NOVEL IMINONITRILE DERIVATIVES

Abstract

The invention relates to a compound of formula (I) wherein X.sup.1 to X.sup.4 and R.sup.C to R.sup.G are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

##STR00001##

Claims

1. A compound of formula (I) ##STR00101## wherein: X.sup.1 is CR.sup.1, N, or NO; X.sup.2 is CR.sup.2, N, or NO; X.sup.3 is CR.sup.3, N, or NO; X.sup.4 is CR.sup.4, N, or NO; wherein at least one of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 alkoxy, mono or bicyclic optionally substituted C.sub.6-C.sub.14 aryl, mono or bicyclic optionally substituted heteroaryl, optionally substituted (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, optionally substituted mono or bicyclic cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, aminoalkyl, alkylcarboxyl, (alkyl)carboxyamido, optionally substituted (aryl)amino, hydroxyl, halogen, C.sub.1-C.sub.6 haloalkyl, optionally substituted heterocyclyl(alkyl)-, optionally substituted heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C.sub.3-C.sub.8 cycloalkoxy, N(R.sup.5).sub.2, CN, NO.sub.2, CO.sub.2H, CONR.sup.AR.sup.B, S(O).sub.nR.sup.5, and optionally substituted heterocyclyloxy having 1 to 2 heteroatoms selected from the group consisting of O, S(O).sub.n, and NR.sup.6; n is 0 to 2; R.sup.A and R.sup.B are independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted mono or bicyclic C.sub.6-C.sub.14 aryl, optionally substituted mono or bicyclic heteroaryl, optionally substituted (aryl)alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.8 cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, C.sub.1-C.sub.6 haloalkyl, optionally substituted heterocyclyl(alkyl), optionally substituted heteroaryl(alkyl), hydroxyalkyl, and perfluoroalkyl; R.sup.5 is independently selected from the group consisting H, C.sub.1-C.sub.6 alkyl, mono or bicyclic C.sub.6-C.sub.14 aryl, mono or bicyclic heteroaryl, (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, aryloxy, heteroaryloxy, C.sub.3-C.sub.6 cycloalkoxy, or heterocyclyloxy having 1 to 2 heteroatoms selected from the group consisting of O, S(O).sub.n, and NR.sup.6; R.sup.6 is independently selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, mono or bicyclic C.sub.6-C.sub.14 aryl, mono or bicyclic heteroaryl, (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, aryloxy, heteroaryloxy, C.sub.3-C.sub.6 cycloalkoxy, or optionally substituted heterocyclyloxy; and R.sup.C to R.sup.G are independently selected from the group consisting of H, halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, heterocycle, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.3 cycloalkyl, CN, —O(aryl), C.sub.2-C.sub.6 alkynyl, C(O)C.sub.1-C.sub.6 alkyl, —O—C.sub.1-C.sub.6 haloalkyl, and optionally substituted aryl; or an isomer thereof, or a metabolite thereof, or a pharmaceutically acceptable salt or ester thereof.

2. The compound according to claim 1 of formula (I-F) ##STR00102## wherein R.sup.1 is hydrogen or halogen; R.sup.2 is hydrogen, halogen, alkyl or alkoxy; R.sup.4 is hydrogen, halogen, alkyl, cycloalkyl, cyano, pyridinyl, alkylpyridinyl, alkylaminocarbonylpyridinyl, alkoxypyridinyl, alkylpyridinyl, halopyridinyl, morpholinylpyridinyl, haloalkylpyridinyl, phenyl, halohydroxyphenyl, halophenyl, phenylamino, diphenylamino, aminocarbonylphenyl, naphthyl, benzo[d][1,3]dioxolyl, morpholinyl, alkylpyrazolyl or alkylpyrimidinyl; R.sup.C is hydrogen or halogen; R.sup.D is hydrogen, halogen or haloalkyl; R.sup.E is hydrogen or halogen; and R.sup.F is hydrogen or halogen; or a pharmaceutically acceptable salt or ester thereof.

