acidified with 1M HCl solution (5 mL). The resulting suspension is extracted twice with DCM (10 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The title compound is obtained as an off-white solid; LC-MS method A: t.sub.R=0.91 min; [M+H].sup.+=465.91.

5.01q: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-3-methyl-piperidine-1-carboxylic Acid Tert-Butyl Ester

(301) A solution of rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.43 mmol) in DMF (6 mL) is treated with dimethylamine 2M solution in THF (0.277 mL, 0.554 mmol) and DIPEA (0.158 mL, 0.924 mmol). Then, HATU (193 mg, 0.508 mmol) is added and the reaction is stirred overnight. DMF is evaporated and the crude is taken up in DCM (10 mL) and extracted three times with NaHCO3 sat sol. (10 mL). The combined organic layers are washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated to yield the product as a slightly orange oil, used as crude for the next step. LC-MS method A: t.sub.R=0.97 min; [M+H].sup.+=493.11.

5.01 h: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid Dimethylamide

(302) rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-dimethylcarbamoyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.27 mmol) is dissolved in MeOH (5 mL) at RT. A 4M solution of HCl in dioxane (0.068 mL, 0.274 mmol) is added and the reaction stirred at RT for 1 h. The reaction mixture is concentrated, dissolved in DCM (10 mL) and treated with aq. sat. NaHCO.sub.3 (10 mL). The organic layer is separated and the aq. phase is extracted twice with DCM (2×10 mL). The combined organic layers are dried over MgSO.sub.4 and evaporated. The crude title compound is obtained; LC-MS A: t.sub.R=0.64 min; [M+H].sup.+=393.15.

(303) Preparation of Building Blocks of Substituted Piperidines of Structure 1 Used as Intermediates in the Preparation of Examples 5.002

(304) In analogy to example BB-5.01 the following amide is prepared:

BB-5.02 (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid ((R)-1-pyridin-2-yl-ethyl)-amide

5.02a: (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-3-((R)-1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(305) The title compound is prepared according to the reaction 5.01g described above using rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester and ((R)-1-pyridin-2-yl-ethyl)-amine; LC-MS method A: t.sub.R=0.78 min; [M+H].sup.+=570.12.

5.02: (3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid ((R)-1-pyridin-2-yl-ethyl)-amide

(306) The title compound is prepared according to the reaction 5.01 h described above by treating (3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-3-((R)-1-pyridin-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester with 4M HCl in dioxane; LC-MS method A: t.sub.R=0.56 min; [M+H].sup.+=470.09.

Example 5.001: (3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid ((R)-1-pyridin-2-yl-ethyl)-amide

(307) A solution of rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide, cyclohexanone (0.046 mL, 0.45 mmol) and AcOH (0.032 mL, 0.56 mmol) in DCM (5 mL) at RT is treated by sodium triacetoxyborohydride (149 mg, 0.67 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is diluted with DCM (5 mL) and washed with aq. sat. NaHCO.sub.3 (10 mL). The organic layer is dried over MgSO.sub.4 and evaporated. The crude residue is purified by prep. LC-MS in basic conditions. The title compound is obtained as a colorless powder. LC-MS method A: t.sub.R=0.69 Min; [M+H].sup.+=552.15.

Example 5.002: rac-(3R*,4R*)-1-Cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic Acid Dimethylamide

(308) The title compound is prepared according to Example 5.001 described above by treating rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-3-carboxylic acid dimethylamide with cyclohexanone; LC-MS method A: t.sub.R=0.76 min; [M+H].sup.+=475.13.

(309) Buildings Blocks:

(310) Preparation of Building Blocks of Structure B-3

(311) ##STR00030##

BB-6.01: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

6.01a: 4-Amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(312) A solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (10 g, 36.9 mmol), in MeOH (140 mL) is treated with 7N ammonia solution in MeOH (25 mL, 1.14 mol) and the resulting solution is heated under reflux for 18 h. The mixture is then cooled to RT and concentrated under reduced pressure. The residue is taken up in DCM (100 mL) and washed twice with water (2×100 mL) and brine (2×100 mL). The organic layer is dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield the crude product as a yellow solid. LC-MS method A: t.sub.R=0.83 min; [M+H− t-Bu].sup.+=202.27.

6.01b: Mixture of rac-(3R*,4R*)-4-amino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester and rac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(313) NaBH.sub.4 (1.73 g, 45.7 mmol) is dissolved in THF (100 mL) and the resulting solution is cooled to −18° C. TFA (13 mL, 169 mmol) is added over 20 min. at −14° C. to −18° C. A solution of the crude 4-amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (9.53 g, 33.9 mmol) in THF (15 mL) is added dropwise over 10 min. The reaction is allowed to warm to 0° C. over 15 min and stirred at this temperature for 1 h. Water (50 mL) is poured onto the reaction mixture and stirring is continued for 10 min. The pH of the resulting solution is brought to pH=11 with 10 N aq. NaOH. The mixture is extracted with DCM (2×100 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The product is obtained as a cis-trans mixture of products, as a yellow foam: LC-MS method A: t.sub.R=0.55 min; [M+H].sup.+=259.34 and 0.58 min; [M+H].sup.+=259.5.

6.01c: Mixture of rac-(3S*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester and rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(314) To a solution of rac-(3R*,4R*)-4-amino-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester and rac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (7.1 g, 23.6 mmol) in DCM (75 mL) at RT is added 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid (6.673 g, 29.1 mmol). DIPEA (9.98 mL, 58.3 mmol) is then added followed by T.sub.3P 50% solution in DCM (34.7 mL, 58.3 mmol). The reaction mixture is stirred for 1 h30 at RT. The pH of the resulting solution is brought to pH=11 with 1 N aq. NaOH and the mixture is washed twice with aq. 1 N NaOH solution (2×100 mL). The organic phase is dried over MgSO.sub.4, filtered and concentrated under reduced pressure to deliver a mixture of cis-trans products (4:1 mixture) as a beige solid. LC-MS method A: t.sub.R=1.07 Min; [M+H].sup.+=465.94 and t.sub.R=1.10 Min; [M+H].sup.+=465.94.

(315) The pure cis isomer rac-(3S*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester is obtained by suspending the cis-trans mixture in MeOH and then filtered off. LC-MS method A: t.sub.R=1.07 Min; [M+H].sup.+=465.96.