3. The compound according to claim 1, wherein R.sup.1 is hydrogen or fluoro.

4. The compound according to claim 1, wherein R.sup.1 is hydrogen.

5. The compound according to claim 1, wherein R.sup.2 is hydrogen, fluoro, methyl or methoxy.

6. The compound according to claim 1, wherein R.sup.2 is hydrogen.

7. The compound according to claim 1, wherein R.sup.4 is alkylpyridinyl or alkylaminocarbonylpyridinyl.

8. The compound according to claim 1, wherein R.sup.4 is methylpyridinyl or methylaminocarbonylpyridinyl.

9. The compound according to claim 1, wherein R.sup.C is hydrogen, chloro or fluoro.

10. The compound according to claim 1, wherein R.sup.C is hydrogen.

11. The compound according to claim 1, wherein R.sup.D is hydrogen or halogen.

12. The compound according to claim 1, wherein R.sup.D is hydrogen, chloro or fluoro.

13. The compound according to claim 1, wherein R.sup.E is halogen.

14. A The compound according to claim 1, wherein R.sup.E is fluoro.

15. The compound according to claim 1, wherein R.sup.F is hydrogen, chloro or fluoro.

16. The compound according to claim 1, wherein R.sup.F is hydrogen.

17. The compound according to claim 1, selected from the group consisting of: N-(3-Chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-cyano-3-hydroxyisonicotinimidoyl nitrile; 2-Cyano-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-fluoro-5-hydroxyIsonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrite; N-(3,4-Difluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrite; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′-methyl-[2,4-bipyridine]-4-carbimidoyl nitrile; N-(3,4-Difluorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(4-Fluorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(phenylamino)isonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-phenylisonicotinimidoyl nitrile, N-(3-Chloro-4-fluorophenyl)-S-hydroxy-2-methoxyisonicotinimidoyl nitrite; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′-methoxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; (N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′,6′-dimethyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; 2-(Benzo[d][1,3]dioxol-5-yl)-N-(3-chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-methylisonicotinimidoyl nitrile; 2-Bromo-N-(3-chloro-4-fluorophenyl)-3-hydroxyIsonicotinimidoyl nitrile; (N-(2-Chlorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2′,6′-difluoro-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chlorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chlorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; 3-Hydroxy-2′-methyl-N-phenyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(2-Chlorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′,6-dimethyl-[2,4-bipyridine]-4-carbimidoyl nitrile; N-(2,4-Difluorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; 3-Hydroxy-N-(3-(trifluoromethyl)phenyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Fluorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chlorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(4-Fluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chlorophenyl)-3-hydroxyisonicotinimidoyl nitrile; 3-Hydroxy-N-(3-(trifluoromethyl)phenyl)isonicotinimidoyl nitrile; N-(3-Fluorophenyl)-3-hydroxyisonIcotinimiidoyl nitrile; N-(3,4-Difluorophenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3,4-Difluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrite; 3-Hydroxy-2′-methyl-N-(3-(trifluoromethyl)phenyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-carbimidoyl nitrile; N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; 3-Hydroxy-2-phenyl-N-(3-(trifluoromethyl)phenyl)isonicotinimidoyl nitrile; 2′-Fluoro-N-(4-fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-[2,3′-bipyridine]-4-carbimidoyl nitrile; N-3,4-Difluorophenyl)-3-hydroxy-2-phenylisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(naphthalen-1-yl)isonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-(diphenylamino)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-6-fluoro-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; 2′-(tert-Butyl)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(2-Chlorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-morpholinoisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-(4-fluoro-3-hydroxyphenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3,4-Difluorophenyl)-6-fluoro-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′-morpholino-[2,4′-bipyridine]-4-carbimidoyl nitrile; 6-Fluoro-N-(4-fluorophenyl)-3-hydroxy-2′-methyl-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-(2-chloro-5-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(naphthalen-2-yl)isonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2′-(trifluoromethyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2′-ethyl-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; 2′-(tert-Butylcarbamoyl)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; 2′-(Butylcarbamoyl)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-[2,4′-bipyridine]-4-carbimidoyl nitrile; 2-(4-Carbamoylphenyl)-N-(3-chloro-4-fluorophenyl)-3-hydroxy-6-methoxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-2-(4-fluorophenyl)-3-hydroxy-6-methoxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)isonicotinimidoyl c nitrile; N-(3-Chloro-4-fluorophenyl)-2-cyclohexyl-3-hydroxyisonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-6′-methyl-[2,3′-bipyridine]-4-carbimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(2-methylpyrimidin-5-yl)isonicotinimidoyl nitrile; N-(3-Chloro-4-fluorophenyl)-3-hydroxy-2-(3-(methylcarbamoyl)phenyl)isonicotinimidoyl nitrile; and N-(3-chloro-4-fluorophenyl)-3-fluoro-5-hydroxyisonicotinimidoyl nitrile.

18. A process for the manufacture of a compound according to claim 1, comprising the sequential steps (a)-(c) (a) reacting a compound of formula (A) ##STR00103## in the presence of a compound of formula (B) and an acid ##STR00104## (b) adding an nitrile ion source; and (c) adding an oxidizing agent; wherein X.sup.1 to X.sup.4 and R.sup.C to R.sup.G are as defined in claim 1.

19-20. (canceled)

21. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or an isomer thereof, or a metabolite thereof, or pharmaceutically acceptable salt or ester thereof, and a therapeutically inert carrier.

22-23. (canceled)

24. A method for the treatment or prophylaxis of cancer, bacterial infection, viral infection, parasitic infection, immune-mediated disorder, autoimmune disorder, inflammatory disease, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or an isomer thereof, or a metabolite thereof, or a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.

25. (canceled)

Description

EXAMPLES

[0330] The following abbreviations are used throughout the present examples and specification.

TABLE-US-00001 General abbreviations and symbols g gram mg milligram ng nano gram L liter mL milliliter mol mole mmol millimole min minutes h hour ° C. degrees Celsius EtOAc Ethyl acetate % percent μM micromolar mM millimolar TLC thin-layer chromatography HPLC high-performance liquid chromatography GC-MS gas chromatography-mass spectrometry LCMS liquid chromatography-mass spectrometry KYN Kynurenine SM starting material eq. equivalent Pd/C Palladium on charcoal nM nanomolar TFE tetrafluoroethylene RT room temperature TMSCN trimethylsilyl cyanide DCM dichloromethane THF tetrahydrofurane DMF dimethylformamide TMEDA tetramethylethylendiamine TFA trifluoroacetic acid DMSO dimethyl sulfoxide LDA lithiumdiisopropylamine TMSOTf trimethylsilyl trifluoromethanesulfonate MOM methoxymehtyl SEM 2-(trimethylsilyl)ethoxymethyl HMPA hexamethylphosphoramide TEA triethanolamine DIPEA N,N-diisopropylethylamine dba dibenzylideneacetone

Procedure A: Preparation of 2-hydroxyarylimidoylnitrile or Iminonitrile in the Presence of Oxygen

[0331] ##STR00019##

[0332] The compound 1-D (1.0 mmol eq.) was dissolved in mixed solvents of TFE and MeCN and then added substituted anilines (1.0 mmol eq.). The resulting mixture was stirred at RT for 1 h. The reaction mass was concentrated and added mixed solvent of DCM and TFE followed by TMSCN (3.5 mmol eq.) at 25° C. The reaction mixture was stirred for 72 h at 25° C. under oxygen balloon. The reaction was monitor by LCMS and after completion of reaction the volatiles were evaporated under reduce pressure to get residue which was purified by column chromatography on silica gel using mixture of suitable solvents of ethyl acetate and hexane to afford iminonitrile (I) as solid.

Procedure B: Preparation of 2-hydroxyarylimidoylnitrile or Iminonitrile in the Presence of MnO.SUB.2

[0333] ##STR00020##

[0334] The compound 1-D (1.0 mmol eq.) was dissolved in mixed solvents of TFE and MeCN and then added substituted anilines (1.0 mmol eq.). The resulting mixture was stirred at RT for 1 h. The reaction mass was concentrated and added mixed solvent of DCM and TFE followed by TMSCN (3.5 mmol eq.) at 25° C. The reaction mixture was stirred for 3 h at 25° C., concentrated, and the crude material was dissolved in mixed solvent of chloroform and tetrahydrofuran and then added activated MnO.sub.2 (1.5 mmol eq.) at room temperature and stirred for 3 h. The reaction was monitor by LCMS and after completion of reaction the reaction mass was filtered through celite bed and washed with 10% MeOH in DCM. Filtrate was evaporated under reduce pressure to give crude residue which was purified by column chromatography on silica gel using mixture of suitable solvents of methanol and DCM as eluent. The obtain product was further purified by trituration with 5% ethyl acetate in hexane to afford iminonitrile (I) as solid.