6.01d: rac-(3R*,4R*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(316) Sodium methoxide solution 25 wt. % in MeOH (7.43 mL, 0.0325 mol) is added to MeOH (15 mL) and methyl acetate (3.9 mL, 0.0488 mol). The mixture is refluxed for 30 min and cooled to RT. Then the mixture of rac-(3S*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester and rac-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (8.37 g, 16.3 mmol) is suspended under nitrogen in dry MeOH (10 mL), and the resulting suspension is injected into the NaOMe solution prepared previously. The mixture is stirred at RT for 1 day. The reaction mixture is treated with aq. sat. NaHCO.sub.3 (10 mL) and MeOH is evaporated at reduced pressure. DCM (25 mL) is added to the residue. The organic phase is separated and the aq. layer is extracted 3× with DCM (3×25 mL). The combined organic layers are dried over MgSO.sub.4, filtered and concentrated. The crude residue is triturated with MeCN (10 mL) to afford the title compound as an off white solid. LC-MS method A: t.sub.R=1.07 Min; [M+H].sup.+=465.94.

(317) General Method I for the Synthesis of Piperidines of Formula (I)

(318) Buildings Blocks:

(319) Preparation of Building Blocks of Structure 1-7

(320) ##STR00031##

BB 7.01: (3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

7.01a: (3R,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(321) N-(Benzyloxycarbonyloxy)succinimide (12.2 g, 48.1 mmol) is added to a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (13.1 g, 48.1 mmol) in THF (100 mL) at 0° C. The reaction mixture is stirred for 10 min at 0° C. and then at RT for 2 h. THF is evaporated and the residue is taken up in DCM (100 mL). The mixture is washed with aq.sat.NaHCO.sub.3 (100 mL), dried over MgSO.sub.4, filtered, concentrated and dried at HV to deliver the crude product as a yellowish oil. LC-MS method A t.sub.R=1.01 min; [M+H].sup.+=407.15.

7.01b: (3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(322) Sodium ethoxide solution 21 wt. % in EtOH (77.4 mL, 0.0465 mol) is added to EtOH (100 mL) and ethyl acetate (14.1 mL, 0.139 mol). The mixture is refluxed for 30 min and cooled to RT. A suspension of (3R,4S)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester in dry ethanol (20 mL) is added dropwise to the NaOEt solution at RT under nitrogen. The mixture is stirred at RT for 24 h. The reaction mixture is treated with water (10 mL) and EtOH is evaporated at reduced pressure. Water (100 mL) is added and the pH of the solution is adjusted to 5 by treatment with aq. 2N HCl. added to the residue. The aq. phase is extracted 3× with DCM (3×100 mL). The combined organic layers are dried over MgSO.sub.4 and filtered. Evaporation of the solvent gives the crude title compound as a yellowish oil, contaminated by 15% of the acid 7.01c. LC-MS method A: t.sub.R=1.01 Min; [M+H].sup.+=407.13.

7.01c: (3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(323) (3S,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester 7.01b (4.07 g, 10 mmol) is dissolved in THF (50 mL) at RT. Aq. 1M NaOH solution (20 mL, 20 mmol) is added and the mixture is stirred at RT for 18 h. The reaction mixture is acidified to around pH=3 with a 2M HCl solution (11 mL, 21 mmol) and evaporated. The resulting suspension is extracted twice with DCM (2×50 mL). The organic phase is dried over MgSO.sub.4 and the solvent is evaporated to give the title compound; LC-MS method A t.sub.R=0.86 min; [M+H].sup.+=379.18.

7.01d: (3S,4S)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(324) A solution of (3S,4S)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (4.26 g, 11.3 mmol) in DMF (40 mL) is treated with 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride (2.17 g, 12.4 mmol), DIPEA (10.2 mL, 58.5 mmol) and HATU (5.136 g, 13.5 mmol). The mixture is stirred 2 h at RT. Aq. saturated NaHCO.sub.3 solution (50 mL) and DCM (80 mL) are added and the aq. phase is extracted with DCM (2×70 mL), dried over MgSO4, filtered and evaporated. The crude is purified by Prep HPLC using basic conditions. The title compound is obtained as a yellowish foam. LC-MS method A: t.sub.R=0.89 Min; [M+H].sup.+=496.11.

7.01e: [(3S,4S)-3-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Benzyl Ester

(325) (3S,4S)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (2622 mg, 5.29 mmol) in MeOH (35 mL) is treated with HCl 4M in dioxane (10.6 mL, 42.3 mmol). The reaction mixture is stirred at 50° C. for 2 h. After evaporation of the solvents, the crude is dried under HV to give the crude title compound; LC-MS method D t.sub.R=0.56 min; [M+H].sup.+=396.07.

7.01f: [(3S,4S)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Benzyl Ester

(326) To a solution of [(3S,4S)-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic acid benzyl ester (3.06 g, 7.09 mmol) in DCM (100 mL) at RT is added cyclopropanecarboxaldehyde (0.54 mL, 7.09 mmol) followed by DIPEA (3.64 mL, 21.3 mmol) and sodium triacetoxyborohydride (3.96 g, 17.7 mmol). The reaction mixture is stirred overnight. The reaction mixture is treated with aq. sat. NaHCO.sub.3 (100 mL) and the resulting suspension is extracted twice with DCM (2×100 mL). The organic phase is dried over MgSO.sub.4 and evaporated. The crude is purified by Prep HPLC using basic conditions. The title compound is obtained as a light yellowish solid. LC-MS method A: t.sub.R=0.63 Min; [M+H].sup.+=450.17.

7.01: (3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(327) A flask is purged with nitrogen, then charged with Pd/C 10% (50% wet) (160 mg, 1.5 mmol) and dry MeOH (10 mL) is added. A nitrogen purged suspension of [(3S,4S)-1-cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic acid benzyl ester (1349 mg, 3 mmol) in dry MeOH (20 mL) is added to the Pd suspension. The atmosphere is exchanged with hydrogen and the mixture is stirred at RT for 3 h. The mixture is filtered and evaporated. The crude is purified by Prep HPLC using basic conditions. The title compound is obtained as a light yellowish solid. LC-MS method A: t.sub.R=0.34 Min; [M+H].sup.+=316.34.

BB 7.02: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

7.02a: rac-(3R*,4R*)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

(328) The title compound is prepared according to the procedure 7.01a starting from building block rac-(3S*,4R*)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester. LC-MS method A t.sub.R=1.00 min; [M+H].sup.+=393.26.

7.02b: rac-(3R*,4R*)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(329) The title compound is prepared according to the procedure 7.01b starting from building block 7.0a. LC-MS method A: t.sub.R=0.96 Min; [M+H].sup.+=393.23.

7.02c: rac-(3R*,4R*)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(330) The title compound is prepared according to the procedure 7.01c starting from building block 7.02b; LC-MS method A t.sub.R=0.86 min; [M+H].sup.+=379.25.

7.02d: rac-(3R*,4R*)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(331) The title compound is prepared according to the procedure 7.01d starting from building block 7.02c; LC-MS method A: t.sub.R=0.88 Min; [M+H].sup.+=496.25.

7.02e: rac-[(3R*,4R*)-3-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Benzyl Ester

(332) The title compound is prepared according to the procedure 7.01e starting from building block 7.02d. LC-MS method D t.sub.R=0.56 min; [M+H].sup.+=396.27.

7.02f: rac-[(3R*,4*)-1-Cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic Acid Benzyl Ester

(333) The title compound is prepared according to the procedure 7.01f starting from building block 7.02e. LC-MS method A: t.sub.R=0.66 Min; [M+H].sup.+=450.09.

7.02: rac-(3R*,4R*)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(334) The title compound is prepared according to the procedure 7.01 starting from building block 7.02f. LC-MS method A: t.sub.R=0.37 Min; [M+H].sup.+=316.29.

Example 7.001: (3S,4S)-1-Cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(335) To a solution of (3S,4S)-4-Amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (50 mg, 0.16 mmol) in DMF (5 mL) is added 4-fluoro-5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid (35.7 mg, 0.08 mmol). DIPEA (0.067 mL, 0.396 mmol) is then added followed by HATU (72.3 mg, 0.19 mmol). The reaction mixture is stirred 21 h at RT. Up to 0.28 mmol of a 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the clear solution is directly purified by prep. LC-MS with method E. LC-MS QC method: t.sub.R=0.60 min; [M+H].sup.+=523.1.

(336) Compounds of Examples 7.002 to 7.016 listed in Table 5 below are prepared by applying one of the above-mentioned general procedures I or J to the building blocks BB-7.01 BB-7.02 coupled with respective carboxylic acid or ester of Structure A-4 (L.sup.1=OH or O-alkyl), which is commercially available or prepared according to/in analogy to the methods described above.

(337) Enantiomerically pure compounds are obtained using one of the above mentioned chiral preparative chromatography methods.

(338) TABLE-US-00005 TABLE 5 Examples 7.002-7.016 LC-MS Mass Example Found Nr Substance Name t.sub.R (min) [M + H].sup.+ 7.002 (3S,4S)-1-Cyclopropylmethyl-4-[(5-o-tolyl-isoxazole-3-carbonyl)-amino]- 0.60 501.4 piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 7.003 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(3,4-dimethyl-phenyl)-isoxazole-3- 0.70 515.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.004 (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4- 1.0 523.2 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.005 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole-3- 0.70 515.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.006 (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole-5- 0.60 523.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.007 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-oxazole-2-carbonyl]- 0.6 505 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 7.008 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazole-3- 0.5 524 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.009 (3S,4S)-4-{[5-(4-Cyano-phenyl)-isoxazole-3-carbonyl]-amino}-1- 0.5 512 cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.010 (3S,4S)-1-Cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.6 523.4 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 7.011 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazole-2-carbonyl]- 0.6 523 amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 7.012 (3S,4S)-1-Cyclopropylmethyl-4-{[1-(2,4,6-trifluoro-phenyl)-1H-[1,2,3]triazole- 1.0 541.4 4-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.013 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(3,4-difluoro-phenyl)-isoxazole-3- 0.6 523 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.014 (3S,4S)-1-Cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isothiazole-5- 0.6 539 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.015 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isothiazole-3- 0.6 539.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide 7.016 (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2- 0.6 540.1 carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)- amide
General Method I for the Synthesis of Piperidines of Formula (I)
Buildings Blocks:
Preparation of Building Blocks of Structure D-9

(339) ##STR00032##

BB 8.01: (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide

8.01a: (3R,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(340) To a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1400 mg, 5.14 mmol)) in DMF (50 mL) at RT is added 1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (1157 mg, 5.14 mmol). DIPEA (4.67 mL, 26.7 mmol) is then added followed by HATU (2346 mg, 6.17 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is purified by prep. LC-MS in basic conditions. The title compound is obtained as a pale yellow solid. LC-MS method A: t.sub.R=1.01 Min; [M+H].sup.+=480.11.

8.01b: (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(341) To a solution of (3R,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1587 mg, 3.41 mmol) in EtOH (14.9 mL, 256 mmol) and EtOAc (7.36 mL, 75 mmol) is added in one portion sodium methoxide powder (776 mg, 13.6 mmol) at RT under an argon atmosphere. The reaction mixture is stirred at RT overnight. The reaction mixture is quenched with sat. aq. NH.sub.4Cl (200 mL) and extracted twice with DCM (2×250 mL). The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo. The crude is purified by prep. LC-MS in basic conditions. LC-MS method A: t.sub.R=0.98 Min; [M+H].sup.+=480.13.

8.01c (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(342) To a solution of (3S,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1000 mg, 2.09 mmol) in THF (30 mL) is added 1 M NaOH (7 mL, 6.26 mmol). The mixture is stirred 4 h at RT. 2 M HCl (3.7 mL, 6.47 mmol, 3.1 eq) is added to reach pH 3 and THF is evaporated until dryness.

(343) The white solid is dried under high vacuum overnight. LC-MS method A: t.sub.R=0.85 min; [M+H].sup.+=451.8.

8.01d: (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(344) A solution of (3S,4S)-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.11 mmol) in DMF (12 mL) is treated with 1-(pyridin-2-yl)cyclopropan-1-amine dihydrochloride (226 mg, 1.11 mmol), DIPEA (1.01 mL, 5.76 mmol) and HATU (5.35 mg, 1.33 mmol). The mixture is stirred 2 h at RT. Saturated NaHCO.sub.3 solution (20 mL) and DCM (20 mL) are added and the aq. phase is extracted twice with DCM (2×20 mL), dried over MgSO.sub.4, filtered and evaporated. The crude is purified by Prep HPLC using basic conditions. The title compound is obtained as a white solid. LC-MS method A: t.sub.R=0.77 Min; [M+H].sup.+=568.29.

8.01: (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic Acid (1-pyridin-2-yl-cyclopropyl)-amide Hydrochloride

(345) (3S,4S)-4-{[1-(2,4-Difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (205 mg, 0.361 mmol) is dissolved in dioxane (8 mL) at RT. A 4M solution of HCl in dioxane (1 mL, 4 mmol) is added and the reaction stirred at RT for 1 h. The reaction mixture is concentrated. The white solid is dried under high vacuum overnight LC-MS A: t.sub.R=0.50 min; [M+H].sup.+=467.83.

BB 8.02: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide Hydrochoride

8.02a: (3R,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(346) The title compound is prepared by treatment of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester and 5-(2,4-Difluoro-phenyl)-oxazole-2-carboxylic Acid lithium salt according to procedure 8.01a. LC-MS method A: t.sub.R=1.07 Min; [M+H].sup.+=480.16.