Example 1

Synthesis of N-(3-chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile (Compound 01)

[0335] ##STR00021##

Step 1: 3-Methoxymethoxy-pyridine

[0336] ##STR00022##

[0337] To a stirred solution of 3-hydroxypyridine (60.0 g, 662.9 mmol) in THF:DMF (120:280 mL) at 0° C. was added t-BuOK (81.8 g, 729.28 mmol) portion-wise. After stirring the reaction mixture for 15 min, methoxymethyl chloride (52 mL, 696.13 mmol) was added to it at 0° C. and the resulting mixture was stirred for 1 h at 25° C. After completion of reaction the reaction mixture was diluted with water and extracted with ethyl acetate (4×500 mL). The combined organic layer ware dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford crude material which was purified by column chromatography using silica (100-200 mesh) and 10% EtOAc-hexane as eluent to afford 3-methoxymethoxy-pyridine (54.0 g, 388.48 mmol, 61.5%) as pale brown liquid. LCMS: (M+H) 140

Step 2: 3-Methoxymethoxy-pyridine-4-carbaldehyde

[0338] ##STR00023##

[0339] To a stirred solution of 3-(methoxymethoxy)-pyridine (2.0 g, 14.388 mmol) in anhydrous THF (40 mL) was added TMEDA (1.83 g, 15.82 mmol) at 25° C. The reaction mixture was cooled to −78° C., n-BuLi (7.3 mL, 15.82 mmol, 2.17 M in hexane) was added drop-wise manner maintaining the temperature −78° C. After stirring for 2 h at −78° C., DMF (1.52 g, 20.86 mmol) was added to it and stirred for 2 h at 25° C. Reaction mixture was cooled to −40° C. and saturated ammonium chloride solution was added drop wise. The reaction mass was extracted with ethyl acetate (2×250 mL), EtOAc part was washed with water followed by brine, dried over sodium sulphate and concentrated under reduced pressure to afford crude product which was passed through a pad of silica (100-200 mesh) using 10% EtOAc-hexane as eluent to afford 3-methoxymethoxy-pyridine-4-carbaldehyde (1.6 g, 9.57 mmol, 66.6%) as pale yellow liquid. GC-MS: 167 (m/z).

Step 3: 3-Hydroxy-pyridine-4-carbaldehyde

[0340] ##STR00024##

[0341] To a stirred solution of 3-methoxymethoxypyridine-4-carbaldehyde (11.0 g, 65.83 mmol) in THF (50 mL) was added 3N HCl (100 mL) and stirred at 60° C. for 1 h. The reaction mixture was cooled under ice bath and pH was adjusted to 7 with solid K.sub.2CO.sub.3. Resulting mixture was extracted with EtOAc (5×250 mL). The organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford crude product which was purified by column chromatography using silica gel (100-200 mesh) and 23% EtOAc/hexane as eluent to afford 3-hydroxy-pyridine-4-carbaldehyde (4.0 g, 32.496 mmol, 49.4%) as pale yellow solid. GC-MS: 123 (m/z), .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ 11.04 (bs, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.20 (d, 1H, J=4.88 Hz), 7.46 (d, 1H, J=4.88 Hz). GC-FID: 99.51%.

Step 4: N-(3-Chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile

[0342] ##STR00025##

[0343] 3-Hydroxypyridine-4-carbaldehyde (3.0 g, 24.39 mmol) was taken in mixed solvent (TFE (20 mL):MeCN (20 mL)) and 4-fluoro-3-chloroaniline (3.55 g, 24.39 mmol) was added to it at 25° C. The resulting mixture was stirred at this temperature for 1 h. The reaction mass was concentrated and added mixed solvent [DCM (10 mL):TFE (10 mL)] followed by TMSCN (10.5 mL, 84 mmol) at 25° C. The reaction mixture was stirred for 72 h at 25° C., under oxygen balloon. The reaction was monitor by LCMS and after completion of reaction the volatiles were evaporated under reduce pressure to get residue which was purified by column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford N-(3-chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile (1.8 g, 6.545 mmol, 26.7%) as yellow solid.

[0344] 3-Hydroxypyridine-4-carbaldehyde (3.0 g, 24.39 mmol) was taken in mixed solvent (TFE (20 mL):MeCN (20 mL)) and 4-fluoro-3-chloroaniline (3.55 g, 24.39 mmol) was added to it at 25° C. The resulting mixture was stirred at this temperature for 1 h. The reaction mass was concentrated and added mixed solvent [DCM (10 mL):TFE (10 mL)] followed by TMSCN (10.5 mL, 84 mmol) at 25° C. The reaction mixture was stirred for 3 h at 25° C., concentrated, and the crude material was dissolved in mixed solvent of chloroform (35 mL): tetrahydrofuran (35 mL) and then activated MnO.sub.2 (3.08 g, 35.4 mmol) at room temperature and stirred for 3 h. The reaction was monitor by LCMS and after completion of reaction the reaction mass was filtered through celite bed and washed with 10% MeOH in DCM. Filtrate was evaporated under reduce pressure to give crude residue which was purified by column chromatography on silica gel using 5% methanol in DCM as eluent. The obtain product was further purified by trituration with 5% ethyl acetate in hexane to afford N-(3-chloro-4-fluorophenyl)-3-hydroxyisonicotinimidoyl nitrile (3.8 g, 13.785 mmol, 56.7%) as yellow solid. .sup.1HNMR: (400 MHz, CD.sub.3CN): δ 11.25 (s, 1H), 8.51 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.71 (d, J=5.1 Hz, 1H), 7.56 (dd, J′=6.5 Hz, J″=2.5 Hz, 1H), 7.44 (t, J=8.8 Hz, 1H), 7.40-7.37 (m, 1H); LCMS: (M+H) 276.

Example 2

Synthesis of N-(3,4-difluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile (Compound 37)

[0345] ##STR00026##

Step 1: 2-Bromo-3-(methoxymethoxy)pyridine

[0346] ##STR00027##

[0347] To a stirred solution of 2-bromo-3-hydroxypyridine (50 g, 287.356 mmol) in THF at 0° C. was added t-BuO-K (51.49 g, 459.7 mmol) portion wise. After stirring the reaction mixture for 15 mins, methoxymethyl chloride (34.473 mL, 459.77 mmol) was added to it at 0° C. and the resulting reaction mixture was stirred for 12 h. at 25° C. Reaction mixture was diluted with water and extracted with ethyl acetate (4×500 mL). Organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford rude mass which was purified by column chromatography using silica gel (100-200 mesh) and 10% EtOAc-hexane as eluent to afford 2-bromo-3-methoxymethoxy-pyridine (45 g) as pale brown liquid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 8.03 (dd, J′=4.5 Hz, J″=1.3 Hz, 1H), 7.60 (dd, J′=8.1 Hz, J″=1.1 Hz, 1H), 7.40 (dd, J′=8.2 Hz, J″=4.5 Hz, 1H), 5.35 (s, 2H), 3.41 (s, 3H).

Step 2: 2-Bromo-3-(methoxymethoxy)isonicotinaldehyde

[0348] ##STR00028##

[0349] To a stirred solution of 2-Bromo-3-Methoxymethoxypyridine (10.0 g, 45.872 mmol) in anhydrous THF (140 mL) was added LDA (79.5 mL, 59.633 mmol, 0.75 M in THF) at −78° C. After stirring for 1 hr at −78° C., ethylformate (5.559 mL, 68.807 mmol) was added to it and stirred for 30 min at −78° C. The cold bath was removed and the reaction mixture was kept at −10° C. and quenched with aq. NH.sub.4Cl solution (50 mL). Reaction mass was extracted with ethyl acetate (3×150 mL), dried over sodium sulfate and was concentrated under reduced pressure to afford crude mass which was passed through a small pad of silica gel (100-200 mesh) using 4% ethylacetate/hexane as eluent to get 2-bromo-3-methoxymethoxy-pyridine-4-carbaldehyde (5.0 g) as pale yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 10.2 (s, 1H), 8.40 (d, J=4.8 Hz, 1H), 7.67 (d, J=4.8 Hz, 1H), 5.25 (s, 2H), 3.55 (s, 3H).