8.02b: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl Ester

(347) The title compound is prepared according to the procedure 8.01b, starting from building block 8.02a; LC-MS method A: t.sub.R=1.04 Min; [M+H].sup.+=480.16.

8.02c (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(348) The title compound is prepared according to the procedure 8.01c, starting from building block 8.02b; LC-MS method A: t.sub.R=0.91 min; [M+H].sup.+=452.18.

8.02d: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(349) The title compound is prepared according to the procedure 8.01d, starting from 8.02c and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LC-MS method A: t.sub.R=0.93 Min; [M+H].sup.+=569.24.

8.02: (3S,4S)-4-{[5-(2,4-Difluoro-phenyl)-oxazole-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide hydrochoride

(350) The title compound is prepared according to the procedure 8.01 described above, starting from building block 2.04c; LC-MS method A: t.sub.R=0.62 min; [M+H].sup.+=469.16.

(351) Buildings Blocks:

(352) Preparation of Amines of Structure 2

(353) ##STR00033##

BB-9.01 1-(1-Oxy-pyrimidin-2-yl)-cyclopropylamine Hydrochoride

9.01a: [1-(1-Oxy-pyrimidin-2-yl)-cyclopropyl]-carbamic Acid Tert-Butyl Ester

(354) To a solution of (1-Pyrimidin-2-yl-cyclopropyl)-carbamic acid tert-butyl ester (200 mg, 0.834 mmol) in DCM (5 mL) at 0° C. is added portionwise 3-chloroperbenzoic acid (226 mg, 0.917 mmol). The reaction mixture is stirred at RT for 72 h. The mixture is diluted with DCM (20 mL) and washed with aq. sat. NaHCO.sub.3 (20 mL). The organic phase is separated and the aq. phase is extracted with DCM (20 mL), The combined organic are dried over MgSO.sub.4, filtered and concentrated. The crude is purified by Prep HPLC using basic conditions. The title compound is obtained as a white solid. LC-MS method A: t.sub.R=0.77 Min; [M+H].sup.+=568.29. to give the tittle compound as a yellowish powder; LC-MS method A: t.sub.R=0.60 min; [M+H].sup.+=252.27.

9.01: 1-(1-Oxy-pyrimidin-2-yl)-cyclopropylamine Hydrochloride

(355) [1-(1-Oxy-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (74 mg, 0.29 mmol) is dissolved in MeOH (3 mL) at RT. A 4M solution of HCl in dioxane (0.44 mL, 1.77 mmol) is added and the reaction mixture is stirred at RT for 18 h. The solvents are evaporated to give the title compound as a yellowish solid; LC-MS method A: t.sub.R=0.21 min; [M+H].sup.+=152.31.

REFERENCE EXAMPLES

Reference Example 1

rac-(3R*,4R*)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(356) The title compound is prepared according to the procedure described for the preparation of Example 7.001 starting from building block 7.02 and 5-cyclopropyl-isoxazole-3-carboxylic acid. LC-MS method A: t.sub.R=0.61 Min; [M+H].sup.+=451.27.

(357) Chiral preparative SFC of rac-(3R*,4R*)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide using a column ChiralPak IC, 5 μm, 4.6×250 mm; with a mixture of A (CO.sub.2) and B (DCM/MeOH/DEA 50:50:01)) as eluent yields both enantiomers:

Reference Compound 1a: (3R,4R)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide or (3S,4S)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(358) Chiral HPLC t.sub.R=1.80 min.; QC LC-MS method: t.sub.R=0.5 min; [M+H].sup.+=451;

(359) IC.sub.50: >10000 nM.

Reference Compound 1b: (3R,4R)-4-[(5-Cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide or (3S,4S)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)-amino]-1-cyclopropylmethyl-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(360) Chiral HPLC t.sub.R=2.48 min.; QC LC-MS method: t.sub.R=0.5 min; [M+H].sup.+=451.3;

(361) IC.sub.50: >10000 nM.

Reference Example 2

(3R,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide and (3S,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

Step 1: rac-(3R*,4S*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

(362) The title compound is prepared according to the procedure 2.01c, starting from building block 6.01c by treatment with NaOH in THF/H.sub.2O, followed by aq. HCl; LC-MS method A: t.sub.R=1.01 min; [M+H].sup.+=452.22.

Step 2: rac-(3R*,4S*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic Acid Tert-Butyl Ester

(363) The title compound is prepared according to the procedure 2.01d, starting from step 1 and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LC-MS method A: t.sub.R=1.06 min; [M+H].sup.+=569.33.

Step 3: rac-(3R*,4S*)-4-{[5-(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(364) The title compound is prepared according to the procedure 2.01, starting from step 2; LC-MS method A: t.sub.R=0.74 min; [M+H].sup.+=469.14.

Step 4: rac-(3R*,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(365) The title compound is prepared according to the method D, starting from step 3; LC-MS method A: t.sub.R=0.71 min; [M+H].sup.+=523.18.

(366) Chiral preparative HPLC of rac-(3R*,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide using a column ChiralPak IC, 5 μm, 4.6×250 mm; with a mixture of A (10% Heptan, 0.05% DEA)) and B (90% EtOH, 0.05% DEA) as eluent and a flow of 1.2 mL/min. Chiral HPLC: yields both enantiomers:

Reference Example 2a: (3R,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(367) Chiral HPLC t.sub.R=12.01 min.; QC LC-MS method: t.sub.R=0.7 min; [M+H].sup.+=523.1;

(368) IC.sub.50: >10000 nM.

Reference Example 2b: (3S,4R)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(369) Chiral HPLC t.sub.R=18.35 min.; QC LC-MS method: t.sub.R=0.7 min; [M+H].sup.+=523.4;

(370) IC.sub.50: 2250 nM.

Reference Example 3

(3S,4S)-1-Cyclopropylmethyl-4-[(5-phenyl-isoxazole-3-carbonyl)-amino]-piperidine-3-carboxylic Acid (1-pyrimidin-2-yl-cyclopropyl)-amide

(371) Reference example 3 is prepared according to example 7.001, starting from (3S,4S)-4-amino-1-cyclopropylmethyl-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide and 4-phenyl-isoxazole-3-carboxylic acid. LC-MS method A: t.sub.R=0.66 min; [M+H].sup.+=487.13.

(372) IC.sub.50: 1330 nM.

(373) Table 6 summarizes NMR characterization data of particular example compounds.