Step 3: 4-Formyl-3-(methoxymethoxy)-N-methyl-[2,4′-bipyridine]-2′-carboxamide

[0350] ##STR00029##

[0351] To a stirred solution of 2-bromo-3-methoxymethoxy-pyridine-4-carbaldehyde (5.0 g, 20.325 mmol) in 1,4-dioxane (250 mL) was added crude N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (3.659 g, 20.325 mmol), K.sub.3PO.sub.4 (27.2 mL, 34.553 mmol, 1.27 M in water) and P(Cy).sub.3 (1.14 g, 4.065 mmol). The reaction mixture was degassed for 20 min with Argon then added Pd.sub.2(dba).sub.3 (1.86 g, 2.033 mmol) and again degassed for another 5 min. The reaction mixture was heated to 100° C. for 2 h. After completion of reaction the reaction mixture was cool to room temperature, the volatiles were removed under reduced pressure to afford crude 4-formyl-3-(methoxymethoxy)-N-methyl-[2,4′-bipyridine]-2′-carboxamide (6.3 g), which was forwarded to the next step as such. LCMS: 302 (M+H).

Step 4: 4-Formyl-3-hydroxy-N-methyl-[2,4′-bipyridine]-2′-carboxamide

[0352] ##STR00030##

[0353] 10% TFA-DCM (60 mL) solution was added to crude 4-formyl-3-(methoxymethoxy)-N-methyl-[2,4′-bipyridine]-2′-carboxamide (6.1 g, 20.266 mmol) in DCM (6 mL) at 0° C. After stirring the reaction mixture for 3 h at room temperature, concentrated under reduced pressure, diluted with water and was basified using solid potassium carbonate, washed with ethyl acetate and the aqueous part was acidified to pH-6 using citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduce pressure to afford crude mass which was purified by trituration using DCM/Et.sub.2O/pentane gave pure 4-formyl-3-hydroxy-N-methyl-[2,4′-bipyridine]-2′-carboxamide (2.8 g) as pale brown solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ 11.26 (s, 1H), 10.31 (s, 1H), 8.84 (d, J=4.6 Hz, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.67 (s, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.17 (dd, J′=5.0 Hz, J″=1.6 Hz, 1H), 7.76 (d, J=4.8 Hz, 1H), 2.85 (d, J=4.8 Hz, 3H); LCMS: 258.2 (M+H).

Step 5: N-(3,4-difluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimidoyl nitrile

[0354] ##STR00031##

[0355] To a stirred solution of 4-formyl-3-hydroxy-N-methyl-[2,4′-bipyridine]-2′-carboxamide (0.2 g, 0.778 mmol) in DCM (3.1 mL) was added 3,4-difluoroaniline (0.077 mL, 0.778 mmol), TMSCN (0.116 g, 1.166 mmol), TMSOTf (0.051 g, 0.233 mmol) at room temperature. The reaction mixture was stirred for 1 hr at 40° C., followed by addition of 10 mmol NH.sub.4OAc buffer (2.3 mL) and further stirred at 40° C. for 20 h. The reaction mixture was filtered through a sintered funnel and washed the solid with MTBE/hexane and dried. The obtained solid material was dissolved in mixed solvent of chloroform (1.0 mL): tetrahydrofuran (1.0 mL) and then activated MnO.sub.2 (0.131 g, 1.517 mmol) at room temperature and stirred for 24 h. The reaction was monitor by TLC and after completion of reaction the reaction mass was filtered through celite bed and washed with 10% MeOH in DCM. Filtrate was evaporated under reduce pressure to give crude residue which was purified by column chromatography on silica gel using 20% EtOAc and hexane as eluent. The obtain product was further purified by trituration with 5% ethyl acetate in hexane to afford N-(3,4-difluorophenyl)-3-hydroxy-2′-(methylcarbamoyl)-[2,4′-bipyridine]-4-carbimido-yl nitrile (0.062 g, 0.157 mmol, 31%) as yellow solid. .sup.1HNMR: (DMSO-d.sub.6, 500 MHz): δ 12.32 (s, 1H), 8.88 (d, J=4.7 Hz, 1H), 8.78 (d, J=5.05 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J=4.75 Hz, 1H), 8.24 (d, J=5.05 Hz, 1H), 7.87 (d, J=3.8 Hz, 1H), 7.76-7.69 (m, 2H), 7.46-7.44 (m, 1H), 2.86 (d, J=5.05 Hz, 3H); LCMS: (M+H) 394.14.

[0356] Compounds of the invention made according to procedures A-B and Examples 1 and 2 as described herein are listed below in TABLE 1. Their characterization is given in TABLE 1A.

TABLE-US-00002 TABLE 1 Proc. CPD Chemical Structure IUPAC Name Type 01 [00032] N-(3-Chloro-4- fluorophenyl)-3- hydroxyisonicotini- midoyl nitrile A, B 02 [00033] N-(3-Chloro-4- fluorophenyl)-2-cyano- 3- hydroxyIsonicotini- midoyl nitrile A 03 [00034] 2-Cyano-N-(4-fluoro-3- (trifluoromethyl)phenyl)- 3- hydroxyisonicotini- midoyl nitrile A 04 [00035] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile A 05 [00036] N-(4-Fluoro-3- (trifluoromethyl)phenyl)- 3- hydroxyisonicotini- midoyl nitrile B 06 [00037] N-(3-Chloro-4- fluorophenyl)-2-fluoro- 5- hydroxyIsonicotini- midoyl nitrile B 07 [00038] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2′- (methylcarbamoyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 08 [00039] N-(3,4- Difluorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 09 [00040] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 10 [00041] N-(3,4- Difluorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 11 [00042] N-(4-Fluorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 12 [00043] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2- (phenylamino)isonico- tinimidoyl nitrile B 13 [00044] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2- phenylisonicotinimidoyl nitrile B 14 [00045] N-(3-Chloro-4- fluorophenyl)-5- hydroxy-2- methoxyisonico- tinimidoyl nitrile B 15 [00046] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2′-methoxy- [2,4′-bipyridine]-4- carbimidoyl nitrile B 16 [00047] (N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2′,6′-dimethyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 17 [00048] 2-(Benzo[d][1,3]dioxol- 5-yl)-N-(3-chloro-4- fluorophenyl)-3- hydroxyisonicotini- midoyl nitrile B 18 [00049] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2- methylisonicotinimidoyl nitrile B 19 [00050] 2-Bromo-N-(3-chloro- 4-fluorophenyl)-3- hydroxyIsonicotinimi- doyl nitrile B 20 [00051] (N-(2-Chlorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 21 [00052] N-(3-Chloro-4- fluorophenyl)-2′,6′- difluoro-3-hydroxy- [2,4′-bipyridine]-4- carbimidoyl nitrile B 22 [00053] N-(3-Chlorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 23 [00054] N-(3-Chlorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 24 [00055] 3-Hydroxy-2′-methyl- N-phenyl-[2,4′- bipyridine]-4- carbimidoyl nitrile B 25 [00056] N-(2-Chlorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 26 [00057] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-2′,6-dimethyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 27 [00058] N-(2,4- Difluorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 28 [00059] 3-Hydroxy-N-(3- (trifluoromethyl)phenyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 29 [00060] N-(3-Fluorophenyl)-3- hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 30 [00061] N-(3-Chlorophenyl)-3- hydroxy-2′- (methylcarbamoyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 31 [00062] N-(4-Fluoro-3- (trifluoromethyl)phenyl)- 3-hydroxy-2′- (methylcarbamoyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 32 [00063] N-(4-Fluorophenyl)-3- hydroxy-2′- (methylcarbamoyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 33 [00064] N-(3-Chlorophenyl)-3- hydroxyisonicotini- midoyl nitrile B 34 [00065] 3-Hydroxy-N-(3- (trifluoromethyl)phenyl) isonicotinimidoyl nitrile B 35 [00066] N-(3-Fluorophenyl)-3- hydroxyisonIcotinimi- doyl nitrile B 36 [00067] N-(3,4- Difluorophenyl)-3- hydroxyisonicotinimi- doyl nitrile B 37 [00068] N-(3,4- Difluorophenyl)-3- hydroxy-2′- (methylcarbamoyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 38 [00069] 3-Hydroxy-2′-methyl- N-(3- (trifluoromethyl)phenyl)- [2,4′-bipyridine]-4- carbimidoyl nitrile B 39 [00070] N-(4-Fluoro-3- (trifluoromethyl)phenyl)- 3-hydroxy-2′-methyl- [2,4′-bipyridine]-4- carbimidoyl nitrile B 40 [00071] N-(4-Fluoro-3- (trifluoromethyl)phenyl)- 3-hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 41 [00072] N-(3-Fluorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 42 [00073] 3-Hydroxy-2-phenyl-N- (3- (trifluoromethyl)phenyl) isonicotinimidoyl nitrile B 43 [00074] 2′-Fluoro-N-(4- fluorophenyl)-3- hydroxy-[2,4′- bipyridine]-4- carbimidoyl nitrile B 44 [00075] N-(3-Chloro-4- fluorophenyl)-3- hydroxy-[2,3′- bipyridine]-4- carbimidoyl nitrile B