(374) TABLE-US-00006 TABLE 6 .sup.1H NMR data of particular example compounds Example Chemical shift (δ) in part per million (ppm) Solvent 1.004 (400 MHz) δ: 8.72 (d, J = 8.6 Hz, 1H), 8.08-8.01 (m, 1H), 7.60-7.54 (m, 1H), 7.36- DMSO-d6 7.30 (m, 1H), 7.08 (d, J = 2.7 Hz, 1H), 4.10-4.05 (m, 1H), 3.78-3.72 (m, 2H), 3.22- 3.15 (m, 1H), 2.93-2.81 (m, 4H), 2.29-2.19 (m, 3H), 1.90-1.68 (m, 9H), 1.61-1.54 (m, 2H), 1.20-1.15 (m, 5H). 1.095 (400 MHz) δ: 8.93 (s, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.94-7.86 (m, 1H), DMSO-d6 7.71-7.64 (m, 1H), 7.39-7.33 (m, 1H), 4.15-4.05 (m, 1H), 3.25- 3.17 (m, 1H), 3.07 (s, 3H), 2.88-2.81 (m, 2H), 2.75 (s, 3H), 2.32- 2.16 (m, 3H), 1.80-1.72 (m, 5H), 1.63-1.55 (m, 2H), 1.18-1.14 (m, 5H). 1.107 (400 MHz) δ: 8.80 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 9.2, 9.2 Hz, 2H), 7.15 DMSO-d6 (s, 1H), 4.38-4.31 (m, 1H), 4.17-4.11 (m, 1H), 4.05-3.91 (m, 1H), 3.83-3.69 (m, 2H), 3.02-2.96 (m, 2H), 2.77-2.68 (m, 1H), 2.27 (dd, J = 6.4, 12.7 Hz, 1H), 2.19-1.98 (m, 5H), 1.83-1.76 (m, 1H), 1.69- 1.59 (m, 1H), 0.83 (dd, J = 6.2, 6.2 Hz, 1H), 0.48-0.44 (m, 2H), 0.10-0.05 (m, 2H). 1.113b (400 MHz) δ: 8.57 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.14 (d, J = 1.2 Hz, 2H), 3.95- DMSO-d6 3.87 (m, 2H), 3.12 (s, 3H), 2.97 (d, J = 11.2 Hz, 2H), 2.62-2.54 (m, 1H), 2.21-2.17 (m, 2H), 2.13-1.95 (m, 2H), 1.82 (dd, J = 3.4, 13.0 Hz, 1H), 1.57-1.48 (m, 1H), 1.11 (s, J = 5.1 Hz, 6H), 0.87-0.77 (m, 1H), 0.45 (d, J = 7.1 Hz, 2H), 0.09-0.05 (m, 2H). 1.118a (400 MHz) δ: 8.99 (s, 1H), 8.57-8.47 (m, 2H), 8.22 (d, J = 8.1 Hz, 1H), 7.94-7.87 (m, DMSO-d6 1H), 7.72-7.64 (m, 2H), 7.39-7.35 (m, 1H), 7.31-7.22 (m, 2H), 4.93-4.87 (m, 1H), 4.06-4.01 (m, 1H), 2.95-2.91 (m, 2H), 2.80-2.73 (m, 1H), 2.15-1.97 (m, 2H), 1.88- 1.74 (m, 2H), 1.59-1.45 (m, 5H), 1.34-1.27 (m, 2H), 1.23 (s, 1H), 1.17-1.13 (m, 3H). 1.189 (400 MHz) δ: 8.43-8.51 (m, 4 H), 7.99 (s, 1 H), 7.97 (s, 1 H), 7.92 (d, J = 2.1 Hz, DMSO-d6 1 H), 7.66 (dd, J.sub.1 = 2.2 Hz, J.sub.2 = 8.5 Hz, 1 H), 7.38 (s, 1 H), 7.18 (t, J = 4.9 Hz, 1 H), 3.99 (m, 1H), 2.70-3.18 (m, 3 H), 1.80-2.23 (m, 6 H), 1.48 (d, J = 3.8 Hz, 1 H), 1.36-1.40 (m, 2 H), 1.16 (m, 1 H), 0.83 (m, 1H) 0.49-0.50 (m, 2 H), 0.10 (d, J = 0.7 Hz, 2 H). 2.019a (400 MHz) δ: 8.72 (d, J = 8.6 Hz, 1H), 8.07-8.00 (m, 1H), 7.58-7.51 (m, 1H), 7.35- DMSO-d6 7.29 (m, 1H), 7.08 (d, J = 2.9 Hz, 1H), 4.14-4.05 (m, 1H), 3.19-3.15 (m, 1H), 3.05 (s, 3H), 2.98-2.92 (m, 2H), 2.76 (s, 3H), 2.51 (s, 1H), 2.00-1.92 (m, 2H), 1.80-1.76 (m, 3H), 1.62-1.59 (m, 3H), 1.48 (t, J = 5.5 Hz, 2H), 1.38-1.29 (m, 2H). 2.031 (400 MHz) δ: 8.73 (d, J = 8.6 Hz, 1H), 8.08-8.01 (m, 1H), 7.60-7.53 (m, 1H), 7.36 - DMSO-d6 7.30 (m, 1H), 7.09 (d, J = 2.9 Hz, 1H), 4.11-4.04 (m, 1H), 3.20-3.14 (m, 2H), 3.06 (s, 3 H), 2.82-2.80 (m, 1H), 2.76 (s, 3H), 2.71-2.63 (m, 1H), 1.88-1.53 (m, 8H), 1.08 (d, J = 19.3 Hz, 6H). 2.073 (400 MHz) δ: 8.49-8.55 (m, 3 H), 8.44 (s, 1 H), 8.05-8.09 (m, 1 H), 7.62 (d, J = DMSO-d6 2.5 Hz, 1 H), 7.57-7.60 (m, 1 H), 7.32-7.37 (m, 1 H), 7.16-7.19 (m, 2 H), 3.96 (dd, J.sub.1 = 4.2 Hz, J.sub.2 = 8.5 Hz, 1 H), 2.92 (d, J = 9.7 Hz, 1 H), 2.74-2.80 (m, 2 H), 2.62-2.68 (m, 1 H), 2.32 (m, 1 H), 2.29 (s, 1 H), 2.17-2.19 (m, 1 H), 1.85-1.89 (m, 1 H), 1.46-1.56 (m, 1 H), 1.36-1.40 (m, 1 H), 1.09 (m, 2 H), 0.99 (d, J = 6.5 Hz, 6 H). 2.074 (400 MHz) □: 8.57 (d, J = 8.5 Hz, 1 H), 8.45-8.50 (m, 3 H), 8.08 (m, 1 H), 7.60 (m, DMSO-d6 1 H), 7.34 (td, J.sub.1 = 2.2 Hz, J.sub.2 = 8.5 Hz, 1 H), 7.16-7.19 (m, 2 H), 3.98 (dd, J.sub.1 = 3.6 Hz, J.sub.2 = 8.1 Hz, 1 H), 2.92 (d, J = 9.1 Hz, 1 H), 2.63-2.82 (m, 3 H), 1.74-1.99 (m, 7 H), 1.46-1.65 (m, 4 H), 1.35-1.39 (m, 1 H), 1.06-1.10 (m, 2 H). 3.003b (500 MHz) δ: 9.26 (d, J = 8.5 Hz, 1 H), 8.18-8.13 (m, 1 H), 7.64 (m, 1 H), 7.39 (td, J.sub.1 = DMSO-d6 8.3 Hz, J.sub.2 = 2.1 Hz, 1 H), 4.10 (m, 1 H), 3.21-3.15 (m, 1 H), 3.07 (s, 3 H), 2.90-2.78 (m, 2 H), 2.76 (s, 3 H), 2.38-2.25 (m, 2 H), 2.17 (t, J = 11.2 Hz, 1 H), 1.85-1.82 (m, 1 H), 1.76-1.68 (m, 4 H), 1.63-1.56 (m, 2 H), 1.30-1.15 (m, 4 H), 1.07 (m, 1 H). 