TABLE-US-00003 TABLE 1A CPD .sup.1H-NMR (400 MHz) proton shift values LCMS 01 CD.sub.3CN: δ 11.25 (s, 1H), 8.51 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.71 (d, [M + H] J = 5.1 Hz, 1H), 7.56 (dd, J′ = 6.5 Hz, J″ = 2.5 Hz, 1H), 7.44 (t, J = 8.8 Hz, 276 1H), 7.40-7.37 (m, 1H) 02 CD.sub.3CN: δ 12.13 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.00 (d, J = 4.9 Hz, [M − H] 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.47-7.46 (m, 2H) 299.2 03 CD.sub.3CN: δ 12.04 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 4.9 Hz, [M − H] 1H), 7.82 (d, J = 6.2 Hz, 1H), 7.77-7.75 (m, 1H), 7.55 (t, J = 9.5 Hz, 1H) 333 04 CD.sub.3CN: δ 12.28 (bs, 1H), 8.69 (bs, 2H), 8.51 (d, J = 5.1 Hz, 1H), [M + H] 8.01 (d, J = 5.8 Hz, 2H), 7.83 (d, J = 5.0 Hz, 1H), 7.62-7.60 (m, 1H), 352.9 7.48-7.42 (m, 2H) 05 CD.sub.3CN: δ 11.23 (s, 1H), 8.53 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), [M + H] 7.75 (dd, J′ = 6.1 Hz, J″ = 2.2 Hz, 1H), 7.72-7.68 (m, 2H), 7.52 (t, = 9.6 Hz, 310.1 1H) 06 DMSO-d.sub.6: δ 11.28 (s, 1H), 8.04 (s, 1H), 7.65-7.59 (m, 2H), 7.43 (d, [M − H] J = 2.6 Hz, 1H), 7.38-7.34 (m, 1H) 292 07 CD.sub.3CN: δ 12.47 (s, 1H), 8.83 (bs, 1H), 8.72 (bs, 1H), 8.56 (d, J = 5.0 Hz, [M + H] 1H), 8.23-8.18 (m, 2H), 7.87 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 6.4 Hz, 410.2 1H), 7.48 (d, J = 7.0 Hz, 2H), 2.98 (d, J = 3.4 Hz, 3H) 08 DMSO-d.sub.6: δ 12.26 (s, 1H), 8.71 (d, J = 5.6 Hz, 2H), 8.51 (d, J = 4.8 Hz, [M + H] 1H), 8.03 (d, J = 4.9 Hz, 2H), 7.82 (d, J = 4.9 Hz, 1H), 7.73-7.66 (m, 336.8 2H), 7.42-7.40 (m, 1H) 09 DMSO-d.sub.6: δ 12.25 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 8.45 (d, J = 4.2 Hz, [M + H] 1H), 7.90 (s, 1H), 7.83-7.79 (m, 2H), 7.77 (d, J = 5.0 Hz, 1H), 7.64 (t, 367.1 J = 9.0 Hz, 1H), 7.53-7.51 (m, 1H), 2.53 (s, 3H) 10 DMSO-d.sub.6: δ 12.31 (s, 1H), 8.57 (d, J = 5.3 Hz, 1H), 8.46 (bs, 1H), [M + H] 7.93 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 4.9 Hz, 1H), 7.72-7.66 (m, 2H), 350.9 7.40-7.38 (m, 1H), 2.56 (s, 3H) 11 DMSO-d.sub.6: δ 12.56 (s, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.50 (bs, 1H), [M + H] 7.91 (s, 1H), 7.84 (s, 1H), 7.80 (d, J = 4.9 Hz, 1H), 7.63-7.59 (m, 2H), 333.1 7.45 (t, J = 8.7 Hz, 2H), 2.56 (s, 3H) 12 CD.sub.3CN: δ 12.08 (s, 1H), 7.89 (d, J = 4.9 Hz, 1H), 7.80 (d, J = 7.9 Hz, [M + H] 2H), 7.63 (bs, 1H), 7.57 (dd, J′ = 6.6 Hz, J″ = 2.4 Hz, 1H), 7.44 (t, J = 8.8 Hz, 367.1 1H), 7.41-7.37 (m, 1H), 7.34 (t, J = 7.9 Hz, 2H), 7.14 (d, J = 5.4 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 13 DMSO-d.sub.6, 500 MHz: δ 12.09 (s, 1H), 8.49 (d, J = 4.1 Hz, 1H), 8.00 (d, [M + H] J = 7.55 Hz, 2H), 7.86 (dd, J′ = 6.6 Hz, J″ = 2.2 Hz, 1H), 7.73 (d, J = 5.05 Hz, 352.0 1H), 7.68 (t, J = 9.0 Hz, 1H), 7.59-7.56 (m, 1H), 7.52-7.44 (m, 3H) 14 DMSO-d.sub.6, 500 MHz: δ 10.57 (s, 1H), 8.04 (s, 1H), 7.66-7.64 (m, 1H), [M + H] 7.61 (d, J = 9.15 Hz, 1H), 7.38-7.35 (m, 1H), 7.07 (s, 1H), 3.84 (s, 3H) 306.24 15 DMSO-d.sub.6, 500 MHz: δ 12.22 (s, 1H), 8.53 (d, J = 5.05 Hz, 1H), [M + H] 8.30 (d, J = 5.35 Hz, 1H), 7.86 (dd, J′ = 6.6 Hz, J″ = 2.2 Hz, 1H), 7.83 (d, 383.0 J = 5.05 Hz, 1H), 7.69 (t, J = 8.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.44 (s, 1H), 3.91 (s, 3H) 16 DMSO-d.sub.6, 500 MHz: δ 12.50 (s, 1H), 8.38 (s, 1H), 7.83-7.79 (m, 3H), [M + H] 7.77 (d, J = 5.05 Hz, 1H), 7.66 (t, J = 8.97 Hz, 1H), 7.52-7.51 (m, 1H), 381.1 2.51 (s, 6H) 17 DMSO-d.sub.6, 500 MHz: δ 12.16 (s, 1H), 8.45 (d, J = 4.75 Hz, 1H), [M + H] 7.86 (d, J = 4.65 Hz, 1H), 7.70-7.66 (m, 2H), 7.63 (dd, J′ = 8.2 Hz, J″ = 1.25 Hz, 396.0 1H), 7.58-7.57 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.10 (s, 2H) 18 DMSO-d.sub.6, 500 MHz: δ 11.50 (s, 1H), 8.21 (s, 1H), 7.80 (dd, J′ = 6.6 Hz, [M + H] J″ = 2.2 Hz, 1H), 7.66 (t, J = 8.97 Hz, 1H), 7.55 (d, J = 5.05 Hz, 1H), 390.1 7.53-7.50 (m, 1H), 2.50 (s, 3H) 19 DMSO-d.sub.6, 500 MHz: δ 11.99 (s, 1H), 8.18 (d, J = 5.05 Hz, 1H), [M + H] 7.81 (dd, J′ = 6.6 Hz, J″ = 2.2 Hz, 1H), 7.76 (d, J = 5.0 Hz, 1H), 7.67 (t, J = 8.97 Hz, 354.06 1H), 7.55-7.52 (m, 1H) 20 DMSO-d.sub.6, 500 MHz: δ 12.67 (s, 1H), 8.73 (d, J = 5.05 Hz, 2H), [M + H] 8.54 (d, J = 4.75 Hz, 1H), 8.06 (d, J = 4.7 Hz, 2H), 7.86 (d, J = 5.0 Hz, 1H), 335.31 7.76 (d, J = 7.9 Hz, 2H), 7.61 (t, J = 7.55 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 21 DMSO-d.sub.6, 500 MHz: δ 12.44 (s, 1H), 8.58 (d, J = 5.05 Hz, 1H), [M + H] 7.92 (d, J = 5.05 Hz, 1H), 7.88 (dd, J′ = 6.6 Hz, J″ = 2.2 Hz, 1H), 7.80 (s, 2H), 389.21 7.69 (t, J = 8.97 Hz, 1H), 7.61-7.58 (m, 1H) 22 DMSO-d.sub.6: δ 12.25 (s, 1H), 8.72 (d, J = 5.2 Hz, 2H), 8.53 (d, J = 4.64 Hz, [M + H] 1H), 8.04 (d, J = 4.44 Hz, 2H), 7.83 (d, J = 4.84 Hz, 1H), 7.63-7.60 (m, 335.0 2H), 7.52 (d, J = 7.84 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H) 23 CD.sub.3CN: δ 12.26 s, 1H), 8.57 (d, J = 5.04 Hz, 1H), 8.50 (d, J = 4.96 Hz, [M + H] 1H), 7.85 (s, 1H), 7.82-7.79 (m, 2H), 7.57 (t, J = 7.94 Hz, 1H), 349.1 7.50-7.46 (m, 2H), 7.35 (d, J = 7.88 Hz, 1H), 2.58 (s, 3H) 24 DMSO-d.sub.6: δ 12.66 (s, 1H), 8.57 (d, J = 5.24 Hz, 1H), 8.51 (bs, 1H), [M + H] 7.91 (s, 1H), 7.84 (bs, 1H), 7.81 (d, J = 4.92 Hz, 1H), 7.59 (t, J = 7.66 Hz, 315.1 2H), 7.52-7.45 (m, 3H), 2.56 (s, 3H) 25 CD.sub.3CN: δ 12.62 (s, 1H), 8.60 (bs, 1H), 8.50 (d, J = 4.48 Hz, 1H), [M + H] 7.89 (s, 1H), 7.83-8.82 (m, 2H), 7.68 (d, J = 7.48 Hz, 1H), 7.61 (d, J = 7.36 Hz, 349.1 1H), 7.55 (t, J = 7.08 Hz, 1H), 7.50-7.48 (m, 1H), 2.60 (s, 3H) 26 CD.sub.3CN: δ 12.01 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.81 (d, [M + H] J = 4.64 Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J′ = 6.48 Hz, J″ = 2.16 Hz, 1H), 381.0 7.49-7.41 (m, 2H), 2.63 (s, 3H), 2.59 (s, 3H) 27 CD.sub.3CN: δ 12.58 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.49 (d, J = 4.96 Hz, [M + H] 1H), 7.85 (s, 1H), 7.81-7.70 (m, 3H), 7.27-7.17 (m, 2H), 2.73 (s, 3H) 351.0 28 CD.sub.3CN: δ 12.33 (s, 1H), 8.74 (bs, 2H), 8.54 (d, J = 4.84 Hz, 1H), [M + H] 8.05 (s, 2H), 7.87 (d, J = 4.84 Hz, 1H), 7.81 (d, J = 4.32 Hz, 2H), 7.76 (s, 1H), 369.0 7.68 (s, 1H) 29 DMSO-d.sub.6: δ 12.38 (s, 1H), 8.57 (d, J = 8.04 Hz, 1H), 8.47 (bs, 1H), [M + H] 7.93 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 4.68 Hz, 1H), 7.65-7.60 (m, 1H), 333.1 7.40 (d, J = 9.32 Hz, 1H), 7.33-7.28 (m, 2H), 2.56 (s, 3H) 30 DMSO-d.sub.6, 500 MHz: δ 12.34 (s, 1H), 8.88 (q, J = 4.3 Hz, 1H) 8.78 (d, [M + H] J = 5.05 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 5.05 Hz, 1H), 8.25 (d, J = 5.05 Hz, 392.21 1H), 7.87 (d, J = 5.05 Hz, 1H), 7.65-7.64 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.85 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 2.86 (d, J = 4.75 Hz, 3H) 31 DMSO-d.sub.6, 500 MHz: δ 12.23 (s, 1H), 8.88 (d, J = 4.05 Hz, 1H), [M + H] 8.77-8.75 (m, 2H), 8.55 (d, J = 4.75 Hz, 1H), 8.25 (s, 1H), 8.05 (d, J = 4.45 Hz, 444.11 1H), 7.93-7.91 (m, 1H), 7.87 (d, J = 4.1 Hz, 1H), 7.79 (t, J = 9.45 Hz, 1H), 2.86 (d, J = 4.75 Hz, 3H) 32 DMSO-d.sub.6, 500 MHz: δ 12.65 (s, 1H), 8.87 (s, 1H), 8.78-8.75 (m, 2H), [M + H] 8.57-8.56 (m, 1H), 8.25 (s, 1H), 7.86 (t, J = 5.05 Hz, 1H), 7.66-7.63 (m, 376.28 2H), 7.47 (t, J = 8.02 Hz, 2H), 2.86 (d, J = 4.75 Hz, 3H) 33 DMSO-d.sub.6, 500 MHz: δ 11.33 (s, 1H), 8.47 (s, 1H), 8.28 (d, J = 5.05 Hz, [M + H] 1H), 7.68 (d, J = 5.05 Hz, 1H), 7.57 (t, J = 8.35 Hz, 1H), 258.01 7.45-7.44 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H) 34 CD.sub.3CN, 500 MHz: δ 11.19 (s, 1H), 8.56 (s, 1H), 8.39 (d, J = 5.4 Hz, [M + H] 1H), 7.79 (d, J = 5.05 Hz, 2H), 7.76 (d, J = 5.35 Hz, 1H), 7.72 (s, 1H), 292.13 7.66-7.64 (m, 1H) 35 CD.sub.3CN, 500 MHz: δ 11.00 (s, 1H), 8.55 (s, 1H), 8.38 (d, J = 5.05 Hz, [M + H] 1H), 7.75 (d, J = 5.05 Hz, 1H), 7.63-7.59 (m, 1H), 7.26-7.22 (m, 2H), 242.13 7.20-7.18 (m, 1H) 36 CD.sub.3CN, 500 MHz: δ 10.75 (s, 1H), 8.54 (s, 1H), 8.38 (d, J = 5.05 Hz, [M + H] 1H), 7.74 (d, J = 5.05 Hz, 1H), 7.49 (q, J = 9.25 Hz, 1H), 7.43-7.39 (m, 260.16 1H), 7.28-7.27 (m, 1H) 37 DMSO-d.sub.6, 500 MHz: δ 12.32 (s, 1H), 8.88 (d, J = 4.7 Hz, 1H), 8.78 (d, [M + H] J = 5.05 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 4.75 Hz, 1H), 8.24 (d, J = 5.05 Hz, 394.14 1H), 7.87 (d, J = 3.8 Hz, 1H), 7.76-7.69 (m, 2H), 7.46-7.44 (m, 1H), 2.86 (d, J = 5.05 Hz, 3H) 38 DMSO-d.sub.6, 500 MHz: δ 12.33 (s, 1H), 8.58 (d, J = 5.05 Hz, 1H), [M + H] 8.48 (d, J = 4.75 Hz, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.89 (d, J = 3.8 Hz, 1H), 383.31 7.82 (bs, 3H), 7.78-7.76 (m, 1H), 2.57 (s, 3H) 39 CD.sub.3CN: δ 12.25 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 4.92 Hz, [M + H] 1H), 7.85-7.73 (m, 5H), 7.54 (t, J = 9.48 Hz, 1H), 2.58 (s, 3H) 401.0 40 CD.sub.3CN: δ 12.26 (s, 1H), 8.70 (d, J = 5.16, 2H), 8.52 (d, J = 4.96 Hz, [M + H] 1H), 8.01 (d, J = 5.56 Hz, 2H), 7.83 (d, J = 4.96 Hz, 1H), 7.80-7.79 (m, 387.0 1H), 7.75-7.73 (m, 1H), 7.54 (t, J = 9.50 Hz, 1H) 41 DMSO-d.sub.6: δ 12.30 (s, 1H), 8.72 (d, J = 5.72 Hz, 2H), 8.52 (s, 1H), [M + H] 8.04 (s, 2H), 7.83 (d, J = 4.92 Hz, 1H), 7.66-7.61 (m, 1H), 7.41 (d, J = 9.36 Hz, 319.0 1H), 7.34-7.29 (m, 2H). 42 CD.sub.3CN: δ 12.15 (s, 1H), 8.47 (d, J = 5.12 Hz, 1H), 8.01 (d, J = 6.88 Hz, [M + H] 2H), 7.78-7.72 (m, 4H), 7.65 (s, 1H), 7.52-7.43 (m, 3H) 368.0 43 CD.sub.3CN: δ 12.76 (s, 1H), 8.51 (d, J = 4.84 Hz, 1H), 8.32 (d, J = 5.04 Hz, [M + H] 1H), 8.03 (d, J = 4.52 Hz, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 337.0 7.54-7.51 (m, 2H), 7.34 (t, J = 8.6 Hz, 2H) 44 CD.sub.3CN: δ 12.24 (s, 1H), 9.21 (s, 1H), 8.62-8.61 (m, 1H), 8.49 (d, [M + H] J = 5.0 Hz, 1H), 8.38-8.36 (m, 1H), 7.79 (d, J = 5.0 Hz, 1H), 7.60 (dd, 353.0 J′ = 6.34 Hz, J″ = 1.82 Hz, 1H), 7.48-7.44 (m, 3H)