3.015 (400 MHz) δ: 8.98 (d, J = 8.8 Hz, 1 H), 8.56 (s, 1 H), 8.32 (d, J = 4.6 Hz, 1 H), 7.99- DMSO-d6 7.93 (m, 1 H), 7.78 (d, J = 3.3 Hz, 1 H), 7.52 (m, 1 H), 7.34-7.20 (m, 3 H), 7.01-6.98 (m, 1 H), 4.05-4.02 (m, 1 H), 3.11-3.01 (m, 2 H), 2.86-2.80 (m, 1 H), 2.51 (s), 2.29- 2.01 (m, 4 H), 1.85-1.82 (m, 1 H), 1.68-1.64 (m, 1 H), 1.49-1.44 (m, 1 H), 1.31 (m, 1 H), 0.87-0.82 (m, 1 H), 0.48 (m, 2 H), 0.09 (m, 2 H). 3.019 (400 MHz) δ: 9.35 (d, J = 8.3 Hz, 1H), 8.15-8.07 (m, 1H), 7.60-7.53 (m, DMSO-d6 1H), 7.39-7.33 (m, 1H), 4.15-4.04 (m, 1H), 3.06 (s, 3H), 2.93-2.80 (m, 3H), 2.77 (s, 3H), 2.34-2.12 (m, 3H), 1.87-1.81 (m, 1H), 1.76- 1.72 (m, 4H), 1.65-1.52 (m, 2H), 1.24-1.18 (m, 4H), 1.14-1.04 (m, 1H). 4.005 (400 MHz) δ: 8.70 (d, J = 8.5 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.58-7.56 (m, 1 H), DMSO-d6 7.33 (td, J.sub.1 = 8.5 Hz, J.sub.2 = 1.9 Hz, 1 H), 7.09 (d, J = 2.8 Hz, 1 H), 4.12-4.03 (m, 1 H), 3.13 (td, J.sub.1 = 10.7 Hz, J.sub.2 = 3.3 Hz, 1 H), 3.06 (s, 3 H), 2.88-2.77 (m, 5 H), 2-38-2.12 (m, 2 H), 1.83 (dd, J.sub.1 = 12.5 Hz, J.sub.2 = 3.9 Hz, 1 H), 1.73 (d, J = 7.3 Hz, 4 H), 1.57 (m, 2 H), 1.25-1.02 (m, 6 H). 4.032 (400 MHz) δ: 8.57 (d, J = 8.5 Hz, 1 H), 8.51 (d, J = 4.8 Hz, 2 H), 8.47 (s, 1 H), 8.05- DMSO-d6 8.11 (m, 1 H), 7.59-7.62 (m, 1 H), 7.35 (m, 1 H), 7.14-7.21 (m, 2 H), 3.94-4.04 (m, 1 H), 3.32-3.40 (m, 1 H), 3.13-3.19 (m, 1 H), 2.95-3.03 (m, 1 H), 2.67-2.77 (m, 1 H), 2.45-2.60 (m, 19 H), 2.16-2.27 (m, 2 H), 2.09-2.14 (m, 1 H), 1.98-2.04 (m, 1 H), 1.84- 1.90 (m, 1 H), 1.55-1.66 (m, 1 H), 1.48-1.52 (m, 1 H), 1.35-1.40 (m, 1 H), 1.04-1.14 (m, 2 H), 0.81-0.89 (m, 1 H), 0.45-0.52 (m, 2 H), 0.04-0.14 (m, 2 H) 4.033 (400 MHz) δ: 8.76 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.09-8.02 (m, 2H), 7.59- DMSO-d6 7.51 (m, 1H), 7.40-7.29 (m, 3H), 7.15-7.06 (m, 2H), 3.99-3.89 (m, 1H), 3.07- 2.99 (m, 2H), 2.81-2.73 (m, 1H), 2.24-2.16 (m, 2H), 2.12-1.98 (m, 2H), 1.88-1.82 (m, 1H), 1.62-1.55 (m, 1H), 1.51 (s, 3H), 1.43 (s, 3H), 0.86-0.82 (m, 1H), 0.51- 0.45 (m, 2H), 0.10-0.05 (m, 2H). 4.052 (400 MHz) δ: 8.57 (d, J = 8.5 Hz, 1 H), 8.48-8.51 (m, 3 H), 8.08 (m, 1 H), 7.59 (m, 1 DMSO-d6 H), 7.34 (m, 1 H), 7.16-7.20 (m, 2 H), 4.00 (d, J = 11.8 Hz, 1 H), 3.15-3.18 (m, 1 H), 3.00-3.03 (m, 1 H), 2.72-2.78 (m, 3 H), 2.32 (d, J = 11.6 Hz, 1 H), 2.21 (m, 1 H), 1.84-1.87 (m, 1 H), 1.62-1.65 (m, 1 H), 1.49 (d, J = 6.0 Hz, 1 H), 1.35-1.39 (m, 1 H), 0.99-1.10 (m, 4 H), 0.66-0.70 (m, 2 H). 4.055 (400 MHz) δ: 8.94-9.02 (m, 2 H), 8.81 (d, J = 0.7 Hz, 1 H), 8.34 (m, 1 H), 8.09-8.14 DMSO-d6 (m, 2 H), 7.59-7.60 (m, 1 H), 7.26-7.37 (m, 3 H), 4.18 (s, 1 H), 3.26-3.46 (m, 7 H), 1.96-1.98 (m, 1 H), 1.47-1.52 (m, 2 H), 1.15-1.19 (m, 2 H), 1.00-1.03 (m, 1 H), 0.56- 0.58 (m, 2 H), 0.25-0.25 (m, 2 H) . 4.081 (400 MHz) δ: 8.88 (s, 1 H), 8.73 (d, J = 8.6 Hz, 1 H), 8.58 (s, 1 H), 8.48 (s, 2 H), DMSO-d6 8.06-8.12 (m, 1 H), 7.57-7.63 (m, 1 H), 7.35 (td, J.sub.1 = 2.0 Hz, J.sub.2 = 8.3 Hz, 1 H), 7.12 (d, J = 3.0 Hz, 1 H), 4.00-4.03 (m, 1 H), 3.34 (s, 4 H), 2.99-3.08 (m, 2 H), 2.68-2.72 (m, 1 H), 2.01-2.25 (m, 4 H), 1.81-1.85 (m, 1 H), 1.61-1.62 (m, 1 H), 1.05-1.30 (m, 1 H), 0.74-0.86 (m, 3 H), 0.47 (d, J = 7.8 Hz, 2 H), 0.08 (s, 2 H) 4.101 (400 MHz) δ: 8.54 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = 4.7 Hz, 2 H), 8.47 (s, 1 H), 8.05- DMSO-d6 8.11 (m, 1 H), 7.57-7.63 (m, 1 H), 7.32-7.36 (m, 1 H), 7.17 (m, 2 H), 3.90-4.00 (m, 1 H), 3.30-3.38 (m, 3 H), 3.12-3.18 (m, 1 H), 2.97-3.03 (m, 1 H), 2.68 (ddd, J.sub.1 = 2.5 Hz, J.sub.2 = 6.3 Hz, 1 H), 2.51 (s, 46 H), 2.18-2.23 (m, 1 H), 2.08-2.14 (m, 1 H), 1.86-1.93 (m, 1 H), 1.47-1.57 (m, 2 H), 1.36-1.40 (m, 1 H), 1.05-1.15 (m, 11 H) 4.102 (400 MHz) δ: 8.59-8.63 (m, 3 H), 8.04-8.10 (m, 2 H), 7.61 (d, J = 2.5 Hz, 1 H), 7.56- DMSO-d6 7.59 (m, 1 H), 7.31-7.35 (m, 1 H), 7.25 (t, J = 4.8 Hz, 1 H), 7.16 (d, J = 3.0 Hz, 1 H), 3.87 (d, J = 11.9 Hz, 1 H), 3.34 (s, 2 H), 2.96-3.01 (m, 1 H), 2.67-2.71 (m, 2 H), 2.19 (d, J = 5.8 Hz, 2 H), 1.97-2.05 (m, 1 H), 1.82-1.86 (m, 1 H), 1.51-1.58 (m, 6 H), 0.81- 0.83 (m, 1 H), 0.45-0.48 (m, 2 H), 0.07 (q, J = 4.7 Hz, 2 H)
II. Biological Assays
In Vitro Assay

(375) The antagonistic effect of the compounds of formula (I) on the CXCR7 receptor are determined in accordance with the following experimental method.

(376) The assay is using the Tango CXCR7-bla U2OS cell line from invitrogen. These cells contain the human chemokine receptor CXCR7 linked to a TEV protease site and a Gal4-VP16 transcription factor stably integrated into the Tango GPCR-bla U2OS parental cell line. This parental cell line stably express a beta-arrestin/TEV protease fusion protein and the beta-lactamase reporter gene under the control of a UAS response element. Upon ligand binding and receptor activation, the protease-tagged beta-arrestin molecule is recruited to CXCR7 which is linked at the C-terminus by a protease cleavage site to a transcription factor. The protease cleaves the transcription factor from CXCR7, which translocates to the nucleus and activates the expression of beta-lactamase. A FRET-enabled substrate allows to detect beta-lactamase expression.

(377) Tango CXCR7-bla U2OS cells are detached from culture dishes with 0.05% trypsin-EDTA and collected in growing medium (McCoy's 5A 90% (v/v), dialyzed FCS 10% (v/v), 0.1 mM NEAA, 25 mM HEPES (pH7.3), 1 mM sodium pyruvate, P/S 1% (v/v) 50 μg/ml Hygromycin, 100 μg/ml Geneticin, 200 μg/ml Zeocin), spinned down and resuspended in assay medium (McCoy's 5A 90% (v/v), dialyzed FCS 1% (v/v), 0.1 mM NEAA, 25 mM HEPES (pH7.3), P/S 1% (v/v)). 10′000 cells per well (in 30 μl) are seeded in a 384 well plate (black-walled, clear bottom). The plate is incubated at 37° C./5% CO.sub.2 for 24 hours. Test compounds are dissolved to 10 mM in DMSO and serially diluted in DMSO to 500× of the final concentration for dose response curves. Compounds are then diluted 1:100 in assay medium to 5× of the final concentration. 10 μl/well of diluted compounds are added to the assay plate and incubated for 15 minutes at 37° C. Thereafter CXCL12/SDF1-α is diluted in assay medium to 5× of the final concentration (its EC80 value for receptor activation) and 10 μl/well are added to the assay plate. The agonist leads to activation of the receptor and therefore to b-arrestin recruitment. Compounds acting as antagonists reduce this activation. The plate is incubated for 22 hrs at 37° C. 10 μl/well of detection reagent (LiveBLAzer™-FRET BIG (CCF4-AM) substrate) is transferred to the assay plate and the plate is incubated for 2 hours at room temperature protected from light. Fluorescent counts are determined (Scan1: Ex 409/20 nm, Em 460/30 nm, Scan 2: Ex 409/20 nm, Em 530/30 nm). The calculated emission ratio is used for IC50 determination. The calculated IC.sub.50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC.sub.50 values from several measurements are given as geometric mean values.