[0357] TABLE 2 is a non-exhaustive list of compounds of the invention that are made using the procedures described herein.

TABLE-US-00004 TABLE 2 CPD Structure IUPAC Name M + 1 45 [00076] N-(3,4-Difluorophenyl)-3- hydroxy-2- phenylisonicotinimidoyl nitrile 336.09 46 [00077] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2-(naphthalen-1- yl)isonicotinimidoyl nitrile 402.08 47 [00078] N-(3-Chloro-4-fluorophenyl)- 2-(diphenylamino)-3- hydroxyisonicotinimidoyl nitrile 443.1 48 [00079] N-(3-Chloro-4-fluorophenyl)- 6-fluoro-3-hydroxy-2′-methyl- [2,4′-bipyridine]-4-carbimidoyl nitrile 385.06 49 [00080] 2′-(tert-Butyl)-N-(3-chloro-4- fluorophenyl)-3-hydroxy-[2,4′- bipyridine]-4-carbimidoyl nitrile 409.12 50 [00081] N-(2-Chlorophenyl)-3- hydroxy-[2,4′-bipyridine]-4- carbimidoyl nitrile 335.07 51 [00082] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2- morpholinoisonicotinimidoyl nitrile 361.08 52 [00083] N-(3-Chloro-4-fluorophenyl)- 2-(4-fluoro-3-hydroxyphenyl)- 3-hydroxyisonicotinimidoyl nitrile 386.05 53 [00084] N-(3,4-Difluorophenyl)-6- fluoro-3-hydroxy-2′-methyl- [2,4′-bipyridine]-4-carbimidoyl nitrile 369.09 54 [00085] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2′-morpholino-[2,4′- bipyridine]-4-carbimidoyl nitrile 438.11 55 [00086] 6-Fluoro-N-(4-fluorophenyl)- 3-hydroxy-2′-methyl-[2,4′- bipyridine]-4-carbimidoyl nitrile 351.10 56 [00087] N-(3-Chloro-4-fluorophenyl)- 2-(2-chloro-5-fluorophenyl)-3- hydroxyisonicotinimidoyl nitrile 404.01 57 [00088] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2-(naphthalen-2- yl)isonicotinimidoyl nitrile 402.08 58 [00089] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2′-(trifluoromethyl)- [2,4′-bipyridine]-4-carbimidoyl nitrile 421.04 59 [00090] N-(3-Chloro-4-fluorophenyl)- 2′-ethyl-3-hydroxy-[2,4′- bipyridine]-4-carbimidoyl nitrile 381.09 60 [00091] 2′-(tert-Butylcarbamoyl)-N-(3- chloro-4-fluorophenyl)-3- hydroxy-[2,4′-bipyridine]-4- carbimidoyl nitrile 452.12 61 [00092] 2′-(Butylcarbamoyl)-N-(3- chloro-4-fluorophenyl)-3- hydroxy-[2,4′-bipyridine]-4- carbimidoyl nitrile 452.12 62 [00093] 2-(4-Carbamoylphenyl)-N-(3- chloro-4-fluorophenyl)-3- hydroxy-6- methoxyisonicotinimidoyl nitrile 425.08 63 [00094] N-(3-Chloro-4-fluorophenyl)- 2-(4-fluorophenyl)-3-hydroxy- 6-methoxyisonicotinimidoyl nitrile 400.06 64 [00095] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2-(1-methyl-1H- pyrazol-4-yl)isonicotinimidoyl c nitrile 356.07 65 [00096] N-(3-Chloro-4-fluorophenyl)- 2-cyclohexyl-3- hydroxyisonicotinimidoyl nitrile 358.11 66 [00097] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-6′-methyl-[2,3′- bipyridine]-4-carbimidoyl nitrile 367.07 67 [00098] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2-(2- methylpyrimidin-5- yl)isonicotinimidoyl nitrile 368.07 68 [00099] N-(3-Chloro-4-fluorophenyl)- 3-hydroxy-2-(3- (methylcarbamoyl)phenyl) isonicotinimidoyl nitrile 409.08 69 [00100] N-(3-chloro-4-fluorophenyl)-3- fluoro-5- hydroxyisonicotinimidoyl nitrile 294.02

Example 3

Reduction of LPS Induced Plasma Kynurenine Levels in C57BL/6 Mice

[0358] Inflammatory mediators such as Lipopolysaccharides (LPS) and Interferon-gamma (IFNg) are well-established inducers of IDO1 expression. Intraperitoneal (i.p.) administration of bacterial lipopolysaccharide (LPS) induces peak IDO1 activity in a variety of tissues within one day after LPS administration resulting in the production and release of kynurenine into the bloodstream (Takikawa, O., et al. (1986) J. Biol. Chem. 261:3648-53; Yoshida, H., et al. (1998) Cell 94:739-750). LPS-injected mice have been used as models to study IDO1 expression and activity. Three—eight fed C57 BL/6 mice (age 7-8 weeks, weight: about 20-22 g) were injected intrapritoneally with bacterial lipopolysaccharide (LPS; 26:B6 Sigma) at a concentration of 6 mg/kg. Animals were then housed in normal condition for 20 hours at which time the test compounds were administered orally in formulation containing 30% polyethylene glycol 400 (PEG 400) and 20% propylene glycol (PG) in normal saline (Dosing volume 10 mL/kg). Blood was drawn through retro-orbital bleeds into a tube containing 100 mM EDTA for plasma collection at the following times: just prior to LPS treatment, just prior to test compound dosing (0 hr) and then at 2 hr, 4 hr, 6 hr, 8 hr, 24 hr and 48 hr post-test compound dosing. Plasma KYN and drug levels were determined by LC/MS/MS using an API4000 mass spectrometer (Applied Biosystems) coupled to a Shimadzu Prominence LC system fitted with a C18 column.

[0359] Representative compounds of the invention were tested as described above and the data is shown in TABLE 3. In vivo pharmacodynamics studies with LPS-injected mouse model show that the compounds of the invention inhibit the activity of IDO1 and reduce plasma kynurenine metabolite, KYN levels in vivo. The percentage of decrease of kynurenine level at two hours is given in TABLE 3. The compounds of the invention decrease kynurenine levels. The compounds of the invention trigger a decrease of kynurenine levels at 2 hrs of at least 5%.

TABLE-US-00005 TABLE 3 Compound % 01 73 02 45 03 25 04 77 05 64 06 73 07 43 08 83 09 71 10 79 11 82 12 15 13 46 14 18 15 47 16 36 17 10 18 53 19 38 20 46 21 21 22 87 23 79 24 81 25 37 26 11 27 64 28 70 29 75 30 64 31 43 32 67 33 80 34 67 35 74 36 79 37 68 38 69 39 67 40 77 41 81 42 32 43 69 44 77

Example A

Film Coated Tablets Containing the Following Ingredients can be Manufactured in a Conventional Manner

[0360]

TABLE-US-00006 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0 mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0 mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate 12.5 mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

[0361] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.

Example B

Capsules Containing the Following Ingredients can be Manufactured in a Conventional Manner

[0362]

TABLE-US-00007 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

[0363] The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection Solutions can have the Following Composition

[0364]

TABLE-US-00008 Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

[0365] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.