(378) TABLE-US-00007 TABLE 7 Example IC.sub.50 Nr [nmol/l] 1.001 1 1.001a 0.3 1.001b 302 1.002 2 1.002a 359 1.002b 1 1.003 564 1.004 764 1.005 198 1.006 414 1.007 780 1.008 394 1.009 66 1.01 82 1.011 282 1.012 58 1.013 238 1.014 289 1.015 429 1.016 275 1.017 489 1.018 317 1.019 145 1.02 198 1.021 282 1.022 198 1.023 743 1.024 118 1.025 51 1.026 627 1.027 117 1.028 916 1.029 315 1.03 201 1.031 855 1.032 154 1.033 591 1.034 772 1.035 520 1.036 693 1.037 295 1.038 490 1.039 492 1.04 7 1.041 91 1.042 532 1.043 843 1.044 556 1.045 565 1.046a 474 1.047 127 1.048 275 1.049 10 1.05 223 1.051 49 1.052 630 1.053 703 1.054 311 1.055 232 1.056 4 1.057 1 1.058 1 1.059 140 1.06 727 1.061 49 1.062 16 1.063 107 1.064 968 1.065 567 1.066 16 1.067 319 1.068 512 1.069 556 1.07 559 1.071 4 1.072 32 1.073 118 1.074 9 1.075 44 1.076 604 1.077 443 1.078 193 1.079 510 1.08 564 1.081 118 1.082 445 1.083 76 1.084 223 1.085 268 1.086 154 1.087 943 1.088 244 1.089 472 1.09 35 1.091 103 1.092 1 1.093 867 1.094 100 1.095 254 1.095a 129 1.096 667 1.097 442 1.098 276 1.099 131 1.1 128 1.101 45 1.102 111 1.103 274 1.104 964 1.105 430 1.106 248 1.107 520 1.108 581 1.109 902 1.11 535 1.111 332 1.111a 944 1.111b 114 1.112 227 1.113 118 1.113a 561 1.113b 48 1.114 626 1.115 566 1.116 614 1.117 68 1.117a 39 1.118 36 1.118a 75 1.119 146 1.12 789 1.121 4 1.121a 742 1.121b 2 1.122 10 1.122a 525 1.122b 17 1.123 15 1.123a 4 1.124 16 1.125 81 1.125a 30 1.126 49 1.127 360 1.128 124 1.129 105 1.129a 647 1.129b 35 1.13 140 1.131 102 1.132 410 1.133 594 1.134 266 1.135 592 1.136 202 1.137 919 1.138 816 1.138a 437 1.138b 83 1.139 50 1.139a 790 1.139b 29 1.14 358 1.141 379 1.142 472 1.143 719 1.144 178 1.145 363 1.146 904 1.147 443 1.148 769 1.149 276 1.15 155 1.151 554 1.152 569 1.153 803 1.154 54 1.154a 46 1.155 315 1.156 92 1.156a 19 1.157 131 1.158 82 1.159 818 1.16 526 1.161 105 1.162 638 1.163 953 1.164 267 1.165 92 1.165a 43 1.165b 537 1.166 52 1.167 134 1.168 728 1.169 5 1.17 16 1.170a 33 1.171 16 1.171a 7 1.171b 446 1.172 72 1.173 110 1.174 36 1.175 673 1.176 6 1.176a 5 1.177 5 1.178 7 1.179 50 1.18 235 1.181 104 1.182 218 1.183 79 1.184 3 1.185 9 1.186 37 1.187a 410 1.187b 981 1.187c 3 1.187d 353 1.188a 3 1.188b 519 1.188c 179 1.188d 362 1.189 36 1.189a 15 1.19 294 1.191 186 1.192 389 1.192a 854 1.192b 122 1.193 191 1.193a 97 1.194a 13 1.195 759 1.196 575 1.197 11 1.198 52 1.199 273 2.001 209 2.002 670 2.003 34 2.004 118 2.005 25 2.006 15 2.007 88 2.008 405 2.009 10 2.01 42 2.011 114 2.013 28 2.014 269 2.015 54 2.016 80 2.016a 49 2.016b 63 2.017 73 2.018 145 2.019 126 2.019a 44 2.02 248 2.021 293 2.022 155 2.023 37 2.023a 9 2.023b 26 2.024 101 2.025 435 2.026 249 2.027 745 2.028 60 2.029 60 2.03 74 2.031 558 2.032 192 2.033 132 2.034 87 2.035 121 2.036 165 2.037 161 2.038 99 2.039 83 2.04 475 2.045 114 2.046 16 2.047 145 2.048 501 2.049 709 2.05 15 2.051 42 2.052 267 2.053 26 2.054 138 2.055 49 2.056 48 2.057 50 2.058 347 2.059 169 2.06 4 2.061 41 2.062 23 2.062a 298 2.062b 14 2.063 219 2.064 84 2.065 1 2.066 359 2.067 18 2.068 12 2.069 6 2.07 11 2.071 8 2.072 1 2.073 20 2.074 25 2.075 554 2.076 71 2.077 112 2.078 72 2.079 38 2.08 311 2.081 118 2.082 342 2.083 777 2.084 8 2.085 179 2.086 111 2.087 84 2.088 45 2.089 975 2.09 3 2.091 62 2.092 95 2.093 26 2.094 2 2.095 18 2.096 634 2.097 650 2.098 94 2.099 343 2.1 396 2.101 29 2.102 411 2.103 4 2.104 195 2.105 60 2.106 13 2.107 114 2.108 3 3.001 965 3.002 435 3.003 105 3.003a 771 3.003b 54 3.004 338 3.005 38 3.006 108 3.007 162 3.009 286 3.01 69 3.011 22 3.012 26 3.013 153 3.014 158 3.015 170 3.016 105 3.016a 90 3.017 661 3.018 198 3.019 778 3.020a 271 3.020b 4 3.021 40 3.022 28 3.022a 25 4.001 133 4.002 60 4.003 333 4.004 319 4.005 388 4.006 149 4.007 52 4.008 150 4.009 573 4.01 6 4.011 43 4.012 49 4.013 145 4.014 363 4.015 783 4.016 463 4.017 114 4.018 343 4.019 151 4.02 222 4.021 126 4.022 369 4.023 69 4.024 56 4.025 439 4.026 15 4.027 8 4.028 32 4.029 2 4.03 1 4.031 4 4.032 3 4.033 0.3 4.034 255 4.035 56 4.036 127 4.037 280 4.038 522 4.039 393 4.04 86 4.041 96 4.042 74 4.043 158 4.044 75 4.045 164 4.046 290 4.047 318 4.048 247 4.049 148 4.05 21 4.051 356 4.052 24 4.053 1 4.054 1 4.055 16 4.056 64 4.057 13 4.058 90 4.059 61 4.06 60 4.061 1 4.062 141 4.063 142 4.064 753 4.065 14 4.066 320 4.067a 20 4.067b 2 4.068 1 4.069 153 4.07 73 4.071 212 4.072 16 4.072a 8 4.073 173 4.074 27 4.075 2 4.076 97 4.077 4 4.078 64 4.078b 15 4.079a 186 4.079b 18 4.08 46 4.080a 851 4.080b 15 4.081 426 4.082 20 4.083 11 4.084 232 4.084b 77 4.085 61 4.086 472 4.087 342 4.088 138 4.089 299 4.09 34 4.091 134 4.092 126 4.093 165 4.094 201 4.095 57 4.096 33 4.097 80 4.098 18 4.098a 12 4.099 852 4.1 159 4.101 71 4.101a 18 4.101b 712 4.102 1 5.001 368 5.002 857 7.001 32 7.002 308 7.003 210 7.004 64 7.005 36 7.006 8 7.007 140 7.008 51 7.009 240 7.01 60 7.011 78 7.012 356 7.013 252 7.014 629 7.015 201 7.016 2 BB 1.01c 206 BB 1.18c 119

(379) Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailability in different species (such as rat or dog); or for their properties with regard to drug safety and/or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.